Condensed azepines as vasopressin agonists

The present invention relates to a class of novel chemicals that act as agonists of the peptide hormone vasopressin. They reduce the excretion of urine from the kidneys and are therefore useful in the treatment of certain human diseases characterized by polyuria. They are also useful in controlling urinary incontinence and abnormal bleeding.

Vasopressin is a peptide hormone secreted by the posterior pituitary gland. It works on the kidneys, increasing water retention and reducing urine output. For this reason, vasopressin is also known as the "antidiuretic hormone." It also works on blood vessels, where it produces a pressor effect. Cellular receptors that mediate these two functions have been identified and shown to be different. Antidiuretic effect is generally V₂ It is mediated by a type 2 vasopressin receptor called a receptor. V₂ The agent that can interact with the receptor and activate it in the same way as vasopressin is V₂ Receptor / agonist (or just V₂ It is called an agonist). The above-mentioned agents have an antidiuretic effect. These agents are V₂ If they interact selectively with the receptors and not with other vasopressin receptors, they do not have the pressor effect of vasopressin. This is an important safety consideration and is attractive for the treatment of diseases of symptoms characterized by polyuria (which is referred to herein as excessive urine production). Produces the above-mentioned active substances.

<chemistry num="1"><img file="JP3813629B2_D0001.tif" /></chemistry>

In fact, such agents have already been used to treat humans. Desmopressin (also known as [1-Desmopressin, D-Arg⁸ ] Vasopressin, Minirin , DDAVP ) is a peptide analog of vasopressin, V₂ It is a selective agonist for the receptor. It is used to treat central diabetes insipidus, a symptom caused by vasopressin deficiency. It is also used to control nocturnal enuresis and can also be used to control nocturnal polyuria. However, desmopressin is not an ideal substance in all respects. Even the best and most up-to-date synthesis of said agents is very long, and desmopressin is not readily available for the most convenient purification techniques, such as crystallization. As a result, desmopressin is relatively expensive. It has very low oral bioavailability, and there are some uncertainties within this parameter.

<chemistry num="2"><img file="JP3813629B2_D0002.tif" /></chemistry>

In summary, selective vasopressin V, which is easy to prepare and purify, and has high and predictable oral bioavailability.₂ There is a need for receptor agonists. The aforementioned properties will probably be obtained with non-peptide compounds. These ideas make other groups non-peptide vasopressin V₂ Leading agonists to research and their results are, for example, International Patent Application Publication Nos. WO97 / 22591, WO99 / 06403, WO99 / 06409, WO00 / 46224, WO00 / 46225, WO00 / It is disclosed in No. 46227 and WO 00/46228. However, the compounds disclosed in these documents are not ideal. In particular, they have low oral bioavailability, probably in part due to their poor solubility in water. The present invention provides compounds with improved solubility and bioavailability.

In addition to its antidiuretic effect, desmopressin is used to increase blood levels of blood coagulation proteins known as factor VIII and von Willebrand factor. In the medical setting, this makes desmopressin useful in the treatment of hemophilia A and von Willebrand's disease. Similar applications would be open to the non-peptide agonists of the invention.

Description of the Invention As described herein, the present invention relates to a series of compounds that are non-peptide agonists of vasopressin, and it is V.₂ Selective for receptor subtypes. The compound has the general formula (1):

<chemistry num="3"><img file="JP3813629B2_D0003.tif" /></chemistry>

{In the formula, A is the following general formula (2) ~ (7):

<chemistry num="4"><img file="JP3813629B2_D0004.tif" /></chemistry>

Bicyclic or tricyclic azepine derivatives selected from; A¹ , A⁴ , A⁷ , And A¹⁰Is CH₂ , O, and NR⁸ Selected independently of each other; A² , A³ , A⁹ , A¹¹, A¹³, A¹⁴, And A¹⁵Are chosen independently of CH and N; A⁵ Is a covalent bond, and A⁶ Is S or A⁵ Is N = CH, and A⁶ Is either a covalent bond; A⁸ And A¹²Are selected independently of NH and S; A¹⁶And A¹⁷Are both CH₂ Or A¹⁶And A¹⁷One is CH₂ And the other is O, SO_x , And NR⁸ Chosen from, V¹ And V² Are both H, OMe or F, or V¹ And V² One is Br, Cl, F, OH, OMe, OBn, OPh, O-acyl, N₃ , NH₂ , NHBn or NH-acyl, and the other is H or V¹ And V² Together = O, -O (CH₂ )_p O-or-S (CH₂ )_p S-is; W¹ Is either O or S; X¹ And X² Are both H or together = O or = S; Y is OR⁵ Or NR⁶ R⁷ Is; Z is S or -CH = CH-; R¹ , R² , R³ , And R⁴ Is selected from H, lower alkyl, lower alkyloxy, F, Cl, and Br; R⁵ Is selected from H and lower alkyl; R⁶ And R⁷ Are selected independently of H and lower alkyl, or together-(CH₂ )_n -And; R⁸ Is H or lower alkyl; n = 3,4,5 or 6; p = 2 or 3; and X is 0,1 or 2. Explained by.

The present invention further comprises pharmaceutical compositions incorporating these vasopressin agonists, which are particularly useful in the treatment of certain diabetes insipidus, nocturnal enuresis, and nocturnal polyuria.

Description of the Invention The present invention is based on the following general formula (1):

<chemistry num="5"><img file="JP3813629B2_D0005.tif" /></chemistry>

Includes N-benzylcarbamyl-pyrrolidine derivatives as defined by.

In this equation, A is the following general equations (2) to (7):

<chemistry num="6"><img file="JP3813629B2_D0006.tif" /></chemistry>

Represents a bicyclic or tricyclic azepine group represented by one of.

A¹ , A⁴ , A⁷ , And A¹⁰Is methylene (-CH₂ -), Oxygen (-O-), and substituted nitrogen (-NR)⁸ Represents a divalent group selected from-). A² , A³ , A⁹, A¹¹, A¹³, A¹⁴, And A¹⁵Represents either a nitrogen atom (-N =) or a methine group (-CH =). A such that the ring containing these two groups is a thiophene ring⁶ If is a sulfur atom (-S-), then A⁵ Can represent a covalent bond. Alternatively, A such that the ring containing these two groups is a pyridine ring.⁶ Represents a covalent bond, A⁵ Can represent the group -N = CH-. R⁸ And A¹²Represents either -NH- or a sulfur atom (-S-). A¹⁶And A¹⁷Represents a divalent group. Both are methylene groups (-CH₂ -) Or one is a methylene group, and the other is hydroxymethylene (-CH (OH)-), difluoromethylene (-CF)₂ -), Oxygen (-O-), Substituted nitrogen (-NR)⁸ -), And sulfur or sulfur oxide (-S-, -SO- or -SO₂ -) Is selected. V¹ And V² Are both hydrogen, methoxy or fluorine, or one is bromine, chlorine, fluorine, hydroxy, lower alkoxy, benzyloxy, phenoxy, acyloxy, azide, amino, benzylamino, and acylamide (Br, Cl, F, OH, O-lower alkyl, OBn, OPh, O-acyl, NH₂ , NHBn, and NH-acyl), but the other is hydrogen or V¹ And V² Is a fragment CV together¹ V² Can represent an oxygen atom such that is a carbonyl group (C = O). V¹ And V² Is a CV¹ V² Ethylene-or propylene-dioxy or -dithiochain (-O (CH), such as 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane or 1,3-dithiane ring₂ )₂ O-, -O (CH₂ )₃ O-, -S (CH₂ )₂ S-, -S (CH₂ )₃ It can also be S-).

W¹ Is either an oxygen atom or a sulfur atom.

X¹ And X² Together they are hydrogen, or together they are fragments CX¹ X² Can be either an oxygen or sulfur atom such that is a carbonyl or thiocarbonyl group (C = O or C = S).

Y is the base-OR⁵ Or group-NR⁶ R⁷ Can be either.

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

R¹ , R² , R³ , And R⁴ Is independently selected from hydrogen, lower alkyl groups, lower alkyloxy groups, and halogens fluorine, chlorine, and bromine.

R⁵ Is either a hydrogen atom or a lower alkyl group.

R⁶ And R⁷ Are each independently a hydrogen atom or a lower alkyl group, or they together, together with the nitrogen atom to which they adhere, such that they form an azetidine, pyrrolidine, piperidine or perhydroazepine ring 3 It can form chains of ~ 6 methylene groups.

R⁸ Can be hydrogen or a lower alkyl group.

In the context of the present disclosure, the term "lower alkyl" is intended to include linear and branched alkyl groups of 1-6 carbon atoms as well as cyclic alkyl groups. For example, methyl, ethyl, isopropyl, tert-butyl, neopentyl, and cyclohexyl are all within the term lower alkyl. The term "acyl" refers to a lower alkyl-carbonyl group such as acetyl, pivaloyl, cyclopropylcarbonyl and the like. It is also possible that formyl is an acyl group.

The specific compound of the general formula (1) can form a salt with an acid or a base. For example, compounds containing one or more nitrogen atoms can form additional salts with inorganic 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 can form salts with bases. Examples of the bases include sodium, potassium, calcium, triethylammonium salts, and tetraethylammonium salts. In addition, compounds with both acidic and basic groups can form internal salts (zwitterions). As long as these salts are pharmaceutically acceptable, they are included in the scope of the present invention.

All compounds according to the general formula (1) have at least one stereogenic center (tetrahedral carbon atom to which four different substituents are attached) and therefore exist as optical isomers such as enantiomers and diastereomers. Can be done. The isomers and mixtures thereof are all intended to be within the scope of the present invention.

In a preferred embodiment of the present invention, A is a group represented by the general formula (2). In another preferred embodiment of the present invention, A is a group represented by the general formula (3). In another preferred embodiment of the present invention, A is a group represented by the general formula (4). In another preferred embodiment of the present invention, A is a group represented by the general formula (5). In another preferred embodiment of the present invention, A is a group represented by the general formula (6).

In another preferred embodiment of the present invention, A is a group represented by the general formula (7). In a more preferred embodiment, A is a tetrahydro-1-benzazepine-1-yl group, i.e. Z is -CH = CH-, and A¹⁶And A¹⁷Is a group represented by the general formula (7), both of which are methylene groups.

In another preferred embodiment, R¹ And R² R where one is chlorine or methyl group and the other is hydrogen, both are hydrogen³ And R⁴ With.

In another preferred embodiment, V¹ And V² One is a methoxy or benzyloxy group and the other is hydrogen.

In yet another preferred embodiment, X¹ And X² Represent the oxygen atom together, and Y is -NR⁶ R⁷ Is.

A particularly preferable embodiment of the present invention has two or more of the above-mentioned preferable properties.

An even more preferable aspect of the present invention is represented by the following general formula (8).

<chemistry num="7"><img file="JP3813629B2_D0007.tif" /></chemistry>

In general formula (8), W¹ , R⁵ , And R⁶ Is as defined above for (1). R^a And R^{b b} One is hydrogen and the other is either chlorine or a methyl group. R^c Is either a methyl group or a benzyl group.

An even more preferred embodiment is a compound of the following general formula (8A) whose stereochemistry is as shown therein.

<chemistry num="8"><img file="JP3813629B2_D0008.tif" /></chemistry>

Another preferred embodiment of the present invention is V.¹ And V² Is a compound represented by the general formula (1) in which both are hydrogen. In a more preferred embodiment, X¹ And X² Are together oxygen atoms, and Y is NR⁶ R⁷ Is. Even more preferable are compounds represented by the following general formula (9).

<chemistry num="9"><img file="JP3813629B2_D0009.tif" /></chemistry>

In general formula (9), W¹ , R⁵ , And R⁶ Is as defined above for (1). R^a And R^{b b} One is hydrogen and the other is either chlorine or a methyl group.

Even more preferred are compounds represented by the following general formula (9A), where stereochemistry is as shown therein.

<chemistry num="10"><img file="JP3813629B2_D0010.tif" /></chemistry>

The individual preferred compounds in the present invention are (but not limited to) the following:

<chemistry num="11"><img file="JP3813629B2_D0011.tif" /></chemistry>

including.

The compounds of the present invention can be prepared using methods commonly known in the art. The following general formula (1):

<chemistry num="12"><img file="JP3813629B2_D0012.tif" /></chemistry>

Compounds can be thought of as consisting of 3 bound fragments (A-C).

The three fragments are generally produced separately and then combined at the end of synthesis. Various groups (R¹ ~ R⁴ , V¹ , V² , X¹ , X² Etc.) will require the use of protecting groups as some examples may be incompatible with this assembly. The use of protecting groups is well known in the art (see, eg, "Protective Groups in Organic Synthesis", TWGreene, Wiley-Interscience, 1981). Specific groups requiring protection are amines (amides or carbamate). Protected as), alcohol (protected as ester or ether), and carboxylic acid (protected as ester). For the purposes of this commentary, it would be taken for granted that the protecting groups are arranged as essential.

The fragments A, B, and C can be combined by two methods to give the compound of formula (1). In 1, the fragments A and B are combined to give a fragment corresponding to AB, which is then combined with fragment C. In 2, fragments B and C are combined to give a fragment corresponding to BC, which is then combined with fragment A. The chemical reaction involved in the condensation of fragments A and B and the chemical reaction involved in the condensation of fragments B and C will be the same regardless of which method comes later. We have found that the first method is more flexible when working on a small scale and in preparation for compound selection. Nevertheless, the second method would be advantageous in the production of large-scale selected compounds.

Formation of fragment AB

<chemistry num="13"><img file="JP3813629B2_D0013.tif" /></chemistry>

Here, {A} and {B} represent the partial structures of fragments A and B, respectively. The formation of amides by condensation of carboxylic acids and amines is well known. In general, acids and amines are condensing agents such as carbodiimides (eg "water-soluble carbodiimides" where they are N-ethyl-N'-(3-dimethylaminopropyl) -carbodiimides) or reactive phosphorus derivatives (eg (benzo). It is mixed in an aproton solvent such as dichloromethane or dimethylformamide in the presence of "BOP"), which is triazole-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate. The reaction is optionally catalyzed by a tertiary amine, such as triethylamine or 4-dimethylaminopyridine. Alternatively, the carboxylic acid can be converted to a more reactive derivative, such as acid chloride. The derivative then reacts with the amine as described above, but without the need for a condensing agent.

Formation of fragment BC

<chemistry num="14"><img file="JP3813629B2_D0014.tif" /></chemistry>

The formation of a urea or thiourea bond between fragments B and C is a derivative of carbonic acid with the primary amine corresponding to fragment B, such as phosgene (where LG is chlorine) or carbonyldiimidazole (where LG is 1-). It can be most easily achieved by reacting with imidazolyl) to form an intermediate of the carbamic acid derivative. W¹ If is sulfur instead of oxygen, thiophosgene or thiocarbonyldiimidazole is used. The reaction is conveniently carried out in an aprotic solvent such as dichloromethane or dimethylformamide in the presence of a tertiary amine such as triethylamine or N, N-diisopropylethylamine. After sufficient time to form the intermediate, the secondary amine corresponding to fragment C is added to the reaction mixture. It is not necessary to separate the intermediates of the carbamate derivative. As a variant of this method, it is possible to reverse the order of addition of the amines corresponding to fragments B and C, such as forming the carbamate derivative from the second amine and then adding the first amine.

In summary, the following intermediates are required for the synthesis of the compounds of the invention.

i) About fragment A

<chemistry num="15"><img file="JP3813629B2_D0015.tif" /></chemistry>

Condensed azepines represented by these general formulas can be produced by the methods reported in the literature. For example: 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, 1977 , 339; Chakrabarti et al., J. Med. Chem. 23, 1980, 878; Chakrabarti et al., J. Med. Chem. 23, 1980, 884; Chakrabarti et al., J. Med. Chem. 32, 1989, 2573; Chimirri et al., Heterocycles 36, 1993, 601; Grunewald et al., J. Med. Chem. 39, 1996, 3539; Klunder et al., J. Med. Chem. 35, 1992, 1887; Liegeois et al., J. Med. Chem. 37, 1994, 519; Olagbemiro et al., J. Het. Chem. 19, 1982, 1501; Wright et al., J. Med. Chem . 23, 1980, 462; Yamamoto et al., Tet. Lett. 24, 1983, 4711; and International Patent Application Publication No. 99/06403.

Some of them are commercial products.

ii) About fragment B

<chemistry num="16"><img file="JP3813629B2_D0016.tif" /></chemistry>

Since primary amines and carboxylic acid groups cannot coexist, they must be prepared and protected separately. Substituted benzoic acids are well known, and carboxylic acids are conveniently protected as their methyl esters. The primary amine can be synthesized from the corresponding nitrile (by reduction) or from an alcohol (by substitution with a nitrogen nucleophile). The best method is Substituent R¹ ~ R⁴ Will depend on the nature of.

iii) About fragment C

<chemistry num="17"><img file="JP3813629B2_D0017.tif" /></chemistry>

This type of pyrrolidine derivative is produced by the method described in the literature. For example, Dugave et al., Tet. Lett. 39, 1998, 1169; Petrillo et al., J. Med. Chem. 31, 1988, 1148; and Smith et al., J. Med. Chem. 31, 1988, 875. checking ...

The defined stereochemical prolines and hydroxyprolines are commercial products and are themselves convenient starting materials.

The present invention further comprises at least one pharmaceutical composition comprising the compound according to the above as an active ingredient. The composition may also include a second drug known in the art to ameliorate bladder dysfunction, such as an antispasmodic or potassium channel blocker. Preferably, the composition comprises only one active ingredient. The composition contains excipients known in the art, selected from binders, leavening agents, dispersants, solvents, stabilizers and the like.

The excipients used depend on the nature of the intended formulation, as well as the intended route of administration. Administration can be oral, transmucosal (eg, sublingual, buccal, intranasal, vaginal, and rectal), transdermal, or by injection (eg, subcutaneous, intramuscular, and static). Oral administration is generally preferred. For oral administration, the formulation will be tablets or capsules. Other formulations include desiccants, liquids, suspensions, suppositories and the like.

In a further aspect, the invention is a method of treating or controlling a particular human physiological dysfunction. The method comprises administering an effective amount of the pharmaceutical composition to a human in need of the treatment described above, wherein the composition comprises the compound according to the above as an active ingredient. Since the compound reduces urine excretion, the method of the invention can be applied to all symptoms caused by increased urine excretion. The compounds also increase the production of blood coagulation proteins known as factor VIII and von Willebrand, which can be used to treat bleeding disorders.

In a preferred embodiment, the symptomatology treated is diabetes insipidus. This is a symptom due to the body's lack of ability to produce and secrete physiologically active vasopressin, resulting in a significant reduction in water reabsorption and a large amount of urine.

In another preferred embodiment, the symptomatology treated is nocturnal enuresis. This is defined as urination while the person is sleeping. It mainly affects children, and many factors are symptoms included in the cause.

In another preferred embodiment, the symptom being treated is nocturnal polyuria. This is defined as the production of enough urine to wake the person during the night and cause him (or her) to urinate. Moreover, this symptom is the result of many factors.

In another preferred embodiment, the symptomatology treated is incontinence. This symptom is characterized in part by a decrease in bladder capacity and control that results in involuntary urination except in the case of frequent urination. Incontinence can be divided into two symptoms: stress incontinence and incontinence. It is believed that many causes should be included. The treatment according to the invention is particularly useful for delaying the need for urination (voiding postponement) to give an incontinence patient a period of several hours (eg, up to 4 hours) without urine. Such delayed urination can also be useful for people who are not incontinent, such as those who are forced to continue meetings for long periods of time.

In another preferred embodiment, the symptomatology treated is hemophilia A or von Willebrand's disease. These are symptoms of decreased factor VIII or von Willebrand factor production, and the person suffering from long bleeding.

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

Administration of the compositions of the invention is generally under the supervision of a physician. The doctor determines the amount of composition to be administered and the administration plan in consideration of the patient's physical condition and therapeutic purpose. For adult patients with diabetes insipidus, a typical dose is 50 mg to 1 g of active compound per day, taken as 1 tablet or 4 tablets throughout the day. For other routes of administration of the oral route, the amount of compound is reduced because the parenteral route tends to be more efficient in delivering the therapeutic agent to the systemic circulation. For the treatment of hemophilia A and von Willebrand's disease, the amount of compound needs to be higher than for the treatment of diabetes insipidus.

All of the above statements are further described herein by a number of non-limiting examples.

<u style="single">Abbreviation</u> The following abbreviations were used. Ac Acetyl AIBN Azo-bis- (isobutyronitrile) Bn benzyl BOC tert-butyloxycarbonyl (BOC)₂ O Di-tert-Butyl Dicarbonate DMF Dimethylformamide Et Ethyl EtOAc Ethyl Acetate IPA Isopropanol iPr Isopropyl MS Mass Analysis Me Methyl NBS N-Bromosuccinimide pet.ether Petroleum ether, fraction Ph phenyl tBu boiled at 60-80 ° C tert-Butyl THF tetrahydrofuranWSCDI Water-soluble carbodiimide<u style="single">Preparation of intermediates</u> Reagents corresponding to Fragments A and C were either commercially available or prepared according to the procedures published in the specific examples except in detail. Reagents corresponding to fragment B were prepared as detailed below.

<u style="single">Example A</u>.<u style="single">4- (tert-Butyloxycarbonylaminomethyl) -3-chlorobenzoic acid</u>

<chemistry num="18"><img file="JP3813629B2_D0018.tif" /></chemistry>

<u style="single">A1.4-Bromomethyl-3-chloromethyl benzoate</u> NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mmol) were added to a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 ml). The mixture was stirred at reflux temperature for 18 hours. The mixture was cooled to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent EtOAc: pet.ether 0: 100 5:95); yield 5.96 g (84%).

<u style="single">A2.4-(tert-butyloxycarbonylaminomethyl) -3-chlorobenzoic acid</u> Methyl 4-bromomethyl-3-chlorobenzoate (5.5 g, 20.9 mmol) of Example A1 was added to a saturated solution of ammonia in ethanol (170 ml). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was ground with diethyl ether and the resulting white crystals were filtered and washed with additional diethyl ether. In water (100 ml), in a solution of this solid in dioxane (100 ml), (BOC)₂ Sodium hydroxide (1.86 g, 46.0 mmol) was added in a solution of O (5.0 g, 23.0 mmol) and in water (100 ml). The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residual aqueous solution was acidified with citric acid and extracted with chloroform / IPA. The organic layer is washed with water and EDTA₄ Moisture was removed and concentrated in vacuo to give a white solid; yield 2.8 g (67%).

<u style="single">Example B</u>.<u style="single">4-Cyano-3-methylbenzoic acid</u>

<chemistry num="19"><img file="JP3813629B2_D0019.tif" /></chemistry>

In THF (100 ml), add a 2.5 M solution of n-butyllithium (4.48 ml, 11.2 mmol) to a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) at -78 ° C under a nitrogen atmosphere. Was added by dropping in. The mixture was stirred at -78 ° C for 1 hour and then poured into solid carbon dioxide (5 g) in THF (50 ml). The mixture was warmed to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified with the addition of concentrated hydrochloric acid and extracted with chloroform (3 times). The combined chloroform extract was washed with water and EDTA₄ Moisture was removed and concentrated in vacuo to give a white solid; yield 1.2 g (73%).

<u style="single">Example C</u>.<u style="single">4-Cyano-2-methylbenzoic acid</u>

<chemistry num="20"><img file="JP3813629B2_D0020.tif" /></chemistry>

4-Bromo-3-methylbenzonitrile (2.0 g, 10.2 mmol) was reacted according to the method of Example B to obtain a yellow solid. This yellow solid was ground with hexane and filtered; yield 0.96 g (59%).

The reagents corresponding to the fragments A, B, and C were combined to obtain specific examples described in detail below.

<u style="single">Example 1</u>.<u style="single">1-(2-Methyl-4- (2,3,4,5-tetrahydro-1-benzazepine-1-ylcarbonyl) benzylcarbamoyl) -L-proline-N, N-dimethylamide</u>

<chemistry num="21"><img file="JP3813629B2_D0021.tif" /></chemistry>

<u style="single">1A.2-Methyl-4-((2,3,4,5-tetrahydro-1H-benzo [b] azepine) -1-carbonyl) -benzonitrile</u> 4-Cyano-3-methylbenzoic acid (0.96 g, 5.95 mmol) in a solution of 2,3,4,5-tetrahydro-1H-benzo [b] azepine (0.80 g, 5.44 mmol) in dichloromethane (50 ml), Triethylamine (0.60 g, 5.95 mmol), 4- (dimethylamino) pyridine (0.73 g, 5.95 mmol), and WSCDI (1.24 g, 6.48 mmol) were added. The mixture was stirred at reflux temperature for 18 hours, cooled and evaporated in vacuo. Residue with EtOAc and 1 M KHSO₄ Distributed among. The organic layer is washed with saturated sodium bicarbonate solution and saline and deli₄ Moisture was removed and concentrated in vacuo. The unrefined product was purified by flash chromatography on silica (eluent EtOAc: pet.ether 30:70); yield 1.10 g (70%).

<u style="single">1B.1- (4- (Aminomethyl) -3-methylbenzoyl) -2,3,4,5-tetrahydro-1H-benzo [b] azepine hydrochloride</u> Concentrated hydrochloric acid (0.98 ml, 11.3 mmol) and 10% on-carbon palladium (0.80 g) were added to a degassed solution of cyanobenzazepine of Example 1A (1.10 g, 3.79 mmol) in methanol (50 ml). Hydrogen gas was aerated through the mixture at room temperature for 5 hours. The catalyst was removed by filtering through a pad of Celite and the filtrate was evaporated; yield 1.23 g (98%).

<u style="single">1C.1- (2-Methyl-4- (2,3,4,5-tetrahydro-1-benzazepine-1-ylcarbonyl) benzylcarbamoyl) -L-proline-N, N-dimethylamide</u> N, N-diisopropylethylamine (43 mg, 0.332 mmol) and carbonyl diimideazepine (0.074 g, 0.453 mmol) in a solution of amine of Example 1B (0.10 g, 0.302 mmol) in DMF (10 ml) under a nitrogen atmosphere. added. The mixture was stirred at room temperature for 40 minutes. A solution of proline-N, N-dimethylamide (0.107 g, 0.756 mmol) was added in DMF (1 ml). The mixture was stirred at room temperature for an additional 16 hours. The solvent was removed in vacuo and the unrefined product was purified by flash chromatography on silica (eluent methanol = dichloromethane 5:95); yield 0.115 g (82%).

<chemistry num="22"><img file="JP3813629B2_D0022.tif" /></chemistry>

<u style="single">Example 2</u>.<u style="single">(4R) -4-Hydroxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepine-1-ylcarbonyl) benzyl-carbamoyl) -L-proline-N, N- Dimethylamide</u>

<chemistry num="23"><img file="JP3813629B2_D0023.tif" /></chemistry>

<u style="single">2A.L-trans-4-hydroxyproline-N, N-dimethylamide hydrochloride</u> N, N-diisopropylethylamine (3.7 ml, 21.24 mmol), 4- (dimethylamino) pyridine (1.74 g, 14.24 mmol), dimethyl in solution of BOC-hydroxyproline (2.99 g, 13.89 mmol) in dichloromethane (100 ml). Amine hydrochloride (1.72 g, 21.09 mmol) and WSCDI (3.17 g, 16.68 mmol) were added. The mixture was stirred at room temperature for 30 hours. The mixture is diluted with dichloromethane (100 ml) and 0.3 M KHSO₄ , Saturated sodium bicarbonate solution, and saline solution and deli₄Moisture was removed and concentrated in vacuo to give a colorless viscous material. The unrefined product was taken up in 4N HCl / dioxane (50 ml), stirred 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%).

<u style="single">2B. (4R) -4-Hydroxy-1- (2-methyl-4- (2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl) benzyl-carbamoyl) -L-proline-N, N-dimethylamide</u> The amine of Example 1B (0.10 g, 0.302 mmol) was reacted with the amine of Example 2A (0.153 g, 0.785 mmol) according to the method of Example 1C. The product was purified by flash chromatography on silica (eluent chloroform: methanol: acetic acid 95: 4: 1); yield 0.95 g (66%).

<chemistry num="24"><img file="JP3813629B2_D0024.tif" /></chemistry>

<u style="single">Examples 3 to 116</u>Further examples shown in the table below were prepared using a similar method.

<chemistry num="25"><img file="JP3813629B2_D0025.tif" /></chemistry>

<tables num="1"><img file="JP3813629B2_D0026.tif" /></tables>

<chemistry num="26"><img file="JP3813629B2_D0027.tif" /></chemistry>

<tables num="2"><img file="JP3813629B2_D0028.tif" /></tables>

<tables num="3"><img file="JP3813629B2_D0029.tif" /></tables>

<tables num="4"><img file="JP3813629B2_D0030.tif" /></tables>

<chemistry num="27"><img file="JP3813629B2_D0031.tif" /></chemistry>

<tables num="5"><img file="JP3813629B2_D0032.tif" /></tables>

<chemistry num="28"><img file="JP3813629B2_D0033.tif" /></chemistry>

<tables num="6"><img file="JP3813629B2_D0034.tif" /></tables>

<tables num="7"><img file="JP3813629B2_D0035.tif" /></tables>

<chemistry num="29"><img file="JP3813629B2_D0036.tif" /></chemistry>

<tables num="8"><img file="JP3813629B2_D0037.tif" /></tables>

<chemistry num="30"><img file="JP3813629B2_D0038.tif" /></chemistry>

<tables num="9"><img file="JP3813629B2_D0039.tif" /></tables>

<tables num="10"><img file="JP3813629B2_D0040.tif" /></tables>

<tables num="11"><img file="JP3813629B2_D0041.tif" /></tables>

<tables num="12"><img file="JP3813629B2_D0042.tif" /></tables>

<chemistry num="31"><img file="JP3813629B2_D0043.tif" /></chemistry>

<tables num="13"><img file="JP3813629B2_D0044.tif" /></tables>

<tables num="14"><img file="JP3813629B2_D0045.tif" /></tables>

<chemistry num="32"><img file="JP3813629B2_D0046.tif" /></chemistry>

<tables num="15"><img file="JP3813629B2_D0047.tif" /></tables>

<chemistry num="33"><img file="JP3813629B2_D0048.tif" /></chemistry>

<tables num="16"><img file="JP3813629B2_D0049.tif" /></tables>

<u style="single">Example 117</u>.<u style="single">Biological characterization in vitro</u> The compound of the present invention is V₂ It is a selective agonist for the receptor. In the conventional radioligand substitution assay, all the compounds are V₂ It produces Ki values below 10 μM for the receptor.

<u style="single">Biological characterization in vivo</u> Brattleboro rats are an established model for vasopressin deficiency (for overview, FD Grant, "Genetic models of vasopressin deficiency", <u style="single">Exp. Physiol.</u> 85, 203S-209S, 2000). The animal does not secrete vasopressin, resulting in a large amount of thin urine. The compounds of the present invention were administered to Brattleboro rats (0.1-10 mg / kg, oral, contained in methylcellulose). Urine was collected hourly and the volume was compared to the animals of interest. Animals were given free food and water throughout the experiment. Representative results are shown in the table. The results for desmopressin are shown for comparison.

<tables num="17"><img file="JP3813629B2_D0050.tif" /></tables>

<u style="single">Example 119</u>.<u style="single">Pharmaceutical composition for tablets</u> A tablet containing 100 mg of the compound of Example 1 as an active substance is prepared from the following: Compound of Example 1 200.0 g Corn starch 71.0 g Hydroxypropyl cellulose 18.0 g Carboxymethyl cellulose calcium 13.0 g Magnesium stearate 3.0 g Lactose 195.0 g Give 2000 tablets of 250 mg containing.

In the above embodiment, compounds within the scope of the present invention are easily produced using conventional chemistry techniques, and these compounds are V.₂ Prove that it has the expected biological properties of a receptor agonist. In particular, the compound is a potent antidiuretic in animal models of vasopressin deficiency. Therefore, it is clear that they will be useful in the treatment of human diseases that can currently be treated with desmopressin, such as certain diabetes insipidus, nocturnal enuresis, and nocturnal polyuria. It is also further suggested that antidiuretics such as desmopressin may be useful for certain types of urinary incontinence. These discussions will extend to the compounds of the present invention.

Desmopressin is also used to treat certain blood coagulation disorders. This function is also V₂ There is sufficient evidence to suggest that it is transmitted through the receptor (eg JE Kaufmann et al., Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V.₂ receptors and cAMP , <u style="single">J. Clin. Invest</u>. 106, 107-116, 2000; A Bernat et al., V₂ receptor antagonism of DDAVP-induced release of hemostasis factors in conscious dogs , <u style="single">J. Pharmacol. Exp. Ther</u>. 282, 597-602, 1997), and from this it would be expected that the compounds of the present invention would be useful anticoagulants.

The scope of the present invention is further clarified in the preceding claims.