Condensed azepines as vasopressin agonists

CONDENSED ASEPINS AS VASOPRESSIN AGONISTS

FIELD OF THE INVENTION

The present invention relates to a class of novel chemical compounds which act as an agonist of the peptide hormone vasopressin. These compounds reduce the urinary output of the kidneys and are thus useful in treating certain human diseases characterized by the occurrence of polyuria. They are also useful in controlling diseases related to urinary incontinence and bleeding.

BACKGROUND OF THE INVENTION

Vasopressin is a peptide hormone secreted by the posterior pituitary gland. It works on the kidneys, increasing water retention and thus reducing urine production. For this reason, vasopressin is alternatively known as an "anti-diuretic hormone". The hormone also acts on the blood vessels where it exerts hypertensive effects. Cellular receptors that mediate these two activities have been characterized and shown to be distinct. The anti-diuretic effect is mediated by 2. vasopressin receptor, commonly referred to as V₂ receptor. Agents capable of reacting with V₂ receptor and activated in the same way as vasopressin is called V₂ receptor agonists (perhaps simply V₂ agonists). Such agents have antidiuretic activity. When these agents react selectively with V₂ receptor and not other vasopressin receptor subtypes, they do not have a hypertensive effect on vasopressin. This is an important safety concern and makes such agents attractive in the treatment of human diseases which are characterized by polyuria (which here refers to excessive urine production).

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<img file="EE200200367A_D0001.tif" />

In fact, one such agent is already used in the treatment of humans. Desmopressin (otherwise

Naming Q (1-desamino, D-Arg] vasopressin, Minirin ™, DDAVP ™) is a peptide analog of vasopressin that is selectively V₂ receptor agonist. It is used to treat central diabetes insipidus, a condition that results in a dysfunction of vasopressin secretion. It is also used to control nocturnal enuresis and can also be used to control nocturia. However, desmopressin is not an ideal agent in every respect. Even the most modern methods of synthesizing matter are sluggish and desmopressin is not subject to the most convenient purification technologies such as crystallization. Consequently, desmopressin is relatively expensive. It has a very low oral bioavailability and exhibits some variability in this parameter.

<img file="EE200200367A_D0002.tif" />

Thus, there is a need for selective vasopressin V₂ receptor agonist which is easy to prepare and to clean and has high and predictable bioavailability.

Such properties are most likely to be achieved with non-peptide compounds. These circumstances have led other research groups to investigate non-peptide vasopressin V₂ agonists, the results of which are disclosed, for example, in International Patent Applications WO 97/22591, WO 99/06403, WO 99/06409, WO 00/46224, WO00 / 46225, WO01 / 46227 and WO01 / 46228. However, the compounds disclosed in these documents are anything but ideal. Specifically, they have poor oral bioavailability, probably due in part to their poor water solubility. The present invention provides compounds with improved solubility and bioavailability.

In addition to its anti-diuretic effect, desmopressin is used to increase the concentration of blood coagulation proteins known as Factor VIII and Willebrand Factor. In a clinical context, it renders desmopressin useful in haemophilia A and

In the treatment of Willebrand's disease. Similar applications would open to non-peptide agonists of the present invention.

SUMMARY OF THE INVENTION

As disclosed herein, the present invention relates to a series of compounds that are non-peptidic agonists of vasopressin and which are selective V₂ for the receptor subtype. The compounds are represented by general formula 1 wherein:

A is a bicyclic or tricyclic azepine derivative selected from general formulas 2 to 7:

<img file="EE200200367A_D0003.tif" />

A¹, A⁴, A⁷ ice¹⁰ each is independently selected from CH₂, O and NR⁸ ;

A², A³, A⁹, A¹¹, A¹³, A¹⁴ ice¹⁵ each is independently selected from CH and N;

A⁵ is either a co - valent bond and⁶ is S or A⁵ is N = CH and A⁶ is a co-bond;

A⁸ ice¹² each is independently selected from NH and S;

A¹⁶ ice¹⁷ both are CH 2 or one A¹⁶ ice^I7one is CH 2 and the other is O, SO_X, and NR⁸ ,

V¹ and V² both are H, OMe or F or one V¹ and V² of which are Br, Cl, F, OH, OMe,

OBn, OPh, O-acyl, N3, NH2, NHBn or NH-acyl and the other is H, or V¹ and V²together are = O, -O (CH2) pO- or -S (CH2)_PS-;

W¹ is O or S;

X¹ and X² both are H or together are = O or = S;

Y is OR⁵ or NR⁶R⁷;

Z is S or = CH = CH-;

R¹, R², R³ and R⁴ is independently selected from H, lower alkyl, lower alkyloxy, F, Cl and Br;

R⁵ is selected from H and lower alkyl;

R⁶ and R⁷ is independently selected from H and lower alkyl, or taken together - (CH₂)_n-;

R⁸ is H or lower alkyl; n = 3, 4, 5 or 6; p is 2 or 3; and x is 0, 1 or 2.

The invention further encompasses pharmaceutical compositions comprising said vasopressin agonists, which compositions are particularly useful for the treatment of central diabetes insipidus, nocturnal enuresis and nocturia.

DESCRIPTION OF THE INVENTION

The present invention includes N-benzylcarbamylpyrrolidine derivatives as defined by general formula (1).

AR⁴

In this formula, A represents a bicyclic or tricyclic azepine group according to one of general formulas 2-7.

<img file="EE200200367A_D0004.tif" />

<img file="EE200200367A_D0005.tif" />

<img file="EE200200367A_D0006.tif" />

A¹, A⁴, A⁷ ice¹⁰ represent divalent groups selected from methylene (-CH 2 -), oxygen (-O-) and substituted nitrogen (-NR 8 -). A², A³, A⁹, A¹¹, A¹³, A¹⁴ ice¹⁵ represent either a nitrogen atom (-N =) or a methine group (-CH =). A⁵ may represent a covalent bond, in which case A⁶ represents a sulfur atom (-S-) such that the ring containing the two groups is a thiophene ring. Alternatively, A⁵ represent -N = CH-, in which case A⁶ represents a covalent bond such that the ring containing the two groups is a pyridine ring. A⁸ ice¹² represent -NH- or sulfur (-S-). A¹⁶ ice¹⁷ represent bivalent groups. Both may be methylene groups (-CH 2 -) or one is methylene and the other is selected from hydroxymethylene (-CH (OH) -), difluoromethylene (-CF 2 -), oxygen (-O-), substituted nitrogen (-NR⁸-) and sulfur or oxidised sulfur (-S -, - SO- or -S0₂-). V¹ and V² both may be hydrogen, methoxy or fluorine, or one may be selected from bromine, chlorine, fluorine, hydroxy, lower alkoxy, benzyloxy, phenoxy, acyloxy, azido, amino, benzylamino and acylamido (Br, Cl, F, OH, O-lower alkyl, OBn). , OPh, O-acyl, NH 2, NHBn and NH-acyl), provided that

... 1.9 the other is hydrogen or V and V together can represent an oxygen atom such that the CV'V fragment² is a carbonyl group (C = O). V¹ and V² may also be an ethylene or propyleneenedioxy or dithio chain (-O (CH₂) 2O-, -O (CH₂) 3O-, -S (CH₂)₂S-, -S (CH₂)₃S-) such that CV V is a 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane or 1,3 dithian ring. W¹ is either an oxygen or a sulfur atom.

j 2

X and X may both be hydrogen or together may represent an oxygen or sulfur atom such that the moiety CX^!X² is a carbonyl or thiocarbonyl group (C = O or C = S).

Y is either -OR⁵ or -NR⁶R⁷.

Z represents either a sulfur atom such that the ring containing it is a thiophene ring or represents a -CH = CH- group so that the ring is a benzene ring.

R¹, R², R³ and R⁴ each is independently selected from hydrogen, lower alkyl, lower alkyloxy and halogen, fluorine, chlorine and bromine.

R⁵ can be either hydrogen or lower alkyl.

7

R and R can each independently be hydrogen or lower alkyl or together form a chain of 3 and 6 methylene groups such that together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine or perhydroazepine ring.

o

R may be hydrogen or lower alkyl.

In the context of this application, the term "lower alkyl" is intended to include a straight chain and branched alkyl groups and cycloalkyl groups of 1 to 6 carbon atoms. For example, methyl, ethyl, isopropyl, tert-butyl, neopentyl and cyclohexyl are all included within the term lower alkyl. The term "acyl" refers to lower alkyl carbonyl groups such as acetyl, pivaloyl, cyclopropylcarbonyl and the like. Formyl is also considered to be an acyl group.

Certain compounds of general formula 1 are capable of forming salts with acids or bases. For example, compounds containing one or more nitrogen atoms may form additional salts with mineral and organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, citric acid and benzoic acid. Compounds containing acidic groups may form salts with bases. Examples of such salts are the sodium, potassium, calcium, triethylammonium and tetraethylammonium salts. In addition, compounds having both acidic and basic groups may form inner salts (zwitterions). Insofar as these salts are pharmaceutically acceptable, they are included within the scope of the invention.

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Compounds of general formula 1 have at least one stereogenic center (a teraether carbon atom bearing four different substituents) and thus may exist as optical isomers such as enantiomers and diastereomers. Such isomers and mixtures thereof are within the scope of the present invention.

In a preferred embodiment of the present invention, A is a group of general formula 2. In another preferred embodiment of the present invention, A is a group of general formula 3. In another preferred embodiment of the present invention, A is a group of general formula 4. In another preferred embodiment of the present invention, A is a group of general formula 6.

In another preferred embodiment of the present invention, A is a group of general formula 7. In a more preferred embodiment, A is a tetrahydro-1-benzazepin-1-yl group, i.e., a group of general formula 7 wherein Z is -CH = CH- and each is A.¹⁶ ice¹⁷ are methylene groups.

In another preferred embodiment, one R is¹ and R²of the chlorine or methyl group and the other is hydrogen, wherein both R³ as well as R⁴ is also hydrogen.

In another preferred embodiment, one is V¹ and V² of which methoxy or benzyloxy is 20 and the other is hydrogen.

In another preferred embodiment, X represents¹ and X² together one oxygen atom and Y is -NR⁶R⁷.

Particularly preferred embodiments of the present invention are those that combine the above two preferred features.

A more preferred embodiment of the present invention is a compound of general formula 8.

<img file="EE200200367A_D0007.tif" />

<img file="EE200200367A_D0008.tif" />

In general formula 8 W¹, R⁵ and R⁶ is as defined above for formula 1. One R^a and R^b of which is hydrogen and the other is chlorine or methyl. R is either methyl or benzyl.

Another preferred embodiment is a compound of general formula 8A wherein the stereochemistry is as depicted herein.

<img file="EE200200367A_D0009.tif" />

<img file="EE200200367A_D0010.tif" />

8A

Another embodiment of the present invention is a compound of general formula 1 wherein V¹ and V² each is hydrogen. In a more preferred embodiment, X¹ and X² taken together is an oxygen atom and Y is a 6 7

NR R. Even more preferred is the compound of general formula 9.

<img file="EE200200367A_D0011.tif" />

In the general formula 9 W¹, R⁵ and R⁶ is as defined above for formula 1. One R^a and R^b of which is hydrogen and the other is chlorine or methyl.

Even more preferred is a compound of general formula 9A having stereochemistry as depicted herein.

<img file="EE200200367A_D0012.tif" />

Individual preferred compounds of the present invention include, but are not limited to:

- (2-Methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L 15 proline-, N, N-dimethylamide, (4R) -4-hydroxy-1 - (2-Methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) -benzylcarbamoyl] -L-pro-N, N-dimethylamide, n

(4R) -1- (3-Chloro-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) 4-methoxy-L-proline-A, N-dimethylamide, (4 R) -1- (2-Chloro-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) δ 4-methoxy-L-proline-N, X-dimethylamide, ( 4R) -4-Benzyloxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline-N, N-dimethylamide, (4R) -4-Methoxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline-N, N-dimethylamide , (4R) -4-Methoxy-1- (3-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline-A, A -dimethylamide, (4R) -1- (2-chloro-4- (5,6,7,8-tetrahydro-4H-thieno- [3,2-b] azepin-4-ylcarbonyl) benzylcarbamoyl) -4-methoxy- L-proline-N (N-dimethylamide, (4R) -1- (4- (10,11-Dihydro-5H-pyrrolo [2,1-c] (1,4) benzodiazepin-10-ylcarbonyl) -220-methylbenzylcarbamoyl) -4-methoxy-L-proline- N - (N-dimethylamide, (4R) ~ 1- (2-chloro-4- (10,11-dihydro-5H-pyrrolo [2,1-c] (1,4) benzodiazepine-10ylcarbonyl) benzylcarbamoyl) -4 -methoxy-L-proline-A (N-dimethylamide), and (4R) -1- (4- (10,11-dihydro-5H-pyrrolo [2,1-c] (1,4) benzodiazepine-10-) ylcarbonyl) -2-methylbenzylcarbamoyl) -4-methoxy-L-proline-N, N-dimethylthioamide.

The compounds of the present invention may be prepared using methods well known in the art. Compounds of general formula 1 may be considered as consisting of three linked moieties (AC).

<img file="EE200200367A_D0013.tif" />

The three fragments are generally prepared separately and then combined during a subsequent synthesis step. Some examples of different groups (R'-R⁴, V¹, V², X¹,

X² , etc.) may not be compatible with this unit and therefore require the use of protecting groups. The use of protecting groups is well known in the art (see, for example, Protective Groups in Organic Synthesis, TW Greene, Wiley Interscience 1981). Specific groups that may need protection include amines (protected as amides or carbamates), alcohols (protected as esters or ethers), and carboxylic acids (protected as esters). For the purposes of this discussion, it is assumed that such protecting groups are present when appropriate.

Fragments A, B and C can be combined according to two strategies to produce compounds of formula 1. In the first, fragments A. and B are coupled to produce a fragment corresponding to AB, which is then combined with fragment C. In the second, fragments B and C are coupled to produce a fragment corresponding to BC, which is then combined with fragment A. The chemical processes involved in the condensation of Fragment A and B and those involved in the condensation of Fragments B and C are the same for both strategies. We found that the first strategy is more flexible, working with small amounts and preparing for compound selection. Nevertheless, it is possible that another strategy may be advantageous for the preparation of large quantities of selected compounds.

Formation of fragment AD

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<img file="EE200200367A_D0014.tif" />

Here, {A} and {B} represent the partial structures of fragments A and B, respectively. The formation of amides by condensation of carboxylic acids with amines is well known.

Generally, an acid and an amine are mixed in an aprotic solution such as dichloromethane or dimethylformamide with a condensing agent such as carbodiimide (e.g. water soluble carbodiimide which is γ-ethyl-N- (3-dimethylaminopropyl) carbodiimide) or a reactive phosphorus derivative (e.g. BOP). which is in the presence of (benzotriazol-1-yloxy) tris (dimethylamino) phosphone hexafluorophosphate). The reaction may optionally be catalyzed by a tertiary amine such as triethylamine or 4-dimethylaminopyridine. Alternatively, the carboxylic acid may be converted to a more reactive derivative, such as an acid chloride. Such a derivative can then be reacted with an amine as described above, but without the need for a condensing agent.

Formation of fragment BC

<img file="EE200200367A_D0015.tif" />

The formation of the urea or thiourea bond between fragments B and C is most easily accomplished by reacting the primary amine corresponding to fragment B with a carbonic derivative such as fogene (where LG is above chlorine) or carbonyldiimidazole (where LG is 1-imidazolyl) to form the intermediate carbamate. If W¹ is sulfur rather than oxygen, thiophosgene or thiocarbonyldiimidazole is used. The reaction is conveniently carried out in an aprotic solution such as dichloromethane or dimethylformamide in the presence of a tertiary amine such as triethylamine or N, NEE 200200367 A diisopropylethylamine. After allowing the intermediate to form for sufficient time, a secondary amine corresponding to Fragment C may be added to the reaction mixture. It is not necessary to isolate the intermediate carbamate derivative.

As an exception to this process, it is possible to reverse the addition of the corresponding amines to fragments B and C such that the carbamate derivatives are formed from the secondary amine and the primary amines are subsequently added.

Among other things, the following intermediates are required for the synthesis of the compounds of the present invention

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<img file="EE200200367A_D0021.tif" />

Fused azepines according to these general formulas may be prepared according to methods reported in the literature. See, e.g., Aranapakam et al., Bioorg. Med. Chem. Lett. 1993, 1733; Artico et al., Farmaco. Ed. Sci. 24, 1969, 276; Artico et al., Farmaco. Ed. Sci. 32, 339 (1977); Chakrabarti et al., J. Med. Chem. 23, 878 (1980); Chakrabarti et al., J. Med. Chem. 23, 884 (1980); Chakrabarti et al., J. Med. Chem. 32, 2573 (1989); Chimirri et al.,

Heterocycles 36, 601 (1993); Grunewald et al., J. Med. Chem. 39, 3539 (1996); Klunder et al., J. Med. Chem. 35, 1992, 1887; Lieges et al., J. Med. Chem. 37, 519 (1994); Olagbemiro et al., J. Het. Chem. 19, 1982, 1501; Wright et al., J. Med. Chem. 23, 1980,

462; Yamamoto et al., Tet. Lett. 24, 4711 (1983); and International Patent Application Publication No. WO99 / ​​06403.

Some of these are commercial products.

<img file="EE200200367A_D0022.tif" />

Because the primary amine and carboxylic acid groups are incompatible, they must be prepared separately and protected. Substituted benzoic acids are well known and the carboxylic acid is suitably protected as its methyl ester. The primary amine can be prepared from the corresponding nitrile (by reduction) or alcohol (by substituting the nitrogen with a nucleophile). The best method depends on the substituents R¹- R⁴ character.

iii) fragment C

<img file="EE200200367A_D0023.tif" />

Pyrrolidine derivatives of this type are prepared according to methods described in the literature. See, e.g., Dugave et al., Tet. Lett. 39, 1169 (1998); Petrillo et al., J. Med.

Chem. 31, 1988, 1148s; and Smith et al., J. Med. Chem. 31, 1988, 875.

Proline and hydroxyproline derivatives having defined stereochemistry are commercial products and are convenient starting materials as such.

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The present invention further encompasses pharmaceutical compositions containing as active ingredient at least one compound as described above. The composition may also contain another pharmacological agent, such as a spasmolytic or potassium channel blocker, said agents being known in the art of improving bladder dysfunction. Preferably, the composition contains only one active ingredient. The composition comprises excipients selected from binders, fillers, dispersants, solvents, stabilizing agents, and the like, such excipients being generally well known in the art.

The excipients used will depend on the intended nature of the formulation, which in turn will depend on the intended route of administration. Administration may be oral, mucosal (e.g., sublingual, buccal, intranasal, vaginal, and rectal), transdermal, or by injection (e.g., subcutaneous, intramuscular, and intravenous). Oral administration is generally preferred. For oral administration, the dosage form is a tablet or capsule. Other formulations include dry powders, solutions, suspensions, suppositories, and the like.

In a further aspect, the present invention is a method of treating or controlling certain human physiological dysfunctions. Said method comprises administering to a human in need of such treatment an effective amount of a pharmaceutical composition comprising, as an active ingredient, a compound of the above description. The compounds act to reduce urine production, so that the method of the invention can be applied to any condition in which increased urine production is a contributing factor. The compounds also increase the production of blood coagulation proteins known as Factor Vill and von Willebrand Factor, so they can also be used to treat bleeding disorders.

In one preferred embodiment, the condition to be treated is diabetes insipidus. It is a condition caused by the inability of the body to produce and secrete physiologically active vasopressin, which results in a significant reduction in water absorption and the production of large quantities of urine.

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In another preferred embodiment, the condition to be treated is nocturnal enuresis. This is defined as the emptying of the bladder while a person is sleeping. It is a condition that primarily affects children, and its etiology may involve a variety of factors.

In another preferred embodiment, the condition to be treated is nocturia. It is defined as the production of enough urine at night to wake a person and force him to empty his bladder. Again, this condition can be caused by a number of factors.

In another preferred embodiment, the condition to be treated is urinary incontinence. This condition is characterized in part by reduced bladder capacity and control over its activity, so that unintentional urination often occurs without bladder emptying completely. Urinary incontinence is divided into two conditions, stress urinary incontinence and urinary incontinence. The reason is believed to be a number of etiological factors. The treatment according to the invention is particularly useful in delaying the need for bladder emptying ("deferral of emptying") to allow a person suffering from urinary incontinence to have a dry period of a few hours (e.g. up to four hours). This postponement of emptying may also be beneficial to the rest of the population, such as people who have to attend longer meetings.

In another preferred embodiment, the condition to be treated is haemophilia A or von Willebrand's disease. These are conditions in which the production of factor VIII or von Willebrand factor is reduced and the person suffers from prolonged bleeding.

In another preferred embodiment, the composition is administered prior to surgery (including dental surgery) to increase blood coagulation and thereby reduce blood loss during surgery.

Administration of the compositions of the present invention will generally be under medical supervision. The physician will determine the amount to be administered and the dosing schedule, taking into account the patient's physical condition and therapeutic goals. A typical dose for an adult diabetic patient may be 50 mg to 1 g of active compound per day taken as a single tablet or up to four tablets per day. In the case of non-oral administration, the amount of the compound is reduced since the non-oral administration is most effective in delivering the therapeutic agent to the high bloodstream. For treating Hemophilia A and von Willebrand's disease, the amount of compound required may be greater than for treating diabetes insipidus.

The foregoing general description is further illustrated by a series of non-limiting examples.

EXAMPLES

Abbreviations

The following abbreviations are used.

Ac Acetyl

AIBN Azo-to- (isobutyronitrile)

Bn Benzyl

BOC (BOC)₂O

DMF

No.

EtOAc

IPA

IR MS

Me tert -Butyloxycarbonyl Di-tert-butyl dicarbonate Dimethylformamide Ethyl

Ethyl acetate

Isopropanol

Isopropyl

Mass spectrometry

Methyl

NBS pet. Ether Ph

N-bromosuccinimide petroleum ether, fraction boiling at 60-80 ° C Phenyl

TBu Ze / 7-butyl

THF Tetrahydrofuran

WSCDI Water soluble carbodiimide

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Preparation of intermediate products

Reagents corresponding to Fragment A and C were either commercially available or prepared according to published procedures, except those detailed in the specific examples. The reagents corresponding to Fragment B were prepared as detailed below.

Example A.

4 - (tert-Butyloxycarbonylaminomethyl-3-chlorobenzoic acid

<img file="EE200200367A_D0024.tif" />

Al. Methyl 4-bromomethyl-3-chlorobenzoate 15

To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 mL) was added NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mol). The mixture was stirred at reflux for 18 hours. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent: dichloromethane)

EtOAc: petroleum ether 0: 100 to 5:95); yield 5.96 g (84%).

A2. 4- (7-tert-Butyloxycarbonylaminomethyl) -3-chlorobenzoic acid

To a saturated solution of ammonia in ethanol (170 mL) was added methyl 4-bromomethyl-325 chlorobenzoate from Example A1 (5.5 g, 20.9 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was triturated with diethyl ether and the resulting white crystals were filtered off and washed with more diethyl ether.

To the aqueous solid (100 mL) was added (BOC)₂O (5.0 g, 23.0 mmol) in dioxane (100 mL) and aqueous sodium hydroxide (1.86 g, 46.0 mmol) in water (100 mL). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The aqueous residue was acidified with citric acid and extracted with chloroform / IPA. The organic layer was washed with water, dried over MgSO 4₄ and concentrated in vacuo to give a white solid; yield

2.8g (67%).

Example B.

4-Cyano-3-methyl-benzoic acid

<img file="EE200200367A_D0025.tif" />

CN

To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 mL) at -78 ° C under a nitrogen atmosphere was added dropwise a 2.5 M solution of n-butyllithium (4.48 mL, 11 mL). 2 mmol). The mixture was stirred at -78 ° C for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 mL). The mixture was allowed to warm to room temperature. Water (200 mL) was added and the mixture was extracted with diethyl ether (3x). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO 4₄ and concentrated in vacuo to give a white solid; yield 1.2 g (73%).

Example C

4-Cyano-2-methyl-benzoic acid

<img file="EE200200367A_D0026.tif" />

4-Bromo-3-methylbenzonitrile (2.0 g, 10.2 mmol) was reacted following the procedure of Example B to obtain a yellow solid which was triturated with hexane and filtered off; yield 0.96 g (59%).

Reagents corresponding to Fragments A, B, and C were combined to give specific examples as detailed below.

Example 1.

1- (2-Methyl-4- (2,3,4,5-tetrahydro-1-benzazepine-lylcarbonyl) -benzyl] -carbamoyl-L-proline-N, N-dimethyl-thiamide

<img file="EE200200367A_D0027.tif" />

1A. 2-Methyl-4 - ((2,3,4,5-tetrahydro-1H-benzo [b] azepine) -1-carbonyl] -benzonitrile

To a solution of 2,3,4,5-tetrahydro-1 H -benzo [b] azepine (0.80 g, 5.44 mmol) in dichloromethane (50 mL) was added 4-cyano-3-methylbenzoic acid (0.96 g, 5.95 mmol), triethylamine (0.60 g, 5.95 mmol), 4- (dimethylamino) pyridine (0.73 g, 5.95 mmol) and WSCDI (1.24 g, 6.48 mmol).

The mixture was stirred at reflux for 18 hours, cooled and evaporated in vacuo. The residue was partitioned between EtOAc and 1M KHSO4. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica (eluent

EtOAc: petroleum ether 30:70); yield 1.10 g (70%).

IB. 1- (4- (aminomethyl) -3-methylbenzoyl) -2,3,4,5-tetrahydro-1H-benzo [biazepine hydrochloride,

To a degassed solution of cyanobenzazepine of Example 1A (1.10 g, 3.79 mmol) in methanol (50 mL) was added concentrated hydrochloric acid (0.98 mL, 11.3 mmol) and 10% palladium on carbon (0.80 g). Hydrogen was bubbled through the mixture at room temperature for 5 hours. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated; yield 1.23 g (98%).

1C. 1- (2-Methyl-4- (2.3.4.5-tetrahydro-1-benzazepin-1-ylcarbonyl) -benzylcarbamoyl- N -proline-N, N-dimethylamide

To a solution of the amine of Example IB (0.10 g, 0.302 mmol) in DMF (10 mL) under nitrogen was added N, N-diisopropylethylamine (43 mg, 0.332 mmol) and carbonyldiimidazole (0.074 g,

0.453 mmol). The mixture was stirred at room temperature for 40 minutes. A solution of proline dimethylamide (0.107 g, 0.756 mol) in DMF (1 mL) was added. The mixture was stirred at room temperature for an additional 16 hours. The solvent was removed in vacuo and the crude material was purified by flash chromatography on silica (eluent: methanol / dichloromethane 5:95); yield 0.115 g (82%).

1 H NMR (CDCR): δ 1.35-1.55 (1H, m), 1.74-2.10 (3H, m), 2.11 (3H, s), 2.17-2.35 ( 1H, m), 2.60-2.82 (2H, m), 2.86 (3H, s), 2.90-3.14 (2H, m), 3.05 (3H, s), 3 , 26 (1H, dd, J = 14.9 &amp; 7.2Hz), 3.40-3.53 (1H, m), 3.64-3.84 (1H, m), 4.03-4, 19 (1H, m), 4.29-4.42 (1H, m), 4.55-4.68 (1H, m), 4.74-4.81 (1H, m), 4.85-. 4.98 (1H, m), 6.58 (1H, d, J = 7.7Hz), 6.75-6.89 (2H, m), 6.91-7.06 (3H, m), 7.16 (1H, d, J = 6.5Hz), 7.93-8.03 (1H, m) ppm.

MS: calcd m / e = 462.26; found [M + H]⁺ - 463, 2

Example 2.

(4R) -4-Hydroxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzylcarbamoyl) -L-proline-N, N-dimethylamide

<img file="EE200200367A_D0028.tif" />

H l \ k X

OH ¥

O

<img file="EE200200367A_D0029.tif" />

/

O

2A. L-trans-4-hydroxyproline-N, N-dimethylamide hydrochloride

To a solution of BOC-hydroxyproline (2.99 g, 13.89 mmol) in dichloromethane (100 mL) was added ΛζΑ10 diisopropylethylamine (3.7 mL, 21.24 mmol), 4- (dimethylamino) pyridine (1.74 g, 14.24) mmol), dimethylamine hydrochloride (1.72 g, 21.09 mmol) and WSCDI (3.17 g, 16.68 mol). The mixture was stirred at room temperature for 30 hours. The mixture was diluted with dichloromethane (100ml) and washed with 0.3M KHSO4, saturated sodium bicarbonate solution and brine, dried over MgSO4.₄ , and concentrated in vacuo to give a colorless gum. This crude material was taken up in 4N HCl / dioxane (50 mL) and shaken at room temperature for 1 hour and then concentrated in vacuo. The residue was azeotroped with toluene and diethyl ether to give a white solid; yield 0.45 g (17%).

2B. (4R) -4-Hydroxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1'-ylcarbonyl) -benzylcarbamoyl) -1-proline-NN-dimethylamide.

The amine of Example 1B (0.10 g, 0.302 mmol) was reacted with the amine of Example 2A (0.153 mg, 0.785 mmol) following the procedure of Example IC. The product was purified by flash chromatography on silica (eluent: chloroform: methanol: acetic acid 95: 4: 1); yield 0.95 g (66%).

@ 1 H NMR (CDCl3₃): δ 1.65-1.80 (2H, m), 1.85-2.00 (3H, m), 2.05-2.25 (1H, m), 2.10 (3H, s) , 2.80-3.10 (3H, m), 2.85 (3H, s), 3.00 (3H, s), 3.40-3.30 (1H, m), 3.45-3 , 55 (1H, m),

3.65 3.95 (1H, m), 4.00-4.10 (1H, m), 4.30-4.55 (1H, m), 4.91 (1H, t, J = 7, 7Hz), 5.15-5.30 (1H, m), 6.10-6.20 (1H, m), 6.55-6.65 (1H, m), 6.85-7.50 (5H, m) ppm.

MS: calcd m / e 478.26; found [M + H]⁺ - 479,2

Examples 3-116

The examples in the following tables were prepared using analogous methods.

<img file="EE200200367A_D0030.tif" />

<img file="EE200200367A_D0031.tif" />

<td>Example No.</td><td>R / S</td><td>V²</td><td>X</td><td>Y</td><td>[M + H]⁺</td>

<td> 3</td><td>S</td><td>H</td><td>h₂</td><td>OMe</td><td> 436,4</td>

<td> 4</td><td>R</td><td>H</td><td>h₂</td><td>OMe</td><td> 436,2</td>

<td> 5</td><td>R / S</td><td>OPh</td><td> 0</td><td>OH</td><td> 528,3</td>

<td> 6</td><td>R / S</td><td>OPh</td><td> 0</td><td>Nm₂</td><td> 555,3</td>

<img file="EE200200367A_D0032.tif" />

X

<td>Example NR.</td><td>R¹</td><td>R²</td><td>V¹</td><td>V²</td><td>X</td><td>Y</td><td>[M + H]⁺</td>

<td> 7</td><td>H</td><td>Me</td><td>H</td><td>H</td><td>O</td><td>OtBu</td><td> 492,5</td>

<td> 8</td><td>H</td><td>Me</td><td>H</td><td>H</td><td>O</td><td>OH</td><td> 436,3</td>

<td> 9</td><td>H</td><td>Me</td><td>H</td><td>OH</td><td>O</td><td>OMe</td><td> 466,0</td>

<td> 10</td><td>H</td><td>Me</td><td>H</td><td>OAc</td><td>O</td><td>NMe₂</td><td> 521,0</td>

<td> 11</td><td>H</td><td>Me</td><td colspan="2"> =0</td><td>O</td><td>NMe₂</td><td> 477,3</td>

<td> 12</td><td>H</td><td>Me</td><td>H</td><td>OH</td><td>O</td><td>OEt</td><td> 480,2</td>

<td> 13</td><td>H</td><td>Me</td><td>H</td><td>OHOCOC₃H₅</td><td>O</td><td>NMe₂</td><td> 547,3</td>

<td> 14</td><td>H</td><td>Me</td><td>H</td><td>OMe</td><td>O</td><td>NMe₂</td><td> 493,5</td>

<td> 15</td><td>H</td><td>Cl</td><td>H</td><td>H</td><td>O</td><td>NMe₂</td><td> 483,4</td>

<td> 16</td><td>H</td><td>Me</td><td>H</td><td>H</td><td>s</td><td>NMe₂</td><td> 479,2</td>

<td> 17</td><td>H</td><td>Me</td><td>H</td><td>H</td><td> 0</td><td>NMeEt</td><td> 477,2</td>

<td> 18</td><td>H</td><td>OMe</td><td>H</td><td>H</td><td> 0</td><td>NMe₂</td><td> 479,2</td>

<td> 19</td><td>H</td><td>Me</td><td>H</td><td>OMe</td><td> 0</td><td>OMe</td><td> 480,2</td>

<td> 20</td><td>H</td><td>Me</td><td>H</td><td>H</td><td> 0</td><td>OiPr</td><td> 478,2</td>

<td> 21</td><td>H</td><td>Me</td><td>H</td><td>OH</td><td> 0</td><td>OH</td><td> 452,1</td>

<td> 22</td><td>H</td><td>Me</td><td>H</td><td>OBn</td><td> 0</td><td>OiPr</td><td> 584,2</td>

<td> 23</td><td>H</td><td>Me</td><td>H</td><td>OH</td><td> 0</td><td>OiPr</td><td> 494,1</td>

<td> 24</td><td>H</td><td>Me</td><td>H</td><td>OBn</td><td> 0</td><td>NMe₂</td><td> 569,2</td>

<td> 25</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 0</td><td>NMe₂</td><td> 463,2</td>

<td> 26</td><td>H</td><td>Me</td><td>H</td><td>OMe</td><td> 0</td><td>OH</td><td> 466,2</td>

<td> 27</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 0</td><td>NMe₂</td><td> 483,1</td>

<td> 28</td><td>H</td><td>Me</td><td>H</td><td>H</td><td> 0</td><td>NMe₂</td><td> 477,3</td>

<td> 29</td><td>H</td><td>Cl</td><td>H</td><td>H</td><td>s</td><td>NMe₂</td><td> 499,2</td>

<td> 30</td><td>H</td><td>Cl</td><td>H</td><td>OBn</td><td> 0</td><td>NMe₂</td><td> 589,2</td>

<td> 31</td><td>H</td><td>Cl</td><td>H</td><td>OH</td><td> 0</td><td>NMe₂</td><td> 499,2</td>

<td> 32</td><td>H</td><td>Me</td><td>H</td><td>OEt</td><td> 0</td><td>NMe₂</td><td> 507,3</td>

<td> 33</td><td>H</td><td>Me</td><td>Br</td><td>H</td><td>o</td><td>NMe₂</td><td> 541,1</td>

<td> 34</td><td>H</td><td>Me</td><td>H</td><td>Cl</td><td>o</td><td>OMe</td><td> 484,1</td>

<td> 35</td><td>H</td><td>Me</td><td>F</td><td>F</td><td> 0</td><td>NMe₂</td><td> 499,2</td>

<td> 36</td><td>H</td><td>Me</td><td>H</td><td>Cl</td><td>O</td><td>OH</td><td> 470,1</td>

<td> 37</td><td>H</td><td>Me</td><td>H</td><td>n₃</td><td>O</td><td>NMe₂</td><td> 504,3</td>

<td> 38</td><td>H</td><td>Me</td><td>H</td><td>Cl</td><td>O</td><td>NMe₂</td><td> 497,2</td>

<td> 39</td><td>H</td><td>Me</td><td>H</td><td>OtBu</td><td>O</td><td>NMe₂</td><td> 535,3</td>

<td> 40</td><td>H</td><td>Me</td><td>Cl</td><td>H</td><td>O</td><td>NMe₂</td><td> 497,2</td>

<td> 41</td><td>H</td><td>Me</td><td>H</td><td>OPh</td><td>O</td><td>OMe</td><td> 542,3</td>

<td> 42</td><td>H</td><td>Me</td><td>H</td><td>F</td><td>O</td><td>OMe</td><td> 468,3</td>

<td> 43</td><td>H</td><td>Me</td><td>H</td><td>F</td><td>O</td><td>OH</td><td> 454,4</td>

<td> 44</td><td>H</td><td>Me</td><td>H</td><td>F</td><td>O</td><td>Nm₂</td><td> 481,3</td>

<td> 45</td><td>H</td><td>Me</td><td>H</td><td>NHBn</td><td>O</td><td>Nm₂</td><td> 568,0</td>

<td> 46</td><td>H</td><td>Me</td><td>OMe</td><td>OMe</td><td>O</td><td>OMe</td><td> 510,3</td>

<td> 47</td><td>H</td><td>Me</td><td>OMe</td><td>OMe</td><td>O</td><td>OH</td><td> 496,2</td>

<td> 48</td><td>H</td><td>Me</td><td>OMe</td><td>OMe</td><td> 0</td><td>Nm₂</td><td> 523,3</td>

<img file="EE200200367A_D0033.tif" />

<td>Example No.</td><td>R²</td><td>V²</td><td>X</td><td>[M + H]⁺</td>

<td> 49</td><td>Cl</td><td>H</td><td> 0</td><td> 489,1</td>

<td> 50</td><td>Me</td><td>H</td><td> 0</td><td> 469,2</td>

<td> 51</td><td>Me</td><td>OH</td><td> 0</td><td> 485,0</td>

<td> 52</td><td>Cl</td><td>OMe</td><td> 0</td><td> 519,3</td>

<td> 53</td><td>Me</td><td>OMe</td><td> 0</td><td> 499,3</td>

<td> 54</td><td>Cl</td><td>OMe</td><td>s</td><td> 535,1</td>

EE 200200367 Α

<img file="EE200200367A_D0034.tif" />

<img file="EE200200367A_D0035.tif" />

<td>Example No.</td><td>R³</td><td>V²</td><td>W¹</td><td>X</td><td>[M + H]⁺</td>

<td> 55</td><td>H</td><td>H</td><td>s</td><td> 0</td><td> 479,4</td>

<td> 56</td><td>H</td><td>OH</td><td>s</td><td> 0</td><td> 495,0</td>

<td> 57</td><td>H</td><td>H</td><td>s</td><td>s</td><td> 495,1</td>

<td> 58</td><td>Me</td><td>H</td><td> 0</td><td> 0</td><td> 477,2</td>

<td> 59</td><td>H</td><td>OBn</td><td>s</td><td> 0</td><td> 585,2</td>

<td> 60</td><td>H</td><td>OBn</td><td> 0</td><td>s</td><td> 585,0</td>

<img file="EE200200367A_D0036.tif" />

<td>Example No.</td><td>R³</td><td>V²</td><td>w¹</td><td>X</td><td>[M + H]⁺</td>

<td> 61</td><td>NEt</td><td>ch₂</td><td>Me</td><td>OMe</td><td> 522,4</td>

<td> 62</td><td>NH</td><td>ch₂</td><td>Me</td><td>OMe</td><td> 494,3</td>

<td> 63</td><td>ch₂</td><td>NiPr</td><td>Me</td><td>OMe</td><td> 536,4</td>

<td> 64</td><td>ch₂</td><td>NH</td><td>Me</td><td>OMe</td><td> 494,5</td>

<td> 65</td><td> 0</td><td>ch₂</td><td>Cl</td><td>OMe</td><td> 515,2</td>

<td> 66</td><td>CH (OH)</td><td>ch₂</td><td>Me</td><td>H</td><td> 479,2</td>

EE 200200367 Α

<img file="EE200200367A_D0037.tif" />

<td>Example No.</td><td colspan="2">A</td><td>V²</td><td>[M + H]⁺</td>

<td> 67</td><td colspan="2">H Mr.</td><td>H</td><td> 518,0</td>

<td> 68</td><td></td><td>ch₃1 (p r \ A</td><td>H</td><td> 532,2</td>

<td> 69</td><td></td><td>ch₃jX iA</td><td>H</td><td> 527,0</td>

<td> 70</td><td colspan="2">ch₃a^!X</td><td>H</td><td> 516,1</td>

<td> 71</td><td colspan="2">ch₃rr ^ ö</td><td>H</td><td> 515,0</td>

<td>Example No.</td><td colspan="2">A</td><td>V²</td><td>[M + H]⁺</td>

<td> 72</td><td colspan="2">'X</td><td>H</td><td> 514,6</td>

<td> 73</td><td colspan="2">aj</td><td>H</td><td> 513,7</td>

<td> 74</td><td> 0</td><td>Z ^ N Cz</td><td>H</td><td> 502,1</td>

<td> 75</td><td colspan="2">_NO</td><td>H</td><td> 500,7</td>

<td> 76</td><td colspan="2">ch₃c / a</td><td>OH</td><td> 547,9</td>

<td> 77</td><td> 0</td><td>i \ r</td><td>OH</td><td> 517,6</td>

<td> 78</td><td colspan="2">ch₃ ch₃aj</td><td>OH</td><td> 546,3</td>

EE 200200367 Α

<img file="EE200200367A_D0038.tif" />

EE 200200367 Α

<img file="EE200200367A_D0039.tif" />

<img file="EE200200367A_D0040.tif" />

<img file="EE200200367A_D0041.tif" />

<td>Example No.</td><td>V¹</td><td>V²</td><td>X</td><td>Y</td><td>[M + H] +</td>

<td> 87</td><td>H</td><td>H</td><td>s</td><td>NMe₂</td><td> 516,2</td>

<td> 88</td><td>H</td><td>OBn</td><td> 0</td><td>NMe₂</td><td> 606,3</td>

<td> 89</td><td>H</td><td>OH</td><td> 0</td><td>NMe₂</td><td> 507,3</td>

<td> 90</td><td>H</td><td>OMe</td><td> 0</td><td>NMe₂</td><td> 530,3</td>

<td> 91</td><td colspan="2">-OCH2CH2O-</td><td> 0</td><td>OMe</td><td> 545,3</td>

<td> 92</td><td>OMe</td><td>OMe</td><td> 0</td><td>OMe</td><td> 547,3</td>

<td> 93</td><td colspan="2">-OCH2CH2O-</td><td> 0</td><td>NMe₂</td><td> 558,3</td>

<td> 94</td><td colspan="2">-SCH₂CH₂S-</td><td> 0</td><td>NMe₂</td><td> 590,2</td>

<img file="EE200200367A_D0042.tif" />

<img file="EE200200367A_D0043.tif" />

<td>Example No.</td><td>R²</td><td>V¹</td><td>V²</td><td>X</td><td>Y</td><td>[M + H]⁺</td>

<td> 95</td><td>Me</td><td>H</td><td>OH</td><td> 0</td><td>NMe₂</td><td> 516,1</td>

<td> 96</td><td>Me</td><td>H</td><td>H</td><td>s</td><td>NMe₂</td><td> 516,2</td>

<td> 97</td><td>Me</td><td>H</td><td>OMe</td><td> 0</td><td>NMe₂</td><td> 530,4</td>

<td> 98</td><td>Me</td><td colspan="2">-OCH2CH2O-</td><td> 0</td><td>OMe</td><td> 545,3</td>

<td> 99</td><td>Me</td><td colspan="2">-OCH2CH2O-</td><td> 0</td><td>OH</td><td> 531,3</td>

<td> 100</td><td>Me</td><td colspan="2">-OCH2CH2O-</td><td> 0</td><td>NMe₂</td><td> 558,3</td>

<td> 101</td><td>Cl</td><td>H</td><td></td><td> 0</td><td>NMe₂</td><td> 551,5</td>

<td> 102</td><td>Me</td><td>H</td><td>OMe</td><td> 0</td><td>NEt₂</td><td> 558,3</td>

<td> 103</td><td>Me</td><td>H</td><td>OMe</td><td> 0</td><td> 0</td><td> 570,3</td>

<td> 104</td><td>Me</td><td>H</td><td>OMe</td><td>s</td><td>NMe₂</td><td> 546,2</td>

<img file="EE200200367A_D0044.tif" />

x

<td>Example No.</td><td>A¹⁰</td><td>R²</td><td>V²</td><td>X</td><td>[M + H]⁺</td>

<td> 105</td><td>O</td><td>Me</td><td>Η</td><td> 0</td><td> 519,3</td>

<td> 106</td><td>NMe</td><td>Me</td><td>H</td><td> 0</td><td> 532,3</td>

<td> 107</td><td>NMe</td><td>Me</td><td>OH</td><td> 0</td><td> 548,1</td>

<td> 108</td><td>NMe</td><td>Me</td><td>OBn</td><td> 0</td><td> 638,2</td>

<td> 109</td><td>NMe</td><td>Me</td><td>OMe</td><td> 0</td><td> 562,3</td>

<td> 110</td><td>O</td><td>Me</td><td>OMe</td><td> 0</td><td> 549,2</td>

<td> 111</td><td>NMe</td><td>Me</td><td>Cl</td><td> 0</td><td> 566,2</td>

<td> 112</td><td>NMe</td><td>Me</td><td>OMe</td><td>s</td><td> 578,2</td>

<td> 113</td><td>O</td><td>Cl</td><td>OMe</td><td> 0</td><td> 569,1</td>

<td> 114</td><td>O</td><td>Me</td><td>OMe</td><td>s</td><td> 565,2</td>

<td> 115</td><td> 0</td><td>Cl</td><td>OMe</td><td>s</td><td> 585,1</td>

<td> 116</td><td>NH</td><td>Me</td><td>OMe</td><td> 0</td><td> 548,2</td>

Example 117

In vitro biological characterization

The compounds of the invention are V₂ receptor selective agonists. In a standard radio ligand transfer assay, all compounds give Ki values ​​of V₂ less than 10 μητ for receptors.

Example 118

In vivo biological characterization

The Brattleboro rat is a recognized model for vasopressin deficiency (see FD Grant, Genetic Models of Vasopressin Deficiency, Exp. Physiol. 85, 203S-209S for an overview,

2000). The animals do not secrete vasopressin and therefore produce large quantities of diluted urine. Brattleboro rats were dosed with the compounds of the invention (0.1-10 mg / kg po in methylcellulose. Urine was collected every hour and compared with the amount of urine in control animals. During the experiment, the animals had free access to food and water.

Representative test results are given in the table below. Desmopressin results are presented for comparison.

<td>Compound according to Example</td><td>Dose</td><td>Inhibition of urine production percentage (per hour)</td>

<td> 1</td><td>Ϊ mg / kg</td><td> 82</td>

<td> 14</td><td>1 mg / kg</td><td> 84</td>

<td> 52</td><td>1 mg / kg</td><td> 90</td>

<td> 54</td><td>1 mg / kg</td><td> 68</td>

<td> 85</td><td>1 mg / kg</td><td> 63</td>

<td> 90</td><td>1 mg / kg</td><td> 60</td>

<td> 101</td><td>1 mg / kg</td><td> 74</td>

<td> 104</td><td>1 mg / kg</td><td> 81</td>

<td> 109</td><td>1 mg / kg</td><td> 73</td>

<td> 110</td><td>1 mg / kg</td><td> 80</td>

<td> 112</td><td>1 mg / kg</td><td> 75</td>

<td> 114</td><td>1 mg / kg</td><td> 85</td>

<td> 115</td><td>1 mg / kg</td><td> 88</td>

<td>Desmopress</td><td>0.1 mg / kg</td><td> 37</td>

<td></td><td>1 mg / kg</td><td> 100</td>

<td></td><td>10 mg / kg</td><td> 100</td>

Example 119

A pharmaceutical composition for a tablet

Tablets containing 100 mg of the compound of Example 1 as active ingredient were prepared as follows:

Compound according to Example 1 Maize starch

Hydroxypropylcellulose

200.0 g

71.0 g

18.0 g

Carboxymethylcellulose calcium

Magnesium stearate

Lactose

Together

13.0 g 3.0 g 195.0 g 500.0 g

The materials are mixed, then 2000 tablets a '250 mg, each containing 100 mg of compound as in Example 5, are compressed.

The foregoing examples demonstrate that compounds within the scope of the invention are readily prepared using standard chemical techniques and that these compounds possess the biological properties₂ receptor agonists. Specifically, the compounds are potent anti-diuretics in animal vasopressin deficiency. Thus, it will be clear that they may also be useful in the treatment of human diseases currently treated with desmopressin, such as central diabetes insipidus, nocturnal enuresis and nocturia. Further, it has been suggested that antidiuretics such as desmopressin may be useful in certain types of urinary incontinence. These arguments would extend to the compounds of the present invention.

Desmopressin is also used to treat certain diseases associated with blood clotting. There is good evidence that this activity is also mediated by V₂ receptors (see, e.g., JE Kaufmann et al., Vasopressin-induced von Willebrand factor secretion from endothelial advantage involves V₂ reeeptors and cAMP, J. Clin. Invest. 106, 107-116, 2000; Bemat et al., V₂ reeeptor antagonism of DDAVP-induced release of hemostatic faetors in conscious dogs, J. Pharmacol. Exp. Ther. 282, 597-602, 1997), therefore, it would be expected that the compounds of the present invention could be useful pre-coagulants.

The scope of the present invention is further defined by the following claims.