3-[4-(DIBENZO[b,f][1,4]OXAZEPIN-11-YL)-PIPERAZIN-1-YL]-2,2-DIMETHYL PROPANOIC ACID FOR USE IN THE TREATMENT OF SLEEP DISORDERS

The present invention relates to methods of treating sleep disorders and to compositions useful in such methods.

Background

Difficulty getting to sleep or getting to sleep is a significant medical problem, for a variety of reasons. In some cases, these problems appear because of exogenous stress, such as the disruptive effect of changing the work schedule and “jet lag”. Whether of endogenous or exogenous origin; The difficulty in finding or keeping sleep results from a problem of drowsiness, which deteriorates the health, quality of life, and safety of those who suffer from it.

The pharmaceutical treatments available to induce sleep are sedatives or hypnotics such as benzodiazepines and barbiturates. These treatments have various drawbacks; including delayed insomnia, delayed onset of sedative effects, persistence of sedative effect after desired sleep period, and side effects due to specified activity, such as psychomotor deficits and memory, including REM inhibition of sleep.

In addition, sedatives and hypnotics can become addictive, and may lose their effects after abuse: and may be metabolized more slowly in some people.

Accordingly, physicians always recommend the prescription of antihistamines as well as mild treatment for sleep disturbances when hypnotics are not appropriate. In addition, several antihistamines have a number of side effects. These adverse effects include prolongation of the QT interval, in the electrocardiography of a subject, as well as side effects in the central nervous system (CNS) such as deterioration of smooth muscle and drooping of the eyelids. Finally, such compounds can be linked to muscarinic receptors which lead to an anti-cholinergic side effect, such as blurred vision, dry mouth, constipation, urinary problems, dizziness and anxiety; Consequently ; There is a need to implement sleep promoting treatments, with reduced side effects, plus, as long as the compounds known to induce sleep are effective in treating sleep - onset of insomnia, for example a subject with depression. trouble finding sleep, there is no medication for the treatment of sustained sleep, i. e, maintain a sleeping subject for a period of normal sleep after the lack of sleep. In addition we find a

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WO / 2006/034414 PCTUS2OO5 / O34O15 need to improve pharmaceutical treatments to maintain sleep, in a subject in need of this treatment.

ABSTRACT

The present invention relates to loxapine analogs and their use to modulate sleep.

Loxapine (LOXAPAC M, LOXITAN ™) is an antipsychotic agent of tricyclic dibenzoxazepine, used in the mode of schizopherenic manifestations. Loxapine (2chloro -11- (4- methyl -1- piperazinyle) dibenz [b, f] [1,4] oxozepine) is under the following formula:

<img file="MA28985B1_D0001.tif" />

In one aspect, the present invention relates to a method of modulating sleep in a subject, by administering to the subject an effective amount of the compound of formula I:

<img file="MA28985B1_D0002.tif" />

<img file="MA28985B1_D0003.tif" />

Re

Rio (CH₂)٥

مجد)

Rice هـء)

at)

Or a pharmaceutically acceptable salt thereof, where: m, n, O, P and q are independently, an integer 0, 1, 2, 3, 4, 5 or 6; X and Y are, independently, absent, O, S, C (O), SO, or SO2, and Ri, R2, R3, R4, R5, R6, R7, and Rg, are independently. H, f. Cl, Br, CF3, CH, straight chain C2- C6 alkyl, branched C3- Cfi alkyl, C3- C7 cycloakyl, heterocyclyl

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WO / 2006/034414 PCT / US2OO5 / O34015 ا 7 ء -3 ء CH3, 0CF3, CH 0CH3, CH CH2OCH3, hydroxyalkyl C1- C6, or alkoxy C1- C6; each hydrogen in the CH groups in the bond, is optionally substituted by H, F, Cl, OH, Br, CF3, straight chain C2-C6 alkyl, C3- C7 alkyl, C3- C7 heterocyclyl, 0HC3, 0HC3 , CH2CH2OH3, CH2OCH2CH3, hydroxyalkyl C1- C6, or alkoxy C1- C6, R12, Independament, denotes H, a straight chain of alkyl C1- C6, branched alkyl C2- C6, or R؟ and Rio together with a carbon atom to which they are attached, are absent or attached to form a spirocycle of 3, 4, 5, 6, or 7 atoms; or Ru and R 12, together with the carbon to which they are attached, form a spirocycle of 3, 4, 5, 6 or 7 atoms, or substituents in two different carbon atoms, attached to form a ring of 3, 4, 5 , 6 or 7; Z is selected from CCH, CO2R13 (where R13 is C1- c٥ alkyl) CONR14R15 (where R14 and R15, are independently hydrogen or lower alkyl) CONHS (0) 2-alkyl, CONHS (0) 2-cycloalkyl , CONS (0) 2- heteroalkyl, CONH (O) 2- aryl, CONHS (0) 2- heteroalkyl, S (O) 2 NHCO- alkyl, SOHCO- alkyl, S (O) 2 NHCO- cycloalkyl, S (O ) 2 NHCO- heteroalkyl, S (O) 2 NHCOaryl, S (0HC0- heteroaryl, CONHS (O) 2 NH- alkyl, CONHS (O) 2 NH- cycloalkyl, CONHS (O) 2 NH- heteroalkyl, CONHS (O) 2 NH- aryl, CONHS (O) 2 NH- heteroaryl, SO3H,

H٢٦ SO2H, SONHCO-alkyl, SONHCO-aryl, SONHCO-heteroaryl, P (O) OH, حلا N

<td>ممارج</td><td>الارج</td><td>٧ نس</td><td>ممارج</td>

<td></td><td>ض</td><td>Ν٨</td><td>μΛ</td>

<td>١ NH</td><td>١ NH</td><td>\ NH</td><td>NH؟</td>

<td> ٥٩</td><td> ٦</td><td> ٦</td><td> '٥</td>

<td>(tetrazole); ٥ 1</td><td></td><td>ج 'or</td><td>ه provided that Z denotes COOH or</td>

COOR13, R٥ denotes H or a Halogen, R١- R12 are not different from hydrogen, provided that m denotes zero, X is absent.

In one example, Z denotes a sulfonamide.

Examples of sulfonamides include alkyl sulfonamides. For example.

<img file="MA28985B1_D0004.tif" />

Z can see the formula ار 'or, where w is a substituent chosen as being useful in modulating the polar surface effects of the part of Z, to achieve the level of oral absorption, CNS penetration, and the level of secretion in urine or bile. Substituents w useful in this field include an alkyl group (optionally having a double or triple bond or a substituted heteroatom, eg, CH OCH orCH OCHCH);

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A cycloalkyl group (optionally having a double bond); a heterocyclyl group, an aryl group or a heteroaryl group, all substituted, as demonstrated by the following:

<img file="MA28985B1_D0005.tif" />

<img file="MA28985B1_D0006.tif" />

Where V is one or more chains chosen to modulate pka of the pertie of acylsulfonamide, or to affect the physical and metabolic characteristics of the compound. Examples of the V chains include halogens such as F, Cl, or Br; C1-C6 alkoxy groups such as OCH or OCH CH3; C1-C6 alkyl or C3-C8 cycloalkyl groups such as CH, CF3 or Cyclopropyl; a substituted heteroatom of C1-C6 alkyl or C3-C8 cycloalkyl; such as CHOCH or CHOCHCH; an electron with designated groups such as CN, an amide.

ي٢'لرلاع ٦ ؛ لبيي a Cetone or a sulffone, تاً; (and pyridyl isomers), ءللآم;

(and pyrimidine isomers, and ا

In one example, Z denotes the sulfonamide. Examples of sulfonamides include acyl sulfonamides.

<img file="MA28985B1_D0007.tif" />

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PCT / US2OO5 / O34O15

W 2006/034414 or

ببي

For example, Z can have the formula

- where Ra and Rb denote, independently, for example an alkyl group, cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, optionally substituted examples include:

لبري لابم ٠ ه

&gt; ده بده

<img file="MA28985B1_D0008.tif" />

(Where V denotes a halogen such as F, Cl, or Br, C1- Cfi alkoxy such as OHC3 or OCHCH; C1- C6 alkyl or cycloalkyl C3- c؟, such as CH3, CF3, or cyclopropyl; heteroatom substituted by a C1- C6 alkyl or C3- Cg cycloalkyl, such as OCHCH or CHOCHCH (one electron with a group such as CN, ketone, amide or sulfone)

<img file="MA28985B1_D0009.tif" />

<img file="MA28985B1_D0010.tif" />

(and pyridyl isomers) or CH3 (pyrimidin isomer).

In one example, the compound of formula I used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) with respect to the binding H1 receptor of at least 500 nM; ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 500 nM e and / or 5 times greater than ki compared to the receptor HI, a higher nonREM peak value exceeds 55% of non-REM sleep, three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes for doses of the compound which maximally produce sleep consolidation; a sleep duration, the longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when it is adjusted using a base value obtained from

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0/2006/034414 PCT / US20O5 / 034015 less than 24 hours before the administration of the compound to the subject; an average sleep period of more than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula I used in the method of the invention has one or more of its following characteristics: constant inhibition (ki) against the binding H1 receptor of at least 300 nM; ki with respect to an objective binding to an objective (off) chosen from M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 1 µm, a higher non-REM peak value exceeds 55% non-REM sleep three hours after administration of a compound to a subject; a high cumulative total in nonREM sleep of not less than 20 minutes for doses of the compound that maximally produce sleep consolidation; a sleep duration, the longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period of more than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula I used in the method of the invention has one or more of its following characteristics a constant inhibition (ki) against the binding H1 receptor of at least 150 nM; ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is higher than 10 pm, a higher value of non-REM peak exceeds 55% non-REM sleep, three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at no less than 20 minutes of doses of the compound which maximally produce sleep consolidation; a sleep duration, longer than 17 minutes, the post-treatment sleep period is greater than or equal to 5 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period of more than 6 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and! administration

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WO / 2006/034414 PCT / US20O5 / 034O15 of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In another example, in the compound of formula I, used in a method of the present invention. Re does not denote hydrogen or halogen.

In another example, in the compound used in the method of the invention, R₆denotes a methyl, methoxy, methoxymethylene (CHOCH) or a hydroxy. In another example, in a compound used in the method of the present invention, Rft denotes methyl, methoxy, methoxymethylene, fluoro, chloro, bromro OR hydroxy.

In another example, in a compound of formula I used in the method of the present invention. Ri- R ؛ and R٧- Rg each denote hydrogen.

In another example, in a compound used in the method of the present invention, an between Ri- R؟ denotes a substituent other than hydrogen and Ri- Rg are

Hydrogen. In another example, in a compound used in the method of the present invention, at least one of the non-hydrogenated R 1 - Rs, independently, denotes methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, OR hydroxy.

In another example, in a compound used in the method specific to the invention, at least two of the substituents ηοη-hydrogen R] -Rg, and the residue R | - Rs denotes 1'1'hydrogen.

In another example, in a compound used in the method according to the invention, at least 2 of Ri-Rs other than hydrogen, independently, denotes a methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, OR hydroxy.

In another example, in a compound used in the method of the present invention, at least three non-hydrogenated RI-R8 substituents, and the residue Ri- Rs denote hydrogen. In another example, in a compound used in the method of the present invention, at least 3 non-hydrogen Ri-Rs, independently, denote methyl, methoxymethylene, fluoro, bromo, OR hydroxy.

In another example, in a compound used in the method according to the invention, R2 denotes a non-hydrogen substituent. For example R2 denotes a methyl, methoxymethylene, fluoro, chloro, bromo OR hydroxy.

In another example, in a compound used in the method according to the invention, R3 denotes a non-hydrogen substituent. For example, R3 denotes methoxy, methyl, methoxymethylene, fluoro, chloro, bromo, OR hydroxy.

In another example, in a compound used in the method of the present invention, R7 denotes a non-hydrogen substituent. For example, R7 denotes a methyl, methoxy, methylene, fluoro, chloro, bromo OR hydroxy.

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In another example, in a compound used in the method according to the invention, R₂and R3 denote non-hydrogen substituents. For example, R2 and R3 denote, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, OR hydroxy.

In another example, in a compound used in the method of the present invention, R2 and Rfi denote non-hydrogen substituents. For example, R2 and R٥ denote, independently, methyl, methoxymethylene, fluoro, chloro, bromo OR hydroxy.

In another example, in a compound used in the method of the present invention, R₂ and R7 denote non-hydrogen substituents. For example, R2 and R? denote, independently, a methyl, methoxy, methoxymethylene, fluoro, chloro, bromo OR hydroxy.

In another example, in a compound used in the method of the present invention, R3 and R6 denote non-hydrogen substituents. For example, R3 and Re denote, independently, methyl, methoxy, methoxymethylene, fluoro, chloro OR hydroxy.

In another example, in a compound used in the method of the present invention, R3 and R7 denote non-hydrogen substituents, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, bromo OR hydroxy.

In another example, in a compound used in the method of the present invention, R٥ and R7 denote non-hydrogen substituents, for example R₆ and R7, independently are methyl, methoxymethylene, fluoro, chloro, bromo or hydroxy.

In another example, in a compound used in the method of the present invention, R denotes a methoxy, and Ri- R ؛ and R7-Rg are hydrogen.

In another example, in the compound of formula I, used in a method according to the invention, R2 denotes a methyl or a methoxy, and R] and R3-Rg denote a hydrogen.

In another example, in a compound used in the method of the present invention, R2 denotes a methyl or a methoxy, and R] and R3- R؟ denote hydrogen.

In another example, in a compound used in the method according to the present invention, R3 denotes a methyl, and R] -R2 and R4-Rs denote hydrogen.

In another example, in a compound used in the method of the present invention, R7 denotes a methoxy and Ri- R6 and R؟ denote hydrogen.

In another example; in a compound used in a method of the present invention, at least one between R2, R6 and R7 does not denote hydrogen. In another example, in the compound of formula 1, used in a method of the present invention, at least one between R2, R6 and R7 denotes fluoro, methyl, or methoxy.

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In an example, R؟ and Rio together with a carbon to which they are linked are absent. In another example, in a compound of formula I, used in a method of the present invention. Ru and R12 denote a methyl.

In another example, in a compound used in the method of the present invention Ru and R12 denote an ethyl.

In another example, in a compound used in the present invention, R] | and R12, together with the carbon to which they are attached, are joined to form a spirocycle of 3 to 7. The spirocycle is, for example, a cyclopropyl ring.

In another example, in a compound of formula I, used in a method of the present invention, q denotes zero.

In another example, q denotes zero, Rg and Rio together with the carbon to which they are linked are absent. In another example, q represents zero, R؟ and Rio together with the carbon to which they are bound are absent, X and Y are absent.

In another example, q represents zero, Rg and Rio together with the carbon to which they are bound are absent, X and Y are absent, and the number of m, n, oetp is 1 or 2.

In another example, the compound used in the method of the present invention is selected from compounds 1-88. for example, the compound used in the methods of the present invention is compound 20, 14,15,16,17,18,19, 11,12,13, 10, 9, 8, 6,7, 5, 2, 3,4'ا, 21,22,23,24,25,26, 27,28,29, 30, 31,32,33) 34,35,36,37,38,39,40,41,42, 43,44,45, 46,47,48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62.63, 64, 65, 66) 67, 68, 69, 70, 71,72,73, 74, 75, 76,77,78, 79, 80, 81, 82,83, 84,85, 86, 87, or 88.

In another example, the compound used in the method of the present invention is compound 1, 12, 13,40, 61, 62, 63, 70, 71, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, or 84.

In another example, the method of the present invention is used to modulate sleep by administering a compound of formula I, for example the method is used to decrease the duration of sleep onset by increasing sleep say and / or maximum sleep increase.

In another example, the method of the present invention is used to treat sleep disorders, by administering a compound of formula I. The sleep disorders are, for example, insomnia, parasmnia, circardient rhythm abnormality. as sleepwalking, disorders of REM sleep behavior,

Sleep apnea disorder, such as, for example, sleep enuresia, sleep bruxism, central sleep apnea, obstructive sleep apnea and mixed sleep apnea, sleep apnea syndrome, narcolepsy or hypersomnia.

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In another example, the method of the present invention is used to treat the abnormality of circardial disorder.

In another example, the method of the present invention is used to treat insomnia, including, for example, psychophysiological insomnia, extrinsic insomnia, insomnia in altitude, blistering jonbe syndrome, periodic limb disorders. drug dependent insomnia, drug dependent insomnia, alcohol dependence insomnia, and alcohol dependence insomnia and insomnia associated with mental disorders.

In another example, the method of the present invention is used to treat sleep apnea. In another example the method of the present invention is used to treat narcolepsy. In another example, the present invention is used to treat hypersomnia.

In another example, in a method of the present invention, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered together with a pharmaceutical composition which includes a pharmaceutically acceptable excipient.

In another example, the method of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof, is co-administered with one or more therapies.

In another example, the subject treated by the method of the present invention is selected from human, pets, laboratory animals, and wild animals. In one example, the subject is a human.

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In another example, the method of the present invention relates to modulating sleep in a subject, by administering to the subject a therapeutically effective amount, of a compound of formula II:

<img file="MA28985B1_D0011.tif" />

Or a pharmaceutically acceptable salt thereof, where: m, n and O are independently 0, 1, 3, 4, 5 or 6, X is absent, O, s, C٠ (O), so, or SOj ؛ R ؛, R3, R «, R? are, independently, selected from H, F, Cl, Br, OH, CF3, CH2CH3, CH (CH) 2, cyclopopyl, OCH, OCF3, CHOCH, and CHOCHCH; R9 and Rio, are independently. H, straight chain alkyl Cl- c ، 6, alkyl branched Cl- Ce, or R9 and Rio together with a carbon to which they are attached, are attached to form a spirocycle of 3, 4, 5, 6 or 7 atoms; Z denotes COOH, COOR13 (where R13 denotes an alkyl Cl- Co), CONH (O) 2- alkyl, CONHS (O) 2-heteroalkyl, CONHS (O) 2-aryl, CONHS (O) 2-heteroaryl, SOHCO- alkyl, S (O) 2 NHCO-heteroalkyl, S (O) 2 NHCO-aryl, SOHCO-heteroaryl, CONHSOH-alkyl; CONHSOH-heteroalkyl, CONHSONH-aryl; CONHS (O) 2 NH-heteroaryl; or tetrazol; with the proviso that Z denotes COOH or COOR 13, and R٥ does not both denote hydrogen, further provided that when m denotes zero, X is absent.

In one example, the compound of formula I used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) by the binding H1 receptor of at least 500 nM; ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, otl, and a2 which is greater than 500nM and / or more than 5 times greater than ki compared to H1 receptor, a higher non-REM peak value exceeds 55% of non-REM sleep, three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep of not less than 20 minutes for doses of the compound that maximally produce sleep consolidation; a length

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WO / 2006/034414 PCT / US2OO5 / 034015, longer than 13 minutes, the sleep period after treatment is greater than or equal to 3 minutes when it is adjusted using a base value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period of more than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula I used in the method of the invention has one or more of the following characteristics:

constant inhibition (ki) against the binding H1 receptor of at least 300 nM; ki with respect to a goal binding to a goal (off) chosen from M1, Μ2, Μ3, D1, D2, al, and a2 which is higher than lpm a higher non-REM peak value exceeds 55% of sleep no - REM, three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at no less than 20 minutes of doses of the compound which maximally produces sleep consolidation; the duration of sleep, longer than 13 minutes, a period of post-treatment sleep is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period of more than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula I used in the method of the invention has one or more of its following characteristics: constant inhibition (ki) against the binding H1 receptor of at least 150 nM; compared to a target binding to an (off) target chosen between M1, Μ2, and Μ3 which is greater than 10 μΜ a higher non-REM peak value exceeds 55% of non-REM sleep, three hours after l administration of a compound to a subject; a high cumulative total in non-REM sleep at no less than 20 minutes of doses of the compound which maximally produces sleep consolidation; the duration of sleep, longer than 17 minutes, a period of post-treatment sleep is greater than or equal to 5 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period of more than 6 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not inhibit

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WO / 2006/034414 PCT / US2OO5 / 034015 not disproportionately locomotor activity relative to normal sleep effects.

In one example, in the compound of formula II used in the method of the invention, R6 does not denote H, E Cl or Br. In another example of formula II used in the method of the present invention, R6 denotes a methyl, methoxymethylene or hydroxy.

In one example, in the compound of formula II used in the method of the invention, R2-R3 and R7 each denote hydrogen. In one example, in the compound of formula II, used in the method of the present invention, R ؛ - R3 and R6- R7 independently denote hydrogen, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo OR hydroxy . In another example, in a compound of formula II, used in a method according to the present invention, R2 does not denote a hydrogen substituent.

In another example, in a compound of formula II utilized in the present invention, R3 denotes a non-hydrogen substituent. In another example, in the compound used in a method according to the invention, R6 is a ηοη-1'hydrogen substituent.

In another example, in a compound of formula II, used in a method according to the invention, R7 denotes a ηοη-hydrogen substituent.

In another example, in a compound of formula II, used in a method according to the present invention, R2 and R3 denote a ηοη-hydrogen substituent. In another example, in a compound of formula II, used in a method of the present invention, R2 and R6 denote a non-hydrogen substituent. In another example, in a compound of formula II, used in a method of the present invention, R2 and R7 denote a non-hydrogen substituent. In another example, in a compound of formula II, used in a method of the present invention, R3 and Re denote a non-hydrogen substituent.

In another example, in the compound of formula II, used in a method of the present invention, R3 and R7 denote a ηοη-hydrogen substituent. In another example, in a compound of formula II, used in a method according to the present invention. Re and R7 denote a ηοη-1'hydrogen substituent.

In another example, in a compound of formula II, used in a method according to the present invention. Re denotes methoxy, and R2, R3, and R7 denote hydrogen.

In another example, in a compound of formula II, used in a method according to the present invention, R2 denotes a methyl or a methoxy, and R3, R6 and R7 denote a hydrogen.

In another example, in a compound of formula II, used in a method of the present invention, R3 denotes methyl and R2, R6 and R7 denotes hydrogen.

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In another example, in a compound of formula II, used in a method of the present invention, where R-7 denotes methoxy and R.2, R.3 and Re denotes hydrogen.

In another example, in a compound of formula II, used in a method of the present invention, R؟ and Rio each denotes a methyl.

In another example, in a compound of formula II, used in a method according to the present invention, Rq and Rio each denote ethyl. In another example, in a compound of formula II, used in a method of the present invention, Rq and Rio, together with a carbon to which they are linked, are attached to form a spirocycle of 3 to 7. For example, the spirocycle is a cyclopropyl ring.

In another example, in a compound of formula II, used in a method of the present invention, O denotes zero. In another example, O is zero, X is absent. In another example, O is zero, X is absent, and the number demetn is 1 or 2.

In another example, the method according to the present invention is used to modulate sleep by administering a compound of formula II, for example the method is used to decrease the duration of sleep ....., increase the duration of sleep, and / or increase sleep time to the maximum.

In another example, the method according to the present invention is used to treat sleep disorders by administering a compound of formula II. Sleep disorder, for example, is an abnormal circardian rhythm with insomnia, sleep apnea syndrome, hypersomnia or narcolepsy.

In another aspect, the present invention relates to a method of modulating sleep in a subject, by administering to the subject a therapeutically effective amount of a compound of formula III:

<img file="MA28985B1_D0012.tif" />

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WO / 2006/034414 PCT / US2OO5 / O34015

Or a pharmaceutically acceptable salt thereof where, m and n denote, independently, 0, 1, 2, 3 or 4, X is absent, o, s, C (O), SO, or SO2; R2, R3, R6 and R7, independently, are selected from H, F, Cl, Br, OH, CF3, CH, CH2CH3, CH (CH) 2, 0CH3, CH2OCH3, and CHOCHCH; Rg and Rio designate, independently. H, straight chain C1- C6 alkyl, branched C2- C6 alkyl, or R؟ and Rio, together with the carbon to which they are linked, attaches to form a spirocycle of 3,4, 5, 6 or 7 atoms.

Z is selected from OH, CONHS (0) 2-alkyl, CONHS (O) 2-cycloalkyl, CONHS (O) 2heteroalkyl, CONHS (O) 2-aryl, CONHS (O) 2-heteroaryl, and tetrazole; with the proviso that Z denotes COOH and R6 denotes H, F, Cl or Br; R2, R3, R7 and R9-Rio is not each hydrogen, further provided that when m is zero, X is absent;

In one example, the compound of formula I used in the method of the invention has one or more of the following characteristics: a constant inhibition (ki) against the binding H1 receptor, of at least 500 nM; ki compared to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is higher than 500nM and / or 5 times greater than ki compared to the Hl receptor , a higher non-REM peak value exceeds 55% of non-REM sleep three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a duration of sleep, longer than 13 minutes, the period of sleep after treatment is greater than or equal to 3 minutes when adjusted using a baseline value obtained, at least 24 hours before the administration of the compound to the subject ; an average sleep period of more than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula I used in the method of the invention has one or more of the following characteristics: a constant inhibition (ki) against the binding H1 receptor, of at least 300 nM; a ki against a goal binding to a goal (off) chosen from M1, Μ2, Μ3, DI, D2, al, and a2 that is higher than lpm a higher value of non-REM exceeds 55% of sleep no - REM, three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at no less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep time, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours before administration of the compound to the subject;

ΜΑ 28985Β1

WO / 2006/034414 PCT / US2OO5 / 034015 an average sleep period of more than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula I used in the method of the invention has one or more of its following characteristics: constant inhibition (ki) against binding H1 receptor, at least 150 nM; a ki against a target binding to a target (off) chosen between M1, Μ2, and Μ3 which is higher than a higher value of non-REM exceeds 55% of non-REM sleep, three hours after the administering a compound to a subject; a high cumulative total in non-REM sleep at no less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 17 minutes, the post-treatment sleep period is greater than or equal to 5 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period of more than 6 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, in a compound of formula III, used in a method of the present invention. R 1 does not denote H, F, Cl, or Br. In another example, in a compound of formula III, used in a method according to the invention, R 2, R 3 and R 7 denote hydrogen. In another example, in a compound of formula III, used in a method of the present invention, R2, R3, and R - R7, independently, denote H, F, Cl, Br, methyl, methoxy, methoxymethylene or hydroxy .

In another example, in a compound of formula III, used in a method of the present invention, Re denotes methoxy.

In another example, in a compound of formula III, used in a method of the present invention, R6 denotes methoxy, and R2, R3 and R7 denote hydrogen.

In another example, in a compound of formula III, used in a method of the present invention, R2 is methyl or methoxy, and R3, R₆, and R7 denote hydrogen

In another example, in a compound of formula III, used in a method of the present invention, R3 denotes a methyl and R2, R and R7 denote a hydrogen.

MY

28985Β1

WO / 2006/034414

PCT / υ S2005 / 034015

In another example, in a compound of formula III, used in a method of the present invention, where R۶ denotes methoxy and R2, R3 and R6 denote hydrogen.

In another example, in a compound of formula III, used in a method of the present invention, R؟ and Rio each denote a methyl. In another example, in a compound of formula III, used in a method of the present invention, R9 and Rio, together with a carbon to which they are linked, are attached to form 3 spirocyclic rings.

In another example, in a compound of formula III, used in a method of the present invention, X is absent. In another example, X is absent, and the number of m and n is 1 or 2.

In one example, the method of the present invention is used to modulate sleep by administering a compound of formula III, for example, the method is used to reduce sleep duration, increase average sleep time, and / or increase the duration of sleep to the maximum. In another example, the method according to the present invention is used to treat sleep disorders. By administering a compound of formula III. Sleep disturbances include, for example, insomnia, an abnormal circardian rhythm, parasomnia, sleep apnea syndrome, narcolepsy or hypersomnia.

In another aspect, the present invention relates to a method of modulating sleep in a subject by administering thereto a therapeutically effective amount of the compound of formula IV:

<img file="MA28985B1_D0013.tif" />

Or a salt of it acceptable on the pharmaceutical hoist.

Or :

test 1, 2, 3 or 4; R2, R3, R6, and R? designate, independently. H, F, Cl, Br, CF3N, CH, OH, OCH, CHOCH, or CHO2CHCH3; Rg- Rio denote H, CH, CH2CH3, or Rg and Rio, together with a carbon to which they are linked, are attached to form a spirocycle of 3, 4, 5, 6 or 7 atoms, Z is chosen from OH, CONH ( O) 2-alkyl, CONHS (O) 2-cycloalkyl, CONHS (O) 2-heteroalkyl, CONHS (O) 2-aryl, CONHS (O) 2-heteroaryl, or tetrazole; at

MY

28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15 condition when Z is COOH and R₆ is H, F, Cl, or Br, R ؛, R3, R7 and R؟ - Rio each denote hydrogen.

In one example, the compound of formula I used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 500 nM; a ki relative to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 500nM and / or 5 times greater than ki relative to the receptor HI, a higher non-REM value exceeds 55% of non-REM sleep three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at no less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula I used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 300 nM; compared to a goal binding to a goal (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is higher than a higher value of non-REM exceeds 55% of non-REM sleep , three hours after administration of a compound to a subject; a cumulative total increases in nonREM sleep at not less than 20 minutes of doses of the compound that maximally produce sleep consolidation; a duration of sleep, longer than 13 minutes, the period of sleep after treatment is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained, at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula I used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) by

MY

28985Β1

WO / 2006/034414 PC77US2OO5 / 034015 ratio to the binding H1 receptor, of at least 150 nM; compared to a target binding to an (off) target chosen between M1, Μ2, and Μ3, higher than ΙΟμΜ a higher value of non-REM exceeds 55% of non-REM sleep, three hours after administration of 'a composes to a subject; a cumulative total elevated in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 17 minutes, the post-treatment sleep period is greater than or equal to 5 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In another example, in the compound of formula IV used in the method of the present invention, t is 1 or 2.

In one example, the compound of formula IV used in the method of the present invention is selected from a compound of formula IVa, IVb, IVd and IVe.

In one example, the method of the present invention is used to modulate sleep by administering a compound of formula III, for example, the method is used to alleviate the duration of onset of sleep, increase the average sleep time, and / or increase the duration of sleep to the maximum. In another example, the method according to the present invention is used to treat sleep disorders. By administering a compound of formula III. Sleep disturbances include, for example, insomnia, an animalistic circardian rhythm, parasomnia, apnea sleep syndrome, narcolepsy or hypersomnia.

In another aspect, the present invention relates to a method of modulating sleep in a subject, by administering to the subject a therapeutically effective amount of a compound selected from the compound

.؟.20,21,22,23,24,2 ,18,19 .16,17 ,15 ,9,10,11,12.13,14 ,7,8 ...

,47,48.49,50 ,38,39,40,41,42,43,44,45,46 37٠ 36٠ ,34.35 ,33 ,30.3132 ,29 .»26,27,2

51,52, 53, 54, 55, 56,57. 58, 59, 60, 61, 62,63. 64, 65, 66,67.68,69.70,71,72,73,74.75,

76, 77, 78.79, 80.81. 82, 83, 84, 85,86,87, or SS.

In another aspect, the present invention relates to a compound of formula I:

ΜΑ 28985Β1

PCT / US2OO5 / O34O15

WQ / 2OO6 / O34414

<img file="MA28985B1_D0014.tif" />

(I)

Or a pharmaceutically effective salt thereof, wherein m, n O, P and q are, independently, an integer 0, 1, 2, 3, 4, 5 or 6; X and Y are, independently, absenO, S, C (O), SO, or SO2; Ri, R2, R3, R4, R5, R6, R7 and Rg are independently selected from H, F, Cl, Br, CF3, CH, C2- C6 straight chain alkyl, C3- Ce branched alkyl, C3- C7 cycloalkyl ; heterocyclyl C3- C7, 0CH3, 0CF3, CHOCHj, CH 0CH3, CHOCHCH, hydroxyalkyl ClC6, and alxoy C1- C6, each hydrogen in the CH groups of the bond is optionally substituted with H, F, Cl, Br, CF3, CH, C2- C6 straight chain alkyl, C3- C6 branched alkyl.

C3-Cl cycloalkyl; heterocyclyl C3-C7, OCH3, OCF3, CHOC, CH OCH, CH2OCH2CH3, hydroxyalkyl C1-C6, or alkoxy C1-C6; R9, Rio and R12 are, independently. H, straight chain C1- C6 alkyl, branched C2- C6 alkyl, or R؟ and Rio together with a carbon to which they are linked, are absent or are linked to form a spiro cycle of 3, 4, 5, 6 or 7 atoms, or Ru and

Gather with a carbon to which they are linked; form a spiro cycle of 3, 4, 5, 6 or 7 atoms, where substituents of two different carbon atoms are linked to form 3, 4, 5, 6 or 7; Z is chosen between CO2R13 (where R13 is C1- C6 alkyl), C0NRR15 (where R14 and R15 are independently hydrogen or lower alkyl), CONHS (O) 2-alkyl, CONHS (O) 2cycloalkyl, CONHS (O) 2- cyloalkyl, CONHS (O) 2- heteroalkyl, CONHS (O) 2- aryl, CONHS (O) 2- heteroaryl, SONCO- alkyl, SOHCO- alkyl, SOHCO- cycloalkyl, SOHCO- heteroalkyl, S (O) 2 NHCO - aryl, SONHCO- heteroaryl, CONHS (O) 2 NH-alkyl, CONHS (O) 2 NH- cycloalkyl, CONHS (O) 2 NH- heteroalkyl, CONHS (O) 2 N-aryl.

COMHS (O) 2 heteroaryl, SO3H, SCH, S (0) NHC0- alkyl, S (O) NHCO- aryl, S (0) NHC0heteroaryl, Ρ (Ο) (ΟΗ) 2, P (O) OH,

HN٦

رش (tetrazole).

<img file="MA28985B1_D0015.tif" />

or ٥, to

<img file="MA28985B1_D0016.tif" />

ΜΑ 28985Β1

PCT / US20O5 / 034O15

WQ / 2OO6 / O34414 condition that when Z is COOH, or COOR 13 and R16 is H or halogen. Ri- R٩ and R7- R١2 do not each denote halogen, and provided that when m is zero, X is absent.

In one example, Z is a sulfonamide, examples on sulfonamides include

لملا -تمدد an acyl sulfonamides. For example, Z can have the formula or n where w is a substituent chosen when needed to modulate the polar surface effect of the portion of Z to achieve the desired level of oral absorption, CNS penetration and level of excretion in urine or bile Examples of w substituents useful for this purpose include an alkyl group (optionally containing a double or triple bond or a substituted heteroatom, eg, CH2CH3 or CH3OCH2CH3); a cycloalkyl group (optionally containing a double bond); a heterocyclyl group, an aryl group, or a heteroaryl group, optionally substituted, as follows:

<img file="MA28985B1_D0017.tif" />

عجب ه

حد

<img file="MA28985B1_D0018.tif" />

ردد

جي

لأمد

<img file="MA28985B1_D0019.tif" />

تمدد مم ١

H \ لم

Where V is one or more of the chains mentioned, chosen to modulate the pka of the acylsulfonamide portion, or to affect the physical or metabolic characteristics of the compound. Examples of the V chains include halogens such as F, Cl, or Br, C 1 -Cfi alkoxy groups such as OCH3 or OCH2CH3; C1-C6 alkyl or C3-C8 cycloalkyl groups such as CH3, CF3, or cyclopropyl, substituted C1-C6 alkyl heteroatom or C3C8 cycloalkyl, such as CH2OCH3 or CH2OCH2 CH3; an electron from designated groups such as CN, بمد؟ مدلج keton, an amide or a sulfone. ء (and pyridyl isomers), (and^هود ٦ /

<img file="MA28985B1_D0020.tif" />

isomers pyrimidine), and ا

In one example, Z is a sulfonamide. Examples of sulfonamides include acyl sulfonamides.

<img file="MA28985B1_D0021.tif" />

ΜΑ 28985Β1

PCT / US2OO5 / O34O15

WQ / 2OO6 / O34414

For example, Z can have the formula

<img file="MA28985B1_D0022.tif" />

, where Ra and Rb are, independently, for example an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, optionally substituted. Examples include the following:

<img file="MA28985B1_D0023.tif" />

(where V is a halogen such as F, Cl or Br; alkoxy C1- C6 such as OCH or 0CHCH3; alkyl C1- C١6 or cycloalkyl C3- Cg, such as CH, CF3, a cyclopropyl, a heteroatom substituted by an alkyl C1 - C6 or cycloalkyl C3- Cg, such as CHOCH, or CHOCHCH; an electron from the group such as CN, a ketone, an amide, or a sulfone).

(and isomers

<img file="MA28985B1_D0024.tif" />

In one example, in a compound of formula I, R6 is other than hydrogen or hologene. In another example, in a compound of formula I, R6 is methyl, methoxy, methoxymethylene or hydroxy.

In another example, in a compound of the formula I, R) - R ؛ and R7- Rg each denote hydrogen.

In another example, in a compound of formula I, at least one R1-R2 does not denote a hydrogen substituent and R1-Rg denote hydrogen. In another example, at least one of R) - Rg, ​​non-hydrogen, is independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, OR hydroxy.

In another example, at least one of R 1-R's are non-hydrogen substituents, and R 1-R's are hydrogen. In another example, at least two of R 1's, not hydrogen, are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo OR! Hydroxy.

MA ϋ٩

WO / 2006/034414 PCT / US2OO5 / O34O15

In another example, in a compound of formula I, at least three of R1-Rg are non-hydrogen substituents, and R1-Rg are hydrogen. In another example, at least three of the non-hydrogen R 1-R's are independently methyl, methoxy, methoxymethylene, fluoro, chloro, bromo OR hydroxy.

In another example, in a compound of formula I, 2 لآ is a nonhydrogen substituent. For example, 2 لآ is methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, OR hydroxy.

In another example, in a compound of formula I, R3 is a nonhydrogen substituent. For example, R3 is methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, OR hydroxy.

In another example, in a compound of formula I, R7 is a nonhydrogen substituent. For example, R7 is methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another example, in a compound of formula I, R2 and R3 are ηοη-hydrogen substituents. For example, R2 and R3 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another example, in a compound of formula I, R2 and Re are ηοη-hydrogen substituents. For example, R2 and Re are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another example, in a compound of formula I, R2 and R7 are ηοη-hydrogen substituents. For example, R2 is R7 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another example, in a compound of formula I, R3 and Re are ηοη-hydrogen substituents. For example, R3 and Re are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, OR hydroxy. In another example, in a compound of formula I, R3 and R7 are non-hydrogen substituents. For example, R3 and R7 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, or hydroxy. In another example, in a compound of formula I, Re and R7 are ηοη-hydrogen substituents. For example, Re and R7 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo, OR hydroxy.

In another example, in a compound of formula I, Re is methoxy, and R1-R5 and R7-Rg are hydrogen. In another example, in a compound of formula I, R2 is methyl or methoxy, and Ri and R3-Rg are hydrogen. In another example, in another compound of formula I, R3 is methyl and R1-R2 and RRg denote hydrogen. In another example, in a compound of formula I, R7 is methoxy, R) -R٥ and Re-Rg denote hydrogen.

ΜΑ 28985Β1

2006/034414 PCT / US2OO5 / O34O15

In another example, at least one between R.2, Re and R7 does not denote hydrogen. In another example, at least one between R2, Re and R7 denotes fluoro, methyl or methoxy.

In another example, R9 and Rio together with the carbon to which they are linked are absent. In an example, in a compound of formula I, Ru and R12 are each methyl.

In another example. Ru and R12 each denote ethyl. In another example. Ru and R12, together with a carbon to which they are linked, form a spiro-cycle of 3 to 7. The spiro-cycle is for example a cyclopropyl cycle.

In another example, q is zero. In another example, q is zero, R9 and Rio for example with a carbon to which they are linked, are absent. In another example, q is zero, R9 and Rio together with a carbon to which they are linked are absent, X and Y are absent. In another example, q is zero, R9 and Rio together with a carbon to which they are linked are absent, X and Y are absent, and the number of m, n, 0 and P is 1 or 2.

In another example, the compound of formula I is selected from compounds 1-88.

In another example, the compound of formula I is chosen from the compounds 1,12,13,40,61,62,63,70,71,74,75,76,77,78,79,80,81, 82,83 and 84.

In another aspect, the present invention relates to a compound of formula II:

<img file="MA28985B1_D0025.tif" />

Or a pharmaceutically effective salt thereof, where: m, n and o are, independently 0,1,2,3,4,5 or 6, X and absenOSCO), so or SO2; R2, R3, Re and R7 are, independently, H, F, Cl, Br, OH, CF3, CH, CH CH, CHCHjCyclopropy 0CH3, OCF3H2OCH3 or CHOCHCH; R9, and Rio are independently. H, a straight chain of C1-C6 alkyl, branched C2-C6 alkyl, or R8 and R10 together with a carbon to which they are linked.

ΜΑ 28985Β1

WO / 2006/034414 PCT / US20O5 / O34O15 form a spiro-cycle of 3,4,5,6 OR 7 atoms; Z and COOH, COOR, 3 (where R13 is C1C6 alkyl) CONHS (O) 2-alkyl, CONHS (O) 2-heteroalkyl, CONHS (O) 2-aryl, CNHS (O) 2-heteroaryl, S (O ) 2 NHCO - alkyl, S (O) 2NHCO-heteroaryl, S (O) 2NHCO-aryl, S (O) 2NHCO-h oaryl, OHNHkyl; CONHS (O) 2NHheteroalkyl; CONHS (0) 2NH-aryl; C0NHS (0) 2NHheteroaryl, or tetrazole, provided that when Z is COOH or COOR13, and R is H or halogen, R1-R5 and R7-R12 do not each denote hydrogen, provided in addition that when m and zero, X is absent.

In another example, in a compound of formula II, R6 is not hydrogen or halogen. In another example, in the compound of formula II, R6 is methy, methoxy, methoxy methylene, or hydroxy.

In another example, in a compound of formula II, R2-R3 and R7 each denote hydrogen.

In another example, in a compound of formula II, R2-R3 and R7 are independently hydrogen, methoxy, methoxymethylene, fluoro, chloro, bromo OR hydroxy.

In another example, in a compound of formula II, R2 is a non-hydrogen substituent. For example, R2 is methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy.

In another example, in a compound of formula II, R3 is a nonhydrogen substituent. For example, R3 is methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another example. In a compound of formula II, R7 is an ηοη-hydrogen substituent. For example, R? is methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydrxy. In another example, in a compound of formula II, R2 and R3 are ηοη-hydrogen substituents. For example, R2 and R3 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another example, in a compound of formula II, R2 and R6 are non-hydrogen substituents. For example, R2 and R6 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another example, in a compound of formula II, R2 and R7 are non-hydrogen substituents. For example, R2 and R7 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another example, in a compound of formula II, R3 and R6 are non-hydrogen substituents. For example, R3 and R6 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo OR hydroxy. In another example, in a compound of formula II, R3 and R7 are non-hydrogen substituents. For example, R3 and R7 are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo or hydroxy. In another example, in a compound of formula II, R6 and R7 are non-hydrogen substituents. For example, Rô and

MA ϋ٩

WO / 2006/034414 PCT / US2O05 / O34O15

R? are, independently, methyl, methoxy, methoxymethylene, fluoro, chloro, bromo OR hydroxy. In another example, in a compound of formula II, R2 is methyl or methoxy, R3 is Rfi and R7 is hydrogen. In another example, in a compound of formula II, R7 is methoxy, R2, R3, and Re are hydrogen.

In another example, in a compound of formula II, R؟ and Rio are each methyl, in another example R9 and Rio are each ethyl. In another example, R٠ and Rio together with a carbon to which they are linked, form a 3 to 7 spiro-cycle. For example the spiro-cycle is a cyclo propyl ring.

In another example, in a compound of formula II, O is zero. In another example, O is zero, and X is absent. In another example, O is zero, X is absent, and the number demetn is 1 or 2. In another aspect, the present invention relates to a compound of formula III:

<img file="MA28985B1_D0026.tif" />

Or a pharmaceutically effective salt thereof, wherein: m and n are independently 0, 1, 2, 3 or 4, X is absent, O, S, C (O), SO or SO2; R1, R2, R3, R and R7 are, independent, selected from H, F, CL, Br١OH١ CF3, CH, CH2CH3, CH (CH) 2, OCH, CH2OCH3 and CHOCHCH; R9 and Rio, are independent H, straight chain C1-C6 alkyl, branched C2-C6 alkyl, or R9 and Rio, together with a carbon to which they are linked form a spiro ring of 3,4,5,6 or 7 atoms, Z is selected from CO 2 H, CO NHS (0) 2-alkyl, CONHS (O) 2-a! Kyl. CONHS (O) 2heteroalkyl, CONHS (0) 2-aryl, CONHS (0) 2-heteroaryl, and tetrazole; with the proviso that when Z is COOH and Re is H, F, Cl or Br, R2, R3, R7 and R9 - Rio do not each denote a hydrogen, provided that when m is zero, X is absent.

In a compound of formula III, Re is not hydrogen or F, Cl or Br and R2, R3 and R7 denote hydrogen.

ΜΑ 28985Β1

WO / 2006/034414 PCT / US2O05 / 034015

In one example, in a compound of formula III, R2, R3, R٥ and R7 are, independently, hydrogen, halogen, methyl, methoxymethylene, methoxy, or hydroxy.

In one example, in a compound of formula III, Re is methoxy, R2, R3, Re and R7 are hydrogen.

In one example, in a compound of formula III, R2 is methyl or methoxy, and R3, Re and R? denote hydrogen. In a compound of formula III, R3 is methyl, R2, Re and R7 denote hydrogen. In another example, in a compound of formula III, R7 is methoxy and R2, R3 and Re denote hydrogen.

In another example, in a compound of formula III, R9 and Rio are each methyl.

In another example, R؟ and Rio, for example with a carbon to which they are linked, form a spiro cycle of 3, for example a cyclopropyl ring.

In another example, in another compound of formula III, X is absent. In another example X is absent, and the number demetn is 1 or 2.

In another aspect, the present invention relates to a compound of formula IV:

<img file="MA28985B1_D0027.tif" />

Or a pharmaceutically acceptable salt thereof, where t is: 1, 2, 3, or 4; R2, R3, Re and R7 are; independently,

H, F, Cl, Br, CFj, CH, OH, OCH, CHOCH, or CHOCHCH; R9-R10 are H, CH, CH2CH3, or Rg and Rio, together with a carbon to which they are linked, form a spiro ring of 3, 4, 5, 6 or 7 atoms; Z is chosen from OH,

CO! (O) i٠all ؛ yl, CONHSCOh-cycloalkyl, CONHS (O) 2٠heteroa! ؛ ٦yl٠ and tetrazole; provided that when Z is COOH and Re is H, F, Cl, or Br; R2, R3, R7 and R؟ - Rio do not each denote hydrogen, and provided that when m is zero, X is absent.

In another example, in a compound of formula IV, t is 1 or 2.

٦٦

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WO / 2006/034414 PCT / US2O05 / O34O15

In another example, the compound of formula IV is selected from a compound of formula IVa, IVb, IVc, IVdouIVe.

In another aspect, the present invention relates to a compound selected from compounds 1, 2, 3

4, 5,6,7, 8,9, 10, 11, 12, 13,14,15,16, 17,18,19,20,21,22,23,24,25,26,27, 28,29,30,

31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,

56.57, 58.59,60,61,62, 63,64,65,66,67,68,69,70,71,72, 73, 74,75,76,77, 78, 79, 80, 5 81, 82, 83, 84, 85, 86.87, or 88.

In another aspect, the present invention relates to a compound selected from compounds 1,12,13, 40, 61, 62, 63, 70, 74, 75, 76, 77 78, 79, 80, 81, 82, 83 and 84.

In another example, the present invention relates to a compound of the formula

<img file="MA28985B1_D0028.tif" />

<img file="MA28985B1_D0029.tif" />

compose 1 ؛ HOOC, or a salt, solvent, hydrate or precursor thereof. For example, the present invention relates to the solvent of compound 1.

In one example, the present invention relates to a compound 1 hydrate. In another example, the present invention relates to a compound 1 precursor.

In another example, the present invention relates to a salt of compound 1, which is pharmaceutically acceptable. For example, the salt can be an acid addition salt, such as a hydrochloride salt.

In one aspect, the present invention relates to a compound

<img file="MA28985B1_D0030.tif" />

COOH

<img file="MA28985B1_D0031.tif" />

<img file="MA28985B1_D0032.tif" />

COOH

In one aspect, the present invention relates to a compound:

MY

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PCT / US2OO5 / O34O15

WO / 2006/034414

In one aspect, the present invention relates to a compound of the formula:

<img file="MA28985B1_D0033.tif" />

<img file="MA28985B1_D0034.tif" />

HOOC (compound 1) or a salt, solvent, hydrate or precursor thereof, and at least one pharmaceutically acceptable excipient. In one example, the composition includes a solvent for compound 1.

In another example, the composition includes a hydrate of compound I. In another example, the composition includes a precursor of compound 1. In another example, the composition includes a pharmaceutically acceptable salt of compound 1.

For example, the salt can be an acid addition salt. An example of an acid addition salt is a hydrochloride salt.

In one example, the present invention relates to a composition of at least one pharmaceutically acceptable excipient.

In another example, the present invention relates to a

<img file="MA28985B1_D0035.tif" />

2HC

<img file="MA28985B1_D0036.tif" />

COOH and composition of “٥” and at least one pharmaceutically acceptable excipient.

In another aspect, the present invention relates to modulating sleep in a subject, by administering to the subject in need a therapeutically effective amount of the compound.

<img file="MA28985B1_D0037.tif" />

I: HOOC or in a pharmaceutically acceptable salt, a solvent, a hydrate, or a precursor thereof. For example, the subject is a human. In one example, the method of

<img file="MA28985B1_D0038.tif" />

mN

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WO / 2006/034414 PCT / US2OO5 / O34O15 The present invention is used to modulate sleep by administering a compound of formula III, for example, the method is used to decrease sleep duration, increase average sleep time, and / or increase the duration of sleep to the maximum. In another example, the method according to the present invention is used to treat sleep disorders. By administering a compound of formula III. Sleep disturbances include, for example, insomnia, an abnormal circarian rhythm, parasomnia, sleep apnea syndrome, narcolepsy or hypersomnia.

In another aspect, the present invention relates to a method of modulating sleep in a subject, by administering to the subject in need, a therapeutically effective amount of compound 1:

<img file="MA28985B1_D0039.tif" />

a pharmaceutically acceptable salt, a solvent, a hydrate or a precursor thereof as a pharmaceutical composition including at least one pharmaceutically acceptable excipient. For example, the subject is a human.

In one example, compound 1 or a pharmaceutically acceptable salt, solvent, hydrate or precursor thereof and co-administered with one or more additional therapies to modulate sleep in a subject. For example, the subject is a human.

The above description brings out the important features of the present invention, to ensure that the detailed description which follows will be understood, and with the aim that the present conditions will be better appreciated. Other features will be more related based on the detailed description which follows, in accordance with the examples.

detailed description

Details of one or more examples of the present invention are set forth in the following description. Also, all methods and meters similar or equivalent to those described here cannot be used in practice or to test the present invention, the methods and meters are described. Other characteristics and advantages of the present invention will become apparent from the description. In a specification, the form of the singular also includes the plural, except where the context indicates otherwise. Unless otherwise, all scientific and technical terms used have the same meaning, as understood by the specialist in the field. In the event of a conflict, this specification will control it.

Wk

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Definitions

For convenience, certain terms used in this specification, examples and appended claims are referred to herein.

The term "treatment" includes any effect, eg reduction, modulation or elimination, which results from amelioration of conditions, disease, disorders; etc.

The term "treatment" includes any effect, eg reduction, elimination or modulation, which results in amelioration of conditions, diseases, disorders, etc.

The term "treating" or "treating" disease includes:

(1) prevention of disease state; i .e, causing the clinical symptoms of the disease state not to develop in a subject who may be prone to or predispose to the disease state, but not yet experience or demonstrate the symptoms of the disease state; (2) inhibit the disease state; ie, to stop the development of the disease or these clinical symptoms; or (3) alleviate the disease; i. e cause temporary or permanent remission of disease or these clinical symptoms. The term "disease" means any disease, condition, symptom or indictment.

The term "alkyl" includes saturated aliphatic groups, including straight chain alkyl groups (eg, methyl, ethyl, propyl, buthyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl), branched chain alkyl groups ( ex, isopropyl, tertbutyl, isobutyl), cycloolkyl (ex, alicyclic) groups (ex: cyclopropyl, cyclopentyl, cyclohexyl, cycloactyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term "alkyl" also includes alkyl groups having oxygen, nitrogen, sulfur or phosphorus atoms, replacing one or more carbon column hydrocarbon atoms; ex heteroatome substitutes CHOCH or CHOCH CH.

In some example the straight chain or branched chain of alkyl has six or a few carbon atoms in its column (eg Cl- Cfi for a straight chain, c؟ - Cft for a branched chain), and in another example , four or a few carbon atoms. Thus, cycloalkyls have three to eight carbon atoms in their structure, and in another example have five or six carbons in the ring structure.

"C1-C6" includes alkyl groups containing 1, 2, 3.4, 5 or 6 carbon atoms. "C2Ce" includes alkyl groups containing 2, 3,4, 5, or carbon atoms.

The term "alkyl" also includes "unsubstituted alkyl" and "substituted alkyl" the latter referring to the alkyl moiety having substituents which replace a hydrogen atom in one or more carbon atoms of the hydrocarbon column. . Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarboneyloxy, alkoxycarrbonyloxy, aryloxycarboneyloxy, carboxylate.

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WO / 2006/034414 PCT / US2OO5 / O34O15 alkylcarboneyl, arylcarboneyl, alkoxycarboneyl, aminocarboneyl, alkylaminocarboneyl, dialkylaminocarboneyl, alkylthiocarboneyl, alkoxcyl, phosphate, phosphonato, phosphonato, phosphinate, alkoxycarboneyl (including alkylarylamio), acylamino (including an alkycarbonylamino, arylcarboneylamino, carbamooyl and ureido), staridono, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trisfluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be substituted, eg, by the substituents described above. An "alkylaryl" or "aralkyl" moist is an alkyl substituted by aryl (eg, phenylmethyl (benzyl)). An "alkyl" can also include a natural or unnatural amino acid. The term "aryl" includes aromatic groups, including 5 and 6 member "non-conjunct" or a singular ring, aromatic groups which may include 0, 1, 2, 3 or 4 heteroatoms, as well as "joint" systems or multicycle, with at least one aromatic cycle. Examples of aryl gorups include benzene, phenyl, pyrazole, furak, thiophene; thiazol, isothiazole, imidazole, trizole, tetrazole, pyrazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and others. Further, the term "aryl" includes multicyclic aryl groups, eg, tricycle, bicycle, eg naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran , deazapurine, or indolizine. Aryl groups having heteroatoms in the ring structure can also be "aryl heterocycles", "heterocyls", "heteroaryls" or "heteroaromatic". The aromatic ring can be substituted in one or more positions of the ring with such substituents as described above, as much as, for example, an alkyl, hologene, hydroxyl, alkoxy, alkylcarboneyloxy, arylcarboneyloxy, alkoxycarboneyloxy, arylcarboneyloxy, carboxylate, alkylcarbonyl, alkylaminocarboneyl, aralkylaminocarboneyl, alkenylaminocarboneyl, alkylcarboneyl, arylcarboneyl, aralkycarboneyl, alkenylcarboneyl, alkoxycarboneyl, aminocarboneyl, alkylthiocarboneyl, phosphate, phosphonato, phosphinato, cyano, amino (including an alkylamino, dialkylamino, arylamino, diarylamino, and an alkylarylamino), acylamino (including an alkylcarboneylamino, arylcarboneylamino, carbamoyl, eturiedo), amidino, imino, suilfhydryl, alkyl, thio, arboxylate alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be linked or can fuse with alicyclic or heterocyclic rings, which are not aromatic to form a multicyclic system (eg tetralin, methylene dioxyphenyl).

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The term "Alkyl" includes unsaturated aliphatic groups, analogous in length and optionally substitutes for the alkyls described above, but which contains at least one double bond. For example, the term "Alkenyl" includes straight chain alkenyl groups (eg, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl), branched chain alkenyl groups, cycloalkenyl groups (eg, alicyclic) (eg, cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), substituted alkyl or alkenyl groups and substituted cycloalkyl or cycloalkenyl groups.

The term "alkenyl" includes, also alkenyl groups, which include oxygen, nitrogen, sulfur or phosphorus, replacing one or more hydrocarbons of carbon columns. In some examples, the straight chain or branched chain of alkynyl groups, contain 1, 2, 3, 4, 5 or 6 carbon atoms in their columns (ex, 2 ء- c₆ for a straight chain, 3 ء- c for a branched chain). On the other hand, cycloalkenyl groups can see 3, 4, 5, or 8 carbon atoms in the ring structure, and in another example, they contain five or six carbon in the ring structure. The term "2 ء- c١6" includes alkenyl groups containing 2, 3,4, 5 or 6 carbon atoms.

The term "alkenyl" also includes "unsubstituted alkenyls" and "substituted alkenyls", the latter refers to alkenyl moieties, having substituents which replace hydrogen, in one or more hydrocarbons of the atom column. of carbon. Such substituents may include, for example, alkyl groups, alkynyl, halogen, hydroxyl, alkylcarboneyloxy, arylcarboneyloxy, alkoxycarboneyloxy, aryloxycarbonyloxy, cardoxylate, alkylacarboneyl, arylcarboneyl, alkoxycarboneyl, aminocarbonyloxy, alkylaminylcarbonyl, carbonyl, alkylaminocarbonyl, dialoxycarboneyloxy, phosphonato, phosphinato, cyano, amino (including NH, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including an alkylcarbonylamino, arylcarboneylamino, carbamoyl, and uriedo), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulfinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trisfluorl, alkyl, cyanoycanoly, heterocaryycyl, heterocaryycyl, or heterocaryycyl, or heterocaryycicyl, or heterocaryycicylcaryycylocaryycylicylocaryycylicylocaryycylicylocaryycylicylocaryycylicyliccarycarycyloarycaryyc half aromatic or heteroaromatic.

The term "alkynyl" includes unsaturated aliphatic groups, analogous in length and possible substitution of the alkyls described above, but which contains at least one triple bond.

For example, the term "alkynyl" includes straight chain alkynyl groups (eg, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, honynyl, decynyl), branched chain alkynyl groups, and alkynyl cycloalkyl or cycloalkenyl substitues. The term "alkynyl" also includes groups having oxygen, nitrogen,

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WO / 2006/034414 PCT / US2OO5 / O34O15 sulfur, or phosphorus which replace one or more hydrocarbons in the carbon column. In some examples, the straight chain or branched chain alkynyl group contains 2, 3, 4, 5 or 6 carbon atoms in its column (ex, 6 ء -2 ء for a straight chain, 6 ء -3 ء for a branched chain) . The term "6 ح -2 ء" includes an alkynyl group containing 2, 3, 4, 5 or 6 carbon atoms.

The term "alkynyl" also includes "unsubstituted alkynyls" and "substituted alkynyls" the latter referring to an alkynyl moiety having substituents which replace hydrogen in at least one or more hydrocarbons in the atom column. of carbons, such substitution may include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarboneyloxy, arylcarboneyloxy, alkoxycarboneyloxy, aryloxycarboneyloxy, carboxylate, alkylcabonyl, arylcarboneyl, alkoxycarboneyl, aminocarboneyl, alkylaminocarboyl, dialklaminocarboneyl, alkylthiocarboneyl, alkylthiocarboneyl, alkoxy, phosphate, cyano, amino (including NH, alkylamino, dialkylamino, arylamino, diarylamino, et alkylcarboneyl, alkylthiocarboneyl, alkylthiocarboneyl, alkoxy, phosphate, cyano, amino) ), amidino, imino, sulfhydryl, alkythio, thiocarboxylate, sulfates, alkylsulfinyl, sulfomato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As long as the number of carbons is specified, "lower alkyl" includes an alkyl group, as defined above, but having 1,2,3, 4, 5, 7, 8, 9 or 10 carbon atoms, in another example , an alkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms in its column structure.

"Lower alkyl" and "lower alkynyl" have a chain length of, for example, 2, 3, 4, 5 or 6 carbon atoms.

The term "acyl" includes compounds and parts which contain an acyl radical (CHCO-) ​​or a carbonyl group. The term "acyl substitutes" includes acyl groups, where one or more of the hydrogen atoms are replaced, for example, by alkyl groups, alkynyl, halogen, hydroxyl, alkylcarboneyloxy, arylcarboneyloxy, alkoxycarboneyloxy, aryloxycarboneyl, carboxylate, alkylcarboneyl, arylcarbone. , alkoxycarboneyl, aminocarboneyl, alkylaminocarboneyl, dialkylaminocarboneyl, alkylthiocarboneyl, alkoxy, phosphate, phosphonate, phosphinate, cyno, amino (including- NH, alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including an alkylcarboneylamino, arylcarboneylamino, carbamoyl, and ureido), amidino, imino, sulflydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinamido, sulfoyido

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WO / 2006/034414 PCT / US2OO5 / O34O15 nitro, trifluoro, cyano, azido, heterocyclyl, alkylaryl, an aromatic moiety or a heteroaromatic.

"Acylamino" includes halves where one acyl half is bonded to an amino group (C (O) N- or NC (O) _). For example, the term includes alkylcarboneylamino, arylcarboneylamino, carbamoyl or ureido groups.

The term "aroyl" includes groups or moieties with a heteroaromatic moiety bonded to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.

The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which additionally include oxygen, nitrogen or sulfide atoms which replace one or more hydrocarbons in the carbon atom column, eg CH CH, CHjNHCHorCHSCH.

The term "alkyloxy" or "alkoxyl" includes substituted or unsubstituted alkyl, alkynyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy (or alkoxyl radical) groups include methoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.

Examples of substituted alkoxy groups include halogen groups. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogenhydroxyl, alkycarboneyloxy, ar lcarboneyloxy, alkoxycarboneyloxy, aryloxycaronyloxy, carboxylate, alkylcarboneyl, arylcarboneyl, alkoxycarboneyl, aminocarboneyl ,alkoxycarboneyl, aminocarboneyle alkyl, alkoxycarboneyl, aminocarboneyle alkyl, alkoxycarboneyl, aminocarboneyl, alkoxycarboneyl, aminocarboneyl, alkylaminkocarbonyl, alkylaminocarbonyl, alkylaminkarbonyl, alkylaminocarbonyl, alkoxycarboneyl, alkylcarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminkarboneyl, alkylcarboneyloxy, phosphinite, cyano, amino, (including- NH, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylacarboneylamino, arylcarboneylamino, carbamoyl, and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphate, alkylsulfinyl, sulphonate, sulphamoyl, sulphonamly, nitro, alkyl, trifluoromethyl, heterocaryycano, cyano-ycano aromatic OR heteroaromatic halves.

Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The terms "heterocyclyl" or "heterocylic" include firm ring structures, eg, 3, 4, 5, 6, 7, 8, 9 or 10- or 4, 5, 6, or 7 member of rings, which include a or more heteroatoms.

In an example, the structure of the ring is 5 or 6 ring members. The term "heteroatom" includes atoms of another element other than carbon or hydrogen. Of

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WO / 2006/034414 PCT / US2OO5 / O34O15 Examples of heteroatoms include nitrogen including nitrogen, oxygen, sulfide and phosphorus.

Heterocyclyl groups can be saturated or ηοη-saturated and include, for example, pyrrolidine, oxylane, thiolane, piperidine, piperazine, morpholine, lactomas, lactams, such as azetidinones and pyrrolidinones, sultams and sultones. Heterocyclic groups, eg pyrrole and fitran may have one character. Heterocyclic groups include fusion ring structures, such as quinoline and isoquinoline. Other examples of the heterocyclic include pyridine and purine.

The heterocyclic ring can be substituted in one or more positions with such a substitute as described above, such as, for example, halogen, hydroxyl, alkylcarboneyloxy, arylcarboneyloxy, alkoxycarboneyloxy, aryloxycarboneyloxy, carboxylate, alkylcarboneyl, alkoxycarboneyl, aminocarboneyl, alkyl, alkoxycarboneyl, aminocarboneyl, alkyl, alkoxycarboneyl, aminocarboneyl, alkoxycarboneyl, aminocarboneyl, alkoxycarboneyl, aminocarboneyl, alkoxycarboneyl, aminocarboneyl, alkoxycarboneyl, aminocarboneyl, alkoxycarboneyl, aminocarboneyl, alkoxycarboneyl, aminocarboneyl, alkyl, alkoxycarboneyloxy, aryloxycarboneyloxy phosphonato, cyanon amino (including- NH, alkyl amino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarboneylamino, arylcarboneylamino, carbamoyl and uureido), amidino, sulfhdryl, alkythio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety. Heterocyclic groups may also be substituted by one or more atom constituents, with, for example, lower alkyl, lower alkenyl, lower alkylthio, lower alkylamino, lower alkylcarboxyl, nitro, hydroxy, FC3 or CN, or the like.

The term "thiocarboneyl" or "thiocarboxy" includes compounds and moieties which contain a carbon atom bonded with a double bond to the sulfide atom.

<img file="MA28985B1_D0040.tif" />

The term "ether" includes a compound or a half which contains oxygen bound to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.

The term "ester" includes a compound or a half which contains a carbon or heteroatom which is bonded to an oxygen atom which is bonded to a carbon of the carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarboneyl, ethoxycarboneyl, propoxycarboneyl, butoxycarboneyl, pentoxycarboneyl, and the like. alkyl, alkenyl or alkynyl groups are defined above.

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The term "thioether" includes compounds or moieties which contain a sulfide atom which are bonded to two different carbons or heteroatoms. Examples of thioethers include, but are not limited to alkylthioalkyls, alkthioalkenyls and desalkthioalkynyls. The term "alkrhioalkyls" includes compounds with an alkyl, alkenyl or an alkenyl group, bonded to a sulfide atom which is bonded to an alkyl group.

Similarly, the terms "alkthioalkenyls" and "alkthioalkynyls" refer to compounds or moieties where an alkyl, alkenyl or alkynyl group is bonded to a sulfide atom which is covalently bonded to an alkynyl group.

The term "hydroxy" or "hydroxyl" includes groups with an - OH or -Ο-.

The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. the term "perhalogen" generally referred to a half where all the hydrogens are substituted by halogen atoms.

The term "substitute ηοη-hydrogen" refers to substituents other than hydrogen. Ηοη-limited examples include alkyl groups, alkoxy groups, halogen groups, hydroxyl groups, aryl groups, etc.

The term "polycyclyl" or "polycyclic radical" refers to two or more cyclic chains (eg: cycloalkyls, cyclokenyls, cycloalkynyls, aryls and / or heterocyclyls) where two or more carbons are common for linked rings. The rings which are linked through non-adjacent atoms are referred to as "intermediate" rings. each ring of the polycycle may be substituted with such substituents as described above, for example, halogen, hydroxyl, alkyl, alkylcarboneyloxy, arylcarboneyloxy, alkoxycarbonyloxy, arylcarboneyloxy, carboxylate, alkylcarboneyl, alkoxycarboneyl, alkylaminocarboneyl, aralkylaminocarbone pararylaminocarboneyle ou, aralkylaminocarbone à alkylaminocarbone à [ aralkylcarboneyl, alkenylcarboneyl, aminocarboneyl, alkylthiocarboneyl, alkoxyl, phosphate, phosphonate, phosphinate, cyano, amino (including NH - alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarboneylamino, arylcarboneylamino, carbamoyl, and lureido), amidino, imino, sulfhydryl, alkylthio, arythio, thialkylocarboxylato, sulfate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. An "anionic group" as used herein, referred to a group which is negatively charged at a physiological pH. Anionic groups include a carboxylate, sulfate, sulfate, suffonate, sulfinate, sulfamate, tetrazolyl, phosphate, phosphonate, phosphinate or phosphorothioate or functional equivalents thereof. “Functional equivalents” of anionic groups include bioisosteres, eg, bioisosteres of the carboxylate group. The

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WO / 2006/034414 PCT / US2OO5 / 034O15 bioisosteres include equivalent bioisosteres and equivalent non-classical bioisosteres. Classical and non-classical bioisosteres are known in the field (even for example,

Silverman, RB The Organic Chemistry of Drug Design and

Drag Action, Academic Press, Inc .: San Diego, Calif., 1992 ,,.

An example of an anionic group is the carboxylate.

“The protecting group” refers to a group of atoms that when bonded to an active group in the caches of molecules, it reduces or prevents reactivity.

Examples of protective groups can appear in Green and wuts, protective groups in Organic chemistry, (wiley, 2nd ed. 1991). Harrison and Harrison et al., Compendium of synthetic organic methods, vols. 1-8 (John Wiley and sons, 1971- 1996), and Kocienski, Protecting groups, (verlag, 3'٥ ed. 2003).

The term "amine protecting group" refers to a functional group which contains an amine, amide, or other nitrogen containing one half in different chemical groups which are substantially inert under the conditions of particular chemical reactions. The amine protecting groups are preferably dissolved easily and selectively under good conditions so as not to affect the other functional groups of the molecule. Examples of the amine protecting groups included, but are not limited, formyl, acetyl, benzyl, t-butyuldimethylsilyl, t-butyldiphenylsilyl, t-butyloxycarboneyl (BOC), p-methoxybenzul, methoxy methyl, toxyl, trifluoracetyl, trimethylsilyl ( TMS), fluorenylmethyloxycarboyl, 2-trimethylsilylethoxycarboneyl, 1- methyl -l (4-biphenylyl) ethoxycarboneyl, allyloxycarbonyl, benzyloxycarboneyl (CBZ), 2-trimethylsilylethanesulfonyl (SES), trityl and substituted trityl groups, to 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarboneyl (NVOC) and the like. Other amine protection groups are simply defined by one skilled in the art.

Hydroxy protecting groups include those where the hydroxy groups are either acyl or alkyl such as benzyl, trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

"A stable compound" and a "stable structure" means a compound which is sufficiently strong to achieve isolation to a useful degree of purity by the reaction mixture, and formulation into an effective therapeutic agent.

In the present specification, the structural formula of the compounds represents a certain isomer as a convenience in some instances, but the present invention includes all isomers such as geometric isomer, asymmetric carbon-based optical isomer, steroisomer, tautomer and the like. , which is structurally and a mixture of isomer, which is not limited to the description of the formula for convenience, and may be

MY

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WO / 2006/034414 PCT / US2005 / O34O15 any isomer of the mixture. Therefore, an asymmetric carbon may be present in the molecule and an optically active compound as well as a racemic compound may be present in the present compound, but the present invention is not limited to these, it does not include. no matter which of them. In addition, a polymorphic crystal can be present but is not limited, but any form of crystal can be a singular or a mixture form of the crystal, or an inidric or a hydrate. In addition, a so-called metabolite, which occurs by degradation of the present compound in vivo, is included within the scope of the present invention.

It will be noted that the structure of certain compounds according to the invention includes the asymmetric carbon (chiral). It is obvious that isomers produced by such an asymmetry are included within the scope of the present invention, unless otherwise. Such isomers can be obtained in substantially pure form, by conventional separation techniques and by controlled stereochemical synthesis.

The compound of the present invention can be in the form of a stereoisomer, therefore it can be produced as an individual stereoisomer or as many mixtures.

The term "isomerism" denotes compounds having an identical molecular formula but also different in their nature or the sequence which binds their atoms or in the arrangement of their atoms in space.

"Isomers" which differ in their spatial arrangement are known as "stereoisomers". stetreoisomers which are not inverted images of one another are known as "diastereoisomers", and stereosiomers which are ηοη-superimposed inverted images are referred to as "enantiomer", or sometimes optical isomers. The carbon atom bonded to four non-identical substituents is referred to by the term "chiral center".

The term "chiral isomer" denotes a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and can be either as an individual enantiomer or a mixture of enantiomers. The mixture containing an equivalent amount of individual enantiomeric form of an opposite chirality is referred to as "racemic mixture".

Another compound having more than one chiral center has a pair of 2 "'enantiomers, where n is the number of chiral centers.

Compounds with more than one chiral center can exist either as an individual diastereoisomer or as a mixture of diasteroisomers, referred to as "diastereoisomeric mixture". When a chiral center is present, the stereoisomer can be characterized by an absolute configuration (R or s) of the chiral center. Absolute confirmation refers to a spatially arranged arrangement of substituents linked to the chiral center. The

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WO / 2006/034414 PCT / US2OO5 / 034O15 substituents linked to the chiral center are arranged in accordance with the sequence governed by cahn (Calm and d, Angew. Chem.

Inter. Edit. 1966, 5.385; errata 511; Cahn et al., Angew. Chem. 1966,78,413; Cahn and Ingold, ر. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956,12, 81; Cahn, J٠, Chem. Educ. 1964,41,116).

The term "geometric isomers" refers to the diastereomer which owes its existence to a hundred rotations on double bonds. These configurations differentiated in their names by the prefix cis and trans, or Z and E, indicate that the groups are in the same opposite side of the double bond in the molecule, according to the rules of cahn-Ingold-Prelog.

Additionally, the structures and other compounds referred to in this application include all atropic isomers thereof. "Atropic isomers" are a type of stereoisomer where the atoms of two isomers are arranged differently in space.

The atropic isomers owe their existence to the restricted rotation caused by a hundred rotation of large groups on the central bond. Such atropic isomers typically exist as a mixture, especially as a consequence of recent advances in chromatography techniques, it has been possible to separate the mixtures of two atropic isomers in selected cases.

The terms "polymorphic crystal" or "polymorphic" or "crystal forms" refer to crystal structures where the compound (a salt or a solvent thereof) can catalyze into different crystal arrangements, all having the same composition. elementary. Different crystal shapes usually have different x-ray diffraction range, infrared spectrum, melting points, degree of density, crystal shape, optical and electrical properties, stability and solubility. Recrystallization of the solvent, level of crystallization, storage temperature and other factors can cause a dominant crystal shape.

The polymorphic crystal of the compounds can be prepared by crystallization under different conditions. For example, the use of different solvents or different mixture of solvents for recrystalisation; crystallization at different temperatures; various modes of cooling, changing from very rapid cooling to very long cooling during crystallization and the like. Polymorphs are also obtained by heating or by dissolving the compounds present, followed by gradual or rapid cooling. The presence of polymorphs is determined by solid-test nuclear and magnetic resonance spectroscopy, solid-test nuclear and magnetic resonance spectroscopy, infrared spectroscopy, differential scanning calorimetry, -X-ray powder diffraction, and other techniques known in the art. specialist in the field.

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In addition, the compounds of the present invention, for example, the salts of the compounds, can be in the form of hydrate or inhydrous (unhydric) or of solvents with other molecule of solvents. Non-limited examples of hydrates include monohydrates, dihydrates, etc. nonlimiting examples of solvents include ethanol, acetone, etc. solvents.

The term "tautomer" refers to compounds having a different structure in the arrangement of atoms, which exist in rapid and easy equilibrium form. It will be understood that when the compounds have tautomeric forms, all tautomeric forms are included within the scope of the present invention, and the compounds do not exclude any tautomeric form.

Certain compounds of the present invention may be in the form of a tautomer which are also included within the scope of the present invention.

The compounds, salts, and drug precursors of the present invention can exist in various tautomeric forms, including the stir and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All of these tautomeric forms are included within the scope of the present invention. Tautomers are in the form of mixtures of tautomerism in solution. In solid form, a tautomer can be described, the present invention includes all tautomers of the compounds present.

A tautomer is one of two or more isomer structures which are in equilibrium and which are converted from one isomeric form to another. This reaction results from the migration of the hydrogen atom, accompanied by the passage of adjacent conjugated double bonds.

In solutions where tautomerization is possible, the chemical equilibrium of the tautomers will be established. The exact level of the tautomers depends on various factors, including temperature, solvent, and PH. The count of tautomers that are interconvertable by tautomerization is referred to as tautomerism.

Among the various types of tautomerism that are possible, two are observed. In keto-enol tautomerism, changes of electrons or hydrogen atoms occur. The chain of tautomerism is exhibited by glucose. This results in the aldehyde group - (CHO) in sugar chain molecule, acting with one of the hydroxy groups - (OH) in the same molecule to provide a cyclic form (ring configuration).

The tautomerizations are catalyzed by: Base: 1- deprotonation; 2- formation of the delocalized anion (eg, an enolate); 3- protonation at different position of the anion; acid: 1protonation; 2- Formation of the relocation of the catione; 3- Deprotonation of different positions adjacent to the cation.

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The pairs of common tautomers are: acid ketone-enol tautomerism, amidevitrile, lactam-lactim, amido-imidic in heterocyclic rings (eg, in bases

<td>nucleairque guamine, thymine.</td><td>and cytosine).</td><td>amine- enamme</td><td>and enamine-enamine. Of</td>

<td>examples include:</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td>

<td>K ئؤ&gt; ه ٠</td><td>ch₂'HSD ؛</td><td>CH ٨ و ٠ ر HSE</td><td>çh₂.٣٧. ىصل ١ أر H ٤ H SP</td>

"Solvents" refers to forms of addition solvent which contain either a stoichiometric and non -stoichiometric amount of the solvent. Some compounds tend to trap a fixed mole percentage in the solvent molecules in the crystaline solid state, these even forming a solvent. If the solvent is water, the solvent formed is a hydrate, when the solvent is alcohol, the solvent formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which water retains its molucular state as much as HO, such as a combination which can form one or more hydrates.

As used herein, the term "analogue" refers to a chemical compound which is structurally similar to another compound, but which is different in composition (as in the replacement of an atom by an atom of a different element or in the presence of a particular functional group or the replacement of a functional group by another functional group).

Therefore, an analogue is a compound which is similar or comparable in appearance and function, but not in structure or origin with respect to the reference compound.

As defined herein, the term "derivative" to compounds which have the same suture core, and are substituted with various groups as described herein. For example, all of the compounds represented by formula I are derivatives of loxapine, and have formula I as a common nucleus.

The term "bioisoster" refers to a compound resulting from the exchange of atom or group of atoms with another similar atom or group of atoms. The objective of the mN

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WO / 2006/034414 PCT / US2O05 / O34O15 replacement of the bioisostery is to set up a new compound with the same biological properties compared to the parent compound.

Bioisosteric replacement can be physicochemically or topologically based.

Examples of bioisosteric carboxylic acid include acyl sulfonimides, tertrazoles, sulfonates, and phosphonates. See for example: Patani and LaVoie, Chem. Rev. 96, 3147-3176 (1996).

In one example, Z is a carboxylic acid or a bioisosteric carboxylic acid.

The term "compounds such as loxapine" or "loxapine-like compounds" "compounds such as loxapine" or "compounds derived from loxapine" include analogues of loxapine or antihistamines which include two aryl groups linked to the same atom which are linked to each other. through a tricylic ring system, ex: a seven member oxygen and nitrogen containing a ring (ie similar to loxapine) bound in the position of the piperazine ring.

The term "antihistamine" refers to a compound which is linked to an H1 receptor and which blocks the activity of histamine, and / or reduces the constitutive activity of the receptor.

As used herein, the term "sleep disorder" includes conditions known to those skilled in the art to be sleep disorders, for example, conditions known in the art or conditions proposed to be sleep disorders or found to be sleep disorders. being sleep disorders.

Sleep disturbances also occur in a subject who suffers from other medical conditions, illnesses, or in a subject treated with other drugs or medical treatments, where the subject, as a result, has difficulty falling asleep and / or keeping sleep, or sleep experiences, or non-restorative sleep experiences or non-restorative sleep, eg, sleep deprivation experiences in a subject.

The term "treating a sleep disorder" includes the treatment of a sleep disorder including other disorders such as CNS disorders (eg, mental or neurological disorders, such as anxiety). In addition, the term "treatment of the sleep disorder" includes the beneficial effects of ameliorating other symptoms associated with the disorder.

The term "peak non -REM sleep" is defined as the duration of peak non -REM sleep per hour after treatment, with the resulting drug administration at circardial time (CT) 18, which is 6 hours after treatment. 'lights out in a laboratory, put in LD 12:12 (12 hours of light and 12 hours of darkness) a light-dark cycle. A normal criterion of 55% non-REM sleep per hour is equivalent to 33 minutes of non-REM sleep per hour.

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As used herein, the term "cumulative non-REM sleep" is defined as the net total of aggregates increasing in the number of minutes of non-REM sleep, measured throughout the duration of the sleep effects of drugs, which typically, but not always results in the first 6 hours after treatment, adjust for the aggregate net total of the number of minutes of non-REM sleep, which results during the corresponding base of non-treatment per 24 hour day, relating to this type of vehicle control treatment.

As defined herein, the term "duration of sleep" refers to a discontinuous episode of continuous or nearly continuous sleep, comprising non-REM sleep, REM sleep, or both stages of non-REM sleep and REM sleep. , delimited before and after the episode by more than 2 times 10 successive seconds of a period of insomnia, as used here, the term "a longer sleep period" is defined as the total number of minutes an animal sleeps (the non-REM and / or REM sleep stages) during the singular long sleep period or "period" that results first at the end, one hour after the treatment. The measure of "sleep period" is measured continuously over a period of 10 seconds, and is marked in the predominant state, computerized or determined as a discrete sleep stage (where the sleep stages are defined as non-REM sleep, REM sleep or insomnia) for 10 seconds intervals which define the duration.

The term "average sleep duration" is defined as an average duration (in minutes) of each sleep duration that begins at a given hour independent of the individual duration of each duration or period.

"Return of insomnia" is defined as a period of return, or compensatory insomnia that results after the effects of sleep from the hypnotic or soporific agent.

“REM sleep inhibition” is defined as a reduction in REM sleep time after treatment at CT-18 (6 hours after lights off; LD 12:12) or at CT-5 hours after return from sleep. light; LD 12:12). Compounds which reduce REM sleep time by more than 15 minutes (relative to base and adjust for vehicle of treatment) when administered to either CT-18 or CT-5 are considered to be unacceptable.

Compared to NREM sleep or insomnia, REM sleep causes respiratory depression and episodic cardiovascular changes.

During the return of insomnia, the physiological effects of REM sleep are amplified and interrupt normal sleep cycles, as defined herein, "disproportionate locomotor inhibitory activity" is a reduction in locomotor activity that exceeds normal and predicts a reduction in locomotor activity. reduction in activity attributable to sleep.

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WO / 2006/034414 PCT / US2O05 / O34O15 "Combination therapy" or "CO-therapy" includes administration of the compound of the present invention and at least a second agent as a specific part of the treatment, which provides the beneficial effect by the combined action of these therapeutic agents, the beneficial effects of the combination, include, but are not limited to, pharmacokinetic or pharmacodynamic CO-action resulting from a combination of the therapeutic agents. These combinations of the compounds of the present invention and other active agents can be administered together in a singular combination or separately.

When using separate administration, administration of one component may be before, during, or subsequent to the administration of the other agents.

The administration of these therapeutic agents in combination is typically carried out over a defined period of time (usually minutes, hours, days or weeks, depending on the combination chosen). In one example, "combination therapy" involves the administration of two or more of these therapeutic agents as part of the separate monotherapy regimen, which accidentally or arbitrarily results from the combinations of the present invention. In another example "combination therapy" involves the administration of these therapeutic agents in a sequential manner, such that, each therapeutic agent is administered at different times, as well as the administration of these therapeutic agents, or at least two. of these therapeutic agents, in a substantially simultaneous manner. Simultaneous administration can be accomplished, for example, by administering to a subject a single capsule having a fixed volume of each therapeutic agent or in multiple or single capsules of each therapeutic agent. Sequential or substantial administration of each therapeutic agent can be effected by any means of administration, but not limited to oral, intravinous, direct absorption through the tissues of the mucous membrane.

Therapeutic agents can be administered by the same means or by different means. For example, the first therapeutic agent of the combination selected can be administered by intravenous injection, as long as the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all of the therapeutic agents can be administered orally or all of the therapeutic agents can be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not prescriptively critical. "Combination therapy" also involves the administration of therapeutic agents as described above in addition to combination with other biologically active ingredients and drug-free therapies (eg, surgery, radiotherapy or medical means). Combination therapy also includes drug-free therapy, drug-free therapy can be at any time

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WO / 2006/034414 PCT / US2OO5 / 034015 as long as the beneficial effect resulting from the CO-action of the combination of the therapeutic agents and the drug-free treatment is completed. For example, in appropriate cases the beneficial effect is completed when the drug-free treatment is temporarily changed from the administration of the therapeutic agents, may be by days or by weeks.

The terms "parenteral administration" and "parenterally administered" as used herein refer to modes of administration other than topical and enteric administration, usually by injection, and include, without limitation, injection and infusion. intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intraperitoneal, transtracheal, subcutaneous subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal.

The term "pulmonary" is used here to refer to any part, tissue or organ whose primary function is the external environment, eg, the exchange 0 ات O, in the patient.

"Pulmonair" typically refers to the tissues of the respiratory tract. Therefore, the phrase "pulmonary administration" refers to the formulations described herein for any part, tissue or organ whose primary function is gas exchange with the external environment (eg, mouth, nose, pharynx, laryngophaynx, larynx, trachea, carina, spit, bronchioles, alveoli). In the context of the present invention, the term “pulmonary” includes a tissue or a cavity which is contiguous to the respiratory tract, in particular the sinuses.

Via "a pharmaceutical composition" is a formulation containing the following compounds in a form suitable for administration to an example, the pharmaceutical composition is in the form of a volume or unit of dosage. The dosage unit form is any diverse form, including, for example, a capsule, IV sachet, tablet, single pump, or aerosol inhaler, or ampoule. The amount of the active ingredient (eg, a formulation comprising a compound or a salt thereof.) In a unit of the composition is an effective amount and will vary depending on the particular treatment.

Those skilled in the art will appreciate that in some cases it is preferable to make routine variations in dosage, depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of means are envisioned, including, the oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms for topical or transdermal administration of the compound of the present invention include powders, spray, patches, creams, lotions, gels, solutions and inhaler. In an example, the

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02006/034414 PCT / US2OO5 / O34O15 active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier, and with no preservatives, diluents, or propellants which are necessary.

The term "flash dose" refers to formulations of the compound which are rapidly dispersing dosage forms.

The term "immediate release" is defined as the release of the compound from the dosage form over a brief period, generally 60 minutes. The term "modified release" is defined to include delayed release, sustained release, or pulsed release. The term "pulsed release" is defined as a series of drug release from the dosage form.

The term "sustained release" or "extended release" is defined as a continuous release of the compound from the dosage form over an extended period of time.

The "subject" includes a mammal, e.g., a human, a pet (e.g., dogs, cats, birds, and the like), farm animals (e.g., cow, rears, pigs, horses, and the like) and laboratory animals (eg rats, mice, guinea pigs, birds and the like). It is preferred that the subject is a human.

As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, composition, vehicles, and / or dosage forms which are within the scope of medical treatment, suitable for their use in contact with human tissue, being an animal, without excessive toxicity, irritation, allergic response, or other problem or complication, as well as benefit / average risk.

"A pharmaceutically acceptable excipient" is an excipient which is useful for the preparation of pharmaceutical compositions which are generally safe, non-toxic and are not biologically or otherwise undesirable, it includes an excipient which is acceptable in the veterinary field as well as in the field. the pharmaceutical field specific to humans. The "pharmaceutically acceptable excipient" as used in the specification or claims includes one or more of such excipient.

The compounds herein are capable of forming more salts. All of these forms are contemplated within the scope of the claims of the present invention.

A "pharmaceutically acceptable salt" of a compound means that the salt is pharmaceutically acceptable and has the desired pharmacological activity of a parent compound.

As used herein, "pharmaceutically acceptable salts" refers to derivatives of those present compounds where the parent compound is modified by an acidic salt or a base thereof.

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Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkaline or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include traditional, non-toxic salts or quaternary ammonium salts of the parent compound, for example, organic or inorganic non-toxic acids. For example, such traditional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from 2acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascobic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, editic, disulfonic ethane, 1, 2- sulfonic ethane, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrocloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, paoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicinic, subacetic, sulfamic, sulfanic, sulfuric, tannic, trataric, toluene sulfonic, and the resulting acids, e.g. glycine, alamine, phenyl alanine, arginine, etc.

Other examples include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3- (4- hydroxybenzoyl) benzoic acid, cinnamic acid, 4- chlorobezenenesulfonic acid, 2-naphthallenesulfonic acid, 4toluensulforic acid, camphorsulfonic acid, 4- methylbiocyclo [2, 2, 2] oct -2ene -1- carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The invention also includes salts formed when an acidic pretone present in the parent compound is either replaced by a metal ion, eg, an alkaline metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base. , such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N methylglucamine, and the like. It will be understood that reference to the included pharmaceutically acceptable salts, addition solvent forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same salt.

The pharmaceutically acceptable salts of the present invention can be formed from a parent compound which contains a basic or acidic moiety by conventional chemical methods.

Generally, such salts can be prepared by reacting a free acid or basic forms of these compounds with a stoichiometric amount of a suitable base or an acid in water or in an organic solvent, or a mixture. both ; usually,

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WQ / 2OO6 / O34414 a non-aqueous medium such as ether, ethyl, ethanol, isopropanol or acetetril are used. For example, the following scheme demonstrates the formation of the pharmaceutically acceptable hydrochloric salt of a parent compound, Compound I, with treatment with hydrochloric acid.

<img file="MA28985B1_D0041.tif" />

Compound 1

<img file="MA28985B1_D0042.tif" />

The number of proton and replica atoms associated with the salt can be controlled and depends on the number of acidic / basic atoms in the parent compound and the amount of the acid which is used to process the parent compound. In one example of the present invention, the monohydrochloride salt of the compound is formed by treatment with hydrochloric acid. In another example, the dihydrochloride salt of the parent compound is formed by treatment with hydrochloric acid.

A list of suitable salts is available from

Remington's Pharmaceutical Sciences ,! ed. (Mack Publishing Company, 1990). for example, salts can include, but are not limited to, the hydrochloride salts and acetate salt of the aliphatic-containing amine, the hydroxyl-containing amine, and the imine containing the compounds of the present invention.

The compounds of the present invention can also be prepared as esters, eg, pharmaceutically acceptable esters. For example a carboxylic acid functional group in a compound can be converted into its corresponding esters, eg methyl, ethyl or esters.

Also, an alcohol group in a compound can be converted to its corresponding esters, eg, an acetate, propionate or other ester.

The compounds of the present invention, can also be prepared as well as precursor, for example pharmaceutically acceptable precursors The terms "precursor" and "pre-cursor" are used interchangeably herein and refer to any compound which releases a. parent drug in vivo.

Since the precursors are known to have improved a number of desirable pharmaceutical qualities (eg: solubulity, bioavailability, preparation, etc.), the compound of the present invention can be in the form of a precursor.

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Accordingly, the present invention covers the precursors of the claimed compounds, the delivery methods and the compositions containing them. "Prosecutors" are intended to include any covalent binding vehicles which release an active, parent drug of the present invention in vivo when such a precursor is administered to a subject. The precursors of the present invention are prepared by modifying the functional groups present in the compound, such that the modifications are cleaved, or by manipulation via the in vivo route, to the parent compound. Prosecutors include compounds of the present invention where a hydoxy, amino, sullhydryl, carboxy or carbonyl group is bonded to any group, can be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy group. or free carbonyl, respectively.

Examples of precursors include, but are not limited to, esters (e.g. derivatives of acetate derivatives, dialkylaminoacetate, formate, phosphates, sulfates, and benzoates) and carbamates (e.g. N, N dimethylaminocarboneyl) functional groups- hydroxy, ester groups (eg ethyl esters, morpholinoethanol ester) and carboxyl functional groups, N-acyl derivatives (eg, N- and the enaminones of amino functional groups, oxime functional groups, acetals,

Ketal and ketone enol esters in compounds of formula I. Ive and the like, see Bundegaard, H. "design of prodrug" p 1-92, Elesevoier, New York-Oxford (1985).

In this specification, the form of the singular also includes the plural, unless the context indicates otherwise, all technical and scientific terms used herein have the same meaning as understood by those skilled in the field. In the event of a conflict, this specification will control.

All percentages and averages used herein, except otherwise, are given by weight.

An "effective amount" of the compound of the present invention is an amount, when administered to a subject suffering from a disease or disorder, resulting from the reduction of the disease or disorder in a subject. The amount of the present compound to be administered to a subject will depend on the particular disorder, the mode of administration, the compounds co-administered, and the characteristics of the subject, such as general health, other diseases, age. , gender, genotype, body weight, and drug tolerance. Those skilled in the art will be able to determine the appropriate dosages depending on this or these factor (s).

As used herein, the term "effective amount" refers to an amount of a compound or a combination of the compound of the present invention effective when administered alone or in combination with a sleep promoting agent. For example, an effective amount denotes an amount of the compound present in a formulation or in a medical unit

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WO / 2006 034414 PCT / US2005 / 034015 administers to a patient or subject, which is sufficient to achieve biological activity. The combination of the compounds is optionally a synergistic combination. Synergy, as described herein, for example by Chou and Talalay, Adv.Enzyme Regul.voL22.pp.27-55 (1984), results when the effect of the compounds, when administered, is greater than the additive effect of the compounds when they are administered alone as well as a single agent. In general, the synergistic effect is most clearly demonstrated at suboptimal concentrations specific to the compounds. Synergy can be a term of lower cytotoxicity, or an increase in sleep promoting effect, previous lesser effect, or other beneficial effects of the combination compared to individual factors.

A "therapeutically effective amount" refers to an amount of a compound, when administered to a mammal, to treat a disease, sufficient to effect such treatment with respect to the disease.

A "therapeutically effective amount" will vary depending on the compound, disease and severity of the condition, as well as the age, weight, etc., of the mammal to be treated.

"Pharmacological effect" as termed herein includes the effects produced in a subject who completes therapy. In one example, a pharmacological effect refers to the subject's primary medications which have been treated, which are reduced, decreased, or ameliorated. For example, the pharmacological effect is a result of the prevention, reduction and mitigation of primary indications in a treated subject. In another example, the pharmacological effect means that the disturbances or symptoms of the primary indications in a patient being treated have been alleviated, reduced or reduced.

For example, a pharmaceutical effect is an effect which results from the prevention or reduction of primary indications in a treated subject, the present invention provides a method of modulating sleep by administering an effective amount of loxapine or an analog of the present invention, which is a part which antagonizes the histamine receptor or the group of histamine receptors. The present invention relates to novel analogs of loxapine.

Effective sleep modulators have certain characteristics which correspond with increasing efficiency and decreasing side effects. These characteristics include the desired half-life in a subject, control of the effects of the desired sedative, and minimal undetectable effects in the psychomotor or other central nervous systems (CNS) relating to side effects (e.g. decreased blood pressure). muscle mass, memory deficit, dry eyelids j. For example, effective sleep modulators have a human half-life of at least 7 hours, at least 6 hours and

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WO / 2006/034414 PCTUS2OO5 / O34O15 of at least 5 hours, at least 4 hours, approximately 3 hours or an average of 3 to 7 hours.

One approach to developing the effective sleep modulator is a strategic derivation of the compound or family of compounds with sleep modulating activity. Derivation of the compound can improve one or more of the biological properties to allow the resulting compound to be effectively improved. Examples of favorable biological properties include, but are not limited to, inducing a discontinuous sleep or hypnotic state, activity of the therapeutic compound for a discontinuous period, penetration through blood barriers from the brain into the CNS, e.g. example, resulting from the substituents of lipophylicity or conformal lipophylicity (i.e., lipophylicity as a result of particular conformation, such as the internal formation of the salt between the carboxyl anion and the proton amine), modulation of the half-life of the therapeutic compound, alteration of the load, alteration of pharmacokinetics, alteration of the log P by a value one or more increase in receptor selectivity, reduction of peripheral half-life, ability to increase dosage,) increase of peripheral elimination, reduction of anti-muscarinic activity, reduction of anticholinergic, and any combination thereof.

Derivation of the compound results from a variety of effects and may alter the mechanism of action. For example, under certain circumstances, the compound containing a particular functional group, such as ester, carboxylic acid, or an alcohol group, possesses high selectivity of the desired receptor versus undesirable receptors when compared with a compound without. this group. In other circumstances, the compound containing a particular functional group is more active as a therapeutic agent for the treatment of sleep disorders than the compound without that group. The effect of the derivative compound depends on the identity of the addition. By deriving the compound for the purpose of improving biological properties and reducing unwanted side effects, it is possible to implement a strategy based on the potential for mechanical effects or interactions. For example, in some compounds, the presence of corboxylic acid results from the ability to form an intramolecular ionic ligand, which includes the corresponding carboxylate ion, e.g. the formation of Zwitterion species with a nitrogen atom in the compound or the formation of the binding salt. This interaction results from favorable biological effects such as lipophylicity, ie, increasing lipophylicity as a result of particular conformation, such as the internal formation of the salt between the carboxylic anion and the proton amine. Such lipophylitis allow penetration through the brain blood barriers into the CNS, moreover, the presence of two polar ions is generally understood as inhibition across the blood barrier of the brain.

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WO / 2006/034414 PCT / US2005 0340) 5 non-polar brain. Another benefit of the presence of the carboxylic acid is the ability of the compound to selectively bind to the desired receptor.

Compounds of the present invention can also be derivatized to produce precursors.

The "precursor" includes a precursor of a drug which is metabolically converted in vivo to produce an active drug. The present invention also contains the use of the precursors which are converted in vivo to the sleep modulating compounds used in the methods of the present invention (see, for example, RBSilvermen, 1992, "the organic chemistry of drug design and drug action », Academic press, chp 8). Such precursors can be used to alter the bioavailability (eg, to allow compounds which do not typically cross the brain blood barrier to cross the brain blood barrier) or the pharmacokinetics of the sleep modulating compound. For example, an anionic group, eg: a carboxyl, a sulfate or a sulfonate which can be esterified, eg: with an alkyl group (eg: a methyl group), or a phenyl group to obtain an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, with reduction or hydrolysis, to reveal the anionic group.

Such an ester can be cyclic, e.g. a cyclic sulfate or sulfone, two or more anionic parts can be esterified by a linking group. An anionic group can be esterified with parts (eg, acyloxymethyl esters) which are cleaved to reveal the sleep modulating intermediate, which subsequently breaks down, to a sleep modulating compound which is active. In one example, the precursor is the reduced form of the carboxyl, sulfate or sulfonate, eg an alcohol or a thiol, which is oxidized in vivo to the sleep modulating compound. In addition, an anionic moiety can be esterified into a group which is actively transported in vivo, or which selectively takes an organic route. This strategy is applied to sleep modulation compounds with the aim of increasing their efficiency and safety during sleep. clinical use. A group of compounds useful in the modulation of sleep relates to loxapine which is a psychotherapeutic agent belonging to the family of compounds known as being tricyclic anti-depressants "TCAs".

Loxapine is a dibenzoxazipine antipsychotic agent, which produces pharmacological responses in several species of animals that are characteristics of those seen in the majority of antipsychotic drugs. The mechanism of action is also known, the administration of loxapine succinate results from the inhibition of spontaneous matrix activity, loxapine is recommended to treat schizophrenia.

Mk

28985Β1

PCT / US2005 / 034015

WO / 2006/034414

In another aspect, the present invention provides a method for modulating sleep in a subject, by administering a therapeutically effective amount of the compound.

<img file="MA28985B1_D0043.tif" />

Z is chosen from CCH, CO2R13, or R13 is C1 - C6 alkyl,

C0NR14 -15, or R14 and

Ri5 are independently CONHS (O) 2 - cycloalkyl, CONHS (O&gt; 2 - heteroalkyl, CONHS (O) 2aryl, CONHS (O) 2 -heteroaryl, s (o) 2 NHCO - alkyl, S (O) 2 NHCO - heteroaryl , CONHS (O)₂NH- alkyl, C0NHS (0) 2NH - cycloalkyl, C0NHS (0)₂NH- heteroaryl, CONHStCNH- aryl, CONHS (O)₂NH٠ heteroaryl, SO3H, SO2H, S (O) NHCO_ alkyl, S (0) NHC0-aryl, S (0) NHC010

ΗΝ / Ν

ح أ

تح ٢ ع (tetrazole), or heteroaryl, Ρ (Ο) (ΟΗ) 2, Ρ (Ο) ΟΗ,

<td>م ٦ ر ٦ رل</td><td>ملاى</td><td>هى</td><td>ابكاى</td>

<td>-ض</td><td>-ض</td><td>NH ر؟</td><td>٣١ΝΗ</td>

<td> ٦</td><td> ٦</td><td> ٠٦</td><td>Og ١١</td>

'٧' ٧ 'OR O provided that when Z is COOH or COOR13, and R₆ is H or hologene, R1-R5 and R7-R12 do not each denote hydrogen, and provided that when m is zero, X is absent.

In one example, the compounds of formula I used in the method of the invention have one or more of the following characteristics: constant inhibition (ki) against the binding H1 receptor, at least 500 nM; a ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 500nM and / or 5 times greater than ki with respect to the receptor HI, a higher non-REM value exceeds 55% of non-REM sleep three hours after administration of a compound to a patient.

MY

28985Β1

W0006 / 034414 PCT / US20O5 / 034015 subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a duration of sleep, longer than 13 minutes, the period of sleep after treatment is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject ن a average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compounds of formula I used in the method of the invention have one or more of the following characteristics: a constant inhibition (ki) against the binding H1 receptor, at least 300 nM; a ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 1 μΜ a higher value of non-REM exceeds 55% of the non-REM sleep, three hours after administration of a compound to a subject; a high cumulative total in nonREM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compounds of formula I used in the method of the invention have one or more of the following characteristics: constant inhibition (ki) against the binding H1 receptor, at least 150 nM; a ki against a target binding to a target (off) chosen from M1, Μ2, and Μ3, which is greater than 10 μΜ, a higher value of non-REM exceeds 55 ٥/٥ of non-REM sleep , three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 17 minutes, the post-treatment sleep period is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; the administration of the compound to a subject does

MN

28985Β1

PCT / US2OO5 / O34O15

02006/034414 not an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

As used herein, the "bond" is a chain of atoms which links the nitrogen in piperazine to the Z group.

The method of the present invention is used to treat a variety of subjects, including, for example, humans, pets, farm animals, laboratory animals and wild animals.

In one example, the compound used in the sleep modulation method is compound

1,2,3,4,5,6,7, 8,9,10,11,12, 13,14,15, 16, 17,18, 19,20,21,22,23,24,25,

26,27,28,29,30, 31, 32, 33,34,35,36, 37,38, 39, 40, 41,42,43,44,45,46,47,48,49, 50,

51, 52,53, 54, 55, 56, 57, 58, 59,60,61,62,63,64, 65, 66,67,68,69,70, 71, 72,73, 74,75,

76, 77,78,79,80,81,82,83,84,85,86,87, or 88

In one example, R5 and Rio with the carbon to which they are linked are absent in one example, R9 and Rio, for example with the carbon to which they are linked, form a spiro cycle from 3 to

In an example. Ru and R12, together with a carbon to which they are linked, form a 3 to 7 spiro cycle. For example, Rg and Rio and the carbon to which they are linked are absent, in one example. Ru and R12, together with a carbon to which they are attached, form a 3 member cyclopropyl spiro cycle.

In one example, Z is CO2 H, tertrazole or acyl sulfonamides. For example Z

هدي can have the formula H or

لخ ؛ w

؛ Or West a substitute chosen to modulate the effect, of the polar surface of half Z, to obtain the level of oral absorption, the CNS penetration, and the level of secretion in urine or bile, examples of substitute w useful in this field include an alkyl group (optionally containing a double or a triple bond or a substituted heteroatom, for example CHOCH or CHOCH CH), a cycloalkyl group (optionally containing a double bond), a heteroaryl group, optionally substituted as follows:

ع | د_٠عس.

PC17US2OO5 / O34O15

MY

28985Β1

WQ / 2OO6 / O34414

<img file="MA28985B1_D0044.tif" />

<img file="MA28985B1_D0045.tif" />

Where V is one or more chains chosen to modulate the PKa of the acylsulfonamide moiety, or affect the physical or metabolic properties of the compound, examples of the V chain include halogens such as F, CI or Br; C1- alkoxy groups. O such as OCH or OCH CH, alkyl C1C or cycloalkyl C3, Cs such as CH, CF3 or cyclopropyl; substituted heteroatom, C1-C6 alkyl or C3-C8 cycloalkyl such as CHOCH CH3, or CHOCH CH3; electron groups such as CN, an atom, an amide or a sulfone.

<img file="MA28985B1_D0046.tif" />

(and pyridyl isomers),

<img file="MA28985B1_D0047.tif" />

(and isomers

In another example, Z is a sulfonamide, for example, Z can have the formula

<img file="MA28985B1_D0048.tif" />

<img file="MA28985B1_D0049.tif" />

'or Ra and Rb are independently, for example an alkyl group, a heteroaryl group, optionally substituted, examples include:

<img file="MA28985B1_D0050.tif" />

VAk

28985Β1

PCT / US2OO5 / O34O15

<img file="MA28985B1_D0051.tif" />

(Where V is halogen such as F, c or Br; C1-C6 alkoxy such as 0CH3 or 0CH2 CH3; C1-C6 alkyl or C3-C8 cycloalkyl such as CH3 or CF3, cyclopropyl, heteroatom substitutes C1-C6 alkyl cycloalkyl C3 -C8 such as CH2OCH3, or CHOCH CH, an electron group such as CN, ketone.

amide or sulfone.

<img file="MA28985B1_D0052.tif" />

<img file="MA28985B1_D0053.tif" />

<img file="MA28985B1_D0054.tif" />

CHa (pyrimidine isomers).

In another example, when Z is COOH, at least one between Ri-Rs and at least one between R9 - Rio denotes hydrogen.

In one example. Re does not denote H or halogen.

In another example, R1-R5 and R7-R8 are each hydrogen, and R٥ does not denote H or halogen.

In one example, at least one of R | R does not denote hydrogen, and the remainder and R1-R؟ are hydrogen.

In another example, at least two of Ri-Rs are not hydrogen.

In another example, at least three of R١-Rs are not hydrogen and the remainder of R-Rg are hydrogen.

In another example, at least four of Ri-Rs are not hydrogen and the remainder of R) -Rg are hydrogen. In another example, R2 is not hydrogen. In another example, R3 is not hydrogen. In another example, Re is not hydrogen. In another example, R7 is not hydrogen. In another example, R3 and Re are not hydrogen. In another example, R2 and Re are not hydrogen. In another example, R3 and R7 are not hydrogen.

In another example, R2 and R7 are not hydrogen. In another example, R2 and R3 are not hydrogen. In another example, R6 and R7 are not hydrogen.

In another example, at least one of Ri-Rs is methylene, chlorine, fluoro, bromo, hydroxy, methoxy, methylene or methoxy. In another example, R2 is methyl, chloro, fluoro, bromo, hydroxy, methoxy, methylene or methoxy.

In another example, R3 is methyl, chloro, fluoro, bromo, hydroxy, methoxy, methylene, or methoxy.

Wk

28985Β1

WO / 2006/034414 PCTUS2OO5 / O34O15

In another example, R6 is methyl, chloro, fluoro, bromo, hydroxy, methoxy methylene or methoxy.

In another example, R7 is methyl, chloro, fluoro, bromo, hydroxy, methoxy, methylene or methoxy.

In another example, at least two of RR's are methyl, chloro, fluoro, bromo, hydroxy, methoxy methylene or methoxy.

In another example, at least two between R] -R؟ are methyl, methoxy methylene, chloro, fluoro, bromo, hydroxy, or methoxy; and Z is COOH.

In another example, at least two of Ri-Rg are methyl, methoxy methylene, chloro, fluoro, bromo, hydroxy or methoxy; R9 and Rio are hydrogen, and Z is COOH.

In another example, R3 and R6 are methyl, methoxy, hydroxy, methoxy methylene, chloro, fluoro, or bromo, and the residues of R1-R2, R4-R5 and R7 -Rg are hydrogen.

In another example, R2 and R6 are methyl, methoxy, hydroxy, methoxy methylene, chloro, fluoro, OR bromo, and the residues of R 1, R3 - R5 and R7-R8 are hydrogen.

In another example, R3 and R7 are methyl, methoxy, hydroxy, methoxy methylene, chloro, fluoro, OR bromo, and the residues of R1-R2, R4-R0 are hydrogen.

In another example, R2 and R7 are methyl, methoxy, hydroxy, methoxy methylene, chloro, fluoro, OR bromo, and the remainder of R1, R3-R0, and Rg are hydrogen.

In another example, R2 and R3 - R6, and R 3 are methyl, methoxy, hydroxy, methoxyethylene, chloro, fluoro, or bromo, and the remainder of R1 and R4-R8 are hydrogen.

In another example, R6 is methyl. In another example, R6 is methyl and R2 or R3 is methyl, methoxy, methoxy methylene, chloro, fluoro, or bromo.

In another example, R6 is methyl, and R2 or R3 is methyl, methoxy, hydroxy, methoxy methylene, chloro, fluoro, or bromo.

In another example, R6 is fluoro and R2 or R3 is methoxy.

In another example, R9 and Rio are hydrogen.

In another example, R9 and Rio are methyl.

In another example, R9 and Rio are methyl, R6 is hydrogen or halogen, and R1-R5 and R7-Rg are hydrogen.

In another example, R9 and Rio are methyl, R6 is hydrogen or halogen, R1-R5 and R7 are hydrogen, and Z is COOH.

In another example, R9 and Rio are ethyl. In another example, R9 and Rio are ethyl, R6 is hydrogen or halogen, R1-R5 and R7-R8 are hydrogen.

In another example, R؟ and Rio are ethyl, R6 is hydrogen or halogen. Ri - R ؛ and R7-R8 are hydrogen, and Z is COOH.

MY

28985Β1

WO / 2006/034414 PCT / US2OO5 / 034015

In another example, Rg and Rio, and the carbon to which they are linked, form a three-membered spiro cycle (cyclopropyl).

In another example, R؟ and Rio and the carbon to which they are linked form a three-membered spirocycle (cyclopropyl), R6 is hydrogen or halogen. Ri- Rs, R7-R8 are hydrogen, in another set, R؟ andRio and the carbon to which they are bound form a three-numbered spiro-cycle (cyclopropyl), R6 is hydrogen or halogen, R1-R5 and R7-R8 are hydrogen, Z is COOH.

In another example, Ry and Rio are methyl, R6 is methoxy, R1-R5 and R7R are hydrogen.

In another example, R؟ and Rio are methyl, R6 is methoxy, R1-R5 and R7-R8 are hydrogen, and Z is COOH.

In another example, R9 and Rio are ethyl, R6 is methoxy. Ri-Rs and R7-R8 are hydrogen, in another example R9 and Rio are ethyl, R6 is methoxy. Ri and R ؛ and R7-R8 are hydrogen, and Z is COOH.

In another example, R9 andRio and the carbon to which they are linked form a three-numbered spirocycle (cyclopropyl), R6 is hydrogen or halogen, R1-R5 and R R -Rg are hydrogen. In another example, Rg and Rio and the carbon to which they are linked form a three-numbered spiro-cycle (cyclo propyl), R6 is methoxy, R1-R5 and R7-R8 are hydrogen, and Z is COOH .

In one example. Ru and R12 are methyl in another example, R11 and R12 are methyl, R6 is hydrogen or halogen. Ri - Rs and R7 - Rio are hydrogen. In another example, RI 1 and R12 are methyl, R6 is hydrogen or halogen. Ri - Rs and R7 - Rio are hydrogen, and Z is COOH.

In one example. Ru and R12 are methyl in another example. Ru and R12 are methyl, R6 is hydrogen or halogen. Ri - Rs and R7 - Rio are hydrogen. In another example. Ru and R12 are methyl, R6 is hydrogen or halogen. Ri - Rs and R7 - Rio are hydrogen, and Z is COOH.

In another example. Ru and R12 are ethyl. In another example, Rii and R12 are ethyl, R6 is hydrogen or halogen. Ri- Rs and R7- Rio are hydrogen. In another example. Ru and R12 are ethyl, R6 is hydrogen or halogen. Ri- Rs and R7-Rio are hydrogen, and Z is COOH.

In one example. Ru and R] 2 is the carbon to which they are bonded form a three membered spiro-ring (cyclopropyl) in another example. Ru and R12 is the carbon to which they are linked form a three-membered spiro-cycle (cyclopropyl), R6 is hydrogen or halogen. Ri -Rs and R7 - Rio are hydrogen. In one example. Ru and R12 is the carbon to which they are

MY

28985Β1

WO / 2006/034414 PCI7US2OO5 / O34O15 lees form a three membered spiro-cycle (cyclopropyl), Re is hydrogen or halogen, R (-R ؛ and R؟ - Rio are hydrogen, Z is COOH.

In one example. Ru and R12 are methyl, R٥ is methoxy, in another example. Ru and R12 are methyl, Re is methoxy, R | R ؛ and R7 - Rio are hydrogen.

In one example, R]] and R12 are methyl. Re is methoxy, in another example. Ru and R12 are methyl. Re is methoxy. Ri -Ré and R? - Rio are hydrogen, Z is COOH.

In one example. Ru and R12 are methyl and Re is methoxy. In another example. Ru and R12 are ethyl, Re is methoxy, R1-R5 and R7-R10 are hydrogen, Z is COOH.

In another example. Ru and R12 and the carbon to which they are linked form a three-membered spiro cycle (cyclopropyl), and Re is methoxy. In another example. Ru and R12 and the carbon to which they are linked form a three membered spiro cycle (cyclo propyl), and Re is methoxy, R1-R5 and R7-R10 are hydrogen. In another example. Ru and R12 and the carbon to which they are linked form a three membered spiro cycle (cyclopropyl), and Re is methoxy, R1-R5 and R7-R10 are hydrogen, Z is COOH.

In one example, in a compound of Formula 1, used in the method of the present invention, q is zero. In another example, q is zero, R9 and Rio together with the carbon to which they are linked are absent. In another example, q is zero, R? and Rio together with the carbon to which they are bound are absent, and X and y are absent.

In another example, q is zero, R9 and Rio together with the carbon to which they are linked are absent, X and Y are absent, and the number of m, n, oetp is 1 or 2.

In another aspect, the compounds of the present invention are used to modulate sleep: by decreasing the duration of onset of sleep, increasing the average duration of sleep and / or maximizing the duration of sleep.

In another aspect, the loxapine analogs of the present invention are used to treat sleep disorders. For example, the loxapine analogs of the present invention are used to treat circardian rhythm abnormality, insomnia, parasomnia, post-sleep syndrome, narcolepsy and / or hypersomnia.

In another example, the loxapine analogs of the present invention are used for the treatment of circardian rhythm abnormality, such as jet lag, labor disorders, delayed sleep phase syndrome, and sleep disorder. - alarm clock within 24 hours.

In another example, loxapine analogues are used in the treatment of insomnia, including, for example, intraseal insomnia, psychopysiologic insomnia, insomnia from altitude, tanblant leg syndrome, painful legs. movement disorders

MN

28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15 periodic parts, drug dependent insomnia, drug dependent insomnia, alcohol dependent insomnia and insomnia associated with mental disorder.

In another example, loxapine analogues are used to treat disorders of parasomnia, such as sleepiness, nocturnal pavor, behavioral disorders of REM sleep, bruximous sleep and enuresia.

In another example, loxapine analogs are used to treat sleep apnea disorders, such as central sleep apnea, obstructive sleep apnea, and mixed sleep apnea.

Pharmaceutical compositions which comprise a compound of formula 1, or pharmaceutically acceptable salts thereof, are used in a method of modulating sleep.

In one example, the com pound of formula I or a pharmaceutically acceptable salt thereof is co-administered with one or more therapies.

In another aspect, the present invention provides a method of modulating sleep in a subject, by administering a therapeutically effective amount of the compound.

<img file="MA28985B1_D0055.tif" />

Or a pharmaceutically effective salt thereof, where m, n, and O are, independently, 0, 1, 2, 3, 4, 5 or 6, X is absent, O, s, c (o), so, or SO2; R2, R3, R6 and R7 are independently selected from H, F, Cl, Br, CF3, CH, CH2CH3, CH (CH3) 2, cyclopropyl, OH, 0CH3, 0CF3, CH2OH3, and CH2OH2CH3; Rg and Rio, are independently. H, straight chain C1-Ce alkyl, branched C2- Ce alkyl, or Rg and Rio together with a carbon to which they are linked, form a spiro ring of 3, 4, 5, 6 or 7 atoms, and Z is COOH, COOR13 (where R13 is

MY

28985Β1

02006/034414 PCT / US2005 / O34O15 un alkyl Cl- c٥) CONHS (O) 2-alkyl, CC) NHS (O) 2-heteroalkyl, CONHS (O)₂- aryl, C ONHS (O) 2-heteroaryl, S (0HC0- alkyl, S (O)₂NHCO-heteroalkyl, SlOfiNHCO-arl, S (O) 2NHCO-heteroaryl, CONHS (O) 2 NH-alkyl; CONHS (O) 2NH 2 heteroalkyl; CONHS (O)₂NH-aryl; CONHSfOhNH-heteroryl; or tetrazole, provided that when Z is COOH or COOR13, and foj is H or halogen. Ri- R ؛ and R7-R12 are not each hydrogen, and provided that when n is zero, X is absent.

In one example, the compound of formula II used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 500 nM; a ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 500nM and / or 5 times greater than ki with respect to the receptor HI, a higher non-REM value exceeds 55% of non-REM sleep three hours after administration of a compound to a subject; an elevated cumulative total in non-REM sleep to no less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula II used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) relative to binding H1 receptor, at least 300 nM; a ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is higher than ΙμΜ, a higher value of non-REM exceeds 55% of the non-REM sleep, three hours after administration of a compound to a subject; an elevated cumulative total in non-REM sleep to no less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and

MY

28985Β1

WO 0Ό34414 PCTUS2005 034015 administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal effects of sleep.

In one example, the compound of formula II used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 150 nM; a ki against a target binding to a target (off) chosen between M1, Μ2, and Μ3, which is higher cj 10 μΜ a higher value of non-REM exceeds 55% of non-REM sleep, three hours after administration of a compound to a subject; a high cumulative total in nonREM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 17 minutes, the post-treatment sleep period is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 6 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In another example, Z is OH or tetrazole.

In another example, when Z is COOH, at least one between R2, R3, Re and R7 and at least one between R؟ - Rio does not denote hydrogen. In another example, O is zero.

In another example, at least one between R2, R3, R6, R7 and at least one between R؟ - Rio does not denote hydrogen when Z is COOH.

In another example, R2, R3 and R7 are each hydrogen and R6 is not hydrogen or halogen.

In one example, R2, R3 and R7 are each hydrogen, and R6 is methyl, methoxy, methoxymethylene or hydroxy.

In another example, at least two of R2, R3, R6 and R7 do not denote hydrogen, and the remainder of R2, R3, R6 and R7 are hydrogen.

In another example, at least three of R2, R3, Re and R7 are hydrogen.

In another example, R2 is not hydrogen. In another example, R3 is not hydrogen. In another example, R6 is not hydrogen. In another example, R7 is not hydrogen.

In another example, R3 and R6 are not hydrogen. In another example, R2 and Re are not hydrogen. In another example, R3 and R7 are not hydrogen. In another example, R9 and Rio are each methyl.

VAN

28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15

In another example, Rg and Rio are each ethyl. In another example, R؟ and Rio are each one hydrogen.

In one example, Rg and Rio, and the carbon to which they are linked, form a spiro cycle of three to seven. For example, in one example, R؟ and Rio and the carbon to which they are bound form a three-membered spiro cycle (cyclopropyl).

In one example, Rg and Rio are methyl, Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen. Rg and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen, and Z is COOH.

In one example, R9 and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen. In another example, R9 and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen, and Z is COOH.

In one example, Rg and Rio, and the carbon to which they are linked, form a three-membered spiro cycle (cyclopropyl). In another example, R9 and Rio and the carbon to which they bind form a three-membered spiro cycle (cyclopropyl). Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen.

In another example, Rg and Rio and the carbon to which they are linked form a three-membered spiro cycle (cyclopropyl), R6 is hydrogen or halogen, and the remainder of R2, R3, and R7 are hydrogen , and Z is COOH.

In one example, in a compound of formula II used in a method of the present invention, O is zero. In another example, O is zero, and X is absent. In another example, O is zero, X is absent, and the number of m and n is 1 or 2.

In another example, the modulation of sleep is for example the reduction in sleep time (onset), the increase in the duration of sleep, and / or the increase in the duration of sleep to the maximum. In one example, sleep modulation treats sleep disorders

Pharmaceutical compositions which include the compound of formula II or a pharmaceutically acceptable salt thereof, are also used in compounds for modulating sleep in a subject. In one example, the compound of formula II or a pharmaceutically acceptable salt thereof is co-administered with one or more therapies.

In another aspect, the present invention provides a compound for modulating sleep in a subject, by administering a therapeutically effective amount of the compound of formula III:

MY

28985Β1

PCT / US2O05 / 034O15

WQ / 2OO6 / O34414

<img file="MA28985B1_D0056.tif" />

Or a pharmaceutically effective salt thereof, wherein m and n are, independently, 1, 2, 3, or 4, X is absent, O or s; R2, R3, R٥ and R7 are, independently, selected from H, F, Cl, Br, CF3, 3 »ء 'OH'CHCH, CH (CH) 2, OCH, CH OCH and CHOCHCH; R9 and Rio are, independently. H, straight chain C1- Ce alkyl, branched alkyl C2- 6 ح, or R9, and Rio, together with the carbon to which they are linked, form a spiro ring of 3, 4, 5, 6 or 7 atoms, and Z is selected from OH, CONH (O) 2-alkyl, CONHS (O) 2-cycloalkyl, CONHS (O) 2heteroalkyl, CONHS (O) 2 aryl, CONHS (O) 2-heteroaryl, and tetrazole; provided that when Z is COOH and R6 is H, F, Cl, or Br, then R2, R3, R ?, and R9- Rio does not each denote hydrogen, and provided that when m is zero, X is absent.

In one example, the compound of formula III used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 500 nM; a ki relative to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 500nM and / or 5 times greater than ki relative to the receptor HI, a higher non-REM value exceeds 55% of non-REM sleep three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject

MN

28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15 does not disproportionately inhibit locomotor activity relating to normal sleep effects.

In one example, the compound of formula III used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) relative to binding H1 receptor, at least 300 nM; a ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 1 μΜ, a higher value of non-REM exceeds 55% non-REM sleep, three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produce sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours before administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula III used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 150 nM; a ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, and Μ3, which is higher than 500nM and / or 5 times greater than ki compared to the Hl receptor, a value higher than non-REM exceeds 55% of non-REM sleep three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 17 minutes, the post-treatment sleep period is greater than or equal to 5 minutes when adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 6 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal effects of sleep.

In one example, Z is CCH or tetrazole. In one example, m is zero. In one example, at least one other R2, R3, Ré and R7, and at least one between R9-R10 do not denote

MY

28985Β1

WO / 2006/034414 PCTUS2005 034015 hydrogen when Z is COOH. in one example, R2, R3 and R7 are each hydrogen and R (, is not hydrogen or halogen.

In one example, R2, R3 and R7 are each hydrogen, and Re is methyl, methoxymethylene, methoxy or hydroxy.

In one example, R2, R3 and R7 are each hydrogen, and Re is not hydrogen or halogen. In one example, R2, R3, and R7 are each hydrogen, and Re is methyl, methoxymethylene, methoxy or hydroxy.

In one example, at least two between R2, R3, Re and R7 do not denote hydrogen, and the remainder of R2, R3, Re and R.7 are hydrogen.

In another example, at least three between R.2, R3, Re, and R7 do not denote hydrogen and the remainder of R2, R3, Re and R7 are hydrogen. In another example, R2 is not hydrogen. In one example, R3 does not denote hydrogen. In one example. Ré is not hydrogen. In one example, R7 is not hydrogen. In one example, R3 and Re are not hydrogen.

In another example, R2 and Re are not hydrogen. In another example, R3 and R7 are not hydrogen.

In another example, Rg and Rio are each methyl. In another example, Rg and Rio are each ethyl. In another example, R9 and Rio are each hydrogen.

In one example, R9 and Rio with the carbon to which they are linked, are attached to form a spiro cycle of three to seven. For example, in an example, Rg and Rio with the carbon to which they are linked, are attached to form a spiro cycle of three limbs (cyclopropyl).

In one example, Rg and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen. In another example, Rg and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen, and Z is COOH.

In one example, Rg and Rio are ethyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen.

In another example, Rg and Rio are ethyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen, and Z is COOH.

In one example, Rg and Rio, along with the carbon to which they are attached, are attached to form a three membered spiro cycle (cyclopropyl).

In another example, Rg and Rio, along with the carbon to which they are attached, are attached to form a three-membered spiro cycle (cyclopropyl). Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen.

ΜΑ 28985Β1

WO / 2006/034414 PCT / US2OO5 / 034O15

In another example, R؟ and Rio and the carbon to which they are linked are attached to form a three-membered spiro cycle (cyclopropyl), R6 denotes hydrogen or halogen, and the remainder of R2, R3 and R7 is hydrogen, and Z is COOH.

In one example, in the compound of formula III used in the method of the present invention, X is absent. In another example, X is absent, and the number demetn is 1 or 2.

In another example, the modulation of sleep is for example the decrease in sleep time (onset), the increase in the duration of sleep, and / or the increase in the duration of sleep to the maximum. In one example, sleep modulation treats sleep disturbances.

Pharmaceutical compositions which include the compound of formula III or a pharmaceutically acceptable salt thereof, are also used in the sleep modulating compounds which relate to the present invention.

In another aspect, the present invention provides a compound for modulating sleep in a subject, by administering a therapeutically effective amount of the compound having formula IV:

<img file="MA28985B1_D0057.tif" />

Or a pharmaceutically effective salt thereof, where test 1, 2, 3 or 4; R2, R3, Rg and R7 independently denote H, F, Cl, Br, CF3, CH, OH, OCH, CHOCH, or CHOCHCH; Rg-Rio denote H, CH, CH2CH3, or Rg-Rio, together with a carbon to which they are attached, are attached to form a spiro cycle of 3,4, 5, 6 or 7 atoms; and Z is selected from OH, CONHS (O) 2-alkyl, CONHS (O) 2-cycloalkyl, C0NHS (0) 2-heter0alkyl, CONHS (O) 2-aryl, CONHS (O) 2-heteroaryl, or tetrazole ; provided that when Z is COOH and R٥ is H, F, Cl or Br, then R2, R3, R7, and Rg-Rio denote hydrogen.

In an example t = lou2.

Mk

28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15

In one example, the compound of formula IV used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 500 nM; a ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 500nM and / or 5 times greater than ki with respect to the receptor HI, a higher non-REM value exceeds 55% of non-REM sleep three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula IV used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 300 nM; a ki with respect to a binding objective to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is greater than 1 μΜ, a higher value of non-REM exceeds 55% non-REM sleep three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, the compound of formula IV used in the method of the invention has one or more of the following characteristics: constant inhibition (ki) against binding H1 receptor, at least 500 nM; a ki with respect to an objective binding to an objective (off) chosen between M1, Μ2, Μ3, DI, D2, al, and a2 which is higher than

ΜΑ 28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15

500ηΜ and / or 5 times greater than ki relative to the H1 receptor, a higher non-REM value exceeds 55% of non-REM sleep, three hours after administration of a compound to a subject; a high cumulative total in non-REM sleep at not less than 20 minutes of doses of the compound which maximally produces sleep consolidation; a sleep duration, longer than 13 minutes, the post-treatment sleep period is greater than or equal to 3 minutes when it is adjusted using a baseline value obtained at least 24 hours before the administration of the compound to the subject; an average sleep period greater than 5 minutes at an absolute peak; administration of the compound to a subject does not produce an appreciable rate of return of insomnia; administration of the compound to a subject does not appreciably inhibit REM sleep; and administration of the compound to a subject does not disproportionately inhibit locomotor activity relative to normal sleep effects.

In one example, Z is OH or teyrazole.

In another example, when Z is COOH, at least one enters R₂, R3, and R7, and at least one between R؟ - Rio does not denote hydrogen.

In an example, R؟ and Rio each denote methyl. In another example, R9 and Rio denote ethyl. In an example, R؟ and Rio with the carbon to which they are attached, are attached to form a spiro cycle of three to seven. For example, in one example, R؟ and Rio, along with the carbon to which they are attached, are attached to form a three-membered spiro cycle (cyclopropyl).

In one example, R9 and Rio denote methyl. Re is hydrogen or halogen; and R₂ R3 and R7 are hydrogen. In another example, R9 and Rio are methyl; R٥ is hydrogen or halogen; and R₂ R3 and R7 are hydrogen; and Z is COOH.

In another example, Rg and Rio are ethyl. Re is hydrogen or halogen; and R₂R3 and R7 are hydrogen. In another example, Rg and Rio are methyl. Re is hydrogen or halogen; and R₂ R3 and R7 are hydrogen; and Z is COOH.

In one example, Rg and Rio, together with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl).

In one example, Rg and Rio, along with the carbon to which they are attached, are attached to form a three membered spiro cycle (cyclopropyl); Re is hydrogen or halogen, and R₂ R3 and R? are hydrogen. In another example, Rg and Rio with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl). Re is hydrogen or halogen, R₂ R3 and R7 are hydrogen, and Z is COOH.

In another example, the modulation of sleep is, for example, decreasing sleep time (onset), increasing sleep duration, and / or increasing sleep time.

PCT / US2OO5 / O34O15

MN ϋ٩

W 2006034414 maximum sleep duration. In one example, sleep modulation treats sleep disturbances.

Pharmaceutical compositions comprising the compound of formula IV or the pharmaceutically acceptable salt thereof are also used in the sleep modulating compounds according to the present invention.

In one example, the formulation IV compound used in the methods of the present invention are IVa, IVb, IVd or IVe.

For example, when Rg and Rio denote methyl, the compounds have the general formula IVa:

<img file="MA28985B1_D0058.tif" />

(IVa) -,

When R؟ and Rio are linked to form a three-membered spiro cycle (cyclopropyl), the compounds have the general formula IVb:

<img file="MA28985B1_D0059.tif" />

<img file="MA28985B1_D0060.tif" />

<img file="MA28985B1_D0061.tif" />

Z i;

When R؟ and Rio denote a metyyl, the compounds have the general formula IVe:

WO / 2006/03444 ا

PCT / US2OO5 / O34O15

ΜΝ

<img file="MA28985B1_D0062.tif" />

(IVc);

When Rg and Rio denote an ethyl, and the Cl carbons are linked to form a three-membered spiro cycle (cyclopropyl), the compounds have the general formula IVd:

<img file="MA28985B1_D0063.tif" />

(IVd);

And when Rg and Rio are hydrogen, the compounds have the general formula IVe:

<img file="MA28985B1_D0064.tif" />

(4th).

In another aspect, the present invention provides a compound according to formula I:

ΜΑ 28985Β1

PCT / US2Q05 / 034015

WO / 2006/034414

<img file="MA28985B1_D0065.tif" />

<img file="MA28985B1_D0066.tif" />

(D

Or a pharmaceutically effective salt thereof, wherein m, n, O, P, q are independently 0, 1, 2, 3, 4, 5 or 6; X and Y are, independently, absent, O, s, c (o), so, or SO ؛ ; R1, R2, R3, R4, R ؛, R7 and Rg are independently selected from H, F, Cl, Br, CF3, CH, straight chain C2- C6 alkyl, branched C3- C6 alkyl, C3- C6 cycloalkyl C7, heterocyclyl C3-C7, OH, OCH3, OCF3, CH2OCH3, CHCHOCH, CHOCHCH, and hydroxyalkyl C1-C6; each hydrogen in the CH groups in the bond is optionally substituted by H, F, CL, Br, CH, CH, straight chain C2-C6 alkyl, branched C3-C6 alkyl, cycloalkyl C3C7, heterocyclyl C3- C7, OCH3, OCF3, CHOCH CHOCHOCH, CHOCHCH, or hydroxyalkyl C1-C6; R ؟, Rio, Ru and R12 are independently. H, C1C6 straight chain alkyl, C2-C6 branched alkyl, or R؟ and Rio together with a carbon to which they are linked, are attached to form a spiro cycle of 3, 4, 5, 6 or 7 atoms, or Ru and R12 together with a carbon to which they are linked, are attached to form a spiro cycle of 3, 4, 5 or 7 atoms; or substitutes in two different atoms are linked to form a ring of 3, 4, 5, 6 or 7 atoms; and Z is selected from OH, CO2R13, where R13 is C1- Ce alkyl, C0NRR15, where R14 and R15 are, independently, hydrogen or lower alkyl, CONHS (O) 2-alkyl, CONH (O) 2cyclokyl, CONHS (O) 2- heteroalkyl, CONHS (O) 2- aryl, CONH (O) 2- heteroalkyl, C0NH (0) zaryl, CONH (O) 2- heteroaryl, δ (ΟΝΗΟ- heteroalkyl, S (O) 2NHCO- aryl , S (O) 2NHCOheteroaryl, CONHSOH- C0NHS (0H- alkyl, C0NH (0) 2NH- cycloalkyl, CONHS (O) 2NH_heteroalkyl; CONHS (O) 2 N- heteroalkyl, SCH, SO2H, S (0) NHC0- alkyl .

I ü٩

WO / 2006/034414 PCT / US2OO5 / O34O15 رأ

S (0) NHC0- aryl, S (0) NHCO-heteroaryl, Ρ (Ο) (ΟΗ) 2, Ρ (Ο) ΟΗ, ١- N, or (tetrazole), or

<td>٧١ ىى</td><td>1ΛΛ</td><td>ه</td><td>د</td>

<td>د NH</td><td>لآه؟</td><td>طس</td><td>ه؟</td>

<td> ٦</td><td> ٦</td><td> ٦</td><td> 0'3</td>

<td>O</td><td>Ο</td><td>ج or</td><td>ه, provided that when Z is COOH or</td>

COOR13, and Re is H or halogen, then Ri- R ؛ and R7-R12 do not each denote hydrogen, further provided that when m is zero, X is absent.

In an example, the compound is a compound

1,2,3)4,5,6,7,8,9,10,11,12,13,

,36,37,38 ,35 ,34 ,33 ,32 ,31 ,30 ,27,28,29 24,25,26٠ ,23 ,18,19,20,21,22 ,15,16,17 ,14

39, 40,41,42,43,44,45,46,47,48,49, 50, 51, 52.53, 54.55, 56, 57, 58, 59, 60, 61,62,63, 64,65,66,67, 68,69,70,71, 72, 73, 74, 75, 76, 77,78,79, 80, 81, 82, 83, 84, 85, 86, 87, or 88 .

In one example, Z is OH, tetrazole, sulfonamide, or sulfonamide. In another example, when Z is COOH, at least one between R) - Rg and at least one between R؟ - R | 2 are not hydrogen.

In one example. Re is not H or halogen, in another example R | - R5 and R7R؟ are each hydrogen and Re is not H or halogen.

In one example, at least one of R) - Rg is not hydrogen, and the remainder of R 1 - Rg is hydrogen. In another example, at least two of R | - Rg are not hydrogen, and the remainder of R] - Rg is hydrogen. In another example, at least three of Ri-Rg are not hydrogen and the remainder of Ri-Rg is hydrogen. In another example, at least four of R 1 - R 8 are not hydrogen and the remainder of R 1 - R 8 are hydrogen. In one example, R2 is not hydrogen. In another example, R3 is not hydrogen. In one example. Ré is not hydrogen. In one example, R7 is not hydrogen. In one example, R3 and Re are not hydrogen.

In another example, R2 and Re are not hydrogen. In another example. R2 and Re are not hydrogen. In another example, R3 and R7 are not hydrogen. In another example, R2 and R7 are not hydrogen. In another example, R2 and R3 are not hydrogen. In another example. Re and R7 are not hydrogen.

In another example, at least one R 1-Rg is metyhl, methoxymethylene, chloro, fluoro, bromo, hydroxy, or methoxy.

In another example, R2 is methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy or methoxy. In another example, R3 is methyl, methyl, methoxymethylene,

لآ ٦

ΜΑ 28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15 chloro, fluoro, bromo, hydroxy, or methoxy. In another example. Re is methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy OR methoxy. In another example. Re is methyl, methoxymethylene, choloro, fluoro, bromo, hydroxy OR methoxy.

In another example, at least two of Ri-Rs are methyl, methoxymethylene, chloro, fluoro, bromo, hydroxy OR methoxy. In another example, at least two of RiRg are methyl, methoxymethylene, choloro, fluoro, bromo, hydroxy OR methoxy; and Z is COOH.

In another example, at least two of R 1 -Rs are methyl, methoxy, methoxymethylene, chloro, fluoro, bromo, hydroxy OR methoxy; R9 and Rio are hydrogen; and Zest COOH.

In another example, at least two of R1-R8 are methyl, methoxy, methoxymethylene, chloro, fluoro, bromo, and the remainder of R1-R2, R4- R؛, and R7- Rg is hydrogen.

In one example, R2 and Re are both methyl, methoxy, methoxymethylene, chloro, fluoro, bromo, and the remainder of R 1, R3, Rs and R7-Rg are hydrogen.

In another example, R3 and R7 are both methyl, methoxymethylene, hydroxy, chloro, fluoro OR bromo, and the remainder of Ri-R2 R} - Re and Rg are hydrogen.

In another example, R2 and R7 are both methyl, methoxy, hydroxy, methoxymethylene, chloro, fluoro, OR bromo, and the remainder of R1, R3-Re, and R8 are hydrogen. In one example, R2 and R3 are both methyl, methoxy, hydroxy, methoxymethylene, chloro, fluoro, OR bromo, and the remainder of R1 and R4-Rg are hydrogen.

In another example. Re is methyl. In another example. Re is methyl and R2 or R3 is methyl, methoxy, methoxymethylene, chloro, fluoro OR bromo. In another example. Re is fluoro and R2 or R3 is methyl, methoxymethylene or methoxy. In another example. Re is methoxy, and R2 or R3 is methyl, methoxy, methoxymethylene, hydroxy, chloro, fluoro OR bromo. In one example. Ré is a fluoro and R₂or R3 is methoxy.

In one example, R9 and Rio, together with the carbon to which they are linked, are attached to form a 3 to 7 spiro cycle. In another example, R9 and Rio, together with the carbon to which they are linked, are absent, and Ru and R12, together with a carbon to which they are linked, are attached to form a spiro cycle of 3 to 7.for example, R9 and Rio together with a carbon to which they are linked or Ru and R1₂ together with a carbon to which they are linked, are attached to form a spiro cyclopropyl of 3 members.

In another example, R9 and Rio are hydrogen. In one example, R9 and Rio are methyl. In another example, R9 and Rio are methyl. Re is hydrogen or halogen, and

Ί6

ΜΑ 28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15

Ri- Rs, R7- Rg are hydrogen. In another example, Rg and Rio are methyl, R6 is hydrogen or halogen. Ri- R ؛, R7- Rg are hydrogen, and Z is COOH.

In one example, Rg and Rio are ethyl. In another example, Rg and Rio are ethyl, R6 is hydrogen, and Ri- Rs, R7-Rg are hydrogen. In another example, Rg and Rio are ethyl, R6 is hydrogen or halogen. Ri- Rs, R7- Rg are hydrogen, and Z is COOH.

In one example, Rg and Rio and the carbon to which they are linked are attached to form a three-membered spiro cycle (cyclopropyl). In another example, Rg and Rio, along with the carbon to which they are linked, are attached to form a three membered spiro cycle (cyclopropyl). Re is hydrogen or halogen, and Ri- Rs, R7-Rg are hydrogen. In another example, Rg and Rio, and the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl). Re is hydrogen or halogen, and Ri- Rs, R7-Rg are hydrogen and Z is COOH. In another example, Rg and Rio are methyl. Re is methoxy, and Ri- Rs, R7- Rg are hydrogen. In another example, Rg and Rio are methyl. Re is methoxy. Ri- Rs, R7- Rg are hydrogen and Z is COOH.

In another example, R8 and R10 are methyl, R6 is methoxymethylene, and Rj-Rs, R7-R8 are hydrogen. In another example, Rg and Rio are methyl. Re is methoxymethylene. Ri- Rs, R7- Rg are hydrogen, and Z is COOH.

In another example, Rg and Rio are ethyl. Re is methoxy, and Ri- Rs, R7- Rg are hydrogen. In another example, Rg and Rio are ethyl, R6 is methoxy, Ri-Rs, R7-Rs are hydrogen, and Z is COOH. In another example, Rg and Rio, along with the carbon to which they are linked, are attached to form a three-membered spoiro cycle (cyclopropyl). Re is methoxy, and Ri- Rs, R7- Rg are hydrogen. In another example, Rg and Rio, along with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl). Re is methoxy. Ri- Rs, R? Rg is hydrogen and Z is COOH. In one example, Rg and Rio together with a carbon to which they are linked are absent.

In one example. Ru and R12 are methyl. In another example. Ru and R12 are methyl. Re is hydrogen or halogen, and Ri-Rs, R7-Rio are hydrogen.

In another example. Ru and R12 are methyl, R6 is hydrogen or halogen. RiRs, R7-Rio are hydrogen, and Z is COOH.

In one example. Ru and R12 are ethyl. In another example. Ru and R12 are ethyl, R6 is hydrogen or halogen, and Ri- Rs, R7-Rio are hydrogen. In another example Ru and R12 are ethyl. Re is hydrogen or halogen. Ri- Rs, R7-Rio are hydrogen, and Z is COOH.

In one example. Ru and R12 with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl). In another example. Ru and R12 with

٦٦

ΜΑ 28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15 the carbon to which they are linked, are attached to form a spirocycle of three members (cyclopropyl). Re is hydrogen or halogen, and R | - Rs, R؟ - Rio are hydrogen. In another example. Ru and R12 with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl). Re is hydrogen or halogen, and R 1 - Rs, R7 - Rio are hydrogen and Z is COOH.

In one example. Ru and R12 are methyl, and Re is methoxy. In another example. Ru and R] 2 are methyl. Re is methoxy, and Ri- Rs, R7-Rio are hydrogen. In another example. Ru and R12 are methyl, in another example. Ru and R12 are methyl. Re is methoxy. Ri- Rs, R7- Rio are hydrogen, and Z is

COOH.

In one example. Ru and R12 are ethyl and Re is methoxy. In another example. Ru and R12 are ethyl. Re is methoxy, and Ri- Rs, R7-Rio are hydrogen. In another example. Ru and R12 are ethyl. Re is methoxy. Ri- Rs, R7-Rio are hydrogen, and Z is COOH.

In one example. Ru and R12 together with the carbon to which they are linked, are attached to form a three membered spiro cycle (cyclopropyl) and Re is methoxy. In another example. Ru and R12 with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl). Re is methoxy, and Ri- Rs, R7-Rio are hydrogen. In another example. Ru and R12 with the carbon to which they are linked, are attached to form a three-membered sopiro cycle (cyclopropyl). Re is methoxy, and Ri- Rs, R7-Rio are hydrogen and Z is COOH.

In one example, q is zero. In another example, q is zero, and R9 and Rio together with the carbon to which they are linked are absent. In another example, q is zero, R9 and Rio together with the carbon to which they are attached are absent, X and Y are absent. In another example, q is zero, Rg and Rio together with the carbon to which they are attached are absent, X and Y are absent, and the number of m, n, oetp is 1 or 2.

Pharmaceutical compounds which comprise the compound of formula I or a pharmaceutically acceptable salt thereof are also used in the method of modulating sleep according to the invention.

In another aspect, the present invention provides a compound of formula II:

W0006 / 034414 PCT / US2OO5 / O34O15

MN ϋ٩

<img file="MA28985B1_D0067.tif" />

(CHalm X

محييه) ها * ه (مء)

Z (II)

Or a pharmaceutically effective salt thereof, wherein m, n, and O are, independently, 0, 1, 2, 3, 4, 5 or 6, X is absent, O, s, (O), so, or SO2; R2, R3, Ré and R؟ are, independently selected from H, F, CH2CH3, CH (CH3) 2, cyclopropyl, OH, OCH, 0CF3, CH3OCH3 and CH2OCH3 CH3, Rg and Rio, are independently C1-C6 straight chain alkyl, branched akyl C2- Ce, or Rg and Rio together with a carbon to which they are linked, are attached to form a spiro ring of 3, 4, 5, 9 or 7 atoms, and Z is COOH, COOR13 (where R13 is an alkyl Cl- Cé) CONHS (O) 2 alkyl, CONHS (O) 2- heteroalkyl, CONHS (O) 2- aryl, CONHS (O) 2- heteroaryl, SONHCO- alkyl, SONHCO-heteroalkyl, SONHCO- aryl, SONHCO- heteroalkyl, CONHSONH- alkyl, C0NHS (0) 2NH- heteroalkyl, CONHS (O) 2 NH- aryl, C0NHS (0) 2NHheteroaryl, or terazole, provided that when Z is COOH or COOR13, and Re is H or halogen. Ri- Rs and R7-R12 are not each hydrogen, further provided that when m is zero, X is absent. In one example, Z is CO2H or tetrazole.

In another example, when Z is COOH, at least one of R2, R3, Re and R7, and at least one of Rg-Rio is not hydrogen. In an example O is zero.

In one example, at least one of R2, R3, Re, R7 and at least one of Rg-Rio is not hydrogen when Z is COOH.

In one example, R2, R3, and R7 are each hydrogen and Re is not hydrogen or halogen. In one example, R2, R3, and R7 are each hydrogen, and Re is methyl, methoxy or hydroxy.

ΜΝ ü٩

WO / 2006/034414 PCTUS2005 034015

In one example, at least two of R.2, R3, R, R7 are not hydrogen, and the remainder of R2, R3, Re, R7 are hydrogen. In another example at least three of R2, R3, Re, R7 are hydrogen and the remainder of R2, R3, Re, R7 are hydrogen.

In one example, R2 is not hydrogen. In one example, R3 is not hydrogen. In one example. Ré is not hydrogen. In one example, R7 is not hydrogen. For example, R3 and Re are not hydrogen. In another example, R2 and Re are not hydrogen. In one example, R3 and R7 are not hydrogen.

In one example, Rg and Rio are each methyl. In another example, Rg and Rio are each ethyl. In another example, R9 and Rio are each hydrogen.

In one example, Rg and Rio with the carbon to which they are linked, are attached to form a spiro cycle of three to seven. For example, in an example, Rg and Rio with the carbon to which they are linked, are attached to form a spiro cycle of three limbs (cyclopropyl).

In one example, Rg and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R? are hydrogen. Rg and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3, and R7 are hydrogen, and Z is COOH.

In one example, Rg and Rio are ethyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 is hydrogen. In another example, Rg and Rio are ethyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen, and Z is COOH.

In one example, R9 and Rio, along with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl). In another example, R9 and Rio with the carbon to which they are linked, are attached to form a three membered ring (cyclopropyl), Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are l 'hydrogen. In another example, Rg and Rio, along with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl). Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen, and Z is COOH.

In one example, in a compound of formula II, O is zero. In another example, O is zero, and X is absent. In another example, O is zero, X is absent, and the number of m and n is 1 or 2.

Pharmaceutically compositions containing a compound of formula II or a pharmaceutically acceptable salt thereof, are also used in sleep modulation methods, according to the invention:

In another aspect, the present invention provides a compound of formula having formula III.

WO / 2006/034414 PCTUS2OO5 / 034015

ΜΑ 28985Β1

<img file="MA28985B1_D0068.tif" />

X

Z R١٥ (III)

Or a pharmaceutically effective salt thereof, wherein m and n are independently 0, 1, 2, 3 or 4, X is absent, O, or S; R ؛, R3, R6 and R7 are independently selected from H, F, Cl, Br, CF3, CH, OH CH2CH3, CH (CH₃)₂, 0CH3, CHOCH, and CH2OCH2CH3; R8 and R10 are independently H, straight chain alkyl C1-Co, branched alkyl C2-Co, or R? and Rio, together with a carbon to which they are linked, are attached to form a spiro cycle of 3, 4, 5, 6 or 7; and Z is selected from CO 2 H, CONHS (O) 2-alkyl, CONHS (O) 2-cycloalkyl, CONHS (O) 2-heteroalkyl, CONHS (O) 2-aryl, CONHS (O) 2heteroaryl, and tetrazole; provided that when Z is COOH and Ro set H, F, Cl or Br, then R2, R3 R7, and Rg-Rio are not each hydrogen, in addition provided that when m is zero, X is absent.

In one example, Z is OH or tetrazole. In one example, m is zero. In one example, at least one between R2, R3, Ro, R7 and at least one between Rg-Rio is not hydrogen when Z is COOH.

In one example, R2, R3 and R7 are each hydrogen and Rfi is not hydrogen or halogen. In one example, R2, R3 and R7 are each hydrogen, and R6 is methyl, methoxy or hydroxy.

In one example, R2, R3 and R7 are each hydrogen or halogen. In one example, R2, R3 and R7 are each hydrogen, and R6 is methyl, methyl, methoxymethylene, methoxy or hydroxy.

In one example, at least two of R2, R3, R6 R7 are not hydrogen, and the remainder of R2, R3, R6 are hydrogen. In another example, at least three between R₂, R3, R6, and R7 are not hydrogen and the remainder of R2, R3, R6 and are hydrogen. In one example, R2 is not hydrogen. In one example, R3 is not hydrogen. In one example R6 is not hydrogen. In one example, R7 is not hydrogen.

ΜΑ n٦

WO / 2006/034414 PCTUS2OO5 / O34O15

In one example, R-3 and Re are not hydrogen. In another example, R2 and Re are not hydrogen. In another example, R3 and R۶ are not hydrogen.

In one example, Rc and Rio are each methyl. In another example, R? and Rio are each ethyl. In another example, R9 and Rio are each hydrogen. In another example, Rg and Rio with the carbon to which they are linked, are attached to form a spiro cycle from three to seven. For example, in one example, R9 and Rio with a carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclopropyl).

In one example, R9 and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen. In another example, Rg and Rio are methyl. Re is hydrogen or halogen, and the remainder of R2, R3 and R7SO are hydrogen, and Z is COOH.

In one example, R8 and R10 are ethyl, R6 is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen. In another example, R8 and R10 are ethyl, Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen, and Z is COOH.

In one example, Rg and Rio, along with the carbon to which they are linked, are attached to form a three membered spiro cycle (cyclo propyl). In another example, Rg and Rio with the carbon to which they are linked, form a three-membered spiro cycle (propyl cycle). Re is hydrogen or halogen, and the remainder of R2, R3 and R7 are hydrogen.

In another example, Rg and Rio with the carbon to which they are attached, are attached to form a three membered spiro cycle (cyclo propyl). Re is hydrogen or halogen, the remainder of R2, R3 and R7 are hydrogen, and Z is COOH.

For example, in the compound of formula III, X is absent. In another example, X is absent, and the number demetn is 1 or 2.

Pharmaceutical compositions comprising the compound of formula III or a pharmaceutically acceptable salt thereof are also used in sleep modulation methods, according to the invention.

In another aspect, the present invention provides a compound IV:

PCT / US2OO5 / O34O15

MN

28985Β1

WQ / 2OO6 / O34414

<img file="MA28985B1_D0069.tif" />

(IV)

Or a pharmaceutically effective salt thereof, wherein t is 1, 2, 3 or 4 R, R3 and Re are independently H, F, Cl, Br, CF3, CH3, OH, oh, CHOCH or CH2OCH3; R9-R10 are H, CH, CH2CH3 or Rg and Rio, together with the carbon to which they are linked, are attached to form a spiro ring of 3,4,5,6 or 7 atoms, and Z is selected from OH, CONHS ( O) 2alkyl, CONHS (O) 2-cycloalkyl, CONHS (O) 2-heteroalkyl, and tetrazole; provided that when Z is COOH and Re is H, F, C1 or Br, then R2, R3, R7 and R9-R10 are not each hydrogen, in addition provided that when m is zero, x is absent.

In one example, the compounds have t 1 or 2. the pharmaceutical compositions comprising a compound of formula IV or a pharmaceutically acceptable salt thereof, are also used in the modulation methods according to the present invention: in one example, Z is CO2H, sulfonamid, sulfonamide or tetrazole. In another example, when Z is COOH, at month one between R2, R3 and R7, and at month one R9-R10 are not hydrogen.

In one example, Rg and Rio are each methyl. In another example, Rg and Rio are each ethyl. In another example, Rg and Rio with the carbon to which they are attached, are attached to form a spiro cycle from three to seven. For example, in one example, Rg and Rio with the carbon to which they are attached, are attached to form a three-membered spiro cycle (cyclo propyl).

In one example, Rg and Rio are methyl; Re is hydrogen or halogen, and R2, R3 and R? are! 'hydrogen. In another example, Rg and Rio are methyl; Re is hydrogen or halogen; and R2, R and R7 are hydrogen; and Z is COOH.

In one example, R9 and R10 are ethyl, Re is hydrogen or halogen, and R2, R3 and R7 are hydrogen. In another example, Rg and Rio are methyl; Re is hydrogen or halogen; and R2, R3 and R7 are hydrogen, and Z is COOH.

In one example, Rg and Rio with the carbon to which they are linked, are attached to form a three-membered spiro cycle (cyclo propyl). In another example, Rg and Rio with the

ΜΑ ϋ١

W 2006/034414

PCT / US2OO5 / O34O15 carbon to which they are linked, are attached to form a three membered spiro cycle (cyclopropyl), Rg is hydrogen or halogen; and R2, R3 and R7 are hydrogen. In another example, Rg and Rio with the carbon to which they are linked, are three members (cyclo propyl), R₆is hydrogen or halogen, and R2, R3 and R7 are hydrogen, and Z is COOH. Pharmaceutical compositions comprising a compound of formula IV or a pharmacetically acceptable salt thereof are also used in the sleep modulation methods according to the present invention.

In one example, the compound of formula IV is IVa, IVb, IVc, IVd or Ive. For example.

when Rg and Rio are methyl, the compounds have the general formula Iva:

<img file="MA28985B1_D0070.tif" />

(IVa);

When Rg and Rio are linked to form a three-membered spiro cycle (cyclo propyl) the compounds are of the general formula IVb:

<img file="MA28985B1_D0071.tif" />

R;

When Rg and Rio are ethyl, the compounds have the general formula IVc:

ΜΑ ϋ٩

PCT / US2OO5 / O34O15

02006/034414

<img file="MA28985B1_D0072.tif" />

(IVc);

When Rg and Rio are ethyl, and the C-1 carbons are linked to form a three-membered spiro cycle (cyclo propyl), the compounds have the general formula IVd:

<img file="MA28985B1_D0073.tif" />

(IVd);

and When Rg and Rio are hydrogen, the compounds have the general formula IVe:

<img file="MA28985B1_D0074.tif" />

(4th).

Some representative compounds of the present invention are mentioned in Table 1.

Table 1: loxapine derivatives.

ΜΑ ü٩

PCT7US2OO5 / O34O15

WO / 2006/034414 lamci «٧ مس ٧٨ تغ UVIHMU٠W

<td>Crnpd</td><td>Rj</td><td>R,</td><td></td><td>R,</td><td>RR "</td><td colspan="2">'T Size ا Rins</td><td> 1</td>

<td> ١'</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>OH</td>

<td> 2</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CHj</td><td> 1</td><td> 3</td><td>OH</td>

<td> 3</td><td>H</td><td>H</td><td> ١١</td><td>H</td><td>CH</td><td> 2</td><td>none</td><td>OH</td>

<td> 4</td><td>H</td><td> ١٩</td><td>F</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>OH</td>

<td> 5</td><td>H</td><td>H</td><td>VS!</td><td>H</td><td>CH</td><td> 1</td><td>none</td><td>OH</td>

<td> 6</td><td>H</td><td>H</td><td>Cl</td><td>H</td><td>CH</td><td> 2</td><td>none</td><td>COOH</td>

<td> 7</td><td>H</td><td>H</td><td>This</td><td>H</td><td>CH</td><td> 1</td><td> 3</td><td>COOH</td>

<td> 8</td><td>H</td><td>H</td><td>Br</td><td>H</td><td>CH,</td><td> 1</td><td>none</td><td>COOH</td>

<td> 9</td><td>H</td><td>H</td><td>Br</td><td>H</td><td>CHj</td><td> 1</td><td> 3</td><td>COOH</td>

<td> 10</td><td>H</td><td>H</td><td>CH</td><td>H</td><td>CH,</td><td> 1</td><td>none</td><td>COOH</td>

<td> 11</td><td>H</td><td>H</td><td>CH,</td><td>H</td><td>CH,</td><td> 2</td><td>none</td><td>OH</td>

<td> 12</td><td>H</td><td>H</td><td>OH</td><td>H</td><td>CH,</td><td> 1</td><td>none</td><td>COOH</td>

<td> 13</td><td>H</td><td>H</td><td>OCH</td><td>H</td><td>CHj</td><td> 2</td><td>nor "</td><td>COOH</td>

<td> 14</td><td>H</td><td>H</td><td>OH</td><td>H</td><td>CH,</td><td>l</td><td>none</td><td>OH</td>

<td> 15</td><td>H</td><td>F</td><td>H</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>OH</td>

<td> 16</td><td>H</td><td>F</td><td>CH,</td><td>H</td><td>CHj</td><td>l</td><td>none</td><td>OH</td>

<td> 17</td><td>H</td><td>Br</td><td>H</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>COOH</td>

<td> 18</td><td>H</td><td>Br</td><td>Br</td><td>H</td><td>CH</td><td> 1</td><td>none</td><td>COOH</td>

<td> 19</td><td>H</td><td>CH</td><td>H</td><td>H</td><td>CHj</td><td> 1</td><td>one</td><td>OH</td>

<td> 20</td><td>H</td><td>CH</td><td>CH,</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>COOH</td>

<td> 21</td><td>H</td><td>OC</td><td>H</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>OH</td>

<td> 22</td><td>H</td><td>OCH,</td><td>F</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>COOH</td>

<td> 23</td><td>H</td><td>OCH</td><td>OCHj</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>COOH</td>

<td> 24</td><td>H</td><td>OH</td><td> ١١</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>OH</td>

<td> 25</td><td>H</td><td>OH</td><td>OH</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>OH</td>

<td> 26</td><td>F</td><td>H</td><td>H</td><td>H</td><td>CH,</td><td> 1</td><td>none</td><td>OH</td>

<td> 27</td><td>F</td><td>H</td><td>CH</td><td>H</td><td>CH,</td><td> 1</td><td>none</td><td>OH</td>

<td> 28</td><td>Br</td><td>H</td><td>H</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>OH</td>

<td> 29</td><td>Bf</td><td>H</td><td>Br</td><td>H</td><td>CKj</td><td> 1</td><td>none</td><td>OH</td>

<td> 30</td><td>CH,</td><td>H</td><td>H</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>OH</td>

<td> 31</td><td>CHa</td><td>H</td><td>CHj</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>OH</td>

<td> 32</td><td>oc</td><td>H</td><td>H</td><td>H</td><td>CH</td><td> 1</td><td>none</td><td>COOH</td>

<td> 33</td><td>OCH,</td><td>H</td><td>F</td><td>H</td><td>CHj</td><td> 1</td><td> -</td><td>COOH</td>

<td> 34</td><td>OCH,</td><td>H</td><td>CHj</td><td>H</td><td>CH</td><td> 1</td><td>none</td><td>COOH</td>

<td> 35</td><td>O</td><td>H</td><td>OCH,</td><td>H</td><td>CH?</td><td> 1</td><td>none</td><td>COOH</td>

<td> 36</td><td>OC</td><td>CHa</td><td>H</td><td>H</td><td>CH</td><td> 1</td><td>none</td><td>COOH</td>

<td> 37</td><td>OH</td><td>H</td><td>H</td><td>H</td><td>CH</td><td> 1</td><td>none</td><td>COOH</td>

<td> 38</td><td>OH</td><td>H</td><td>OH</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>OOH</td>

<td> 39</td><td>H</td><td>H</td><td>H</td><td>OCH,</td><td>CH,</td><td> 1</td><td>none</td><td>COOH</td>

<td> 40</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>CONHOCH</td>

<td> 41</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CH,</td><td> 1</td><td>none</td><td>tetraaole</td>

<td> 42</td><td>H</td><td>OCH</td><td>H</td><td>OCH,</td><td>CHj -٠- ^</td><td> 1</td><td>none</td><td>OH</td>

<td> 43</td><td>H</td><td>OC</td><td>CHj</td><td>H</td><td>CHj</td><td> 2</td><td>none</td><td>OH</td>

<td> 44</td><td>H</td><td>Br</td><td>H</td><td>CH,</td><td>CHj</td><td>ل</td><td>none</td><td>OH</td>

<td> 45</td><td>H</td><td>H</td><td> ١١</td><td>Br</td><td>CH,</td><td> 1</td><td>none</td><td>COOH</td>

<td> 46</td><td colspan="2">HH</td><td>H</td><td>CH</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

PCT / US2OO5 / O34O15

I ϋ٩

WO / 2006/034414

<td>Cmpd #</td><td>R *</td><td>Rj</td><td>R٥</td><td>Rr</td><td>RR٠</td><td>T</td><td>size Ring</td><td>z</td>

<td> 47</td><td>H</td><td>F</td><td>Br</td><td>H</td><td>CHj</td><td> 1</td><td>none</td><td>COOH</td>

<td> 48</td><td>H</td><td>F</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 49</td><td> 1-1</td><td>Br</td><td> ١٩'</td><td>Br</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 50</td><td>H</td><td>Br</td><td>CHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 51</td><td>H</td><td>Br</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 52</td><td>H</td><td>CHa</td><td>H</td><td>CHa</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 53</td><td>H</td><td>CHa</td><td>F</td><td>H</td><td>CHa</td><td>i</td><td>none</td><td>COOH</td>

<td> 54</td><td>H</td><td>CHa</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 55</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td>CHa</td><td> 1</td><td>none</td><td>OH</td>

<td> 56</td><td>H</td><td>OC</td><td>CHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 57</td><td>CHa</td><td>H</td><td>Br</td><td>H</td><td>CH</td><td> 1</td><td>none</td><td>COOH</td>

<td> 58</td><td>CHa</td><td>H</td><td>OCHa</td><td>H</td><td>CH</td><td> 1</td><td>none</td><td>COOH</td>

<td> 59</td><td>H</td><td>H</td><td>CH</td><td>H</td><td>H</td><td>l</td><td>none</td><td>COOH</td>

<td> 60</td><td>H</td><td>H</td><td>CHa</td><td>H</td><td>H</td><td> 2</td><td>none</td><td>OOH</td>

<td> 61</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>H</td><td> 1</td><td>none</td><td>COOH</td>

<td> 62</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>H</td><td> 2</td><td>one</td><td>OOH</td>

<td> 63</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td> 3</td><td>COOH</td>

<td> 64</td><td>H</td><td>Br</td><td>Br</td><td>H</td><td>CHa</td><td> 2</td><td>none</td><td>COOH</td>

<td> 65</td><td>H</td><td>CHa</td><td>Br</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 66</td><td>H</td><td>OH</td><td>OH</td><td>H</td><td>CHa</td><td> 2</td><td>none</td><td>COOH</td>

<td> 67</td><td> ١٩</td><td>OCHa</td><td>H</td><td>F</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 68</td><td>H</td><td>CHa</td><td>H</td><td>F</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 69</td><td>H</td><td>H</td><td>H</td><td>F</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 70</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>tetrazole</td>

<td> 71</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>CONHOCHa</td>

<td> ٦2</td><td>Br</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 73</td><td>OH</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 74</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>H</td><td> 1</td><td>none</td><td>tetrazole</td>

<td> 75</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>H</td><td> 1</td><td>one</td><td>CONHSOCH</td>

<td></td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>H</td><td> 2</td><td>none</td><td>tetrazole</td>

<td>٦ آ</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>H</td><td> 2</td><td>one</td><td>CONHSOCI</td>

<td> 78</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 2</td><td>one</td><td>tetrazole</td>

<td> 79</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 2</td><td>none</td><td>CONHSOCHa</td>

<td> 80</td><td> ١١</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td> 3</td><td>tetrazole</td>

<td> 81</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 1</td><td> 3</td><td>CO-CHj</td>

<td> 82</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 2</td><td> 3</td><td>tetrazole</td>

<td> 83</td><td>H</td><td> ١٩</td><td>OCHa</td><td>H</td><td>CHa</td><td> 2</td><td> 3</td><td>CONHSOCHj</td>

<td> 84</td><td>H</td><td>H</td><td>OCHa</td><td>H</td><td>CHa</td><td> 2</td><td> 3</td><td>COOH</td>

<td> 85</td><td>H</td><td>OCHa</td><td>F</td><td>H</td><td>CHa</td><td> 1</td><td colspan="2">COOH ؛ none</td>

<td> 86</td><td> ١٩</td><td>Br</td><td>H</td><td>OCHa</td><td>CHa</td><td> 1</td><td>none</td><td>COOH</td>

<td> 87</td><td>H</td><td>CHa</td><td>H</td><td>OCHa</td><td>CHa</td><td></td><td>none</td><td>OOH</td>

<td> 88</td><td>THIS</td><td>H</td><td>F</td><td>H</td><td>CHa</td><td></td><td>none</td><td>COOH</td>

Cmpd: compose size ring: the volume of the cycle * none: none.

Some examples include:

MY

28985Β1

WQ / 2OO6 / O34414

PCT / US2OO5 / O34O15

<img file="MA28985B1_D0075.tif" />

<img file="MA28985B1_D0076.tif" />

<img file="MA28985B1_D0077.tif" />

ΜΑ 28985Β1

WQ / 2OO6 / O34414

PCT / US2OO5 / 034015

<img file="MA28985B1_D0078.tif" />

Compound η

<img file="MA28985B1_D0079.tif" />

<img file="MA28985B1_D0080.tif" />

<img file="MA28985B1_D0081.tif" />

<img file="MA28985B1_D0082.tif" />

HOOC

Compound 14

HOOC

Compound 15

<img file="MA28985B1_D0083.tif" />

<img file="MA28985B1_D0084.tif" />

<img file="MA28985B1_D0085.tif" />

HOOC

Compound 17

<img file="MA28985B1_D0086.tif" />

<img file="MA28985B1_D0087.tif" />

HOOC

Compound 16

HOOC

Compound 18

<img file="MA28985B1_D0088.tif" />

<img file="MA28985B1_D0089.tif" />

HOOC

<img file="MA28985B1_D0090.tif" />

Compound 20

<img file="MA28985B1_D0091.tif" />

Compound 21

MY

28985Β1

WQ / 2OO6 / O34414

PCT / US2OO5 / O34O15

<img file="MA28985B1_D0092.tif" />

<img file="MA28985B1_D0093.tif" />

<img file="MA28985B1_D0094.tif" />

<img file="MA28985B1_D0095.tif" />

HOOC

Compound 22

<img file="MA28985B1_D0096.tif" />

Compound 26

Compound 25

<img file="MA28985B1_D0097.tif" />

HOOC

<img file="MA28985B1_D0098.tif" />

Compound 27

<img file="MA28985B1_D0099.tif" />

Compound 28

<img file="MA28985B1_D0100.tif" />

Compound 29

<img file="MA28985B1_D0101.tif" />

HOOC

Compound 30

PCT / US2OO5 / O34O15

<img file="MA28985B1_D0102.tif" />

VAN n٩

WO / 2006/034414

<img file="MA28985B1_D0103.tif" />

HOOC

Compound 31

<img file="MA28985B1_D0104.tif" />

HOOC

Compound 32

<img file="MA28985B1_D0105.tif" />

HOOC

Compound 33

<img file="MA28985B1_D0106.tif" />

Compound 34

<img file="MA28985B1_D0107.tif" />

HOOC

Compound 35

<img file="MA28985B1_D0108.tif" />

HOOC

Compound 36

<img file="MA28985B1_D0109.tif" />

<img file="MA28985B1_D0110.tif" />

HOOC

Compound 37

<img file="MA28985B1_D0111.tif" />

<img file="MA28985B1_D0112.tif" />

Compound 39

MY

28985Β1

WQ / 2OO6 / O34414

PCT / US2005 / 0340! 5

<img file="MA28985B1_D0113.tif" />

Compound 42

Compound 41

Compound 40

<img file="MA28985B1_D0114.tif" />

Compound 45

Compound 44

Compound 43

<img file="MA28985B1_D0115.tif" />

COOH

Compound 46

<img file="MA28985B1_D0116.tif" />

<img file="MA28985B1_D0117.tif" />

<img file="MA28985B1_D0118.tif" />

COOH

<img file="MA28985B1_D0119.tif" />

COOH

Compound 48

Compoud 47

ΜΑ 28985Β1

PCT / US2OO5 / 034015

WQ / 2OO6 / O34414

<img file="MA28985B1_D0120.tif" />

COOH

Compound 49

<img file="MA28985B1_D0121.tif" />

CO

Compound 50

<img file="MA28985B1_D0122.tif" />

COOH

Compound 51

<img file="MA28985B1_D0123.tif" />

<img file="MA28985B1_D0124.tif" />

<img file="MA28985B1_D0125.tif" />

COOH

Compound 52

<img file="MA28985B1_D0126.tif" />

Compound 53

<img file="MA28985B1_D0127.tif" />

COOH

Compound 54

<img file="MA28985B1_D0128.tif" />

Compound 55

<img file="MA28985B1_D0129.tif" />

COOH COOH COOH

Compound 57

Compound 56

MY

28985Β1

WO / 2006/034414

PCT / US2OO5 / O34O15

<img file="MA28985B1_D0130.tif" />

<img file="MA28985B1_D0131.tif" />

COOH

Compound 58

<img file="MA28985B1_D0132.tif" />

Compound 59

<img file="MA28985B1_D0133.tif" />

Compound 63

Compound 62

Compound 61

<img file="MA28985B1_D0134.tif" />

Compound 64

<img file="MA28985B1_D0135.tif" />

ΜΑ 28985Β1

PCT / US2OO5 / O34015

<img file="MA28985B1_D0136.tif" />

WQ / 2OO6 / O34414

<img file="MA28985B1_D0137.tif" />

Compound 67

<img file="MA28985B1_D0138.tif" />

HOOC

Compound 69

CO

<img file="MA28985B1_D0139.tif" />

CONHSO2CH3

Compound 71

Ν ^ Ν

Compound 70

<img file="MA28985B1_D0140.tif" />

<img file="MA28985B1_D0141.tif" />

Compound 74

Compound 73

Compound 72

ΜΑ 28985Β1

PCT / US2OO5 / O34O15

WQ / 2OO6 / O34414

<img file="MA28985B1_D0142.tif" />

Compound 75

<img file="MA28985B1_D0143.tif" />

Compound 77

<img file="MA28985B1_D0144.tif" />

Compound 78

<img file="MA28985B1_D0145.tif" />

Compound 79

<img file="MA28985B1_D0146.tif" />

ΜΑ 28985Β1

PCT / US20O5 / 034015

WO / 2006/034414

<img file="MA28985B1_D0147.tif" />

<img file="MA28985B1_D0148.tif" />

<img file="MA28985B1_D0149.tif" />

Compound 83 Compound 84 Compound 5 لإ

<img file="MA28985B1_D0150.tif" />

* compound: compound.

In general, in another aspect, the present invention relates to the use of loxapine-analogs I-Ive to modulate sleep. Preferably, the compounds of formula I. Ive modulate sleep with reduced side effects, e.g. compounds do not inhibit REM sleep (therefore, sleep induced by these compounds may resemble natural sleep cycles in people), use of compounds does not Insomnia does not return, and / or the compounds do not interfere with locomotor activity or otherwise affect body temperature. The in vitro selection criteria for the loxapine analogs of the present invention are set out in Table 2.

ΜΑ 28985Β1

WO / 2006/034414 PCT / US20O5 / O34015

Table 2

<td>Hl link (primary channel)</td><td>ki &lt;500nMolair</td>

<td>Link lane off. -chollinergic Ml, Μ2, Μ3 -Dopamine D1, D2 -Ademergic al, a2 -adrenergic</td><td>- ki&gt; 10 times The Hl measurement of the ki receptor - ki&gt; 10 times The Hl measurement of the ki receptor - ki&gt; 10 times The Hl measurement of the ki receptor</td>

In one example, the off ki binding pathway is 50 times the H1 measurement of the ki receptor. For example, the off ki binding pathway is 100 times the H1 measurement of the ki receptor.

In in vitro binding assays are used to determine H1 binding (ie the primary binding pathway) and M1 binding, Μ2 and Μ3 (ie, the off binding pathway). These binding assays measure the ability of loxapine analogues to displace the known classics of VH1, M1, Μ2 and Μ3 receptors, where H1 is a histamine receptor, and M1, Μ2 and Μ3 are cholinergic (muscarinic) receptors. Similar tests were performed with H1 and dopamine receptors (D1 and D2); and with H1 and adrenergic receptors (a1 and a2).

Binding studies against the histamine receptor, H1, indicate binding affinity, hence the results of binding assays are an indication of the activity of the loxapine compound.

Binding studies against muscarinek receptors indicate the extent to which the compounds bind muscarinek receptors responsible for the anti-cholinergic activity of the compound. Binding to muscarinic receptors results from various unwanted side effects of several known antihistamines, eg, dry mouth. The reduction in the binding of compounds to the ML Μ3 receptors, relative to the binding of the compound to the H1 receptor, is an indication of the high specification of the compound relative to the histamine receptor through the muscarinic receptor. In addition, the drug with high specificity for histamine receptor has more anti-cholinergic side effects.

The H1 binding of loxapine analogs according to the present invention (also referred to as both test compounds or compounds of the present invention is determined by measuring the specific binding of the test compound, or series of test compounds, to the H1 receptor, and comparing it with specific binding as (ie, reference compound).

ΜΑ 28985Β1

WO / 2006/034414 PCT / US2005 / 034015 references used in the H1 binding assay include, for example, triprolidine (ki 3.3nM); chlorpheniramine (ki 103, OnM), pyrilamine (ki 1,9ηΜ), cyproheptadine (ki 8.5 nM) cimetidine (ki&gt; 10,000) and dimaprit (ki&gt; 10,000). (See for example

Chang et al., J. Neurochem.) 32: 1653-63 (1979) (with modifications); Martinez-Mr et al., Brain Res, 526: 322-27 (1990); and Haaksme, et al., Pharmac. Ther., 47: 73-104 (1990).

For example, in an example of the H1 binding assay, the H1 receptor is a bovine cell membrane, and the radioligand, [³H] pyrilamine (15-25 ci / mmol) at the final ligand concentration of 2.OnM is used to detect specific binding of the H1 receptor. Characteristics of the assay include a Ko (binding affinity) of 1.3 nM and a tissue Bmax (receptor number) of 6.2 fmol / mg (weight). Tripolidine (10μΜ) is used as much as a non-specific determinant, the reference compound is a positive control. The binding reactions are carried out in 50mM ΝΑ-ΚΡΟ4 (PH 7.5) at 25٥c for 60 minutes. The reaction is determined by rapid vacuum filtration in glass fiber filters. The level of radioactivity in the filters is measured and compared to control values ​​to ensure no interaction between the test compound mentioned and the M1 binding site.

The H1 binding assays determine the M1 binding of the test compound by measuring the specific binding of the compound of the M1 test mention and comparing it with a specific binding of the reference compound.

(See for example,

Buckley, et al., Mol. Pharmacol. 35: 469-76 (1989) (with modifications)), reference compounds used in the M1 binding assay include, for example, xopolamine, methyl Br (ki 0.09 nM); 4- DAMP methiodide (ki 0.27 nM); pirenzepine (ki 0.60 nM); HHSID (ki 5.00 nM); and methoctramine (ki 29.70 nM);

For example, in an example of the M1 binding assay, the M1 receptor, the M1muscarinic receptor is a M1 recombinant expressed in CHO cells, and a radioligand, H), scopolamine, N-methyl chloride (80-100 Ci / mmol) at a final ligand concentration of 0.5nM to detect specific binding of M1. Assay characteristics include a Kb (binding rate) of 0.05nM and a Bmax (receptor number) protein of 4.2 pmol / mg. (-) - scopolamine, methyl-, bromide (methylscopolamine bromide) (1.0 μΜ) is used as much as ηοη-specific determinant, a reference compound and a positive control. The binding reactions are carried out in PBS for 60 minutes at 25٥c. The reaction is determined by rapid vacuum filtration in glass filters. The level of radioactivity in the filters is measured and the values ​​are compared with regard to certain interactions between the test compound mentioned and the muscarinic cloned of the M1 binding site. The bond test Μ2

ΜΑ 28985Β1

2006/034414 PCT / US2OO5 / O34O15 determines the Μ2 binding of the test compound by measuring the specific binding of the test compound mentioned at Μ2 and compares it with a specific binding of the reference compound (See for example,

Buckley, et al. Mol. Pharmacol. 35: 469-76 (1989) (with modifications)). Reference compounds used in the Μ2 binding assay include, for example, scopolamine, methyl Br (ki 0.3 nM); 4- DAMP methiodine (ki 20.0 nM); methoctramine (ki 20,460 nM); HHSDI (ki 212.7 nM), and pirenzepine (ki 832.9ηΜ).

For example, in an example of the Μ2 binding assay, the muscarinic Μ2 receptor is a human Μ2 recombinant and a radioligand, [H-scopolamine, N-methyl chloride (80100 Ci / mmol) at a final ligand concentration of 0 .5 nM to detect specific binding of M1. Assay characteristics include a Kb (binding rate) of 0.29 nM and Bmax (receptor number) of 4.2 pmol / mg. Protein (-) - scopolamine, methyl, bromide (methylscopolamine bromide) (1.0 μΜ) is used as far as ηοη-specific determinant, a reference compound and a positive control. Binding reactions are performed in PBS for 60 minutes at 25 ° C. The reaction is determined by rapid vacuum filtration in glass filters. The level of radioactivity in the filters is measured and the values ​​are compared with regard to certain interactions between the test compound mentioned and the muscarinic cloned of the Μ2 binding site. The Μ3 binding assay determines the Μ3 binding of the test compound by measuring the specific binding of the test compound mentioned at Μ3 and comparing it with a specific binding of the reference compound (See for example,

Buckley, ١./ه؛ج Mol. Pharmacol. 35: 469-76 (1989) (with modifications)). Reference compounds used in the Μ3 binding assay include, for example, scopolamine, methyl Br (ki 0.3 nM);

4- DAMP methiodine (ki 0.8 nM); methoctramine (ki 700.0 nM); HHSDI (ki 14.5 nM), and pirenzepine (ki 153.3 nM).

For example, in an example of the Μ3 binding assay, the muscarinic Μ3 receptor is a Μ3 recombinant expressed in CHO cells, and a radioligand, [³H], scopolamine, Nmethyl choride (80-100 Ci / mmol) at a final ligand concentration of 0.2nM to detect specific binding of M1. Test characteristics include a Kd (binding rate) of 0.14 nM and a Bmax (receptor number) of 4.2 pmol / mg. protein (-) - scopolamine, methyl-, bromide (methylscopolamine bromide) (1.0 μΜ) is used as a nonspecific determinant, a reference compound and a positive control. The binding reactions are carried out in PBS for 60 minutes at 25٥c. The reaction is determined by rapid vacuum filtration in glass filters. The level of radioactivity in the filters is measured and compares the values ​​with regard to certain interactions between the test compound mentioned and the muscarinic clone of the Μ3 binding site.

100

ΜΑ 28985Β1

WO / 2006/034414 PCT / US20O5 / O34015

The in vitro selection criteria for the loxapine analogs of the present invention are demonstrated in Table 3.

Table 3.

<td>Hl link (primary objective)</td><td>KiOOnMolair</td>

<td>Binding target off ' ٠ cholinergicMl ٠ cholinergic Μ2 ٠ cholinergic Μ3</td><td>٠ ki&gt; 10M ٠ ki&gt; 10M ٠ kiOM</td>

other in vitro selection criteria for the loxapine analogs of the present invention are demonstrated in Table 4.

<td>Hl link (primary objective) table 3</td><td>Ki&gt; 150 η Molar</td>

<td>٠ binding target off ٠ cholinergicMl ٠ cholinergic Μ2 ٠ cholinergic Μ3</td><td>٠ ki&gt; 10M ٠ ki&gt; 10M ٠ ki&gt; 10M</td>

H1 binding (primary binding target) and M1, Μ2, Μ3 binding (off binding target) are determined using the H1, M1, Μ2, Μ3 binding assays described above.

Other in vitro selection criteria for the loxapine analogs of the present invention include hERG binding. The primary binding target and the off binding target are determined as described above.

If the test compound designates a primary target (Hl) binding and the primary target / ration of the off binding target, hERG binding (off binding target) is determined using a block hERG comparative study to assess l effect of a test compound in the cloned hERG channel expressed in mammalian cells (see, e.g., Brown and Rampe, Pharmaceutical News 7: 15-20 (2000); Rampe et al., FEBS Lett., 417: 28-32 (1997); Weirich and Antoni, 'Basic Res. Cardiol. 93 Suppl. 1: 125-32 (1998); and Yap and Camm, Clin. Exp. Allergy, 29 Suppl 3,174-81 (1999)).

The goal of binding off hERG, the cardiac potassium channel responsible for delaying the current rectifier (I) in the human ventricle, is evaluated because inhibition of Ikr is the largest cause of cardiac action of the potential prolongation by non-cardiac drugs (see eg browne and Rampe (2000), weirich and antoni Basic Res cardiol. 93 SUpp. 1: 125-32 (1998), and Yap and Camm (1999)). The increase of 101

MY

28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15 the potential action of the duration, causes the prolongation of the QT interval which is associated with the dangerous ventricular arrhythmia, torsade de pointes. (Brown and Rampe (2000)).

In the hERG assay, the hERG channels are expressed in the human embyonic cell line (HEK 293) which are endogenous I.

Expression in the mammalian cell line is preferable for trans expression. In xenopus oocytes, the latter demonstrates a sensitivity of less than 10-100 to the hERG blocking channels (see. Rampe 1997).

In an example of a hERG assay, the positive control (ie reference compound) is ter fenadine (sigma, St Louis Mo), which is shown, at a concentration of 60 nM, to block the hERG current at approximately 75%. . the test compounds are delivered in an HEPESdiluent physiological saline (HB-PS) t 0.1٥ / ο dimethyl sulfoxiole (DMSO).

Each test compound is applied at a concentration of 10μΜ to ΗΕΚ293 cells expressing hERG (n&gt; 3, where n = the number of cells) the cells are exposed to the test compound, for a period necessary to achieve stability of the state blocking, but not longer than 10 minutes.

The positive control (60 mM terfenadine) is applied to the cells (n 2 ة).

The hERG - exposed cells are then transferred to the recording chamber and perfused with HB-PS solution.

The pipette solution of all recorded cells included potassium aspartate (130 nM) MgCl2 (5mM), EGTA (5mM), ATP (4mM)&gt; and HEPES (10mM) at a Ph adjusted to 7.2 with KoH. The onset and the stability of the blocking of the hERG current due to the test compound are measured using a prototype pulse with a fixed amplitude (depolarization: + 20mv of 2 seconds; repolarization: -50 mV of 2 seconds); repeat at 10 seconds interval, starting from the saving potential of 80 mV.

The peak current is measured for 2 seconds at -50 mV. The steady state is maintained for at least 30 seconds before applying the test compound or the positive control compound. The peak current is measured until a new steady state is achieved.

In addition to the in vitro selection criteria described above, the loxapine analogs of the present invention are selected using in vivo sleep-wake and physiological assessment. Non-REM sleep: Loxapine analogues are selected if, in adult male wistar rats, (i) the amount of the non-REM peak exceeds 55% non-REM per hour, not more than three hours after treatment;

And (ii) the nature of the increase in non-REM sleep, is such that the cumulative total increase in non-REM sleep within 6 hours after treatment (adjusted to a base of the circardian stage corresponding to 24 hours front, and relating to the control vehicle

102

MY

28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15 treatment) is not less than 20 minutes in total, with respect to the doses of the compound which produce maximum sleep consolidation as a measure of the duration of sleep, when the drug is released orally.

The term peak non-REM sleep is defined as an absolute peak amount of non-REM sleep per hour of treatment, with drug administration operating at a circardian time (CT) 18, which is 6 hours after the lights are turned off. in a laboratory rat put in a 12:12 LD (12 hours of light, and 12 hours of darkness) a light-dark cycle. A nominal criterion of 55% non-REM sleep per hour is equivalent to 33 minutes of non-REM sleep per hour.

As used herein, the term cumulative non-REM sleep is defined as the net aggregate increase in the number of minutes of non-REM sleep, a measure over the period of the drug's sleepiness, which typically, but not always occurs. in the first 6 hours after treatment, adjusts to a net aggregate total of the number of minutes of non-REM sleep that occurs during the bases corresponding to the non-treatment of days recorded 24 hours before, relating to the treatment control vehicle.

As defined herein, the term sleep duration refers to a separate or continuous or almost continuous period of sleep, comprising non-REM sleep, REM sleep, both non-REM and REM sleep stages, delimited before and after the period by two times. 10 seconds of insomnia. The following unbounded description illustrates this concept:

, where each letter represents the predominant state of awakening (S = sleep, w = awakening) observed every 10 seconds. The measured sleep time is 21 tenseconds or 3.5 minutes.

WWWWSISSSSSSSWWSSSSSSSWIV

Sleep Consolidation: Loxapine analogues are selected if, in an adult wistar rat, (i) the absolute duration of continuous sleep stages (i, th duration of sleep) after treatment exceeds 13 minutes; (ii) the net duration of sleep after treatment exceeds or is equal to 3 minutes when it is adjusted for the basis of 24 hours before, and calculated relative to the vehicle of the treatment, and (iii) the absolute time of each duration of sleep at an average per hour, per hour-to-hour basis, exceeds or equals 5 to minute.

The selection criterion mentions assumes that the stages of sleep and awakening are continuously determined every 10 seconds (ex: 10 second of “step” sleep), sleep and awakening are measured polygraphically using an EEG and EMG criterion, and the Sleep stages (including non-REM and / or REM sleep) are defined as continuous "durations" until the 10-second continuous stages of insomnia.

103

VAN

28985Β1

WO / 2006/034414 PCT / US2OO5 / O34O15

As used herein, the term "longest sleep duration" is defined as the total number of minutes the animal remains asleep (non-REM and / or REM sleep stages) during the single long sleep duration that occurs at the start. , at a certain time after the treatment. The "length of sleep duration" measurement assumes that sleep is measured continuously for 10 seconds, and is counted under the predominant state, counts, or determines as a discontinuous sleep stage (where the sleep stages are. defined as much as non-REM sleep, REM sleep, or insomnia). During 10 second intervals which define the duration.

The term "average sleep length" is defined as an average duration (in minutes) of each and all stages of sleep, or duration that begins at a given time independent of the individual duration of each stage or duration.

The side effects measured: loxapine analogues are selected if, in adult male wistar rats, these compounds (i) do not produce appreciable amounts of returning insomnia; (ii) do not inhibit REM sleep; and (iii) do not disproportionately inhibit locomotor activity and / or motor mass relative to the normal effects of sleep itself.

The definitions of these three variable side effects are as follows:

"Return of insomnia" is defined as a period of return, REM, or compensatory insomnia that occurs after the sleep promoting effects of a hypnotic or soporific agent. return of insomnia is typically observed during the usual cricardial phase of 6-18 hours after treatment at CT-18 (6 hours after lights out, LD 12:12), but can occur at any time during the initial 30 hours after treatment.

The return is unacceptable when, in an adult insomnia is associated with the return of insomnia exceeding 10% reduction in the mean duration of non-REM sleep after treatment in the circardial phase (light).

In adults, poorly wistar rats, the return of insomnia manifests as an increase in relative insomnia at the base of the corresponding durations (24 hours before) subsequent to the drug inducing the effect of sleep, and the return of insomnia is measured cumulatively.

"REM sleep inhibition" is defined as the reduction in REM sleep time after treatment at CT-18 (6 hours after light-off; LD 12:12) or at CT-5 (5 hours after handing over the light; LD 12:12).

Compounds which reduce REM sleep time to more than 15 minutes (relative to baseline and adjust for vehicle of treatment) when administered to either CT-18 or CT-5 are considered unacceptable.

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As defined herein, the term "disproportionate inhibition of locomotor activity" refers to a reduction in locomotor activity which exceeds the norm and predicts the reduction in activity attributable to sleep. Logic tends to dictate that if the animal is asleep, there will normally be a corresponding reduction in locomotor activity.

If a hypnotic or soporific compound reduces the levels of locomotor activity to 20٥ / ο more than that explained by sleep, the compound remains unacceptable for locomotor activity (AML) or motor mass can be objectively quantified using any what form of locomotor activity monitor (non-specific movements, basic telemetry monitor activity, 3-dimensional motion detection, exploration measurements, electromyographic recording, etc.). As long as this will be measured with the goal of insomnia sleep measurements in the same animal.

In one example, locomotor activity in a caged animal is measured using a biotelemetry tool surgically implanted into the paratoneal cavity of an animal, the implant tool and the associated telemetry receiver detect how many times and how the animal 15 moves in a cage. Sleep and insomnia are measured at a 10 second period simultaneously, the numbers of locomotor activity per unit time are measured by the current amount of insomnia per the same unit; inducing a measure of internal locomotor activity (LMAI) for the unit of time.

The hypnotic and soporific compounds administered at CT-18 (6 hours after the extinction of the light, LD 12:12) which decreases the locomotor activity per unit of awakening time by more than 20٥ / ο relative to the vehicle which will be deemed unacceptable.

In another example, the loxapine analogs of the persent invention are selected using in vivo physiological endpoints and waking sleep, are demonstrated in Table 5;

Table 5

<td>Score- 2000</td><td>Absolute value</td><td>Changing the basic value for the vehicle only</td>

<td>Non-REM peak time</td><td>&gt; 55٥ / ο sleep / peak hour</td><td>Not applicable</td>

<td>Non cumulative REM</td><td>Not applicable</td><td>&gt; 20 minutes at ED 100 for MSBLàTi.6</td>

<td>Sleep duration</td><td>&gt; 17 minutes of absolute peak</td><td>&gt; 5 minutes</td>

<td>Average sleep time</td><td>&gt; 6 minutes of absolute peak</td><td>Not used in the shot SAR</td>

<td>Return of insomnia</td><td>&lt;10٥ / ο reduction in the average</td><td>Not applicable</td>

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<td></td><td>non-REM sleep time per hour during the post-treatment circardial phase (light on)</td><td></td>

<td>REM sleep inhibition</td><td>Not applicable</td><td>Does not exceed 15 minutes, RxtoCT5</td>

<td>LMAI</td><td>Not applicable</td><td>Do not exceed 2% of the LMAI reduction</td>

The methods for evaluating sleep criteria and physiological evaluation are described above. "The absolute value" designated in the second column of Table 5 referred to the value as determined by each test compound, while the "change" in value demonstrated in the third column of Table 5 reflects an adjusted value where the absolute value 5 is different of the vehicle, when the vehicle values ​​are adjusted for the base.

In some examples, the long sleep duration exceeds 13 minutes in others, it exceeds 17 minutes, in some examples, the long sleep duration after treatment exceeds or is equal to 3 minutes, in others, it exceeds or is equal to 6 minutes.

Other in vivo criteria relating to sleep-wakefulness and physiological assessment used in the present invention include measurement of body temperature and constant body temperature as a change in vehicle-related basis.

The acute body temperature change should not exceed O.5O٥C, and the constant body temperature change should not exceed + O.5O٥C at 1-6 hours. The acute body temperature (Τ1.6) is adjusted to the corresponding base 24 hours before, relative to the vehicle (the reduction by the vehicle). The constant body temperature, measured 7-18 hours after treatment with drug (Τ7-18) is adjusted for the corresponding basis, measured 24 hours before, relative to the vehicle (denial of the vehicle).

The present invention provides a method of modulating sleep by administering to a subject a therapeutically effective amount of the compound of formula LIVE or a pharmaceutically effective salt thereof comprising it modulates sleep by various means, including demining the onset of sleep. sleep time, increasing sleep duration, increasing maximum sleep duration.

The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intrapleural, intrathecal and parentheral. In one example, the compound is administered orally. The specialist in the field will recognize the advantages of certain routes of administration.

The method of modulating sleep by administering to the subject a therapeutically effective amount of the compound of formula Ive or a pharmaceutically acceptable salt thereof, is

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WO / 2006/034414 PCT S2OO5 / O34O15 used to treat a variety of sleep disorders, including an abnormality of the circardian rhythm, insomnia.

Parasomnia, sleep syndrome after narcolepsy and / or hypersomnia. In one example, the method treats circardian rhythm abnormalities such as jet lag and workload disorders, delayed sleep phase syndrome, advanced sleep phase syndrome, and non-wake-up sleep disorder. hours.

In another example, the method treats insomnia including extrinsic insomnia, psychophyscological insomnia, insomnia at altitude, periodic part movement disorder, medication-dependent insomnia, sleep-dependent insomnia. alcohol and insomnia associated with mental disorders.

In another example, the method treats parasomnia, including sleepwalking, pavor noctumus, REM sleep disorder, sleep bruxism, and sleep enuresia. In another example, the method treats sleep apnea disorders, including central sleep apnea, obstructive sleep apnea, and mixed sleep apnea. In addition, the method treats other sleep disorders such as narcolepsy or hypersomnia. In another example, the compound of formula I. Ive is administered as a pharmaceutically acceptable salt. Those skilled in the art will recognize the various methods for preparing a pharmaceutically acceptable salt and identifying suitable in an example the compound or pharmaceutically acceptable salt and identifying suitable salts in an example, the compound or the salt. a pharmaceutically acceptable salt thereof, is included in the pharmaceutical composition as used herein, the term sleep disorder includes conditions recognized by the skilled in the art as being sleep disorders e.g. conditions known in the art or those proposed to be sleep disorders or discovered to be sleep disorders See for example, Torpy w International Classification of Sleep Disorders, Revised. ' Diagnostic and Coding MaaL American Sleep Disorders Association; Rochester, Minneota 1997; and TCD-9-CM, International Classification of Diseases. Ninth Revision. Clinical Modification.ilV

Center for Health Statistics, Hyattsville, MD.

for example, sleep disorders can generally be classified into dysomnias, such as intrasek and extrasek, circadian rhythm disorders; parasomnia, eg on waking, sleep-to-wake transition, and rapid eye movement (REM) associated with disorders, and other parasomnias; disorders associated with mental, neurological, and other medical disorders, and other sleep disorders.

Intrasek sleep disorders include, for example, psychophysiological insomnia, state of sleep misperception, idiopathic insomnia, narcolepsy, hypersomnia

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WO / 2006/034414 PCT / US2OÛ5 / O34O15 recurrent, idiopathic hypersomnia, hypersomnia after trauma, obstructive sleep apnea syndrome, central apnea sleep syndrome, central alveolar hyperventilation syndrome, periodic movement disorder parts, and cloudy leg syndrome.

Extrinsic sleep disorders include, for example, inadequate sleep hygiene, environmental sleep disorders, insomnia at altitude, sleep adjustment disorders, sleep insufficiency syndrome, limitation syndrome. sleep disorder, sleep onset disorder, insomnia due to food allergy, nocturnal eating syndrome, hypnotic- sleep-dependent disorder, alcohol-dependent sleep disorder, and toxin-induced sleep disorder.

Circardial rhythm sleep disorders include, for example, weather change syndrome (jet lag), schedule change disorder, irregular sleep and awakening, delayed sleep phase syndrome, advanced sleep, and sleep disorder - non-24 hour awakening waking sleep disorders including, for example, confused waking, walking in full sleep and sleep terrors, sleep-waking transition disorders include, for example, rhythmic movement disorder, onset of sleep, talking while sleeping, and leg cramps.

Sleep disorders associated with REM include for example, sleep paralysis, nightmares, decreased sleep due to penile erection, sleep related to painful erections, REM sleep related to sinusitis cessation, and REM sleep behavior disorder.

Other parasomnias include, for example, sleep bruxism, enuresis during sleep, sleep related to abnormal swallowing syndrome, nocturnal paraxysmal dystonia, sudden and inexplicable nocturnal death syndrome, sleep apnea in patients. childhood, conginital central hyperventilation syndrome, sudden death syndrome in children, and benign neonatal myoclone sleep.

Sleep disturbances also occur in a subject who suffers from other medical conditions such as illnesses or injuries, or a subject treated with other drugs or medical treatments, where the subject therefore suffers from difficulty in falling asleep and / or to keep sleep, or a non-restorative or non-estorative sleep, for example the experiences of sleep deprivation in a subject for example, some people have difficulty getting to sleep after previous medical treatment for other conditions, eg; chemotherapy or surgery, or as a consequence of pain or other effects of physical injury.

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It is well known in the field that certain medical disorders, for example disorders of the central nervous system (CNS), ex: mental or neurological disorders, ex: anxiety, can have an element of the sleep disorder, ex: deprivation some sleep. Consequently. Treatment of sleep disorder also includes treatment of the sleep disorder component of other disorders, eg CNS disorders. In addition, concomitant treatment of the sleep disorder (CNS) disorder may have a beneficial effect on improving other symptoms associated with the disorder, for example, in some anxiety subjects with deprivation. of sleep, the treatment of the element of sleep deprivation also treats the element of anxiety. Accordingly, the present invention includes a method of treating such disorders, for example, sleep disorders associated with mental disorders include psychosis, mood disorders, anxiety disorder, panic disorders, addictions and the like. Specific mental disorders include, for example, depression, obsessive compulsive disorder, affective neurosis disorder, depressive neurosis disorder, anxiety neurosis, dysthimia disorder, behavioral disorder, mood disorder. , schizophremia, manic depression, delirium and alcoholism.

Sleep disorders associated with neurological disorders include, for example, degenerative brain disorders, dementia, parkinsonism, Huntington's disease, Alzheimer's, fatal familial insomnia, sleep related to epilepsy, epileptic electrical state of sleep, and sleep related to headache, sleep disorders associated with other medical disorders include, for example, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep related to asthma, sleep related to gastroesophageal reflux, stomach ulcer, and fibrotic syndrome.

In some circumstances, sleep disturbances are also associated with pain, e.g. neuropathic pain associated with restless leg syndrome, migraine, fibromyalgia, pain, exaggerated or elevated sensitivity to pain, such as hyperalgesia, causalgia, and allodynia; increased pain, burning pain, atypical facial pain, neuropathic pain, regional pain complex syndrome I and II; arthritis pain, pain from sports injuries, pain related to infection, e.g. HIV, post polio syndrome, phantom limb pain, labor pain, cancer pain, pain after chemotherapy , post-stroke pain, post-operative pain, conditions associated with viceral pain including irritable bowel syndrome, migraine and angina.

Other sleep disorders include, for example, short sleep duration, long sleep duration, sub-insomnia syndrome, myoclonus aftagment, sleep hyperhidrosis, menstrual sleep disorder, sleep disorder associated with pregnancy.

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WO / 2006/034414 PCT / US2O05 / O34O15 sleep related to neurogenic tachypnus, sleep related to laryngeal spasm, and shock sleep syndrome.

Insomnia is typically classified as insomnia at onset of sleep, where the subject takes more than 30 minutes to fall asleep, and sleep maintenance insomnia, where the subject spends more than 30 minutes awake during a period of sleep. contemplates, or, for example waking up before the desired waking time, with difficulty or inability to regain sleep.

The present compounds may be effective in treating sleep onset and maintaining insomniacal sleep, insomnia resulting from circardian rhythm adjustment disorders, or insomnia resulting from CNS disorders.

One example is the treatment of a subject for cicardian rhythm adjustment disorder another example is the treatment of insomnia resulting from a mood disorder, in another example the subject is treated for sleep apnea, sleepwalking, nightmares, restless leg syndrome, insomnia of onset of sleep, and / or maintenance of insomniac sleep; or preferably, sleep insomnia or insomnia sleep maintenance.

The present compounds may be effective for the treatment of insomnia onset of sleep, the present compounds may also be effective for the treatment of insomnia sleep maintenance.

The dosage regimen which utilizes the compounds is selected having regard to a variety of factors including the type, species, age, weight, sex, and medical condition of the patient; the severity of the conduction to be treated, the mode of administration, the renal and hepatic function of the patient, and the particular compound or salt thereof used. The ordinary physician in the field or veterinarian can determine the effective amount of the drug useful in preventing, arresting or arresting the progress of the condition.

The oral dosages of the present invention, when they are used for the effects indicated will be of the order of 0.05 mg / day orally, the effective amount of the compounds is typically of the order of 0.01 mg / kg per day at 100 mg / kg per day, and preferably between 0.1 mg / kg per day to 10 mg / kg per day. Techniques for administering the present compounds of the present invention may be found in Remington: the science and practice of pharmacy, 19^Ihpublishing, mack publishing co, Easton, PA (1995).

For example, in some examples, an acidic salt of the compound containing an amine or other basic group is obtained by reacting the compound with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acid acetic, perchloric acid and the like. Compounds with a quaternary ammonium group contain

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WO / 2006/034414 PCT / US2OO5 / O34O15 also a replica anion and the like such as chloride, bromide, iodide, acetate, perchlorate and the like.

Other examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (eg: (ا) - tartrates, (-) - tartrates or a mixture thereof including racemic mixtures), succinates, bezoates and salts with amino acids such as glutanic acid.

Salts of compounds having the carboxylic acid or other acidic functional group are prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt is made with a base which provides a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth salts (especially calcium and magnesium), aluminum salts. and ammonium salts, moreover the salts are prepared from physiologically acceptable organic bases such as trimthylamine, trithylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N, Ν'- dibenzylethylenediamine, 2hydroxyethylamine, bis (2- hydroxyethyl) amine, tri (2- hydroxyethyl) amine, procaine, dibenzylpiperidine, N- benzyl β-phenethylamine, dehydroabirtylamine, N, Ν'bisdehydroabietylamine, glucamine, methylglucamine, collidine, quinine, quinoline, and a basic amino acid such as lysine and arginine.

In some examples, certain compounds and their salts also exist in solvent form, for example hydrates, and the present invention includes each solvent and mixtures thereof.

In one example, the compounds described herein, and pharmaceutically acceptable salts thereof, are used in preparations in combination with pharmaceutically acceptable carriers or diluents. Pharmaceutically acceptable vehicles include inert solid filters or diluents, as well as sterile aqueous or organic solutions.

The compounds will be present in such pharmaceutical compositions in an amount effective to provide the desired dosage amount in a volume described herein.

Techniques relating to the formulation and administration of the present compounds can be described in remington: The Science and Practice of pharmacy, supra.

Typically, the compound is prepared for oral administration, where the present compounds or salts thereof are combined with liquid or solid carriers or diluents to form capsules, tablets, pills, powders, syrups, solutions, etc. suspensions and the like.

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Tablets, pills and capsules, and the like contain from about 1 to about 99 percent by weight of the active ingredient and ligand such as acacia gum, tragacanth, or gelatin; excipient such as calcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate, and / or a sweetening agent such as sucrose, xylitol and the like. When the dosage form is a capsule, it always contains, in addition to materials of the type mentioned, a liquid carrier such as fatty oil.

In some examples, various materials are present as much as coating or to modify the physical form of the dosage unit. For now, in some examples, the tablets are coated with sugar or a lacquer or both.

In one example, the syrup or elixir contains, in addition to the active ingredient, sacrose as a sweetening agent, methyl and propylparbens as preservatives, and coloring or flavoring agents such as orange or cherry flavor, and the like. .

For certain examples which relate to parental administration, the following compounds, or salts, solvents or polymorphs thereof, may be combined with an aqueous or organic sterile intermediate, to form a solution or suspension. The injectable compositions are preferably isotomic solutions or suspensions. The compositions can be sterilized and / or add adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, promoters in solution, salts for regulating the osmotic pressure and / or diluents. In addition, they can also include other valuable therapeutic substances. The compositions are prepared according to a traditional mixing, coating or granulating methods, respectively, and contain about 0.1 to 57%, preferably 1 to 50%, of the active ingredient.

For example, injectable solutions are produced using solvents such as peanut sesame oil or an aqueous propylene glycol, as well as aqueous solutions of hydrophilic, pharmaceutically acceptable salts of these cmopses. In some examples, the dispersions are prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations of condoms to prevent the development of microorganisms. The terms "parenteral administration" and "parenterally administered" as used herein, describe modes of administration other than topical and enteric administration, usually by injection, and include, without limitation, intravenous injection or infosion, intramuscular, intraarticular, itrathecal, intracapsular, intrabital, intracardiac, intraperitioneal, transtracheal, subcutaneous, subcuticular, intraarticular, subarachnoic, intraspinal and intrastemal.

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For rectal administration, suitable pharmaceutical compositions are, for example, preparations, suppositories or enemas. The suppositories are advantageously prepared by means of fatty suspensions or emulsion. The compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifiers, promoters in solution, salts for the regulation of osmotic pressure and / or diluents.

In addition, they may also contain other valuable therapeutic substances.

The compositions are prepared by conventional mixing, granulation or coating methods and contain around 0.1 to 75%, preferably around 12 to 50%.

٥/٥ of the active ingredient.

In some examples, the compounds are formulated to deliver an active agent by pulmonary administration, eg: administration of an aerosol formulation containing the active agent, for example, by a manual spray pump; nebulizer or pressurized predetermined dose inhaler.

In some examples, suitable formulations of this type also include other agents, such as antistatic agents, to maintain the present compounds as effective aerosols. The drug delivery means relating to aerosol releases, comprising a suitable aerosol with a valve containing a pharmaceutical aerosol formulation, as described, and a pulser adapted to contain the container which allows the drug to be released. The drug delivery means has an upper space, representing approximately 15% of the total volume of the container. Thus, the polymer for pulmonary administration is dissolved, suspended or emulsified into a mixture of solvent, surfactant or a pulser. The mixture is kept under pressure in a container which is closed by a valve.

For nasal administration, either a liquid or a solid vehicle is used. The solid vehicle includes a powder with a volume of about, for example, 20 to 500 microns and such a formulation is administered by rapid inhalation through the nose. In some examples where the liquid vehicle is used, the training is administered as much as a nasal spray or a dose comprising oily or aqueous solutions of the active ingredients.

Also contemplated are formulations which are rapidly dispersing dosage forms, also known as "flash dose" forms. In particular, certain examples of the present invention are formulated as compositions which release their active ingredients over a short period of time, eg: Typically less than five minutes, preferably less than a ninth of a second, preferably less than a third of a second. second, and preferably less than a tenth or a fiftieth of a second. Such formulations are suitable for administration

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2006/034414 PCT / US2OO5 / 034015 to a subject via various modes, for example by inserting it into the body cavity or applying it to a part of the body surface, or into an open wound.

Typically, a "flash dose" is a solid dosage administered orally, which disperses quickly in the mouth, and does not require great effort to swallow, and allows the compound to be digested rapidly or absorbed through the mouth. oral mucous membranes. In one example, the appropriate forms which disperse rapidly in a suitable manner are also used in other applications, including the treatment of wounds and other physical injuries and disease states where release of the drug by external moisture is not possible. .

“Flash dose” forms are known in the field; see for example, effervescent dosage forms and rapid release coatings of insoluble microparticles in us. Pat. NOS 5, 578, 322 and 5, 607, 697; liquid and dry cold foams in US pat. Nos. 4, 642, 903 and 5,631,023, the foams solutions of the assays in US Pat. NOS 4, 855, 326, 5,380, 473 and 5,518, 730; solid and free manufacturing forms in US Pat No. 6, 471, 992, Basic vehicle matrix- Sacharides and liquid ligands in US Pat. Nos. 5, 587, 172, 5,616, 344, 6,277, 406 and 5,622, 719; and other forms known in the art.

The loxapine analogs of the present invention are also formulated as "pulse release" formulations where the analogs are released from the pharmaceutical compositions in a series of release (ie, pulse). Loxapine analogs are also formulated as "continuous release" formulations where the analogs are released from the pharmaceutical composition over an extended period of time.

It is also envisaged formulations, eg: liquid formulations, comprising encapsulating agents or cyclic or acyclic isolation, eg: cyclodextrins, polyethers, or polysaccharides (eg, methylcellulose) or preferably polyanionic derivatives pcyclodextrin with a salt Sodium sulfonate separated from the lipophilic cavity with a space gourp of alkyl ether or polysaccharides.

In one example, the agent is methylcellulose. In another example, the agent is a polyanionic derivative p-cyclodextrin with a sodium sulfonate salt separated from the lipoid cavity by a butyl ether separating group, eg: CAPTISOL® (CyDex, Overland, KS) the specialist in the field may assess the appropriate agent / compound formulation levels by preparing a solution of the agent in water, e.g. 4% by weight of the solution, preparing serial dilutions, e.g. to achieve solutions of 20 ٥/٠, 10.5%, 2.5 ٥/٠, 0% (control) and the like, adding an excess (compared to the amount that can be dissolved by the agent) of present compounds, mix under suitable conditions, e.g. heating,

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W 2006/034414 PCT / US2OO5 / 034015 shaking, sonication, and the like, centrifugation and filtration of the resulting mixture to obtain clear solutions, and analyze the solutions for the concentration of the compound present.

In addition to the therapeutic formulations described above, the therapy comprising the compounds of the present invention optionally include co-administration with one or more therapies, eg: drug or physical treatments (eg: light therapy, electrical stimulation, behavior modification. , congnetive therapy, alteration of circardian rhythm, and the like). Such practices refer to "combination therapy". Other therapies or combination therapies which include therapies known to those skilled in the art to be the desirable combination with the compound of the present invention, for example, therapies known in the art. or therapies which are proposed or discovered in the art to treat sleep disorders or to treat bone diseases related to sleep disorders, for example, therapies for any sleep disorders or other conditions.

In some examples, the compound is administered as a combination therapy where it is administered as a monotherapy in other examples.

Typically, the compound is administered as a monotherapy.

Those skilled in the art will appreciate that the therapy administered with the compounds of the present invention is straightforward with respect to the objective of the same or different disorder as being derived from the compounds of the present invention. Administration of the compound of the present invention is first, followed by further therapy; or alternatively, the administration of therapy may be first. Other therapies are any therapy known in the art to treat, prevent, or reduce symptoms of the disorders; ex: sleep disorders, other disorders, ex: CNS disorders. In addition certain examples of the present invention have compounds administered in conjunction with other therapy known for the purpose of the disorder. Additionally, other therapies include any agent beneficial to the patient when administered in combination with the compound present.

For example, in some examples where the other therapies are drugs, they are administered as much as a separate formulation or as much as the same formulation as the compound of the present invention. A compound of the present invention is administered in therapeutic combination with one or more commercially available, according to medical prescription, including, but not limited to antihistamines, antimicrobial agents, germicidal agents, antiarrhythmic agents, agents. coronary dilation, spasmolycitis, antihypertensive agents, antidepressants,

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WO / 2006/034414 PCT / US2OO5 / O34O15 antianxiety, other psychotherapeutic agents, steroids, corticosteroids, analgesics, cold medications, vitamins, sedatives, hypnotics, contraceptives, anti-drugs. -infalmatory ηοη-steroïdal, blood glucose lowering agents, cholesterol lowering agents, anticonvulsion agents, anti-epeliptic agents, anticholinergic immunomodulators, sympatholitics, sympathomimetics, vasodilators, anticoagulants, antiarrhythmic agents, prostaglandins with various pharmaceutical activities, diuritics, antihistamines, antineoplastic agents, encolytic agents, antiandrogens, antimalarial agents, antileprosy agents, and various other types of medication. See Goodman and Gilman's, The basis of therapeutics (eighth Edition, Pergamon Press, Inc., USA, 1990) at The Merck Index (Eleventh Edition, Merck 8 Co. Inc., USA, 1989).

Examples of medicaments used in combination with the compounds of the present invention include, but are not limited to,

AU® STILNOX® (zolpidem tartrate), indiplon, ESTORRA ™ (eszopiclone), neuron ™ ® (gabapentin), LYRICA® (pregabalin), eplivanserin, SONATA® (zaleplon), ESTORRA ™ (eszopiclone), ZOPICLONE, ™ (imovane) ™ (imovane) ™ DESYREL ™ (trazodone hydrochloride), SEROQUEL® (quetiapine fumarate), CLOZARIL® (clozapine), ZYPREXA ™ (olanzapine), RISPERDAL * (risperidone), Μ100907 and LUNESTA ™.

In one example, the compounds of the present invention are used in combination with mechanical therapy, such as CP AP. The "CP AP" or "positive ar pressure" is a mechanical means for the treatment of sleep apnea and other sleep disorders, (including snoring). Treatment with (CPAP) is typically given through the nose or mouth to the patient.

Under treatment with CPAP, the subject inserts a mask from a plastic rod through the nose when sleeping. The mask is attached to a compressor, which sends air into the subject's nose.

The principle of the method is that the pressurization of the air offers a mechanical "portion" action, which prevents or avoids the drop in air, obstructive sleep apnea. An effective therapeutic response is also observed in a large number of subjects who are under treatment with CPAP, many subjects cannot tolerate the device or the pressure, so they refuse the treatment. In addition, recent studies demonstrate that long-term compliance with CPAP treatment is very poor. It is known that subjects take off their masks when they fall asleep.

In another aspect, the compound of the present invention is administered in conjunction with the CPAP means to promote sleep. In another aspect, the compound of the

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WO 06/034414 PCT / US2OO5 / O34O15 The present invention is administered in conjunction with the CP AP means to promote sleep. In one aspect, the compound of the present invention is administered in conjunction with the CPAP means to promote compliance with respect to CPAP treatment. Without intending to be bound by theory, it is clear that by administering an effective amount of the sleep promoting compound of the present invention to a subject, in conjunction with the CPAP treatment, the subject will sleep better and where the mask is not. not withdraw.

In one example, the compound of the present invention is administered prior to CPAP treatment. In another example, the compound of the present invention is administered, at substantially the same time as the CPAP treatment. In one example, a parallel administration of an effective amount of the compound is accomplished by adding an additional aerosol channel to the treatment portion using air pressure CPAP, this by administering the tablet of the present invention in a nebulized form via the nose or an oral mask of means CPAP.

Alternatively, an effective amount of the compound can be added to water or to a liquid reservoir, which is typically part of the means of the CPAP treatment.

Using the treatment with the CPAP mask, the compound of the present invention is administered in a slow concentration overnight, or in high concentrations, such as a bolus, at different times at the start and during the night.

All documents and publications described herein are incorporated by reference, such documents and publications are specifically and individually indicated as incorporated by reference.

Citation of publications and documents does not denote admission to the fact that؟ a denotes preceding art, and does not constitute admission as much as components or date of the meme. The present invention has been described by means of writing, it will be recognized by those skilled in the art that the present invention can be practiced in various examples and that the foregoing examples and descriptions are by way of illustration and in no way limit them. following claims.

EXAMPLE 1 Syntesis of loxapine analogues.

The compounds of the present invention, and the derivatives relating to them, can be synthesized by methods known to those skilled in the art.

EXAMPLE 2: Sleep inducing the properties of the compounds of the present invention.

Sleep in mammals can be broken down into sleep resulting in periods of rapid eye movement (REM); accompanied by substantial brain activity; and periods of non-REM sleep (NREM) accompanied by a reduction in brain activity. Typically, a normal period of nighttime sleep is occupied

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WO / 2006/034414 PCT / US20O5 / 034O15 primarily by NREM sleep, and therefore NREM accumulation can serve as a measure of aggregate sleep accumulation, e.g. significant NREM regression can be associated with insomnia and sleep accumulation. "Average sleep", eg, an accumulation of physiological need for sleep which tends to persist until more sleep is accumulated. So, an increase in treatment-associated NREM indicates the effectiveness of treatment in treating insomnia.

The quality of sleep can be associated with the continuity of sleep or its control. For example, a subject with apnea sleep wakes up several times during the sleep period, eg the subject finds it difficult to maintain continuous sleep. Also, such a subject may accumulate a typical night's sleep, eg 8 hours, the sleep is unsatisfactory or non-restorative because of the awakening due to sleep in apnea. Therefore, an increase in sleep duration (LUSB, also known as sleep period) associated with treatment may indicate effective treatments in improving sleep continuity, and in treating sleep that controls insomnia. .

Wake-up sleep, locomotor activity and body temperature monitored in a male wistar rat treated with test compound (ie, loxapine analogue) initially at a concentration of 10 mg / kg. Lower and higher doses were tested for the selected compounds (ex: at more than 45 mg / kg and low as much as necessary for a dose without effect). Treatments are administered at CT-18, the peak of activity of the dominant period (6 hours after the light is turned off), and the production of soporific effects (inducing sleep) characterized by the increase in time of non-REM sleep, increased sleep continuity, but no onset of inhibition of REM sleep or return of insomnia. Sleep- wakefulness, locomotor activity and body temperature are evaluated in vivo with certain sleep inducing agents (e.g. compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 14, 17 , 19, 20, 21, 23, 30, 31, 32, 39, 40, 42, 46, 50, 51, 52, 54, 56 and 58) and other compounds listed in Table 1. male, adult Wistar rats (25 g at the time of surgery, Charles River laboratories, Wilmington MA) were anesthetized (2% isoflorane in an average of medical oxygen) and prepared chirorgically with a cramia implant to allow electro - chronic encephalogram (EEG) and electromyogram recording (EMG).

Body temperature and locomotor activity were assessed using a miniature transmitter (Mini-Motter, Bend, OR) surgically placed in the abdomen. The cranial implant consists of a stainless steel defect (two frontal (+ 3.2 AP from bergma, ± 2.0 ML) and two accipital (-6.9 AP, ± 5.5 ML) for EEG recording. Two Teflon®- covered stainless steel cable are positioned next to the trapezoid muscles of the neck for

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02006/034414 PCT / US2OO5 / 034015 EMG registration. All are bonded to a connector before surgery, and the sterilized gas is ethylene oxide. The entire implant is fixed to the skull with a serrated acrulic. A minimum of three weeks is required to recover from the surgery.

Each rat is housed in its cage equipped with separate and ventilated compartments, with the usual stainless steel cabins. Each cage is fitted with a filter. Superior and air conditioning tube switch. Food and water are available ad libitum. After 24 hours of a light, dark cycle (12 hours of light, 12 hours of darkness) are maintained during the study. Animals are not disturbed for at least 48 hours before and after treatments.

Sleep and wakefulness are determined using "SCORE - 2000 ™" (Hypnion, Worcester, MA). A sleep-wake-up internet base and a physiological monitoring system. The evaluated system amplifies EEG (bandpass 1-30 HZ), built-in EMG (bands 10- 100 HZ), body temperature and non-specific locomotor activity (AML) via rangefinder, patenting activity, continuously and simultaneously .

Insomnia states are classified online as non-REM sleep (5NREM), REM sleep, wakefulness, or theta dominant arousal. Every 10 seconds. Total abbreviation and locomotor activity, and body temperature are quantified and recorded every minute, using EEG with extraction and a means of conjugate algorithms. From these data, we obtain the duration of uninterrupted sleep (LUSB). The algorithm classification using individually an EEG-insomnia-plaques, plus the EMG criterion to differentiate REM sleep from theta-dominant wakefulness, plus. The behavior depends on contextual rules (eg: if the animal drinks, if it is awakened). Drinking and locomotor activity (LMA) are recorded every 10 seconds, and body temperature and body temperature is recorded every minute. Locomotor activity is detected by means of a telemetric receiver (Mnini-Mitter) placed next to the cage.

Telemetry measurements (AML and body temperature) are not a part of the recorded algorithm; therefore, sleep records and telemetry data are independent measurements

The compounds are administered at CT-18, the peak of activity-dominant period, and sufficient time is allowed to see the duration of the effect of the treatment before light (6 hours after the treatment). The compounds are suspended in 0.25% or 0.5 ٥/٠ methylcellulose stele (1-2 ml / kg). Treatments are administered orally as well as bolus. Parallel study groups are used. The control vehicles are extracted from various baths (N&gt; 200): a remainder of the control vehicle is selected, base and computerized during the 24 hours before the base of the treatment of the active treatment group.

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The results of the NREM and LUSB parameters are measured for loxapine drifts as well as compounds

1 "2, 3, 5,6,7) 8,9,10" 12,14,17 "19.20,21,23, 30, 31,32,39, 40,42, 46, 50, 51, 52, 54,56, and 58 and other compounds listed in Table 1. Representative results are referred to in Table 6,

Table 6: sleep inducing the properties of compounds

<td> #</td><td>dose</td><td>NREM</td><td>LUSB</td><td rowspan="34"></td><td>α</td><td>dose</td><td>NREM</td><td>LUSB</td>

<td rowspan="3"> 1</td><td> 1</td><td></td><td> 6.0 ±2.3</td><td rowspan="3"> 21</td><td> 1</td><td></td><td></td>

<td> 3</td><td> 39 ±6</td><td> 18.8±3.0</td><td> 3</td><td></td><td> 9.9± 1.8</td>

<td> 10</td><td></td><td> 19.7*6.7</td><td> 10</td><td> 49*5</td><td> 9.2 ±3.4</td>

<td rowspan="3"> 2</td><td> 1</td><td></td><td></td><td rowspan="3"> 23</td><td>ا</td><td></td><td></td>

<td> 3</td><td></td><td></td><td> 3</td><td></td><td> 4.8 ±2.6</td>

<td> 10</td><td> 33 ±7</td><td> 12.6 ±3.4</td><td> 10</td><td> 28 ±7</td><td> 0.6 ± 2.0</td>

<td rowspan="3"> 3</td><td> 1</td><td></td><td></td><td rowspan="3"> 3٠</td><td>ا</td><td></td><td></td>

<td> 3</td><td></td><td></td><td> 3</td><td></td><td> 9.2 ±3.3</td>

<td> 10</td><td> 32*8</td><td> 6.1 ±1.8</td><td> 10</td><td> 30 ±7</td><td>± 2.4 0.7 ا</td>

<td rowspan="3"> 5</td><td> 1</td><td></td><td></td><td rowspan="3"> 31</td><td>ا</td><td></td><td></td>

<td> 3</td><td></td><td> 13.5 ±4.0</td><td> 3</td><td></td><td> 17.5 ±7.6</td>

<td> 10</td><td>38 ά 9</td><td> 8.7 ± 3.3</td><td> 10</td><td> 42 ±8</td><td> 20.7*2.9</td>

<td rowspan="3">β</td><td> 1</td><td></td><td></td><td rowspan="3"> 32</td><td> 1</td><td></td><td></td>

<td> 3</td><td></td><td> 10.5±1.7</td><td> 3</td><td></td><td></td>

<td> 10</td><td> 46*5</td><td> 17.0± 5.0</td><td>ΙΟ</td><td> 34 ±8</td><td> 16 ± 2.6</td>

<td rowspan="3"> 7</td><td> 1</td><td></td><td></td><td rowspan="3"> 39</td><td> 1</td><td></td><td></td>

<td> 3</td><td></td><td></td><td> 3</td><td></td><td></td>

<td> 10</td><td> 27*9</td><td> 11.3*3.5</td><td> 10</td><td> 33 ±5</td><td> 12.2 ±2.7</td>

<td rowspan="3"> 8</td><td> 1</td><td></td><td></td><td rowspan="3"> 42</td><td> 1</td><td></td><td></td>

<td> 3</td><td></td><td></td><td> 3</td><td></td><td></td>

<td> 10</td><td> 47±١0</td><td> 16.7 ±3.0</td><td> 10</td><td> 14±7</td><td> 4.8± 2.7</td>

<td rowspan="3"> 9</td><td>ل</td><td></td><td></td><td rowspan="3"> 46</td><td> 1</td><td></td><td> 4.1 ± 1.6</td>

<td> 10</td><td> 36 ±7</td><td> 17.7 ±4.2</td><td> 3</td><td></td><td> 17 ±4.4</td>

<td> 30</td><td></td><td> 8.9 ±3.7</td><td> 10</td><td> 50±8</td><td> 11.1 ±3.7</td>

<td rowspan="3">to</td><td> 1</td><td></td><td> 12.5 ±3.1</td><td rowspan="3"> 50</td><td> 1</td><td></td><td></td>

<td> 3</td><td></td><td> 17.0±4.9</td><td> 3</td><td></td><td></td>

<td> 10</td><td> 37 ±7</td><td> 14.5 ±3.2</td><td></td><td> -11 ±6</td><td> 3.4 ±2.6</td>

<td rowspan="3"> 12</td><td> 1</td><td></td><td> 7.7 ±3.2</td><td rowspan="3"> 51</td><td>ا</td><td></td><td></td>

<td> 3</td><td></td><td> 8.3 ±3.0</td><td>ن</td><td></td><td></td>

<td> 10</td><td> 49 ±10</td><td> 18.1*2,1</td><td> 10</td><td> 49 ±9</td><td> 10.1*3,6</td>

<td rowspan="3"> 14</td><td>I</td><td></td><td></td><td rowspan="3"> 52</td><td> 1</td><td></td><td></td>

<td> 3</td><td></td><td> -2.9+1.8</td><td> 3</td><td></td><td></td>

<td> 10</td><td> 26 ±7</td><td> 5.1 ±1.4</td><td> 10</td><td> 24 ±6</td><td>ذ, 2 ± 15.9</td>

<td rowspan="3"> 17</td><td> 1</td><td></td><td></td><td rowspan="9"></td><td rowspan="3"> 54</td><td>ا</td><td></td><td></td>

<td> 3</td><td></td><td></td><td> 3</td><td></td><td></td>

<td>ΙΟ</td><td> 39±10</td><td> 5.0 ±2.0</td><td> 10</td><td> 23 ±6</td><td> 11-1*2.9</td>

<td rowspan="3"> 19</td><td>ا</td><td></td><td></td><td rowspan="3"> 56</td><td> 1</td><td></td><td></td>

<td> 3</td><td></td><td> 18.6 ±33</td><td> 3</td><td></td><td></td>

<td> 10</td><td> 44±6</td><td> 11.7 ±4.0</td><td> 10</td><td> 20 ±4</td><td> 11,7*2.3</td>

<td rowspan="3"> 20</td><td> 1</td><td></td><td></td><td rowspan="3"> 58</td><td> 1</td><td></td><td></td>

<td> 3</td><td></td><td></td><td> 3</td><td></td><td></td>

<td> 10</td><td> -11*5</td><td> 4.7 ±2,3</td><td> 10</td><td> 34 ±8</td><td> 12.2*2.5</td>

<td rowspan="4"> 40</td><td> 3</td><td></td><td> 5.6 ±2.1</td><td></td><td colspan="4"></td>

<td> 10</td><td> 30*7</td><td> 7.6 ±4.2</td><td colspan="5" rowspan="2"></td>

<td> 30</td><td> 43 ±4</td><td> 16.4 ±2.9</td>

<td colspan="3"></td><td colspan="5"></td>

* the dose is in mg / kg, NREM and LUSB are designated in minutes.

EXAMPLE 3: Side effects of the Irwin trial

The Irwin trial can provide useful information on the potential side effects of the compounds, generally in physiological and behavioral functions. The essay is

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WO / 2006/034414 PCTUS2OO5 / O34O15 performs by administering the test compounds orally in 0.25% aqueous methylcellulose using male Wister rats, the use of the species in such studies and for which the above data are valid .

The Irwin test tests numerous parameters in animals which have received the test compound. For example, the test may include: cage effects, eg: dispersal, breathing level, motor activity, combat, indifference, and exophthalamus; in arena effects, eg: transfer insomnia, spatial locomotion, piloerection, positional passivity, touch space, catalepsy, stiffness reflex, visual placement, pinnacle, brain response, and wire maneuvers; the parameters observed in handling, e.g. cyanosis, cutaneous blood flow, hypothermia, body mass, pupil volume, pupil response to light, lacrimation, salivation, grooming, and bites caused, general scores, e.g. : irritability, gait abnormality, apprehension, body stature abnormality, convulsion, bizarre behavior, vocalization, diarrhea, handwriting, number of facations, number of urination, morbidity, infection and abnormalities detected. Full details can be found in: Irwin, s: Comprehensive obesservational asseesment: la. A systematic, quatitative procedure for assessing the behavioral and physiological state of the mouse. Psychopharmacology (Berl) 13: 222-257, 1968, all the teachings are incorporated herein by reference.

The Irwin test of present sleep inducing agents is applied by covance (Princeton, NJ) against Irwin, above; Covnace standard operating procedure (current revision of SOP PHARM 8,10); ICH regulatory authority guide (International committee for Harmonization) guide (Yopic S7A; CPMP / ICH / 539/00) in pharmacological studies of health for human pharmaceuticals (November 2000); and all procedures applied to live animals are the subject of the provisions of the laws of the United Kingdom, in particular the Animals (Scientific Procedures) Act, 1986. which obliges all laboratories in the United Kingdom to follow an ethical procedure which ensures that the use of animals is justified; and that everything is taken into consideration. Regarding any possibility of reduction, replacement and refinement and that the high standards of accommodation are completed.

All chemicals used are from Colocron, Ltd, Dartford Kent, UK, unless otherwise specified they are also high purity reagents of ACS. All the formulations of the test compound are prepared in the day by Harrogate Dispensary covance assay.

The test compounds are formulated in 0.25% aqueous methylcellulose at the highest concentration. Lower doses are obtained by serial dilution of the highest concentration, using 0.25 ٥/٥ aqueous methylcellulose. We designate the levels of

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WO / 2006/034414 PCT / US2OO5 / O34O15 dose in terms of the amount of the test compound administered without taking into consideration the purity or the active ingredient. All formulations are stored at room temperature (normally 10-30 ° C) in sealed containers protected from light.

An adequate number of male Wistar rats (Cri: Wl (Gl IX / B RL / HAN) BR: WH) were obtained from Charles River Ltd (Margate, Kent, united KING DOM).

The rats are approximately 5 weeks old and weigh between 150 and 170 g on arrival. Animals are housed in groups not exceeding six groups, in polypropylene cages (33 O 150 13 Cm) or 45 O 28.20 Cm) with solid floors and 10 wooden levels (datesand Ltd, Cheshire, unted kigdom) as a link. The cages are cleaned before use. The chewy paper blocks are placed in the cages as a form of environmental enrichment. Usually, the storage chambers are under an acceptable temperature, and relative humidity (normally 19 to 25٥ c and 40% to 70 ٥/٥, respectively). These chambers are illuminated by fluorescent light for 12 hours on each 24 hour cycle, and are intended to receive at least 15 air refreshes per hour. Diet (RMI. (E) SQC. (Pecial Diets Services Ltd. Witham, United kimgdom) and tap water, are provided ad libitum (except during handling). It is routinely bogged down for specific constituents and does not contain any biological or chemical antites that could interfere with the test system. On arrival, all the animals are examined for health.

The animals are aclimated for a period of at least 5 days. During this time, the animals are identified by the label of their cage. Veterinary examination is applied before the start of any experimental procedure, to make it suitable for the study. Before the start of each study, animals are haphazardly divided into treatment groups and are individually marked to keep on hand. At the end of the study, the animause is euthanized.

Each animal receives a single oral administration of the vehicle or test article, using a constant dose of 1 mg / kg.

Single doses are based on individual body weight, obtained on the day of dosing.

The above Irwin test parameters are performed systematically in accordance with the relevant controls. In general, drug inducing changes, absent in normal animals, are recorded using whole numbers raised with normal "O" (t / - present / absent may be used).

The parameters present in normal animals are recorded using an integer which allows the recording of increases and decreases. The observations

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WO 0034414 PCT / US2OO5 / O34O15 detailees are performed 30, 60, 90, 180 and 300 minutes after the dose. The animals are kept for a period of 7 days after the dose, during which they are observed daily for signs of morbidity and mortality.

EXAMPLE 4: The side effects of hERG of the present agents

The cardiac potassium channel, hERG, is responsible for the delayed rapid current (Ikr) in the human ventricle. This channel was selected for evaluation, because inhibition of Ikr is the greater cause of potential prolongation than cardiac action by non-cardiac drugs. The potentially elevated duration of action causes prolongation of the QT interval which is associated with dangerous ventricular arrhythmia, torsade de pointes (Brow, Am; Rampe, D. (2000). Drug inducing OT syndrome: is hERG the remedy for all ailments? and pharmaceutical information 7, 15-20; pampe,

D; Roy, ML; Dennis, A; Brown, Am (1997), reference).

HRG channels are expressed in human embryonic cell type (HEK 293) which lack Ikr endrogens. Expression in mammalian cells is preferably transient expression in xenopi, due to the fact that these last show a consistency of 10-100 sensitivity to the blocking hERG channel.

See also: for example: the mechanism for the pro-arrhythmic effects of cisapride (propulsid): high affinity of heart potassium channel blockade in human hERG. FEBS Lett. 417, 28-32; Weirich, ل; antoni, H. (1998); rate- dependence of anti-arrhythmic and pro-arrhythmic properties of class I and class II anti- arrhythmic druggs. Basic Res cardiol 93 Suppl 1, 125-132; and Yao, YG; Cnm, AJ. (1999); and arrhythmogenic mechanisms of non-sedacting antihistamines, clin. Exp. Allergy. 29 Suppl 3, 174-181, all of the teachings of the foregoing articles are incorporated herein by reference.

The in vitro effects of sleep-inducing agents in the hERG (the human ether gene at - go- go-) of the current channel (Ikr, the rapid activation, the current of the cardiac rectifier of potassium) are determined by the chan test. (Cleveland, OH) based on standard chan procedures.

All chemicals are obtained from Sigma (St. Louis, MO) unless otherwise specified and are reagents of purity or greater than ACS. Storage solutions of est and terfenadine (positive controte) articles are prepared using dimethyl sulfoxide (DMSO) stored and frozen. The test article and the concentrations of the positive test are prepared by diluting the stored solutions in HEPES (N- [2-hydroxyethyl] piperazine -Ν'- [2-ethanesulfonic acid]) - buffered saline solution pyhsiologique 5ΗΒ- PS) (composition in mM): NaCl, 137; KU1, 4.0; CaCl, 1.8; MgC, 1; HEPES, 10; glicose, 10; PH adjusted to 7.4 with NaOH (prepared weekly and frozen until use).

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Since the predicted results show that 0.3% DMSO does not affect the channel current, all tests and contole solutions will cost 0.1% DMSO. If the final DMSO concentration must exceed 0.3% to achieve a specific test article concentration, a vehicle control test is performed with n&gt; 2 at high DMSO final concentrations. The test and control solutions are prepared from the stock solutions on a daily basis.

The cells used are human embryonic epithelial cells (HEK 293; source strain, American type culture collection ,, Manassas, VA; bub- strain, chan test, Cleveland, OH), transformed with adenoverus 5 DNA and transfected with hERG cDNA . Stable transfectionants are selected by co-expression with a G 418 resistance gene incorporated into the expression plasmid. Pressure selection is maintained by including G 418 in the culture medium. The cells are used in an interim Dulbecco's modifies eagle / nutrient mixture F- 12 (D- MEM / F- 12) adding 10% fetal bovine serum, 10 u / me penecillin G sodium, lOOpg / ml steptomyaine sulfate and 500 μg / ml of G418.

Acquisition data and analyzes are performed using the pCLAMP programs (Axon Instrument, CA). The constant state is an average costing limit of time change (linear time dependence) before and after application of the test article.

Decreasing the current amplitude under constant effect is useful for calculating the percentage of blockage relative to the control.

All the experiments are carried out at an ambient temperature (18٥ c-24٥C). Each cell acts as its own control.

A concentration (10 μΜ) of each test article is applied to cells expressing hERG (n 3 ة, where n = the number of cells). The duration of exposure of each concentration is limited to the time necessary to achieve the block-constant state, but it does not exceed 10 minutes. A concentration of the positive control article (30 nM terfenadine) is applied to two cells (n&gt; 2). The cells are transferred to the recording chamber and are perfused with HB-PS solution.

The pipette solution for all the cells recorded are (composition in mM): potassium aspartate, 130; Mg Cl, 5; EGTA (ethylene glycol tetraacetate), 5; ATP (adenosine triphophate), 4; HEPES, 10, PH adjusts to 7.2 with KOH. The pipette solution is prepared in patches, aliquots, and frozen, and fresh aliquots each day. The pippette patches are manifested through a glass capillary tube using micropipette pulser P-97 (sutter instruments, CA). A marketed amplifying field patch is used for all

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WO / 2006/034414 PCT / US2OO5 / O34015 registrations. Before digitization, the recorded currents are a low pass filter at one fiftieth of the sampling frequency.

The constant and onset state of the hERG current block due to the test item is measured using one of several means with fixed amplitudes (depolarization: + 20mV for 2s, repolarization: - 50m V for 2s) repeated at 10s interval from the storage potential of -80 mV. The current peak is measured during a step of 2s at -50mV. The constant state is maintained for at least 30 seconds before application of the test article or positive control. Peak currents are measured until the completion of a new constant state.

Table 7 demonstrates blockage of the hERG channel at the concentrations indicated for various sleep inducing agents. Typically, values ​​of 12% to 30% may be acceptable if the compound has strong sleep-inducing performance and does not have other significant side effects; values ​​exceeding 30% are undesirable. Table 7: hERG blocking.

<td>Compound</td><td>hERG at 10 micromolar</td><td>Compound</td><td>hERG at 1٠ micromolar</td>

<td> 1</td><td> 6.2%</td><td> 30</td><td> 4.50%</td>

<td> 2</td><td> 19%</td><td> 31</td><td> 3.80%</td>

<td> 3</td><td> 3.8%</td><td> 32</td><td> 1.60%</td>

<td> 4</td><td> 8%</td><td> 35</td><td> 0.10%</td>

<td> 5</td><td> 36%</td><td> 39</td><td> 61.40%</td>

<td> 6</td><td> 27%</td><td> 40</td><td> 5.6%</td>

<td> 7</td><td> 42.8%</td><td> 42</td><td> 5.80%</td>

<td> 8</td><td> 49%</td><td> 44</td><td> 65.90%</td>

<td> 9</td><td> 59%</td><td> 46</td><td> 20.40%</td>

<td> 10</td><td> 14%</td><td> 50</td><td> 45.00%</td>

<td> 12</td><td> 7.20%</td><td> 51</td><td> 32%</td>

<td> 14</td><td> 0.30%</td><td> 52</td><td> 19.80%</td>

<td> 17</td><td> 30.10%</td><td> 54</td><td> 6.10%</td>

<td> 19</td><td> 9.90%</td><td> 56</td><td> 0.30%</td>

<td> 20</td><td> 5.30%</td><td> 58</td><td> 0.20%</td>

<td> '21</td><td> 0%</td><td> 72</td><td> 10.90%</td>

<td> 23</td><td> 8.90%</td><td> 86</td><td> 86.90%</td>

* compound: compound * hERG at 10 micromolar: hERG at 10 micromolar

EXAMPLE 5: Specificity of Histamine H1 Receptors

Binding assays are performed using sleep inducing agents and derivatives selected from those listed in Table 1 in competitive binding assays with known standards for histamine H1 receptors, and muscarinic M1 receptors, Μ2, Μ2, alpha 1 and alpha 2 receptors, and D1 and D2 receptors.

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The histamine H1 assays are described in chang, et al .. Heterogeneity of Histamine H] - Receptors: species variations in [³H] Mepyramine Binding of Brain Membrane. Journal of neurochemistry. 32: 1653-1663 (1979); Martinez-Mir, Μ.Ι., Pollard, H., Moreau, ل., Et al.

Three Histamine receptors 5hl, h2 and Η3) visualized in the human brain and non-human primates. Brain Res. 526: 322-327 (1190); Haaksma, EEJ, their, R. and Tinnerman, H. Histamine Receptors: Subclasses and specific ligands. Pharmac. Ther. 47: 73104 (1190). Muscarinic assays are described in Buckey, NJ, Bonner, Τ.Ι, Buvkley, CM, and Brann, MR, antagonist Biding properties of five domed Muscarinic Receptors Expressed in CHO-K1 Cells. Mol. Phamacol. 35: 469-476 (1989).

The tests are carried out according to the previous articles, with the following modifications. The following chemical reagents are obtained from sigma, St. Louis, MO.

For the H1 histamine assays, the receptors are obtained from bovine brain membrane tissue, with a Bma (number of receptors) of 0.2 femtomol / mg tissue (weight) and KD (binding affinity) of 1.3 nM. A radioactive ligand ([³H] pyrilamine (15- 25) ci / mmol), ki 1.9 nM, final concentration 2.0 nM) is used, and 10 μΜ triprolidine (ki 3.3 nM) used as a non-specific determinant, reference compound, and a control positive. The receptor and the radioactive ligand are combined with the test compound at an average concentration of the test compound compound of about 10! ٥ to about 10'٥ M, and the mixture is incubated in 50mM Na-KPOs (PH 7, 5) at 25٠c for 60 minutes. The reaction is terminated by rapid vacuum filtration in glass filters. The radioactivity of the displaced radiactive ligand placed in the filters is determined and compared to the control values ​​in order to measure any interaction of the compound with the histamine H1 binding site.

For muscarinic assays, receptors are obtained by human recombinant receptors expressed in CHO cells (perkinelmer. Inc. Wellesley, MA). The radioactive ligand used is [³H] - scopolamine, N- Methyl chloride (80-100 ci / mmol).

(-) methylscopolamine bromide, 1.0 μΜ, is used as the nonspecific determinate, compound of reference, and a positive control. After the incubation, the reaction is determined by rapid vacuum filtration through glass fiber filters. The radioactivity of the displaced radioactive ligand placed in the filters is determined and compared to the control values ​​in order to measure any interaction of the test compound with the respective receptor.

For the Μ2 receptor test, the Bmax (number of receptors) is 2.1 picomol / mg of the protein, and Ko (binding affinity) of the receptor is 0.29 nM. The radioactivity of the ligand is used at a final concentration of 0.5 nM, while (-) methylscopolamine bromide at a kide 0.03nM.

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The receptor and the radioactive ligand are combined with the test compound at an average of concentrations of the test compound from around 10'2ا to around 10'5'4, incubated in Dulbecco's phosphate (PBS) saline buffer for 60 minutes at 25٥ c, and work as denoted above.

For the Μ3 receptor test, the Bmax (number of receptors) is 4.2 picomol / mg of the protein, and Ko (binding affinity) of the receptor is 0.29 nM. The radioactivity of the ligand is used at a final concentration of 0.5 nM, while (-) methylscopolamine bromide at a ki of 0.3 nM.

The receptor and the radioactive ligand are combined with the test compound at an average of concentrations of the test compound of around 10'2 to around 10 ؛ Μ, incubated in Dulbecco's phosphate (PBS) saline buffer for 60 minutes at 25 ° C. , and work as designated above.

For the Μ3 receptor test, the Bmax (number of receptors) is 4.0 picomol / mg of the protein, and Ko (binding affinity) of the receptor is 1.4 nM. The radioactivity of the ligand is used at a final concentration of 0.2 nM, while (-) methylscopolamine bromide at a ki of 0.3 nM.

The receptor and the radioactive ligand are combined with the test compound at an average of concentrations of the test compound from around 0'2 to around 10 ؛ ٠Μ, incubated in 50mM Tris- HCl (PH 7.4) containing 10 mM Mg c , ImM EDTA for 60 minutes at 25 ° C, and work as designated above.

Adenosine, the purinergic A1 binding assay is performed according to published procedures. See for example هعللآنأ, et al., Naunyn Schmiedebergs Arch. Pltannacol. , 2&gt; ٦S (V١٠. 59 ذه (1987), with minor modifications; and Ferlany, et al. Drug Dev. Res. 9: 85-93 (1986).

Adenosine, the Α2-purinergic binding assay is performed according to published procedures. See for example

JarviSjetaZ., / Pharmacol. Exper. Then 251 (3): 888-93 (1989) with modifications; and Bruns, et al., Mol. Pharmacol. 29 (4): 33146 (1986) with modifications.

Dopamine, Di binding assay (human recombinant) is performed according to published procedures. See for example

Jarvie, and ر ./٥. ReceptRes., 13 (1-4): 573-90 (1993); and

Billiard ”et al. Life Sciences, 35 (18): 1885-93 (1984), with modifications.

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Dopamine, Di binding assay (human recombinant) is performed according to published procedures. See for example

Jarvie, et al. A. Recept Res., 13 (1-4): 573-90 (1993); and Gundlach, et al. Life Sciences, 35 (19): 1981-8 (1984) with modifications.

Binding to H1 may be indicative of the desired sleep inducing activity of the present compound. Binding to muscarinic receptors demonstrates nonspecific binding, and may indicate anti-cholinergic activity, which may result from unwanted side effects, eg side effects of several known antithistamines, eg blurred vision, dry mouth, constipation, urinary problems, anxiety and the like. The decrease in the binding of compounds to the M1 - Μ3 receptors, relative to the binding of the compound to the H1 receptor, is an indication of the high specificity of the compound at the histamine receptor through the muniscarinic receptor. In addition, the drug having high specificity for the histamine receptor will have more anticholinergic side effects.

Table 8 demonstrates the constant inhibition ki in nM for H1 and muscarinic receptors.

It is clearly visible that the compounds have a high specificity for H1 through the muscarinic receptors. Therefore, the present compounds can have a good sleep inducing performance, with limited side effects associated with inhibition of the muscarinic receptor.

Table 8: Specificity for the histamine H1 receptor.

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<td>CMPD</td><td>Hl (bovine)</td><td>Ml</td><td>Μ2</td><td>Μ3</td><td>Alphal</td><td>Alpha2</td><td>DI</td><td>D2</td>

<td> 1</td><td> ؟40.3</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;18000</td><td>&gt; 10,000 rat and human</td><td>&gt; 10,000 rat and human</td>

<td> 2</td><td> 51.4</td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10.000</td>

<td> 3</td><td> 7.33</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 4920</td><td> 1190</td>

<td> 4</td><td></td><td> &gt;10,000</td><td></td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> -</td>

<td> 5</td><td> 23.9</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 3020</td><td> &gt;10,000</td><td> 4520</td><td> 1610</td>

<td> 6</td><td> 13-8</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 2730</td><td> &gt;10,000</td><td> 7170</td><td> 96.1</td>

<td> 7</td><td> 217</td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10.000</td><td> 1730</td><td> 222</td>

<td> 8</td><td> 11.7</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 3350</td><td> 434</td>

<td>Q</td><td> 36</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;100</td><td> 1120</td><td> 53.3</td>

<td> 10</td><td> 39.6</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 3160</td><td> 1670</td>

<td> 12</td><td> 137</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10000</td><td> &gt;10,000</td><td> 5220</td><td> 1240</td>

<td> 14</td><td> 283</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 942</td><td> &gt;10,000</td>

<td> 17</td><td> 12</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 1990</td><td></td><td> 3450</td><td> 883</td>

<td> 19</td><td> 39.5</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 6800</td><td> 3160</td>

<td> 20</td><td> 76.8</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> 1980</td><td> &gt;10.000</td><td> 1930</td><td> 1590</td>

<td> 21</td><td>و 57</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;100</td><td> &gt;10,000</td>

<td> 23</td><td> 135</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10,000</td>

<td> 30</td><td> 90.6</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10,000</td><td> 5060</td><td> &gt;10,000</td>

<td> 31</td><td> 239:337:244</td><td> &gt;10,000</td><td></td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10-000</td><td> 8٠73</td><td> 2200</td>

<td> 32</td><td> 3770</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10,000</td>

<td> 35</td><td></td><td> &gt;10,000</td><td></td><td> &gt;10.000</td><td> &gt;100</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td>

<td> 39</td><td> 98.7</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;1000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10,000</td>

<td> 40</td><td> ؛22.8</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10.000</td><td>&gt; 10,000 rat and human</td><td>&gt; 10,000 rat 18701η human</td>

<td> 42</td><td> 110</td><td> &gt;10,000</td><td></td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10,000</td>

<td> 44</td><td> 41.4</td><td> &gt;10,000</td><td></td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10,000</td><td></td><td></td>

<td> 48</td><td> 18.8</td><td> &gt;10,000</td><td></td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10000</td><td> &gt;10.000</td><td> &gt;10,000</td>

<td> 48</td><td> 27.1</td><td> &gt;10.000</td><td></td><td> &gt;10-000</td><td> &gt;10.000</td><td></td><td></td><td></td>

<td> 50</td><td> 31.8</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> 595</td><td> 1.950</td><td> 1140</td><td> 360</td>

<td> 51</td><td> 27.8</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> 148</td><td> 966</td><td> 1040</td><td> 170</td>

<td> 52</td><td> 55.4</td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10.000</td><td></td><td> &gt;10,000</td>

<td> 54</td><td> 40.4</td><td> &gt;10,000</td><td> &gt;10,000</td><td></td><td> 1210</td><td> 5820</td><td> 4970</td><td> 1080</td>

<td> 56</td><td> 117</td><td> &gt;10.000</td><td></td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10.000</td><td> &gt;10,000</td>

<td> 58</td><td></td><td> &gt;10.000</td><td> &gt;10,000</td><td> &gt;10,000</td><td> &gt;10.000</td><td> &gt;10,000</td><td> 2000</td><td> 4030</td>

<td> 72</td><td></td><td> &gt;10,000</td><td></td><td> &gt;10,000</td><td> &gt;10.000</td><td></td><td> 514</td><td> 470</td>

'11.5 In rats; 23.7 in humans;

258.8 In rats, 31.7 in humans;

2730 ذ In rats.

EXAMPLE 6: Evaluation of loxapine analogues

The following pharmaceutical parameters are computerized by the individual plasma concentrations of the modified antihistamine compound, using a noncomportmental approach and an appropriate pharmacokinetic valid software (ex: WinNonlin

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Professional). The concentration values ​​report as much as BLQ are zero. If concentration data is available, interim calculations are made (nonQC data) between periods if possible. The increase in dose is not dependent on pharmaceutical calculations.

Descriptive statistics, including the mean, standard deviation, coefficient of variation, geometric mean, intermediate, and minimum and maximum are counted for each pharmacokinetic parameter by dose group.

Descriptive statistics of the log-natural transforms AUC (O-inf), and Cmax are provided for each dose level

In addition, the mean and intermediate concentration versus time graphs are provided.

The dose proportion after drug study is explored by analysis of the natural log-transforms pharmacokinetic variables AUC (0-t), AUC (ο-inf), and Cmax with a linear model comprising the natural log of dose transformed as much as covariant. The proportion of the dose is concluded if 95% interval of the covariate includes the value of 1. Linear dose of AUX (ο-inf), and Cmax is also explored by a linear model. See for example: Gibaldi and Perrier, Pharmacokinetics, Second Ed., Marcel Dekker. New York, New York (982 ؛). Nominal samples are used in calculations, except when the current sample times are outside of the protocol-specific acceptable time levels. The following parameters are estimated:

Cmax the maximum of the plasma concentration Tmax time of the maximum concentration Cmax and Tmax where they are reported directly from the data - medium concentration AUCo-t under the curve of all plasma concentrations of 9 times at at least one point of measurable concentrations estimated by the trapezoidal linear rule.

AUCo-00 medium under the plasma concentration step curve explored for affinity, calculated using the formula:

AUCo AUC C٥Ao

Where Ct is the last measurable concentration in plasma and λζ is the terminal phase of constant elimination, estimated using log-linear regression during the terminal phase of elimination. The number of points used in the compute λζ is determined by visual inspection of the data that describes the terminal phase. At least three time points with measurable values ​​are used in the λζ compute. the number of points used in the compute n λζ based on the best correlation (r adjusts) to obtain the time points that describe the

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WO / 2006/034414 PCT / US2OO5 / O34O15 terminal phase of elimination. The value A ٢2 fits for the regression line is considered to define the terminal phase of elimination if the value is&gt; 0.7.

T elimination of the half-life, determined by In (2) λζ.

CL systemic clearance, for intravenous bolus or infusion, calculated using the formula:

CL = Dose / AUC0-00 Report CDT, where F = absolute bioavailability, for all other modes of administration.

the volume of distribution of all administration methods, calculated using the formula: V_z = CLXz CL / F is used to calculate ٧2 / F for the extravascular mode of administration.

Pharmacokitic analysis is performed using Win Nonlin Professional Edition (pharsight corporation. Version 3.3 or 4.1).

Descriptive statistics, such as Medium and Classic Deviation are Microsoft Excel (version 80).

The metabolism of the test articles in cryopreserved hepaticytes of monkeys and humans is carried out as follows:

Materials

<td>Materials</td><td colspan="2">Manafactured, Lot number, and expiration date</td>

<td rowspan="2">Cellzdirect hepatocytes</td><td>Monkey</td><td></td>

<td>human</td><td></td>

<td>Intermediate Williams</td><td colspan="2">Sigma W1878. exp 2 ^ 04-11</td>

<td>Calf fetus serum</td><td colspan="2">Fisher BW 14-501F, lotOl 104637, exp 17 Feb 10</td>

<td>0.45 Blue trypam</td><td colspan="2">Biowhittaker 17-942Ε, lot 01104637, exp 14 ئ.</td>

<td>Stock solution of test equipment</td><td colspan="2">CB-l / 16</td>

<td>DMSO</td><td colspan="2">Fisher ΒΡ231-100, lot 041215, exp 12 Jul 09</td>

<td>10mM ethoxy coumarin in methanol</td><td colspan="2"> -</td>

<td>ACN</td><td colspan="2">Fisher Α998 ^, 1Ι181٠ exp 6/07</td>

<td>Formic acid</td><td colspan="2">Fisher 032879, exp 0314Ό6</td>

Pre-incubated part:

The sample is diluted with DMSO to prepare 100 μΜ of stocks. 0.1% formic acid in acetonitrile is prepared by adding 1 ml of formic acid per IL 131

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WO / 2006/034414 PCT / US2OO5O34O15 of acetonitrile (stored at room temperature for 3 months). 96-well quenching plates, 10 minutes, 60 and 120 minutes, are prepared with 150 μL of acetonitrile 0.1 ب% formic acid in each well. Store in ice or refrigerated.

Subsequently, the hepatocytes are dissolved and 100 μL of cell suspension are placed in a centrifuge tube with 100 μL 0.4% of Trypan blue solution and carefully mixed by inversion.

A small amount of the stained cell suspension (approximately 15 µl) is placed in a hemacytometer with a lid. The hemacytometer is placed in a stage of the energy microscope and the lens is adjusted until a singular square fills the domain. The number of cells of the four corners of the unscrewed edges concerned with the hemacytometer is counted. Viable cells are shiny, round, and pale with dark lines. Non-viable cells are dark, opaque blue.

The viability ٥/٠ is calculated as the number of cells deviated by the total of cells X 100.

The density of viable cells and the total number of viable cells are calculated: density of viable cells (D) = denotes 3 viable cells counted (C) X 14 X ² ا, the total number of viable cells (E) = DX 26 (volume of the suspension). The additional intermediate required to complete the concentration of lx 10⁶ cells / ml is calculated:

Volume of additional intermediary =

Total viable cells (E) -26 mL.

X 10٥

The cells are diluted and stored at room temperature.

Incubations

198 µl of hepatocytes are transferred to the previous wells and to the assay plates. The remainder of the hepatocyte suspension is combined and placed in a suitable container of boiling water and allowed 5 minutes for inactivated cells (for inactivated controls and standard curve preparation).

198 µl of deactivated hepatocytes are transferred to the control wells and 198 µl of white intermediate is transferred to the buffers of the control wells. The plates are pre-incubated for at least 15 min.

Reactions are performed with 2 µl of the appropriate test compound dilution from the assay plate. The plates are incubated in an incubator at 37 ° C. for approximately 10 minutes, then 50 μl of the incubated product are shaken for 10 minutes on the stirring plate with a concentration of 150 μl of acetonitrile + 0.1 ٥/٥ of formic acid and are stored or refrigerated, or put in ice.

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After 60 minutes, 50 μΐ of the incubated products is stirred at 60 minutes from the stirring plate, containing 150 μΐ of acetonitrile + 0.1% formic acid and stored or refrigerated or placed in ice.

After 120 minutes, 50μ1 of the incubation is 120 minutes away from the extinguishing plate, containing 150μ1 of acetonitrile + 0.1٥ / ο formic acid and store, refegered or put in ice, the remainder of 50μ1 is frozen in incubation plates.

The tubes are centrifuged at ~ 4٥c at ~ 1400 X g for ~ 10 minutes, 10μ1 of supemageamt is diluted with 10μ1 of water in the analysis plates, the plates are frozen at -2O٥C before analysis.

Preparation of standard curves:

0.1 μΐ standard is prepared by adding 2μ1 of 10μΜ of dosing solution to 198μ1 of dasactive hepatocytes, in standard preparation plates, 150μ1 of acetonitrile 0 اه 0.1 ا of formic acid is added to the standard extinction plate, 150μ1 0.1 μΜ standard is transferred to a column of standard plate, 75 μ1 of deactivated hepatocytes are added to the rest of the wells.

75μ1 of standard Ο.ΙμΜ is transferred to the adjacent well in a column of the well, and mix the well by evaluation.

A serial dilution is carried out, 75 μL is displaced from the final standard (all the wells contain 75 μΐ) the plates are incubated at approximately 37٥c for 10 minutes.

50μ1 are transferred into standard extinguishing plates, containing 150μ1 acetonitrile 0.1 ؛% formic acid, the plates are centrifuged with samples and dilute the supernatant 1: 1 with water as designated above, samples are stored in ~ 2O٥C.

For compound 5, hepatocytes remaining 120 minutes after treatment at lpm, is 75.105 for primates and 90.405 for humans.

EXAMPLE 7: Clinical evaluation of loxapine analogues.

The aim of human clinical experience is to collect data on the effects of loxapine derivatives, such data include, for example, clinical signs and symptoms of physical examination, negative effects, laboratory safety (eg: hematology, chemical, clinical serum, urinalysis), vital signs (e.g. blood pressure, temperature, heart rate, respiration level), and EKG data (ECG) clinical experiments are conducted as follows:

I- subject selection:

a minimum of 18 subjects are used (12 rolling groups of 9 subjects each). Applicants having the following criteria are suitable to participate in the study.

healthy adult male subjects, aged 18-45 years.

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A body weight of at least 60Kg and which is 15 / o in their ideal weight (see the appropriate weight table for adults, Metropolitan life Insurance company, 1983).

Good medical health of the subject with insignificant clinical results (eg profile, laboratory, medical history, ECGS, physical examination). Applicants with any of the following are not suitable for study participation.

History of the presence of cardiovascular, pulmonary, hepatic, renal, hematological, gastro-in testinal, endorin, immunological, dermatological, neurological, or psichiatric disease.

History of the presence of sleep disorders.

History of the presence of chronic or seasonal allergy, which requires treatment with H1 receptor antagonists (ie terfenadine, astemizole) within 90 days before the study.

History of the presence of alcohol or drug abuse in the previous 2 years.

Conne hypersensitivity or idiosyncrastic reaction to the study drug, possible excipients for the study formulation (captisol ®; sodium saccharin, Fcc; glycerin, usp; orange flavor, 400 centipoise methylcellulose, usp; purified water ) or related compounds.

Donation (standard donation amount) of blood or blood products within 90 days prior to the study.

Participation in another chemical experiment within 90 days of the first dose.

History of the presence of any disease, medical condition, or surgery, which may affect drug absorption, metabolism, distribution, or excretion.

Weight gain or loss (± 10٥ / ο) within 30 days of the study.

Regular consumption (eg more than days) of excessive amount of caffeine containing one drink (eg more than 5 cups of coffee or equivalent, per day) in the 30 days before the study.

Any condition, in the opinion of the investigator or the sponsor, which renders the subject unfit for study.

The use of any concomitant medication which is prohibited. each subject who has all of the study ratings, meets all eligibility criteria, and is acceptable for the study is provided with a unique identification number and receives specific doses of modified histamine and placebo according to the randomization scheme, which is only valid for the clinical pharmacist staff preparing the drug

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WO / 2006/034414 PCT / US2OO5 / O34O15 (which are not included in the administration of the drug) and which are not valid for subjects, analysts, or members of staff responsible for the use and evaluation of the drugs. reverse experiences. Subjects may be withdrawn from the study by the principal investigator for the following reasons:

Secondary effects of most criteria.

To protect their health

Contrary effect

Difficulty collecting blood.

To protect the integrity of the study.

Protocol violation

Error in fulfilling the directions of the study.

The clinical report includes the reasons why the subject was excluded, as well as the details of this judgment.

Subjects who were excluded from the experiment before the end of the study undergo all procedures scheduled for the end of the study.

Subjects excluded due to a negative effect (either serious or non-serious) or a significant clinical abnormality evaluation test in the laboratory, are evaluated by the researcher, or the physicist, and they are treated and / or monitored until symptoms return to normal or at acceptable levels, as determined by the researcher.

II- Study restriction

Subjects do not take any prescriptions or other drugs (including the herbs) for 7 days prior to the study until the final pharmacokinetic sample period sample is collected, in addition, food and drug consumption. Beverages containing the following substances are prohibited as indicated:

methyl xanthine: 72 hours before each dose and during the sample collection period, caffeinated drinks and the like (eg: chocolate bars) are prohibited.

Alcohol: 72 hours before each dose and during the sample collection period. All medications taken during the 30 days before the start of the study are recorded.

All medications taken for chronic or seasonal allergies within 90 days of the start of the study are recorded.

Purification of the subject before the study: the constant form is administered for purification, within 14 days before the dosage, medical history and demographic data,

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Each subject is given a physical example, including complete vital signs, 12 ECG, and laboratory tests as specified, laboratory tests include the following:

a) hematology including hemoglobin, CVD, red blood cell count, hematocrit, MCHC, white blood cell with a differential palette and MCH;

b) chemical serum including albumin, ALT (SGOT), creatine, alkaline phosphate, glucose, total bilirubin, creatine posphokinases (CPK), sodium, uric acid, AST (SGOT) and triglycerides.

c) Uranalyses, showing appearance and color, glucose, nitrile, PH, ketons, urobilinogen, specific gravity, bilirubin, leukocytes, protein and blood;

d) Additional tests, including HIV, evaluation of drug levels in urine, HbsAg, cannabinoids, HCV, benzodiazepine, HCV, amphetamineshepatitis A (IgM), opiates, alcohol, cocaine, and continine. Subject management: subjects are placed at least 36 hours before the dosage until the end of the 24 hours after the dosage

The subject will return for a visit, one week after the final dose or during premature discontinuation.

Subjects remain semi-reclined in bed for the first four hours after dosing, however, as secondary events occur at the same time, subjects are placed in appropriate positions where they are allowed to rest. put themselves as they want, the subjects do not practice any strenuous activity during the confinement period.

Standard meals are provided on day 1, and day 2, subjects should fast for a minimum of 10 hours overnight, before receiving the dose and at least 4 hours after, however, if the dose option provided in the food is used in period 3 of group 2, a standard very fatty meal is given 30 minutes after the dose. In this case the high fat breakfast (i, e approximately 50% of calories in fat) consists of two fresh eggs in butter, two pieces of bacone, two slices of toast butters, four grams of sautéed potatoes and eight grams of whole milk, food and drinks containing caffeine or equivalent (ex: chocolate bars) are prohibited during confinement, water is not allowed during the 2 hours before until 2 hours after the dosage,

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Water is allowed the rest of the time, standard meals are provided at approximately 4 and 9 hours after dosing; and at the appropriate times.

III- Administration of the drug:

Subjects receive a dose for each designated time period, according to the dosing sequence randomization schedule for each dose group (roll) Subjects receive a designated dose in a glass dosing cup, and in each dose group, all doses, active and placebo, are given with the same volume to maintain the double bond, subjects must swallow the dose of a total of 240 ml of water is given with the dose. A designated portion of water (designated by the pharmacist based on the dosage volume) is added to the empty dosage cup, stirred to rinse it, and swallowed by the subject, this process is repeated twice and the remainder of The water is then consumed by the subject. The starting dose for the first level of human dose, based on toxicity and safety profiles in clinical studies the equivalent body surface area of ​​human to rat conversion is 1/6 (toxicoolgical Handbook, Michall, ل) Dereleko, CRC press, Boca Raton, FL) based on NOAEL of 30 mg / kg / day for the rat and the equivalent body surface criterion, the equivalent dose in a 60 kg individual is 300 mg / day (1/6 x30 mg / kg / day [rat NOAELx 60Kg).

Based on the NOAEL dose in rats (30mg / kg / day), the 3mg dose and approximately 1/10 of the NOAEL dose in rats.

The largest proposed dose of 160mg and also below the NOAEL in rats.

If the toxicity-limiting dose (grade 3 or 4 on the grade scale modified by the common WHO-Appendis I toxicity endpoint) is found to be related to study meditation is observed in any of the 2 of the 6 subjects at any dose level, intensifications were stopped, and the first dose was considered the maximum tolerated dose (MTD).

if a subject at any level cannot cope with dose-limiting toxicity experiments, the principal investigator (in consultation with spensor) decides, using clinical judgment, to either proceed to the next dose level, or to adjust the dose level, in addition, the planned dose is substituted with intermediate doses if tolerence or safety becomes apparent (i.e., there is no grade 3 or 4) per pretending dose that suggests the need to increase it more slowly.

A staged dose is only permitted if, from the point of view of the principal investigator, adequate tolerance and safety have been demonstrated at various lower doses.

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In all cases, the principal investigator uses good clinical judgment in deciding whether to adjust the dose or discontinue the study based on the assessment of all factors relevant to the safety of the subject.

The principal investigator reviews all the data (ex: results of physical examinations, vital signs, questionnaire and clinical laboratory results (ex: chemical serum, hematology, uranalysis, and evaluation of drugs in urine) for significant clinical changes or period expected.

The principal investigator will determine whether the subject will receive the dose or be excluded from the study based on the examination.

IV. Clinical observation

The haematological register, the chemical serum register and the analyzes are carried out at evaluation, at each registration, 24 hours after each dose, and one week after the final dose, or after stopping. Blood samples are taken (approximately 7 ml) intravenously through the catheter in a glass tube, containing predosed sodium heparin and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6 , 8, 10, 12, 18 and 24 hours after the dose. The pre-dose urine samples collected during 0-8 hour intervals of each period. Samples collected during the interval are not pooled. Each void is considered a sample. Empty times are programmed at will (with the exception of the empty pre-dose and the vacuum at the end of 8 hour intervals).

Vital signs are measured during the assessment. When the vital signs stages coincide with the ECG only, the vital signs are taken 10 minutes before the ECG. When the vital signs stage coincides with the blood test or the blood test and ECG, the vital signs are taken 10 minutes before the blood test. Respiration levels and temperature are taken on recording, 24 hours after each dose, and one week after the final dose, or on stopping.

Singular measurements of blood pressure and level of heart rate are taken after at least 5 minutes in a semi-lying position. The measurements taken during the containment study are checked with an AVS machine at recording: 0 (predose); 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours after the dose, and one week after the final dose, or on stopping.

For any heart rate level measurement exceeding 100 beats per minute, the heart rate level will be re-evaluated 2 minutes later. On day 1, approximately 24 hours before dosing, three measurements of blood pressure and heart rate level, taken two minutes after, are taken as described above.

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A standard ECG-12 is taken for each subject evaluated, on day 1 at times that coincide with the times on day 1 of 1 hour before the dose and 1, 1.5, 2, 3, 4, and 6 hours after the dose ; on day 1 to 1 hour before the dose and 1, 1.5, 2, 3, 4, 6 and 24 hours after the dose; and one week after the final dose or during premature discontinuation. In addition, ECGs can be performed at other times if necessary. All standard ECGs-12 are recorded at 10 seconds. The timing and recording technique of ECGs is standardized for all subjects. Subjects should lie down at least 1 minute before each ECG-12 assessment.

The principal investigator will assess the PR, QRS, QT and QTc intervals. When the ECG step coincides with the blood test, the ECG will be taken after stopping.

The physician will examine each subject at each assessment, each recording, 24 hours after each dose, and one week after the final dose under premature discontinuation. Additional examinations are performed at other times if necessary.

Immediately after measurements of vital monkeys, 1 hour before dose and at 1, 2, 6 and 24 hours after dose (vital signs are taken 10 minutes before the designated blood test at these times, and subjects are presented at a similar visual level and asked to draw 100mm vertical lines at the variation point between very asleep and alert / all awake, which best describes the level of alert at that time.

The subject is asked to inform the study physician or staff of any intercurrent event or disease during the experiment. In addition, the specific teaching with respect to adverse events is applied before dosing, at 2, 4, 8 and hours after the dose, and one week after the final dose, or during premature discontinuation. The questions are asked in a non-specific way, so that؟ a is not an answer. Any subject with negative events (either serious or not serious) or laboratory test values ​​of clinically significant abnormality, is evaluated by the investigator, or the physician, and is treated and / or followed until. whether symptoms or values ​​return to normal or to acceptable levels, as judged by the investigator.

The doctor, whether in the site or next to the hospital emergency room, will administer treatment for any negative event. When appropriate, midicals tests and reviews are performed to document event resolution. The results are classified as, for example, resolved, improve unchanged, fatal, or unknown (lost to follow-up).

V. report

All negative events resulting from clinical experience are recorded. Adverse events are coded using Med DRA (version 4.1). Event/

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WO / 2006/034414 PCT / US2005 / O34015 negative experience (AE) is any unjustified medical accident, in a patient or a clinical investigator to whom a pharmaceutical product is administered which does not necessarily have a reaction. causal with this treatment (ICH / WHO).

A negative event 5ΑΕ), here, is any unexpected and undesirable sign (including, for example, a laboratory abnormality), symptom, or disease temporarily associated with the use of medical products, whether related or not to the medical product (ICH / WHO).

The investigator will study each event and establish its relation to the drug treatment (ie, unrelated, possible, probable, certainly). Each sign or symptom reported is kept in 3 points of severity (medium, moderate, or severe) as well as the date and time, extension of time for the dosage of the drug, and the result of each event is noted.

The severity measurement definitions are used:

(1) medium: negative event is easily tolerated and does not interfere with daily activity;

(2) moderate: the negative event interferes with daily activity, but the subject is still able to act; (3) Server: The negative event is a disability and requires medical intervention.

If any of the negative events are serious, special procedures will follow. All serious negative events are reported to the sponsor within 24 hours and are followed up by a written report within 48 hours, whether or not related to medication.

Serious Adverse Event (SAE) is any medical incident which at any dose, causing death, is a lifelong treatment, resulting in permanent disability, hospitalization of the patient, prolonged hospitalization of the patient is an anomaly congeintal, may endanger the subject or may require intervention to prevent one or more of the consequences referred to above.

VI. Pharmacokinetics

The following pharmacokinetic parameters are taken from the individual plasma concentrations of the modified hestamine compound using a non-behavioral approach and validated and appropriate software pharmacinitics (eg: WinNonlin Professional).

The concentration values ​​reported as BLQ are zero. If the concentration data is valid, interim calculations are performed (non-QC data) between periods if possible. Staggered doses are independent of pharmacokinetic calculations.

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Descriptive statistics, including mean, standard deviation, coefficient of variation, geometric mean, medium, minimum, and maximum are counted for each pharmacinitic parameter by dose group. The statistics, descriptive of the natural log transformed AUC (0-t), AUC (O-inf), Cmax are provided for each dose level. In addition, the Average and Intermediate concentration versus time graphs are provided. The dose proportionality according to the medical study is explored by analyzing the transformed log-natural of the phrmacokinetics variables AUC (ot), UC (0-inf), and Cmax with a linear model, including the natural log-transformed dose as a covariant. The proportionality dose is concluded if 95% of the confidence interval for the inclination of the covariate includes the value of 1. The linearity dose for AUC (Ο-t), AUC (O- inf), and Cmx is also explored by a linear model.

VII- risk assessment

By treatment of subject- negative results data list including term, verbatim, preferred term, treatment, severity, related to treatment is provided.

The number of negative results in a number of subjects tested and the number of negative results are summarized by the dose level using frequent counts.

Risk data including laboratory assessments and assessment of vital signs are summarized by dose level and time of collection. Descriptive statistics are calculated for the quantitative risk data and the corresponding compounds are developed for the classification of the quantitative risk data.

In addition, the baseline table change medium is provided for vital signs and the change table which describes the normal level of changes is provided for clinical laboratory results.

ECG results are classified as normal and abnormal and are summarized using frequent counts by dose group and time of collection. Descriptive statistics are calculated for PR, QRS, QT and QTc.

The changes to the physical examinations are described in the text of the final report. Heart rhythm data is summarized by treatment group and stage using descriptive statistics, as an individual change from baseline. The results of the baseline change means, are used to compare the active dose groups to the placebo at each stage. Data from six complete subjects per dose level should provide 80% to detect the difference of 20 beats per subject per minute. An interim analysis is completed after each period.

VIII effectiveness evaluation

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VAS calm numbers are summarized by stage of collection for each dose level using descriptive statistics.

EXAMPLE 8: Preclinical evaluation of loxapine analogues

Before, pre-clinical tests are performed. The clinical evaluation includes the following tests:

i- preclinical absorption of compounds in humans, distribution. Metabolism and excretion.

The compound is administered to rats, dogs, and cynomological monkeys at doses of approximately 3 mg / kg orally and intravenously. Plasma samples are collected from all species for pharmacokinetic analysis.

Tmax and half-life (in hours) is measured in rats, dogs and monkeys. The percentage of protein binding in rats and humans is also measured. Brains are collected from rats after oral administration, for the purpose of determining brain levels of the parent drug.

Cytochrome Ρ450 inhibition is studied in vitro. In addition, the in vitro level of metabolism in rat, dog, monkey, and human hepatocyte cultures is determined for each compound.

ii- development of cardiac effects:

The primary toxicological study during the clinical selection phase of the candidates is an extension of the QT interval.

Historically, H1 antagonists have been associated with this effect. QT prolongation in rare instances can develop a threat of cardiac arrhythmia. The best in vitro test to prevent the likelihood of the compound causing QT prolongation, hERG binding, is the test system taken to investigate the potential of the compound to produce this effect. The human hGERG channel, transfected to a stable cell line, is studied electrophysiologically and the percentage of inhibition of the channel current is reported.

To determine if the compound can produce any change in the QT interval, the compound is studied in telemetric beagle dogs. Dogs (groups of

4) are studied in a -latin- crossing square, each dog receives 3 different doses and placebo. Two studies conducted with doses of 0.3,1.3, 10 and 30 mg / kg.

iii- Acute study of the rat

The purpose of this study is to assess the toxicity and maximum tolerated dose (MTD) of the test items, when given by oral gavage to rats. Male Cri rats: CD® (SD) IGS BR (3 / groups) are divided into 5 groups. At the start of dosing the animals are approximately 7 weeks old with a body weight of 172-206 g. each group receives

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50, 100, 150, 200 or 250 mg / kg of the compound per day for 5 days. All living anima sacrificed at 6^era day. The toxicity assessment is based on mortality, clinical observations, and body weight.

iv- acute study in dogs

The aim of the present study is to assess the toxicity and maximum tolerated dose (MTD) of the compound when administered in divided doses orally to dogs. Two purebred Beagles are used for the study. Prior to dosing, animals are at least 6 months old and have a body weight of 8.0-10.9 kg. Dogs are administered the preparations containing it once a day for 5 days in staggered doses of 25, 50 or 75 mg / kg.

Dogs are observed at 0.25, 0.5, 0.75, 1.0, 1.5 and 2.0 hours ± 5 minutes and 4, 6, 8, and 24 hours ± 15 minutes after the dose. They are weighed at I^er and 6٥ ™ ٥ day.

An EKG is performed and blood pressure is taken before dosing and at 1, 4, and 24 hours after the 40 mg / kg dose on 5^th day. Based on the rate of serveritis of the clinical signs observed, the MTD is calculated for the compound.

V- 14 جاه days of the rat study with the cure study. The aim of the present study is to assess the toxicity of the compound when administered by oral gavage to rats, at least for 14 days, and to assess the reversibility, persistence or delay of any effect after the healing period exceeding. 14 days.

Cri: CD® (SD) IGS BR female and male rats are divided into seven groups, 4 essential study groups and three toxicokinetics groups. Each group receives dose preparations containing 0.25 ٥/٥ of methylcellulose, 400 cps in 200 mM acetate buffer, or 10, 30 or 150 mg of test article / kg of body weight (mg / kg / day ) at a dose volume of 5 ml / kg.

The toxicity assessment is based on mortality, clinical and ophthalmic observations, body weight, food consumption, clinical pathologies, organ weight, and macroscopic and microscopic findings. Blood samples are collected for toxicinetics evaluation.

14-day study of dogs with healing phase

The toxicity and toxiconicity of the compound of the present invention when administered by oral gavage (phase 1) or capsules (phase 2) to dogs for or less 14 days is determined. The reversibility, persistence and delay of the observed effests after 7 days (phase 1) or 14 days (phase 2) of the healing period is also evaluated. Doses of 3, 10, 30 and 70 mg / kg day are studied. All dogs from phase 1 and 2 survived until sacrifice.

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The above compounds and protocols are useful in the preclinical evaluation of the loxapine compounds of the present invention.

EXAMPLE 9: Evaluation of the analgesic activity

The analgesic activity of the loxapine analog after oral administration is analyzed. Analgesic activity is assessed by abdominal spam testing in rats and mice.

Analgesic activity is also evaluated using the tail cut test in mice, and the small tail test in rats, Randall-Selitto test in rats and comparisons are made with a control vehicle groope.

ASA (acetylsalicylic acid) reference compounds and morphine are also included for comparison.

The tail and tail cut tests provide useful information on the central analgesic activity of the test article. The Randall-Selitto test provides information on the ability of compounds to modify hyperalgesic state and abdominal spam testing provides information on the peripheral analgesic activity of the test article. The test article administered by oral gavage, being a clinical means of administration. The dose levels used are expected to be effective and provide an adequate safety margin.

Test product, reference compound and irritant formulation.

All formulations are prepared on each dosing day. The test product is formulated in 0.25% (w / v) MC at the highest concentration required. Lower doses are obtained by serial dilutions of the concentration using 0.25% (w / v) MC. The reference compound, acetylsalicylic acid, is formulated in 0.25% (wv) MC at the required concentrations.

Brewer's Yeast is formulated in Water for Injection at the required concentration. Acetic acid is diluted with water for injection, in order to provide the concentration required for administration.

Dose levels will be expressed in terms of the amount of the test I compound of reference / irritant, administered without regard to purity and active ingredient.

Animals

A suitable number of Cri: CD-I (ICR) BR male mice and Wistar rats were obtained from Charles River (UK) Ltd., Margate, Kent. The mice are approximately 4 weeks old and weigh about 18-22 g on arrival. The rats are approximately 5 weeks old and weigh 150-170 on arrival. Age and weight

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WO / 2006/034414 PCT / US2OO5 / 034O15 its animals at the start of the study are documented in the first data and in the final report.

The animals are placed in groups appropriate for the size of the cage used, cages conforming to the code of practice concerning the rehousing and welfare of animals used in scientific procedures (home office animals Scientific Procedures Act 1986).

Each week using wooden sticks (Date and Ltd, Manchester, UK).

The literature is analyzed for specific contaminants and the results are within the range of covance.

The cages are cleaned and dried before use. Aspen chew blocks are placed in the cages as an environmental enrichment.

Usually, chambers are maintained at acceptable temperatures and relative humidity (normally 19 to 25٥ C and 40 to 70% respectively). These chambers are fluorescently illuminated for 1.2 hours each 24 hour cycle and are designed to accommodate at least 15 fresh air changes per hour.

RMI. (E). SQC., (Special Diets Services Ltd, Witham, UK) and tap water are provided ad libitum, except as specified below. This is usually analyzed for specific constituents and is known to contain a biological or chemical entity which may interfere with the test system. The treatment groups used for the study are demonstrated in Table 9:

Table 9: Treatment groups

Treatment groups Dose (mg / kg) conc (mg / ml) # animal.

<td> 1</td><td>Vehicle</td><td> ٠</td><td> -</td><td> 8</td>

<td> 2</td><td>Loxapine</td><td> 3</td><td>لآ. تاً</td><td>ؤ</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td> 3</td><td>Loxapine</td><td> 10</td><td> 1.0</td><td> 8</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td> 4</td><td>Loxapine</td><td> 30</td><td> 3.0</td><td> 8</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td> 5</td><td>Morphine</td><td> 100</td><td> 10.0</td><td>S</td>

Pressure measurements are taken in the pulse of the right and left hand of each animal, immediately or before administration of the vehicle, test article or reference compound and at 30, 60, 12 and 24 minutes after the test. oral administration. The order of pressure measurements is the left pulse followed by the right pulse.

Test for abdominal spasm in rats.

Each animal receives a single administration of vehicle, test article or reference compound by oral gavage, using a constant dose volume of 10 mg / kg.

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Individual dose volumes are based on the individual body weight obtained on the day of dosing. The treatment groups are shown in Table 10.

Table 10; -Processing groups

Treatment groups Dose (mg / kg) conc (mg / ml) # animal.

<td> 1</td><td>Vehicle</td><td> -</td><td> -</td><td>ج</td>

<td> 2</td><td>Lo pine</td><td> 3</td><td> 0.3</td><td>e</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td> 3</td><td>loxapine</td><td>٠ ت</td><td> 1.0</td><td> 6</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td> 4</td><td>hoxapine</td><td> 30</td><td> 3.0</td><td>ج</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td> 5</td><td>ASA</td><td> 100</td><td> 10.0</td><td> 6</td>

Forty-five minutes after oral administration, each animal receives 1 ml of an intraperitoneal injection of 1% acitic acid. The animals are placed immediately in individual observation rooms and the number of abdominal spasms during the next 25 minutes is recorded.

Each animal receives a single administration of vehicle, test product or reference compound by oral gavage, using a constant dose volume of 10 mL / kg. Iniquitous dose volumes are based on body weights obtained on the day of dosing. The treatment groups are shown in Table 11.

Table 11: Treatment groups.

Treatment groups Dose (mg / kg) conc (mg / ml) # animal.

<td> 1</td><td>Vehicle</td><td> -</td><td> -</td><td>ة</td>

<td> 2</td><td>Joxapine</td><td> 3</td><td> 0.3</td><td>ج</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td> 3</td><td>Lcocapine</td><td> 10</td><td> 1.0</td><td>ج</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td> 4</td><td>Laxapine</td><td> 30</td><td> 3.0</td><td> 6</td>

<td></td><td>Analog</td><td></td><td></td><td></td>

<td>S</td><td>ASA</td><td> 100</td><td> 10.0</td><td> 6</td>

<td>Forty five</td><td>minutes later</td><td>!'administration</td><td>oral, ا</td><td>each animal receives 25 ml of</td>

intraperitoneal injection of 0.5% acetic acid. Animals are immediately placed individually in observation chambers and the number of spasms during the next 25 minutes is recorded.

Terminal procedures:

At the end of each test, animals are humanely killed with the compound 1 schedule (eg, exposure to carbon dioxide gas at high concentrations by dislocation of the neck), and cleared without necropsy.

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If the animal shows any serious uncomfortable sign during the study, it will be sacrificed immediately and humanely. Any animal found dead or killed prematurely during the study is subject to necropsy. Macroscopic examination is carried out, after opening the thoracic and abdominal cavity, observing the appearance of the tissues instut any abnormal is recorded.

EXAMPLE 10 Synthesis of acylsulfonamides.

The synthesis of acylsulfonamide compound 40 is summarized by Scheme I. This procedure is applicable as a general synthesis of acylsulfonamides of the corresponding acids described herein.

Diagram I

NaH Îî

DMF

HO s)

CHjCEtOH

<img file="MA28985B1_D0151.tif" />

<img file="MA28985B1_D0152.tif" />

H

Dioxane

<img file="MA28985B1_D0153.tif" />

170-1801’

Pocytoluene

Dimcthylaniline

<img file="MA28985B1_D0154.tif" />

O

٠١

N &lt;OAc)₃BH / ءبه

CHjClj

<img file="MA28985B1_D0155.tif" />

t) ΟΗ / ΕίΟΗΗΟ

2) HCt (aq)

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HNOCH LC

2) HCl ٩ ي)

I) Wdimrthyliino) للاصا "/ (water-soluble) carbodtimide

<img file="MA28985B1_D0157.tif" />

HCl

HY- 10427

Compound 40 ^ fCONHSOjCHj

Treatment of tricyclic 10Η- Dibenzo [b, F] [1, 4] oxazepine -11-one (3) with phosphorous oxychloride in the presence of N, N-dimethylamine in toluene affords imidoyl chloride (3 ), which is converted to 11-piperazine -1-yl-dibenzo [b, F] [1, 4] oxazepine (5) upon reaction with an exes of piperrazine. Reductive amination of tricyclic amidine (5) with 2-carboxymethoxy -2-methyl propionaldehyde gives piperazine alkyl (6), which is purified through silica gel. Basic hydrolysis of the 5-methyl ester in aqueous ethanol, followed by acidification, gives the carboxylic acid (7). The carboxylic acid (7) is converted to acyl methyl sulfonamide by coupling it with methane sulfonamide, in

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Acidification of the coupled product gives the desired acylsulfonamide compound 40 (HY10427) as well as bis-HCl salt.

Other examples

Since the invention has been described in conjunction with the above detailed description, the description tends to be illustrative, and not to limit the scope of the present invention, which is defined by the scope of the appended claims.

Other aspects, advantages and modifications are within the scope of the following claims. It will be understood that those skilled in the art will know that changes in form and detail may be made without departing from the scope of the present invention, including the appended claims.