Derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5h-benzazepine, its salt and pharmaceutical composition comprising thereof

The scope of the invention

The present invention relates to a new derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine or its salt that can be used as medicines, especially as drugs for the treatment of Central diabetes insipidus (central diabetes insipidus) or nocturia, and a medicine comprising the compound as an active ingredient.

Prior art

Arginine-vasopressin (AVP) is a peptide consisting of 9 amino acids, which biosynthesized and secreted from the hypothalamus/pituitary. AVP receptors are subdivided into three subtypes, namely V_1aV_1band V₂. It is known that a major pharmaceutical action of AVP on the periphery are vasoconstriction, oposredstvovaniya V_1Areceptor, and antidunes, mediate V₂the receptor. As drugs for the selective stimulation of V₂receptor was synthesized desmopressin (removing amino acids cysteine in position 1 AVP, and the conversion of arginine in position 8 in d-form), and its use for the treatment of Central diabetes insipidus (Journal of Japanese Academy of Endocrinology, 54, 676-691, 1978). However, intended for oral administration, the agent desmopressin has a very low bioavailability and requires the use of high doses. Thus, the composition of desmopressin is and is expensive, and often there are side effects associated with differences in absorption of the drug by different individuals. There is therefore a need in creating ones antidiuretic agent, which selectively stimulates the V₂receptors and has a high biological availability.

In addition, in accordance with various methods of treatment of the aging of the population now rarely use a single drug and in most cases at the same time or at intervals impose various types of drugs. The same is true of drugs to stimulate AVP. The drug is inactivated by the enzyme carrying out its metabolism in the liver, and converted into the metabolite, and among these enzymes is the most important cytochrome P450 (ALL). There are several types of molecular species ALL, but if several types of drug metabolism which is due to the same molecular type ALL competing for the enzyme metabolism, believe that the metabolism of several inhibited, although the degree of inhibition varies depending on the affinity of each of the medicines in relation to ALL. As a result of interaction between drugs appear such facts as the increased concentration in the blood or prolonged term half-life in blood, etc.

Such interaction between l is kartami unwanted, except when you want to achieve synergies, and often lead to unexpected side effects. There is therefore a need in the creation of pharmaceutical preparations having a low affinity against ALL, and such that little interaction between themselves or with other medicines.

As usual ones compounds that selectively stimulate the V₂receptor and demonstrate the antidiuretic action of tricyclic compounds represented by the General formula (A), General formula (B) or General formula (C)are disclosed in WO 99/06409, WO 99/06403 and WO 00/46224.

(Each character has the values listed in the above publications).

In addition, condensed derivatives azepine represented by the General formula (D)are disclosed in WO 01/49682.

(Each character has the values listed in the above publication).

In addition, derivatives benzazepine represented by the General formula (E)are disclosed in WO 97/22591 and in Japanese patent No. 2926335, and benzoheterocycles compounds represented by General formula (F) or General formula (G), disclosed in Japanese patent No. 3215910, and in Japanese patent publications Nos tokkaihei 11-349570 and tokkai 2000-351768.

(Each character has the values stated the above publications).

However, in none of the publications are not disclosed derivatives of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine.

In addition, although in WO 95/06035 and WO 98/39325 and in Japanese patent publication No. tokkaihei 9-221475 disclosed derivatives of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine, which have antagonistic activity against AVP receptor, or antagonistic activity against receptor oxytocin, none of them solved agonistic activity against V₂receptor and efficacy in the treatment of Central diabetes insipidus and nocturia.

Accordingly, there is a need to create ones antidiuretic agent, which can be used for the treatment of Central diabetes insipidus and/or nocturia, and such, which would have a high biological availability.

The invention

The authors as a result of numerous studies of compounds with agonistic action on the V₂receptor, and effective for the treatment of Central diabetes insipidus and/or nocturia, found that derivatives of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine possess such properties, and accomplished the present invention. In addition, the authors found that the compound of the present invention has a very low inhibitory activity against EN zymes the basic drug metabolism CYP3A4 and CYP2C9, compared with derivative benzazepine having agonistic activity against receptor V₂, and completed the present invention.

The aim of the present invention is the creation of a new derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the following General formula (I)or its pharmaceutically acceptable salt that can be used as drugs for the treatment of Central diabetes insipidus and/or nocturia; and drugs containing the compound as an active ingredient, especially medications for the treatment of Central diabetes insipidus or nocturia, or medicine representing an agonist of the receptor V₂arginine-vasopressin.

where each character has the following meanings:

R¹represents-OH, -O-lower alkyl, or optionally substituted amino;

R²represents lower alkyl which may be substituted by one or more halogen atoms, or halogen;

R³, R⁴: one is-H, lower alkyl, or halogen and the other represents an optionally substituted nonaromatic cyclic amino, or optionally substituted aromatic cyclic amino; and

R⁵is-H, lower alkyl, or halogen.

The compound of the present invention differs t is m, it contains two groups of the fluorine atom of carbon benzazepine ring, and the carbon atom adjacent to the carbon atom substituted replacement methylidene group in the ring. Further, since the double bond conjugated with a carbonyl group, not samaritana because the two groups of the fluorine compound of the present invention has sufficient stability even in a living organism.

Preferred new derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the General formula (I)or its pharmaceutically acceptable salt, where R¹represents a group represented by the General formula (II), or a group represented by the General formula (III):

where each character has the following meanings:

A represents A simple bond, a lower alkylene or lowest alkylen-C(=O)-;

R¹¹represents lower alkyl which may be substituted by a group selected from the group consisting of-OH, -O-lower alkyl, -CO₂H, -CO₂is lower alkyl and carbamoyl, which may be substituted by one or two lower alkilani, or-H;

R¹²is: (1) if A represents A simple bond or a lower alkylene, R¹²represents aryl, cycloalkyl, aromatic heterocycle, or the non-aromatic heterocycle, each of which may be substituted, or-H, -OH, -O-lower and the keel, -CO₂H;

-CO₂is lower alkyl or carbarnoyl, which may be substituted by one or two lower alkilani.

(2) if A is lowest alkylen-C(=O)-, R¹²represents a group represented by the General formula (III), or a group represented by the General formula (IV)

B represents a simple bond or a lower alkylene;

R¹³, R¹⁴are optionally substituted non-aromatic cyclic amino group that is associated with the neighboring nitrogen atom.

More preferred are a new derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the General formula (I)or its pharmaceutically acceptable salt, where R¹represents a group represented by the General formula (II), or a group represented by the General formula (III); R³is optionally substituted nonaromatic cyclic amino, or optionally substituted aromatic cyclic amino; R⁴is-H, lower alkyl, or halogen; and R⁵is-H.

Even more preferred is a new derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the General formula (I)or its pharmaceutically acceptable salt, where R¹represents a group represented by the General formula (II), or a group represented by the General formula (III); R is optionally substituted nonaromatic cyclic amino, or optionally substituted aromatic cyclic amino; R⁴is-H; and R⁵is-H.

Most preferred is a new derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the General formula (I)or its pharmaceutically acceptable salt, where R¹represents a group represented by the General formula (II), or a group represented by the General formula (III); R³is methylpyrazole, pyrrolidinyl, or methylpyrrolidinyl; R⁴is-H; and R⁵is-H.

Among these compounds, particularly preferred are the compound or its pharmaceutically acceptable salt, selected from compounds of group A and compounds of group B, and the preferred compound or its pharmaceutically acceptable salt, selected from compounds of group A.

Compounds of group A include:

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(pyridine-2-ylmethyl)ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-[1-(2-chloro-4-pyrrolidin-1-aventyl)-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-(3-methyl-1H-pyrazole-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)2-{4,4-debtor-1-[4-(3R)-3-methylpyrrolidine-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-[(3R)-3-methylpyrrolidine-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-hydroxyethyl)ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-debtor-1-[4-(3S)-3-methylpyrrolidine-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-[(3-methyl-1H-pyrazole-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]-N-(2-hydroxyethyl)ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3R)-3-methylpyrrolidine-1-yl]benzoyl}-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene)ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3S)-3-methylpyrrolidine-1-yl]benzoyl}-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene)ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-(4-methyl-1H-pyrazole-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{1-[4-(3,4-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide; and

(2Z)-2-{4,4-debtor-1-[2-methyl-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

Compounds of group B include:

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-[3-(hydroxymethyl)phenyl]ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-[4-(hydroxymethyl)phenyl]but Itemid;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-[(6-methylpyridin-2-yl)methyl]ndimethylacetamide;

3-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl)amino]benzamide;

4-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl)amino]benzamide;

4-{[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl)amino]methyl}benzamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-[3-(methoxymethyl)phenyl]ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-[3-(1-hydroxyethyl)phenyl]ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-[3-(methylsulphonyl)phenyl]ndimethylacetamide;

(2Z)-N-(3-acetylphenyl)-2-{1-[2-chloro-4-{3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(3-were)ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(3-forfinal)ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-t is trihydro-5H-1-benzazepin-5-ilidene}-N-[3-(2-hydroxyethyl)phenyl]ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-hydroxy-1,1-dimethylethyl)ndimethylacetamide;

1-((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl)piperidine-3-carboxamide;

(2Z)-N-[4-(aminosulfonyl)benzyl]-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-hydroxycyclohexyl)ndimethylacetamide;

(2Z)-N-[3-(2-amino-2-oxoethyl)phenyl]-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]ndimethylacetamide;

3-{3-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl)amino]phenyl}propanamide;

(2E)-3-{3-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl)amino]phenyl)acrylamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-oxopyrrolidin-3-yl)ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-oxitetraciclina-3-yl)ndimethylacetamide;

3-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl)amino]-N-methylbenzamide;

(2)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-{2-[2-(hydroxymethyl)piperidine-1-yl]-2-oxoethyl}ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-{2-[3-(hydroxymethyl)piperidine-1-yl]-2-oxoethyl}ndimethylacetamide;

(2Z)-N-[3-(acetylamino)phenyl]-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-externalization-3-yl)ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3,3-dimethylpiperidin-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(pyridine-2-ylmethyl)ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3,3-dimethylpiperidin-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{1-[2-chloro-4-(3-ethyl-3-methylpyrrolidine-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{1-[2-chloro-4-(3,3-dimethylpiperidin-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{1-[2-chloro-4-(3-phenylpyrrolidine-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3,3-dimethylpiperidin-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-hydroxyethyl)ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-phenylpyrrolidine-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{1-[2-chloro-4-(3-ethyl-3-methylpyrrole the DIN-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-[(3R)-3-methylpyrrolidine-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-hydroxyethyl)ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-[(3R)-3-methylpyrrolidine-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{1-[2-chloro-5-fluoro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide; and

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-[4-(1,2-dihydroxyethyl)phenyl]ndimethylacetamide.

The next objective of the present invention is the creation of a new derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the following General formula (V)or its pharmaceutically acceptable salts which are useful as intermediate compounds for obtaining the derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the above General formula (I)or its pharmaceutically acceptable salt that can be used for the treatment of Central diabetes insipidus and/or nocturia.

where each character has the following meanings:

R²¹is lower alkyl;

R²²represents chlorine or trifluoromethyl;

R²³, R²⁴: one is-H and the other is not necessarily secure hydratherapy and

R ²¹is preferably methyl or ethyl, more preferably methyl.

Further, the present invention is disclosed in more detail.

In determining the General formula for the compounds of the present invention, the term "lower alkyl" means a monovalent group with an unbranched or branched carbon chain containing from 1 to 6 carbon atoms, and examples include methyl, ethyl, propyl, butyl, pentyl and hexyl and their structural isomers such as isopropyl, tert-butyl and the like, and preferred alkali containing from 1 to 3 carbon atoms, such as methyl, ethyl, propyl, and isopropyl.

The term "lower alkenyl" means a monovalent group with an unbranched or branched unsaturated carbon chain containing from 2 to 6 carbon atoms, and its examples include vinyl, allyl, 1-butenyl, 2-butenyl, 1-hexenyl and 3-hexenyl and their structural isomers, such as 2-methylallyl and the like, and preferred vinyl and allyl.

The term "lower alkylene" means a divalent group with unbranched or branched carbon chain containing from 1 to 6 carbon atoms, and examples include the methylene, ethylene, trimethylene, METROTILE, mutilation, dimethylmethylene etc.

The term "cycloalkyl" means a monovalent non-aromatic hydrocarbon ring group containing 3 to 8 the volume of carbon which may be partially unsaturated, and its examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctadiene etc.

The term "aryl" means a monovalent mono - to tri-cyclic aromatic hydrocarbon ring group containing from 6 to 14 carbon atoms, and examples include phenyl, naphthyl and the like, and preferred phenyl.

The term "aromatic heterocycle" means a monovalent mono - to tri-cyclic aromatic ring group containing a heteroatom such as nitrogen atom, oxygen atom, sulfur atom and the like, and its examples include pyridyl, thienyl, furyl, benzimidazolyl, pyrazinyl, pyridazinyl, thiazolyl, pyrimidinyl, benzothiazolyl, pyrazolyl, indazoles, pyrrolyl, oxazolyl, thiazoyl, tetrazolyl, indolyl, hinely, isothiazolin, isoxazol, imidazolyl and the like, and preferred pyridyl.

The term "the non-aromatic heterocycle" means a monovalent five - semicolony ring group containing a heteroatom such as nitrogen atom, oxygen atom, sulfur atom and the like, which may be partially unsaturated and may be condensed with aryl or aromatic heterocycle, and its examples include pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinil, azepine, maronil, tomohon, tetrahydrofuryl, tetrahydrothieno etc., and neither is preferred pyrrolidinyl, tetrahydrofuryl and tetrahydrothieno.

The term "aromatic cyclic amino" means a monovalent five - semicolony aromatic cyclic amino group which may contain nitrogen atom, oxygen or sulfur, and its examples include benzimidazolyl, indolyl, pyrazolyl, indazoles, pyrrolyl, imidazolyl and the like, and preferred pyrazolyl.

The term "non-aromatic cyclic amino" means a monovalent three - decatising, preferably five-semicolony, non-aromatic cyclic amino group which may be partially unsaturated and includes a nitrogen atom, oxygen or sulfur, and its examples include pyrrolidinyl, piperidinyl, azepine, maronil, tomohon, piperazinil, pyrazolidine, indolinyl, isoindolyl, dihydropyrrole, pyrrolidyl, dihydropyridines and the like, and preferred pyrrolidinyl, piperidinyl and dihydropyrrole.

The term "halogen" means a monovalent group of a halogen atom, and examples include fluorine, chlorine, bromine, iodine, etc.

As a group substituents, which can be defined by the term "optionally substituted" or "which may be substituted"can be used those which are usually used as groups, substituents for each corresponding group, and each group can contain one or more of the groups of substituents./p>

In the definition of R¹the term "optionally substituted amino group" include groups represented by the above General formulas (II) and (III).

As groups, substituents, which can be used in the case of aryl, cycloalkyl, aromatic heterocycle or a nonaromatic heterocycle, each of which may be substituted" in the definition of R¹²and "optionally substituted non-aromatic cyclic amino group" and "optionally substituted aromatic cyclic amino group" in the definition of R¹³, R¹⁴, R³and R⁴, examples include the following groups (a) to (h).

R^Andrepresents a lower alkyl group which may be substituted by one or more groups selected from the group consisting of-OH, -O-lower alkyl, amino which may be substituted by one or two lower alkilani, carbamoyl, which may be substituted by one or two lower alkilani, aryl, aromatic heterocycle, and halogen.

(a) halogen;

(b) -OH, -O-R^A, -O-aryl, -OCO-R^A, oxo(=O);

(c) -SH, -S-R^A, -S-aryl, -SO-R^A, -SO-aryl, SO₂-R^And, -SO₂-aryl, sulfamoyl, which may be substituted by one or two R^A;

(d) amino which may be substituted by one or two R^A,

-NHCO-R^A, -NHCO-aryl, -NHSO₂-R^A, -NHSO₂-aryl, nitro;

(e) -CHO, -CO-R^A, -CO₂H, -CO₂-R^A, carbarnoyl, which may be substituted by one or two R^A, cyano;

(f) aryl or cycloalkyl, each of which may be substituted by one or more groups selected from the group consisting of-OH, -O-lower alkyl, amino which may be substituted by one or two lower alkilani, carbamoyl, which may be substituted by one or two lower alkilani, aryl, aromatic heterocycle, halogen and R^A;

(g) aromatic heterocycle or the non-aromatic heterocycle, each of which may be substituted by one or more groups selected from the group consisting of-OH, -O-lower alkyl, amino which may be substituted by one or two lower alkilani, carbamoyl, which may be substituted by one or two lower alkilani, aryl, aromatic heterocycle, halogen and R^A;

(h) lower alkyl or lower alkenyl, each of which may be substituted by one or more groups selected from the group of substituents disclosed in (a) to (g).

As protective groups, which can be used to "optional secure hydratherapy" in the definition of R²³and R²⁴you can use the ones that are usually used as protective groups for amino groups, and those that are disclosed in "Protective Groups in Organic Synthesis", third edition, edited by Greene and Wuts. And the examples include acetyl, methoxycarbonyl, etoxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, phthalimide and the like, and preferred tert-butyloxycarbonyl.

The connection represented by the General formula (I)may contain asymmetric carbon atoms in accordance with the types of groups substituents, and may exist optical isomers based on asymmetric carbon atom. The compound of the present invention includes a mixture of optical isomers or dedicated isomers. In addition, the tautomers can be included in the compound of the present invention, and the compound of the present invention includes these isomers in a mixture or in the selected form.

In addition, the compound of the present invention may form a salt, which is included in the present invention, unless it is pharmaceutically acceptable. Examples of salts include salts of accession of mineral acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methansulfonate to the slot, econsultancy acid, p-toluensulfonate acid, aspartic acid, glutamic acid and the like; salts of inorganic bases, such as salts of sodium, potassium, magnesium, calcium and the like, or salts of organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like, and ammonium salts, etc. In the present invention also includes a hydrate and a solvate of the compounds and their pharmaceutically acceptable salts of the present invention, and those that have the polymorphism. In addition, the compounds of the present invention include compounds, so-called prodrugs that are metabolized in vivo into a compound of General formula (I) or its salt. As examples of compounds forming prodrugs, you can specify those disclosed in Prog. Med., 5; 2157-2161, 1985, and Hirokawa Shoten, 1990, "Development of medicine" Vol. 7, Molecular Design, pp 163-198.

Ways to get

The compound and its pharmaceutically acceptable salt can be obtained in various known synthesis methods, using the characteristics of the main chain or group types of the substituents. Typical methods of obtaining will be illustrated in more detail. And in accordance with the types of functional groups, in some cases it is beneficial from the point of view of methods of obtaining substitute a functional group suitable protective group, i.e. the group is, which is easy to turn to the functional group at the stage of obtaining source materials or intermediate compounds. Then, if necessary, the protective group is removed, getting the right connection. Examples of functional groups include hydroxy, carboxy and amino groups, and examples of protective groups include those that are disclosed in "Protective Groups in Organic Synthesis", third edition, edited by Greene and Wuts. It is preferable to use them appropriately depending on the reaction conditions.

The first way to obtain

(The first stage)

(where R², R³and R⁴have the above meanings; and one of X and Y is-H, lower alkyl or halogen, and the other is tsepliaeva group, or amino group).

At this stage, tsepliaeva group X or Y in the compound (1a) substitute optionally substituted non-aromatic cyclic amine or aromatic cyclic amine ("(1b)") to obtain compound (1c) or the amino group of X or Y is transformed into the group, pyrrol-1-yl. Examples tseplyaesh groups X or Y include a halogen atom, methylsulphonyl, 1H-benzotriazol-1 iloxi, methanesulfonate, p-toluensulfonate, tripterocalyx.

If one of R³and R⁴is pyrrole, one of X and Y represents an amino group, and in this case, the compound (1C) can be obtained by methods which have J.Med. Chem., 28(10), 1405, 1985.

And, if X or Y are tsepliaeva group, preferably I, Br, or tripterocalyx, the compound (1C) can be obtained by carrying out the reaction mix using Pd(0). The reaction mix can be made by way Tetrahedron Letters, Vol. 38, No. 66, pp. 6359-662, 1997.

And, if X represents tsepliaeva group, preferably F or Cl, the compound (1C) can be obtained by reaction of substitution. The above reaction can be conducted without solvent or in an inert solvent including aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and the like; N,N-dimethylformamide (DMF), dimethylacetamide (DMA), N-organic; dimethyl sulfoxide (DMSO); esters such as ethyl acetic acid (EtOAc); acetonitrile and the like, or an alcohol solvent, such as methanol (MeOH), ethanol (EtOH), 2-propanol and the like, at room temperature or by heating under reflux using equal molar amounts of the compounds (1a) and compound (1b), or an excessive amount of one of them.

Depending on the connection that you want to obtain, it is advantageous to conduct the reaction in the presence of an organic base (preferably triethylamine, Diisopropylamine is mine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine), or a salt of an alkali metal (preferably potassium carbonate, cesium carbonate, sodium hydroxide or sodium hydride). And, if one of R³and R⁴is optionally substituted pyrazolidinone group, the substitution reaction can be carried out using optional protected hydrazine, preferably hydrazine, a protected mono tert-butyl oxycarbonyl instead of the compound (1b), and then, if necessary, the protective group is removed for the reaction of a protected form of aldehyde arylacetamides (for example, dimethylacetal of acetylaldehyde) to education optionally substituted pyrazol ring. Education pyrazol ring advantageously carried out in the presence of acid, preferably hydrochloric acid, triperoxonane acid, p-toluensulfonate acid and the like), at room temperature or when heated.

The second stage

At this stage, the compound (1c)obtained in the first stage of the first method of obtaining, hydrolyzing to obtain the compound (1d).

The reaction can be conducted in a solvent inert in respect of the compound (1c), such as an aromatic hydrocarbon, ether, halogenated hydrocarbon, alcohol, DMF, DMA, DMSO, pyridine, water and the like, in the presence of a mineral acid,such as sulfuric acid, hydrochloric acid, Hydrobromic acid, in the presence of organic acids, such as formic acid, acetic acid, etc. or in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, or ammonia, in terms of cooling or heating under reflux. The reaction temperature you can choose accordingly depending on the connection.

The third stage

(where R⁵has the above values).

At this stage, the compound (1d) of the present invention is obtained by amidation of the compound (1d)obtained in the second stage of the first method of obtaining, or its reactive derivative, compound (1e).

As the reactive derivative of compound (1d) can use conventional ester such as methyl ester, ethyl ester, tert-butyl ester and the like; gelegenheid, such as the acid chloride, bromohydrin and the like; acid azide; an active ester of N-hydroxybenzotriazole, p-NITROPHENOL or N-hydroxysuccinimide and the like; symmetric acid anhydride; a mixed acid anhydride of alkylaminocarbonyl etc. and alkylboron of ester halogencarbonic acid, pivaloyloxy, the acid chloride p-toloo the sulfonic acid and the like; and mixed andrid acid type phosphate, produced by the interaction of diphenylphosphinylchloride and N-methylmorpholine.

And, if the compound (1d) is used in the form of a free acid or an active complex ether without separation, it is preferable to use a condensing agent such as dicyclohexylcarbodiimide (DCC), 1,1'-carbonylbis-1H-imidazole(CDI), diphenylphosphoryl (DPPA), diethylphosphoramidite hydrochloride and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI-HCl), etc.

In particular, in the present invention typically use a method using the acid chloride, the method of conducting the reaction in the presence of active tarifitsiruemih agent or condensing agent, or a method consisting in the normal processing of ester with the amine, as it is easy to obtain the compound of the present invention. The reaction, although it varies depending on the reactive derivative or condensing agent, lead in an inert organic solvent such as halogenated hydrocarbon, aromatic hydrocarbon, ether, ester, acetonitrile, DMF or DMSO and the like, under cooling, under cooling to room temperature, or at room temperature, or when heated to the ambient temperature.

When carrying out this reaction, so that it will crack the Ala smoothly, in some cases it is advantageous to use the compound (1e) in excess, or to conduct the reaction in the presence of a base, such as N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, lutidine, etc.. And you can use a salt of strong acid and weak base, such as pyridine hydrochloride, p-toluensulfonate pyridine, hydrochloride N,N-dimethylaniline, etc. in Addition, pyridine can be used as a solvent.

In particular, it is preferable to conduct the reaction in a solvent such as acetonitrile, DMF and the like, in the presence of a base, such as pyridine, N,N-dimethylaniline and the like, or salts such as hydrochloride, pyridine, etc.

The fourth stage

(where NRR' represents optionally substituted amino, preferably a group represented by the General formula (II) or (III)).

At this stage, the compound (1f) of the present invention obtained in the third stage, the first method of obtaining, hydrolyzing to obtain the compound (1g) of the present invention and then the compound (I) of the present invention is obtained by amidation of the compound (1g) or its reactive derivative of compound (1h).

Each reaction can be performed in accordance with the second stage or the third stage of the first method of receipt.

The second way to obtain

In this method, the compound (1e) hydrolyzing the first stage to obtain the compounds (2a), the compound (2b) is obtained by amidation of the compound (2a) or its reactive derivative of compound (1h) in the second stage, and then the compound (I) obtained by amidation of the compound (2b) of the compound (1d) or its reactive derivative at the third stage.

The reaction in the first stage can be maintained in accordance with the second stage of the first method of production, and reactions at the second and third stages in accordance with the third stage of the first method of receipt.

The third way to obtain

In this method, compound (3b) is obtained by amidation of the compound (2b)obtained in the second stage the second the production method, compound (3a) or its reactive derivative at the first stage and the second stage tsepliaeva group X or Y of the obtained compound (3b) substituted compound (1b) or optionally substituted hydrazine to education optionally substituted pyrazol ring, as shown in the first stage of the first method of production, resulting in the compound (I) of the present invention. Tsepliaeva group in X or Y is a group defined for the first stage of the first retrieval method.

The reaction in the first stage can be implemented in the CE is provided with the third stage of the first method of obtaining, and the reaction in the second stage in accordance with the first step of the first method of receipt.

The fourth way to obtain

(I) In this method, compound (4a) is obtained by amidation of the compound (1e) of the compound (3a) or its reactive derivative at the first stage, the obtained compound (4a) hydrolyzing to obtain the compound (4b) in the second stage, the compound (3b) is obtained by amidation of the obtained compound (4b) or its reactive derivative, compound (1h) at the third stage, and then in the fourth stage tsepliaeva group X or Y of the obtained compound (3b) substituted compound (1b) or optionally substituted hydrazine to obtain optional substituted pyrazol ring, as shown in the first stage of the first method of obtaining, receiving the compound (I) of the present invention. Tsepliaeva group X or Y is a group as defined in the first stage of the first method of receipt.

Response to the first and third stages can be performed in accordance with the third stage of the first of the production method, the reaction in the second stage in accordance with the second stage of the first method of obtaining, and the reaction in the fourth stage in accordance with the first step of the first method of receipt.

The fifth way to obtain

In this method, the first stage tsepliaeva group X or Y compounds (4a)obtained in the first stage of the fourth method of obtaining, replacing compound (1b) or optionally substituted hydrazine with education optionally substituted pyrazol ring, as shown in the first stage of the first retrieval method, thereby obtaining the compound (1f) of the present invention, which is hydrolized to obtain a compound (1g) of the present invention in the second stage, and then the compound (I) of the present invention is obtained by amidation of the compound (1g) or its reactive derivative of compound (1h) at the third stage. Tsepliaeva group X or Y has a value as determined at the first stage of the first method of receipt.

The reaction in the first stage can be performed in accordance with the first stage of the first of the production method, the reaction in the second stage in accordance with the second stage of the first method of obtaining, and the reaction in the third stage, in accordance with the third stage of the first method of receipt.

Thus obtained compound of the present invention is isolated and purified either in its free form or in the form of its salts. The salt of compound (I) can be obtained by subjecting his usual reaction to obtain salt. Isolation and purification of exercise, use the I conventional chemical methods, such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography, etc.

Different types of isomers can be distinguished in the usual way, using the differences in the physico-chemical characteristics of the isomers. For example, racemic compounds can be distinguished using conventional methods of separation of racemic compounds, for example, the way in which racemic compounds turn then reduced to diastereoisomeric salts using an optically active compound, such as tartaric acid and the like, and then subjected to optical separation. Diastereoisomer can be divided by fractional crystallization, or by using various types of chromatography or the like, in Addition, optically active compounds can be obtained by using a suitable optically active educt.

The compound and the salt of the present invention have an excellent stimulant effects receptor V₂arginine-vasopressin. Thus, the compound of the present invention, with antidiuretic action and effects release agents, blood coagulation factor VIII and the factor a background of Villebranda, can be used for treatment of various diseases of the genitourinary system, polyuria or hemorrhagic States, and it is an effective p and diagnosis, the prevention and treatment of polyuria, urinary incontinence, Central diabetes insipidus, nocturia, nocturnal enuresis, spontaneous bleeding, hemophilia, a disease von Willebrand's disease, uremia, congenital or acquired platelet dysfunction, bleeding with trauma or surgery, hepatocirrhosis etc.

Since the compound of the present invention has a small inhibitory activity against enzymes of drug metabolism CYP3A4 and CYP2C9, there are fewer problems in relation to interactions with other drugs which are metabolized oposredstvovanii CYP3A4 or CYP2C9, compared with the known derivatives benzazepine providing agonistic activity against V₂receptor arginine-vasopressin, and this connection can be safely used in a combined treatment with various drugs.

Examples of drugs which are metabolized oposredstvovanii CYP3A4 include simvastatin, lovastatin, fluvastatin, midazolam, nifedipine, amlodipine, nicardipine and the like, and examples of drugs which are metabolized oposredstvovanii CYP2C9 include diclofenac, ibuprofen, indometacin, tolbutamide, glibenclamide, losartan, etc. (General Clinic, 48(6), 1427-1431, 1999).

The pharmaceutical efficacy of the compounds of the present invention was confirmed by the following tests:

(1) analysis of the binding of V₂re is atarov

The sample cell membranes of Cho, expressing the V₂man, prepared in accordance with the method Tahara, et al. (British Journal of Pharmacology. Vol 125, p. 1463-1470, 1998). 2 μg of membrane sample is incubated in a total amount of 250 μl of 50 mm buffer solution of Tris-charnawati acid (pH7,4), containing 10 mm MgCl₂and 0.1% bovine serum albumin (BSA), together with [³H]-arginine-vasopressin (hereinafter referred to as [³H]-vasopressin) (0.5 nm, specific activity = 75 Curie/mmol) and test compound (10^-10˜10^-5M) at 25° within 60 minutes. Then allocate free [³H]-vasopressin and binding receptors [³H]-vasopressin, using cell collection, and binding receptors [³H]-vasopressin adsorb on the glass filter Unifilter Plate GF/B, well dried and then mixed with scintillation cocktail for microplates. The number of binding receptors [³H]-vasopressin determine, using the highest count, and the degree of inhibition calculated using the following equation.

The degree of inhibition(%) = 100-(C₁-B₁)/(C₀-B₁) X 100

C₁represents the number of [³H]-vasopressin, is associated with the membrane sample, when the sample membrane receptors is treated in the presence of test compounds of known concentration and [ ³H]-vasopressin C₀represents the number of [³H]-vasopressin, is associated with the membrane sample, when the sample membrane receptors treated with [³H]-vasopressin, in the absence of the test compound

B₁represents the number of [³H]-vasopressin, is associated with the membrane sample, when the sample membrane receptors treated with excess amount of vasopressin (10^-6M) and [³H]-vasopressin.

Using the above equation, calculate the concentration of the tested compounds, appropriate to the degree of inhibition of 50% (IC₅₀), and from this calculate the degree of affinity of the test compound to the receptor, i.e. the coefficient of dissociation (Ki)using the following equation.

The coefficient of dissociation(Ki) = IC₅₀/(1+[L]/Kd),

where [L] is the concentration of [³H]-vasopressin.

Kd is the ratio of the dissociation of [³H]-vasopressin for receptor, calculated on the basis of the analysis of saturation binding.

As control was used the compound of example 32, disclosed in WO 97/22591 (connection name: 2-[(5R)-1-(2-chloro-4-pyrrolidin-1-aventyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]-N-isopropylacetate).

As follows from the results of table 1, it was confirmed that the compound of the present invention have a high affinity to V₂the receptor.

(2) Analysis of antidiuretic ability (intravenous)

In this analysis using 5 male Wistar rats (aged 10-12 weeks) in each group. Animal groups And intravenous 0.3 mg/kg compound of example 135, animal groups In intravenous B, 0.3 mg/kg compound of example 201, and the animal group With intravenously injected 1 ml/kg saline solution containing DMSO as a control. After 15 minutes orally administered 30 ml/kg of distilled water (water load). Within 2 hours after water load urine are collected in the cells to determine the metabolism and the amount of urine when water load reaches 100%, calculated as the rate of urine output. This analysis uses the average speed of the urinary tract for each of the first group during the 1 hour and 2 hours after a water load. The results are presented in the following table 2.

As follows from the results of table 2, it was confirmed that the compound of the present invention has excellent antidiuretic action.

(3) analysis of the antidiuretic action (oral administration)

In this analysis, we used male Wistar rats (aged 10-12 weeks). The test compound is administered orally, and after 15 minutes orally administered 30 ml/kg of distilled water (water load). Within 4 hours after water load urine are collected in the cells to determine the metabolism and the amount of urine when water load reaches 100%, calculated as the rate of urine output. In the same analysis used the number of tested compounds necessary to reduce the rate of urine output by 50% (ED₅₀). The results are presented in table 3.

As can be seen from table 3, it was shown that the compound of the present invention has excellent antidiuretic action when administered orally as well as intravenously.

(4) analysis of the inhibition of the enzyme cytochrome P450 (3A4)

The analysis is carried out in accordance with the method Crespi, et al. (Analytical Biochemistry, 248,188-190, 1997).

Use the tablet with a 96-hole and 7-benzyloxy-4-(trifluoromethyl)coumarin (5x10^-5M) as a substrate, test the connection (4,9x10^-8˜5x10^-5M) and enzyme (5x10^-9M) are incubated in a total count of 200 μl of 200 mm phosphate buffer solution (pH 7,4)containing of 8.2 μm NADP+, 0,41 mm glucose-6-phosphate,0,41 mm MgCl ₂and 0.4 u/ml glucose-6-phosphate dehydrogenase at 37° within 30 minutes. Then it is added 0.5 M aqueous solution of 2-amino-2-hydroxymethyl-1,3-propane diol, containing 80% acetonitrile to stop the reaction, and the fluorescence intensity is measured using a device for determining the fluorescence of the tablet (excitation at a wavelength of 409 nm, the wavelength of fluorescence at 530 nm). The degree of inhibition calculated using the following equation, and calculate the concentration of the tested compounds, appropriate to the degree of inhibition of 50% (IC₅₀).

The results are presented in the following table 4.

The degree of inhibition (%) = 100-(C₁-B₁)/(C₀-B₁)x100

C₁the fluorescence intensity in the presence of a known concentration of test compound, enzyme and substrate;

C₀the fluorescence intensity in the presence of enzyme and substrate, but in the absence of the test compound;

B₁the fluorescence intensity of the control wells.

(5) Effects of inhibition of the enzyme cytochrome P450 (2C9)

This analysis is carried out in accordance with the method Crespi, et al. (Analytical Biochemistry, 248, 188-190, 1997).

Use 96-well plate and 7-methoxy-4-(trifluoromethyl)coumarin (7,5x10^-5M) as a substrate, test the connection (4,9x10^-8˜5x10^-5M) and the enzyme (10^-8 M) are incubated in a total volume of 200 μl of 200 mm phosphate buffer solution (pH7,4), comprising of 8.2 μm NADP+, 0,41 mm glucose-6-phosphate, 0,41 mm MgCl₂and 0.4 U/ml glucose-6-phosphate dehydrogenase at 37° within 45 minutes. Then it is added 0.5 M aqueous solution of 2-amino-2-hydroxymethyl-1,3-propane diol, containing 80% acetonitrile, to stop the reaction and measure the intensity of fluorescence, using a device for measuring fluorescence on the tablet (wavelength excitation 409 nm, the wavelength of fluorescence at 530 nm). The degree of inhibition calculated from the above in (4) equations and calculate the concentration of the tested compounds, appropriate to the degree of inhibition of 50% (IC₅₀).

The results are presented in the following table 4.

As shown in table 4, the compound of the present invention shows a very low effects ingebyra the project enzymes of drug metabolism CYP3A4 and CYP2C9. As control using the same connection as in table 1.

The pharmaceutical composition of the present invention can be obtained by conventional means, using one or more of the types of compounds of the present invention and pharmaceutical carriers, fillers and other additives commonly used in the preparation of medicines.

They can be administered either orally in the form of tablets, pills, capsules, granules, powders, solutions, etc. or in the form of parenteral drugs for injection, such as intravenous injection, intramuscular injection and the like, or in the form of suppositories, or in the form of preparations for nasal administration, the introduction of a mucous membrane, or percutaneous injection, etc.

Solid compositions intended for oral administration, in accordance with the present invention is used in the form of tablets, powders, granules, etc. Upon receipt of such solid compositions one or more of the active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate or magnesium aluminate. Typically, the composition may contain additives, different from the inert diluent, which include lubricating agents such as magnesium stearate, divide the Commissioner, agents, such as glycolate, calcicolous, stabilizing agents, such as lactose, and agents that promote solubilization, such as glutamic acid or aspartic acid. If necessary, tablets or pills may be coated by the sugar-coated or film soluble in the gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose, or the like

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. and contain a generally used inert diluent such as purified water or ethanol. Besides inert diluents, the composition may contain auxiliary agents, such as moisturizing agents, and suspendresume agents such as sweeteners, flavoring agents, fragrances and preservatives.

Injections for parenteral introduction include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of aqueous solutions and suspensions include distilled water for injection and physiological solutions.

Examples of non-aqueous solutions and suspensions include vegetable oils such as propylene glycol, polyethylene glycol, olive oil or the like, alcohols such as ethanol, Polysorbate 80 and the like, Such component is icii can in addition, to contain auxiliary agents, such as antiseptic and moisturizing agents, dispersing agents, stabilizers (e.g., lactose), and agents that promote solubilization (for example, glutamic acid or aspartic acid). These compositions are sterilized, for example, by filtration through a retaining bacteria filter, mixing with bactericidal agents, or using irradiation. In another embodiment, they can be used, creating the beginning of sterile solid compositions, and then dissolving them in sterile water or a sterile solvent for injection before use.

In the case of preparations for oral administration, the daily dose is approximately 0,0001˜50 mg/kg body weight, preferably about 0.001 to 10 mg/kg and more preferably about 0.01 to 1 mg/kg, and the daily dose is administered once a day or dividing it into 2 to 4 doses per day. In the case of intravenous administration, a daily dose of approximately of 0.0001-1 mg/kg body weight, preferably approximately of 0.0001-0.1 mg/kg, and the daily dose is given once a day or divided into several doses per day. Dose approximately determine, given the symptoms, age and sex, etc. of the patient requiring treatment. Since the dose varies depending on the conditions, in some cases, enough is nazyvautsa smaller doses.

The preferred embodiment of the invention

Further, the invention is disclosed more clearly with reference to examples, but these examples in no way limit the present invention. In this regard, new substances included in the original substance, which is used in the examples and the methods of obtaining the starting substances of known substances disclosed in the comparative examples.

Comparative example 1

of 20.85 g of methyl 2-chloro-4-perbenzoate dissolved in 150 ml of N-methylpyrrolidone, and to this add 30,68 g of potassium carbonate and 9,38 ml of 3-methylpyrazole, and this mixture was stirred at 120° within 3 hours. In addition, they add to it to 1.79 ml of 3-methylpyrazole and this mixture was stirred at 120°C for 3 hours. The reaction solution is cooled, mixed with water, and extracted with EtOAc. The organic layer was washed with water and brine and then dried over magnesium sulfate. The solvent is evaporated and then the residue purified using a chromatographic column with silica gel (hexane-EtOAc (20:1)), getting a 9.25 g of methyl 2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoate.

Compounds of comparative examples 2-40 get in the way of comparative example 1.

Comparative example 41

2.0 g of methyl 4-amino-2-chlorobenzoate dissolved in 10 ml of acetic acid, to this add 2.0 ml of 2,5-dimethoxyethane-hydrofuran and this mixture on Renaut at boiling under reflux for 15 minutes. After cooling the reaction solution, the solvent is evaporated. The resulting residue is mixed with EtOAc and saturated aqueous NaHCO₃and extracted. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (hexane-EtOAc (4:1))to give 2.1 g of methyl 2-chloro-4-(1H-pyrrol-1-yl)benzoate.

The compound of comparative example 42 receive by way of comparative example 41.

Comparative example 43

2.0 g of methyl 4-bromo-2-methylbenzoate dissolved in 20 ml of toluene, and to this added 1.08 ml pyrrolidine, 4.0 g of cesium carbonate, 200 mg of Tris(dibenzylideneacetone)-diplodia (0) and 200 mg (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and then this mixture is heated at boiling under reflux for 6 hours. The reaction solution is cooled, mixed with water and EtOAc and extracted. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is purified using a chromatographic column with silica gel (hexane-EtOAc (25:1)), getting 0,784 g of methyl 2-methyl-4-pyrrolidin-1 eventuate.

The compound of comparative example 44 get in the way of comparative example 43.

Comparative example 45

a 9.25 g of compound of comparative example 1 Rast is oraut in 10 ml of acetic acid and 10 ml of 6 M aqueous HCL solution and then this mixture is heated at the boil under reflux for 13 hours. The reaction solution is cooled, and then poured into ice water, and the thus obtained crystals are filtered, getting 8,56 g of 2-chloro-4-(3-methylpyrazole-1-yl)benzoic acid.

Comparative example 46

10.7 g of the compound of comparative example 2 are dissolved in 60 ml of MeOH and 20 ml of 5M aqueous NaOH solution and this mixture is heated at the boil under reflux for 2 hours. The reaction solution is cooled, and then neutralized with 2 M aqueous solution of HCL, and the solvent is evaporated. To the resulting residue is added water and the resulting crystals hoteltravel getting 10,17 g of 2-chloro-4-pyrrolidin-1-eventing acid.

Compounds of comparative examples 47-88 get in the way of comparative example 46.

The structure and physical characteristics of the compounds of comparative examples shown in tables 5-8.

In the tables, the symbols have the following meanings:

Rf stands for the number of the comparative example;

MS represents the results of mass spectrometric studies (FAB-MS(M+H)⁺if there are no other indications, MM, MN, and ME respectively mean FAB-MS(M)⁺, FAB-MS(M-H)⁺and EI-MS(M)⁺);

R^b, R^c, R^drepresent groups of substituents in the General formula (Me: methyl, Et:, iPr: isopropyl, cPr: cyclopropyl, tBu: tert-butyl, Ph: phenyl, pra: pyrazolyl, pyrr:pyrrolidinyl, mor: morpholinyl, the: thienyl imid: imidazolyl, bimid: benzimidazolyl, pipe: piperidyl, di: di). The number in front of a group of Deputy specifies the position of the substituent. Thus, for example, 3-Me-1-pra corresponds to 3-methylpyrazole-1-DRS, 3,3-diMe-1-pyrr corresponds 3,3-dimethylpiperidin-1-DRS, and 3-(2-the)-1-pra corresponds to 3-thiophene-2-alprazol-1-ILU.

Table 5
A number of comparative example	Deputy Rb	Deputy Rc	The results of mass-spectrometric studies
1	Cl	3-Me-1-pra	FAB-MS(M+H)+:251
2	Cl	1-pyrr	FAB-MS(M+H)+:240
3	Cl	1-pra	FAB-MS(M+H)+:237
4	Cl	4-mor	EI-MS(M)+:255
5	Cl	3-phenyl-1-pra	FAB-MS(M+H)+:313
6	Cl	4-Br-1-pra	FAB-MS(M+H)+:315,317
7	Cl	3-(2-the)-1-pra	FAB-MS(M+H)+:319
8	Cl	indazol-1-yl	FAB-MS(M+H)+:287
9	Cl	3,5-diMe-1-pra	FAB-MS(M+H)+:265
10	Cl	2-Me-imid	FAB-MS(M+H)+:251
11	Cl	1-bimid	FAB-MS(M+H)+:287
12	Cl	5-Me-1-pra	FAB-MS(M+H)+:251
13	Cl	2-Me-1-pyrr	FAB-MS(M+H)+:254
14	Cl	3-(R)-Me-1-pyrr	FAB-MS(M+H)+:254
15	Cl	3-(S)-Me-1-pyrr	FAB-MS(M+H)+:254
16	Cl	3,3-diMe-1-pyrr	FAB-MS(M)+:267
17	Cl	3-F-1-pyrr	FAB-MS(M+H)+:258
18	Cl	3-phenyl-1-pyrr	FAB-MS(M+H)+:316
19	Cl	3-Me-3-Et-1-pyrr	FAB-MS(M+H)+:282
20	Cl	3,5-diMe-1-pipe	FAB-MS(M+H)+:282
21	Cl	3-Me-1-pipe	FAB-MS(M+H)+:268
22	Cl	3-Et-1-pra	FAB-MS(M+H)+:265
23	Cl	3-iPr-1-pra	FAB-MS(M+H)+:279
24	Cl	3-cPr-1-pra	FAB-MS(M+H)+:277
25	CF3	1-pyrr	FAB-MS(M+H)+:274
26	CF3	3-Me-1-pra	FAB-MS(M+H)+:285
27	CF3	3-(R)-Me-1-pyrr	FAB-MS(M+H)+:288
28	CF3	3-(S)-Me-1-pyrr	FAB-MS(M+H)+:288
29	CF3	3,4-diMe-1-pyrr
30	CF3	3,3-diMe-1-pyrr	FAB-MS(M)+:30
31	CF3	2,5-dihydropyrrol-1-yl	FAB-MS(M+H)+:272
32	CF3	3-iPr-1-pra	FAB-MS(M+H)+:313
33	CF3	3-F3C-1-pra	FAB-MS(M+H)+:339
34	CF3	3,5-diMe-1-pra	FAB-MS(M+H)+:299
35	CF3	4-Me-1-pra	FAB-MS(M+H)+:285
36	CF3	3-tBu-1-pra	FAB-MS(M+H)+:327
37	CF3	5-Me-1-pra	FAB-MS(M+H)+:285
39	Cl	1-pipe	EI-MS(M)+:253
40	Cl	azepin-1-yl	EI-MS(M)+:267
41	Cl	pyrrol-1-yl/td>	FAB-MS(M+H)+:236
42	Cl	2,5-diMe-pyrrol-1-yl	FAB-MS(M)+:263
43	Methyl	1-pyrr	FAB-MS(M+H)+:220
Table 6
A number of comparative example	Deputy Rc	Deputy Rd	The results of mass-spectrometric studies
38	3-Me-1-pra	F	FAB-MS(M+H)+:269
44	H	1-pyrr	FAB-MS(M+H)+:240
Table 7
A number of comparative example	Deputy Rb	Deputy Rc	The results of mass-spectrometric studies
45	Cl	3-Me-1-pra	FAB-MS(M-H)+:235
46	Cl	1-pyrr	FAB-MS(M+H)+:226
47	Cl	1-pra	FAB-MS(M+H)+:223
48	Cl	4-mor	FAB-MS(M-H)+:241
49	Cl	3-phenyl-1-pra	FAB-MS(M-H)+:297
50	Cl	4-Br-1-pra	FAB-MS(M-H)+:299,301
51	Cl	3-(2-the)-1-pra	FAB-MS(M-H)+:303
52	Cl	Indazol-1-yl	FAB-MS(M-H)+:271
53	Cl	3,5-diMe-1-pra	FAB-MS(M-H)+:249
54	Cl	Pyrrol-1-yl	FAB-MS(M-H)+:220
55	Cl	2-Me-1-imid	FAB-MS(M+H)+:237
56	Cl	1-bimid	FAB-MS(M+H)+:273
57	Cl	5-Me-1-pra	FAB-MS(M-H)+:235
58	2-Me-1-pyrr	FAB-MS(M+H)+:240
59	Cl	3-(R)-Me-1-pyrr	FAB-MS(M+H)+:240
60	Cl	3-(S)-Me-1-pyrr	FAB-MS(M+H)+:240
61	Cl	3,3-diMe-1-pyrr	FAB-MS(M+H)+:254
62	Cl	3-F-1-pyrr	FAB-MS(M+H)+:244
63	Cl	3-phenyl-1-pyrr	FAB-MS(M-H)+:300
64	Cl	3-Me-3-Et-1-pyrr	FAB-MS(M+H)+:268
65	Cl	3,5-diMe-1-pipe	FAB-MS(M-H)+:266
66	Cl	3-Me-1-pipe	FAB-MS(M-H)+:252
67	Cl	3-Et-1-pra	FAB-MS(M+H)+:251
68	Cl	3-iPr-1-pra	FAB-MS(M+H)+:265
69	Cl	3-cPr-1-pra	FAB-MS(M+H)+:263
70	Cl	2,5-diMe-pyrrol-1-yl	FAB-MS(M-H)+;248
71	CF3	1-pyrr	FAB-MS(M+H)+:258
72	CF3	3-Me-1-pra	FAB-MS(M+H)+:271
73	CF3	3-(R)-Me-1-pyrr	FAB-MS(M+H)+:274
74	CF3	3-(S)-Me-1-pyrr	FAB-MS(M-H)+;272
75	CF3	3,4-diMe-1-pyrr	FAB-MS(M+H)+:288
76	CF3	3,3-diMe-1-pyrr	FAB-MS(M+H)+:288
77	CF3	2,5-dihydropyrrol-1-yl	FAB-MS(M+H)+:258
78	CF3	3-iPr-1-pra	FAB-MS(M+H)+:299
79	CF3	3-F3C-1-pra	FAB-MS(M-H)+:323
80	CF3	FAB-MS(M+H)+:285
81	CF3	4-Me-1-pra	FAB-MS(M+H)+:271
82	CF3	3-tBu-1-pra	FAB-MS(M+H)+:313
83	CF3	5-Me-1-pra	FAB-MS(M+H)+:271
84	IU	1-pyrr	FAB-MS(M+H)+:206
85	Cl	1-pipe	FAB-MS(M-H)+:238
86	Cl	Azepin-1-yl	FAB-MS(M-H)+:252
Table 8
A number of comparative example	Deputy Rc	Deputy Rd	The results of mass-spectrometric studies
87	3-Me-1-pra	F	FAB-MS(M+H)+:255
88	H	1-pyrr	FAB-M(M+H) +:226

Comparative example 89

8.0 g of methyl (2Z)-(4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene)acetate was dissolved in 20 ml MeOH and 20 ml THF. To this add 45 ml of 1M aqueous NaOH solution and the resulting mixture was stirred at room temperature for 15 hours. The reaction solution is concentrated under reduced pressure and the residue is neutralized 1 M aqueous HCl solution. The reaction solution is mixed with chloroform and shaken out. The organic layer was washed with brine, dried over sodium sulfate and the solvent is evaporated, receiving of 4.57 g of carboxylic acid intermediate connection. of 4.57 g of carboxylic acid, an intermediate compound is dissolved in 45 ml of DMF. This type of 22.2 ml of 2-picolylamine, 3.6 g of 1-hydroxybenzotriazole (HOBt) and 5.6 g of the hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI-model HC1) and this mixture was stirred at room temperature for 18 hours. The reaction solution is mixed with water and EtOAc and extracted them. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (chloroform-MeOH (25:1)), getting 6,849 g (2Z)-2-(4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene)-N-(pyridine-2-ylmethyl)ndimethylacetamide.

FAB-MS; 330. ([M+H]⁺).

Comparative example 90

To a solution of 1.37 g with the organisations of example 6, 0.45 g of HOBt and 0.63 g of EDCI-HCl in 15 ml of DMF, add and 0.46 g of the hydrochloride of the methyl ether complex of sarcosine and 0.47 g of triethylamine and the resulting mixture was stirred at room temperature overnight. The reaction solution is mixed with an aqueous solution of NaHCO₃and EtOAc and extracted. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent the obtained ester intermediate compound was dissolved in 20 ml of MeOH, to this add 5 ml of 1 M aqueous NaOH solution and this mixture was stirred at room temperature for 1 hour. To the crude product obtained after evaporation of the solvent, add 1M aqueous solution of HCI and loose in the precipitated white crystals are filtered, washed with water and dried under reduced pressure, getting 1,43 g [((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl(methyl)amino)acetic acid.

FAB-MS; 529. ([M+H]⁺).

Example 1

To the suspension to 21.0 g of 2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoic acid in 200 ml of 1,2-dichloroethane added at room temperature, 15 ml of thionyl chloride and 3 drops of DMF and this mixture was stirred at 70° within 2 hours. The reaction solution is cooled to room temperature, the solvent is evaporated and the residue is dried, obtaining a connection in the form of PI is rangered. This type of 22.5 g of methyl (2Z)-(4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene)acetate, then to this add 200 ml of pyridine under ice cooling, and this mixture was stirred at room temperature for 20 hours. After completion of the reaction the solvent is evaporated, and the residue is mixed with diluted hydrochloric acid and EtOAc, and extracted. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (hexane-EtOAc (9:1˜4:1))to give 38.0 g of methyl (2Z)-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetate.

Example 2

To a solution of 3.0 g of 4-bromo-2-methylbenzoic acid in 20 ml of THF and 1 drop of DMF added under ice cooling 1.9 ml of oxalicacid and this mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue is mixed with 3 ml of toluene and again concentrated. The resulting residue is mixed with 20 ml of pyridine and 3.5 g of methyl (2Z)-(4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene)acetate and this mixture was stirred at room temperature for 12 hours. The reaction mixture is concentrated and then added to the mixture chloroform and 1 M aqueous NaOH solution and extracted. The organic layer is raybaut water and brine and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (hexane-EtOAc (6;1)), getting 5,94 g of methyl (2Z)-[1-(4-bromo-2-methylbenzoyl)-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]acetate.

Example 3

The solution to 4.62 g of 2-(trifluoromethyl)benzoic acid in 30 ml of sulfuric acid type of 3.48 g of 1,3-dibromo-5,5-dimethylhydantoin. The resulting mixture was stirred at room temperature for 15 hours and then added dropwise to ice water. To the reaction solution was added 5 M aqueous solution of NaOH to bring the pH of the solution to 12 and then the reaction solution is extracted with chloroform. To the aqueous layer add concentrated hydrochloric acid to bring the pH of the solution to 1 and then the reaction solution is extracted with chloroform. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate.

After evaporation of the solvent the residue is added 20 ml of THF and 1 drop of DMF, and to this added under ice cooling to 2.5 ml of oxalicacid, and then this mixture was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the residue is mixed with 10 ml of toluene and again concentrated. To the obtained residue is added 20 ml of pyridine and 6.2 g of methyl (2Z)-(4,4-debtor-1,2,3,4-tetrahydro-5H-1-benazep is n-5-ilidene)acetate and this mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the residue is mixed with chloroform and 1 M aqueous HCl solution, and extracted. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (hexane-EtOAc(6:1)). Obtained by concentration under reduced pressure the residue is crystallized from EtOH, getting 3,66 g of methyl (2Z)-{1-[4-bromo-2-(trifluoromethyl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetate.

Example 4

To a solution of 2.0 g of the compound of example 2 in 30 ml of toluene added to 22.35 g of tert-butyl of hydrazinecarboxamide, 1,43 g of cesium carbonate, 400 mg of Tris(dibenzylideneacetone)diplegia(0) and 740 mg of 1,1'-bis(diphenylphosphino)ferrocene and this mixture was stirred at 100° within 4 hours. After cooling, the reaction solution is insoluble substances ofintravenous and to the filtrate add EtOAc and 10% aqueous citric acid solution for the extraction of the filtrate. The organic layer was washed with water and brine and dried over anhydrous anhydride sodium sulfate.

After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (hexane-EtOAc (2:1))to give 1.0 g of tert-butyl 1-(4-{[(5Z)-4,4-debtor-5-(2-methyl-2-oxoethylidene)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenylhydrazine of carboxylate.

Example 5

To a solution of 1.0 g of compound of example 4 in 10 ml of EtOAc add 10 ml of 4 M HCl-EtOAc and this mixture was stirred at room temperature for 4 hours. The reaction solution is concentrated under reduced pressure, and the residue is mixed with saturated aqueous NaHCO₃and chloroform, and extracted. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After evaporation of the solvent to the residue add 40 ml of MeOH and 275 mg of dimethylacetal of acetylaldehyde and the resulting mixture is heated at the boil under reflux for 1.5 hour. To the reaction solution add 3 drops of concentrated hydrochloric acid and the resulting mixture was again heated at the boil under reflux for 30 minutes. The reaction solution is cooled and then concentrated under reduced pressure. The residue is mixed with saturated aqueous sodium bicarbonate and chloroform and shaken out. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (hexane-EtOAc(4:1)), getting 561 mg of methyl (2Z)-{4,4-debtor-1-[2-methyl-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetate.

Example 6

38.0 g of the compound of example 1 rest the accelerate in 120 ml MeOH and 120 ml of THF, add 100 ml of 1 M aqueous NaOH solution at room temperature and this mixture is stirred for 10 hours. Approximately 200 ml of the solvent is evaporated under reduced pressure, to the residue under cooling with ice added 0.5 M aqueous HCl solution and the resulting mixture is stirred for 1 hour. The resulting white precipitate filtered and dried, obtaining 36.5 g (2Z)-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)-benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-1H-1-benzazepin-5-ilidene}acetic acid in powder form.

Example 7

To a solution of 229 mg of the compound of the example of 6.71 mg HOBt and 101 mg of EDCI-HCL in 3 ml of DMF added 35 mg of thiophene-2-ylmethylamino and the resulting mixture was stirred at room temperature overnight. The reaction solution is mixed with saturated aqueous sodium bicarbonate and chloroform and shaken out. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. Then the residue purified using a chromatographic column with silica gel (chloroform-MeOH (30:1)). The residue obtained by concentration under reduced pressure, crystallized from a solvent mixture of 2-propanol-diisopropyl ether, receiving 61 mg of (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl]benzoyl}-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(thiophene-2-ylmethyl)ndimethylacetamide.

Example 8

210 mg of the compound of example 6 is dissolved is in 20 ml of dichloroethane, add 2 ml of thionyl chloride and this mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, and the residue is mixed with toluene and again concentrated. The obtained acid chloride was dissolved in 30 ml of acetonitrile and added dropwise to 30 ml of ammonia water at room temperature. After stirring at room temperature for 12 hours, the resulting white precipitate filtered and dried, obtaining 259 mg 2(Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-benzazepin}ndimethylacetamide in powder form.

Example 9

915 mg of the compound of example 14 was dissolved in 20 ml MeOH, add 3 ml of 1M aqueous NaOH solution and the resulting mixture was stirred at room temperature for a period of 15.5 hours. The solvent is evaporated under reduced pressure and then the residue is acidified with 1M aqueous HCL solution and extracted with chloroform. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After evaporation of the solvent the obtained carboxylic acid, an intermediate compound, dissolved in 10 ml of DMF, and to this type of 0.24 ml of 2-picolylamine, 0.39 g HOBt 0,61 g EDCI-HCL, and this mixture was stirred at room temperature for 84 hours. The reaction solution is mixed with water and EtOAc and extracted. The organic layer is included which indicate the brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (chloroform-MeOH (35:1)). The residue obtained by concentration under reduced pressure, dissolved in EtOAc, to this add 0.4 ml of 4M HCl-EtOAc and the solvent is evaporated under reduced pressure. The resulting residue is crystallized from EtOH, getting 0,456 g of hydrochloride (2Z)-2-[1-(2-chloro-4-pyrrolidin-1-aventyl)-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]-N-(pyridine-2-ylmethyl)ndimethylacetamide.

Example 10

0.25 g of the compound of example 93 was dissolved in 10 ml MeOH, add 10 ml of 1M NaOH and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution is neutralized 1 M aqueous HCl solution and extracted with chloroform. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is crystallized from a solvent mixture of EtOAc-hexane, getting 116 mg [((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}acetyl)amino]acetic acid.

Example 11

To a solution of 258 mg of the compound of example 10, 71 mg of HOBt and 101 mg of EDCI-HCL in 5 ml of THF, add 0.5 ml of a 2.0 M solution of methylamine-THF and this mixture was stirred at room temperature overnight. The reaction solution smesi the Ute with saturated aqueous NaHCO ₃and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate. The resulting evaporation of the solvent the crude product is purified using a chromatographic column with silica gel (chloroform-MeOH (30:1)). Obtained by concentration under reduced pressure the residue is crystallized from a solvent mixture of 2-propanol-hexane, receiving 51 mg of (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-[2-(methylamino)-2-oxoethyl]ndimethylacetamide.

Example 12

To a solution of 265 mg of the compound of comparative example 90 in 5 ml of THF added 82 mg of 1,1'-carbonylbis-1H-imidazole and the mixture was stirred at room temperature for 1 hour. Then to the reaction solution was added ammonia water and this mixture was stirred at room temperature for 22 hours. The reaction solution is mixed with water and EtOAc and extracted with this mixture. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. Obtained after evaporation of the solvent the crude product was then purified using a chromatographic column with silica gel (chloroform-MeOH(100:1)). The residue obtained by concentration under reduced pressure, crystallized from a solvent mixture of 2-propanol-diisopropyl ether, receiving 41 mg of (2Z)-N-[2-amino-2-kaatil]-N-methyl-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide.

Example 13

To a solution of 0.35 g of the compound of comparative example 85 in 10 ml of THF and 1 drop of DMF added under ice cooling to 0.22 ml of thionyl chloride and this mixture was stirred at room temperature for 2.5 hours. The reaction solution is concentrated under reduced pressure, and the residue is mixed with 3 ml of toluene and again concentrated. The resulting residue is dissolved in 20 ml of acetonitrile, add 0.4 g of the compound of comparative example 89 and 0.4 ml of pyridine and this mixture was stirred at 80° for 17 hours. After cooling the reaction solution, the solvent is evaporated, and the residue is mixed with chloroform and 10% aqueous citric acid solution, and extracted with this mixture. The organic layer was washed with saturated aqueous sodium bicarbonate and brine and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is purified using a chromatographic column with silica gel (chloroform-MeOH-ammonia water (25:0:0,1)). The residue obtained by concentration under reduced pressure, dissolved in EtOAc, this type of 0.18 ml of 4M HCl-EtOAc and the solvent is evaporated under reduced pressure. The resulting residue is crystallized from EtOH, getting 0,176 g of hydrochloride (2Z)-2-[1-(2-chloro-4-piperidine-1-aventyl)-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]-N-(pyridine-2-ylmethyl)ndimethylacetamide.

Structure and physico-chemical characteristics of the compounds of examples are presented in table 9. In addition, the structure and physico-chemical characteristics of the compounds obtained in the same method of production, are also presented in tables 9-16. Symbols in the tables have the following meanings:

Ex represents the number of the sample;

Salt refers to salt;

Syn means the method of synthesis (the Number indicates the number of the example, which illustrates this method);

R^A, R^B, R^With, R^D, R^1Arepresent a group of the substituent in the General formula (nPen: normal pencil, cHex: cyclohexyl, Ac: acetyl, Ms: masil, Boc: tert-butyloxycarbonyl, py: pyridyl, fur: furyl, thia - thiazolyl, bthia - benzothiazolyl. So, as examples: -NHCH_2-(2-py) denotes pyridine-2-flotillin, -NHCH₂-(4-HO-3-MeO-Ph) means 4-hydroxy-3-methoxybenzylamine, and 2-HOCH₂-1-pipe means 2-hydroxyethylpiperazine-1-yl.)

Table 9
The number of sample (g)	Deputy RA	Deputy RB	Deputy RC	MC	The method of synthesis
1	-OMe	Cl	3-Me-1-pra	472	1
2	-OMe	Me	-Br	452	2
3	-OMe	CF3	-Br	504	3
4	-OMe	Me	-N(Boc)NH2	502	4
5	-OMe	Me	3-Me-1-pra	452	5
6	-OH	Cl	3-Me-1-pra	458	6
7	-NHCH2-(2-the)	Cl	3-Me-1-pra	553	7
8	-NH2	Cl	3-Me-1-pra	457	8
9(HCl)	-NHCH2-(2-py)	Cl	1-pyrr	538	9
10	-NHCH2CO2H	Cl	3-Me-1-pra	515	10
11	-NHCH2CONHMe	Cl	3-Me-1-pra	528	11
12	-N(Me)CH2CONH2	Cl	3-Me-1-pra	528	12
13(HCl)	-NHCH2-(2-py)	Cl	1-pipe	551	13
Table 10
The number of sample (g)	Deputy RB	Deputy RC	MS	The method of synthesis
14	Cl	1-pyrr	461	1
15	Cl	2-Me-1-pyrr	475	1
16	Cl	3-Me-1-pyrr	475	1
17	Cl	3-(R)-Me-1-pyrr	MM;474	1
18	Cl	3-(S)-Me-1-pyrr	475	1
19	Cl	3,3-diMe-1-pyrr	489	1
20	Cl	3-Me-3-Et-1-pyrr	503	1
21	Cl	3-F-1-pyrr	479	1
22	Cl	3-phenyl-1-pyrr	538	1
23	CF3	1-pyrr	495	1
24	CF3	3-(R)-Me-1-pyrr	509	1
25	CF3	3-(S)-Me-1-pyrr	509	1
26	CF3	3,4-diMe-1-pyrr	523	1
27	CF3	3,3-diMe-pyrr	523	1
28	Me	1-pyrr	441	1
29	Cl	1-pra	458	1
30	Cl	5-Me-1-pra	472	1
31	Cl	3-Et-l-pra	486	1
32	Cl	3-iPr-1-pra	500	1
33	Cl	3-cPr-1-pra	498	1
34	Cl	3,5-diMe-1-pra	486	1
35	Cl	4-Br-1-pra	536,538	1
36	Cl	3-phenyl-1-pra	534	1
37	Cl	3-(2-the)-1-pra	540	1
38	CF3	3-Me-1-pra	506	1
39	CF3	3-Me-1-pra	506	5
40	CF3	4-Me-1-pra	506	1
41	CF3	5-Me-1-pra	506	1
42	CF3	3-iPr-1-pra	534	1
43	CF3	3-F3C-1-pra	560	1
44	CF3	3-tBu-1-pra	548	1
45	CF3	3,5-diMe-1-pra	520	1
46	Cl	3-Me-1-pipe	565	1
47	Cl	3,5-diMe-1-pipe1	579	1
48	Cl	4-mor	477	1
49	Cl	pyrrol-1-yl	457	1
50	Cl	2,5-diMe-pyrrol-1-yl	485	1
51	CF3	2,5-dihydro-1H-pyrrol-1-yl	493	1
52	Cl	2-Me-imidazol-1-yl	472	1
53	1-bimid	508	1
54	Cl	indazol-1-yl	508	1
55	CF3	-N(Boc)NH2	556	4
Table 11
The number of sample (g)	Deputy RAnd	Vice-tel RIn	MS	The method of synthesis
56	3-HO-1-pyrr	Cl	527	7
57	3-HO-1-pipe	Cl	541	7
58	3-H2NOC-1-pipe	Cl	568	7
59	4-H2NOC-1-pipe	Cl	568	7
60	2-HOCH2-1-pipe	Cl	555	7
61	3-HOCH2-1-pipe	Cl	555	7
62	-NH-(2-HO-cHex)	Cl	555	7
63	-NHPh	Cl	533	7
64	-NH-(2-HO-Ph)	Cl	549	7
65	-NH-(3-HO-Ph)	Cl	549	7
66	-NH-(4-HO-Ph)	Cl	549	7
67	-NH-(S-Ac-Ph	Cl	575	7
68	-NH-(3-HO2C-Ph)	Cl	577	7
69	-NH-(3-MeO2C-Ph)	Cl	591	7
70	-NH-(2-H2NOC-Ph)	Cl	576	7
71	-NH-(3-H2NOC-Ph)	Cl	576	7
72	-NH-(4-H2NOC-Ph)	Cl	576	7
73	-NH-(3-MeNHCO-Ph)	Cl	590	7
74	-NH-(3-Me-Ph)	Cl	547	7
75	-NH-(2-HOCH2-Ph)	Cl	563	7
76	-NH-(3-HOCH2-Ph)	Cl	563	7
77	-NH-(4-HOCH2-Ph)	Cl	563	7
78	-NH-(3-HO(CH2)2-Ph)	Cl	577	7
79	-NH-(3-MeCH(OH)-Ph)	Cl	577	7
80	-NH-(2-HOCH2CH(OH)-Ph)	Cl	593	7
81	-NH-(4-HOCH2CH(OH)-Ph)	Cl	593	7
82	-NH-(3-MeOCH2-Ph)	Cl	577	7
-NH-(3-H2NOCCH2-Ph)	Cl	590	7
84	-NH-(3-H2NOC(CH2)2-Ph)	Cl	604	7
85	-NH-(3-H2NOC-(E)-CH=CH-Ph)	Cl	602	7
86	-NH-(3-F-Ph)	Cl	551	7
87	-NH-(3-Ms-Ph)	Cl	611	7
88	-NH-(3-AcNH-Ph)	Cl	590	7
89	-NH-(3-the)	Cl	539	7
90		Cl	540	7
91		Cl	541	7
92		Cl	557	7
93	-NHCH2CO2Me	Cl	529	7
94	-NHCH2CONH2	Cl	514	7
95	-NHCH2Ph	Cl	547	7
96	-NHCH2-(4-HO-Ph)	Cl	563	7
97	-NHCH2-(3-HO-Ph)	Cl	563	7
98	-NHCH2-(2-HO-Ph)	Cl	563	7
99	-NHCH2-(3,4-diHO-Ph)	Cl	579	7
100	-NHCH2-(4-MeO-Ph)	Cl	577	7
101	-NHCH2-(3,4-diMeO-Ph)	Cl	607	7
102	-NHCH2-(4-HO-3-MeO-Ph)	Cl	593	7
103	-NHCH2-(4-HO2C-Ph)	Cl	591	7
104	-NHCH2-(4-MeO2C-Ph)	Cl	605	7
105	-NHCH2To(4-H2NOC-Ph)	Cl	590	7
106	-NHCH2-(3-H2NOC-Ph)	Cl	590	7
107	-NHCH2-(3-HOCH2-Ph)	Cl	577	7
108	-NHCH2-(4-F-Ph)	Cl	565	7
109	-NHCH2To(4-H2NO2S-Ph)	Cl	626	7
110(HCl)	-NHCH2-(2-py)	Cl	548	7
111	-NHCH2-(6-HO-2-py)	Cl	564	7
112	-NHCH2-(5-MeO-2-py)	Cl	578	7
113(HCl)	-NHCH2-(6-MeO-2-py)	Cl	7
114	-NHCH2-(6-iPrO-2-py)	Cl	606	7
115	-NHCH2-(6-H2NOC-2-py)	Cl	591	7
116	-NHCH2-(6-Me2NOC-2-py)	Cl	619	7
117	-NHCH2-(6-cyano-2-py)	Cl	573	7
118	-NHCH2-(5-Me-2-py)	Cl	562	7
119(HCl)	-NHCH2-(6-Me-2-py)	Cl	562	7
120(HCl)	-NHCH2-(6-HOCH2-2-py)	Cl	578	7
121(HCl)	-NHCH2-(6-H2N-2-Me-3-py)	Cl	577	7
122(HCl)	-NHCH2-(6-H2N-2-py)	Cl	563	7
123	-NHCH2-(6-Me2N-2-py)	Cl	591	7
124	-NHCH2-(6-F-2-py)	Cl	566	7
125	-NHCH2-(6-Cl-2-py)	Cl	582	7
126(HCl)	-NHCH2-(3-py)	Cl	548	7
127	-NHCH2-(3-the)	Cl	553	7
128	-NHCH2-(2-fur)	Cl	537	7
129	-NHCH2-(2-thia)	Cl	554	7
130	-NHCH2-(4-thia)	Cl	554	7
131(HCl)	-NHCH2-(pyrazol-2-yl)	Cl	549	7
132	-NHCH2-(pyridazin-3-yl)	Cl	549	7
133	-NHCH2-(pyrimidin-4-yl)	Cl	549	7
134	-NHCH2-(pyridazin-4-yl)	Cl	549	7
135(HCl)	-NHCH2-(2-bimid)	Cl	587	7
136(HCl)	-NHCH2-(1-Me-2-bimid)	Cl	601	7
137	-NHCH2-(2-bthia)	Cl	604	7
138	-NHCH(CONH2)2	Cl	557	7
139	-NH(CH2)2OH	Cl	501	7
140	-(R)-NHCH(Me)CH2OH	Cl	515	7
141	-(S)-NHCH(Me)CH2OH	Cl	515	7
142	-(R)-NHCH2CH(Me) - OH	Cl	515	7
143	-(S)-NHCH2CH(Me) - OH	Cl	515	7
144	-NHC(Me)2CH2OH	Cl	529	7
145	-NHCH2C(Me)2OH	Cl	529	7
146	-NH(CH2)2OMe	Cl	515	7
147	-NH(CH2)2CONH2	Cl	528	7
148	-NHCH(CO2Me)CH2OH	Cl	559	7
149	-NHCH(CONH2)CH2OH	Cl	544	7
150	-NHCH(Ph)CH2OH	Cl	577	7
151	-NH(CH2)3OH	Cl	515	7
152	-NHCH2CH(OH)CH2OH	Cl	531	7
153	-NHCH(CH2OH)2	Cl	531	7
154	-NH(CH2)4OH	Cl	529	7
155	-NHnPen	Cl	527	7
156	-NMe2	Cl	485	7
157	-N(Me)(CH2)2OH	Cl	515	7
158	-N((CH2)2OH)2	Cl	545	7
159	-N(CH2 CONH2)((CH2)2OH)	Cl	558	7
160	-N(CH2-2-py)((CH2)2OH)	Cl	592	7
161	-N(CH2CONH2)2	Cl	571	7
162	-NH2	CF3	491	9(8)
163	-NH(CH2)2OH	CF3	535	9
164	-NHCH2CONH2	CF3	548	9
165(HCl)	-NHCH2-(2-py)	CF3	582	9
166	-NHCH2CONH2	Me	494	9
167	-NH2	Me	437	9(8)
Table 12
The number of sample (g)	Deputy RIn	Deputy RWith	MS	The method of synthesis
168	Cl	1-pyrr	446	9(8)
169	Cl	3,3-diMe-1-pyrr	474	9(8)
170	Cl	3-F-1-pyrr	464	9(8)
171	Cl	3-phenyl-1-pyrr	522	9(8)
172	Cl	3-Me-3-Et-1-prr	488	9(8)
173	Cl	3-(S)-Me-1-pyrr	460	9(8)
174	Cl	3-(R)-Me-1-pyrr	460	9(8)
175	CF3	1-pyrr	480	9(8)
176	CF3	3-(R)-Me-1-pyrr	494	9(8)
177	CF3	3-(S)-Me-1-pyrr	494	9(8)
178	CF3	3,3-diMe-1-pyrr	508	9(8)
179	CF3	3,4-diMe-1-pyrr	508	9(8)
180	CF3	4-Me-1-pra	491	9(8)
181	CF3	5-Me-1-pra	491	9(8)
182	CF3	3-iPr-1-pra	519	9(8)
183	CF3	3-tBu-1-pra	533	9(8)
184	CF3	3-F3C-1-pra	545	9(8)
185	CF3	3,5-diMe-1-pra	505	9(8)
Table 13
The number of sample (g)	Deputy RIn	Deputy RWith	MS	The method of synthesis
186(HCl)	Cl	2-Me-1-pyrr	551	9
187(HCl)	Cl	3-Me-1-pyrr	551	9
188(HCl)	Cl	3,3-diMe-1-pyrr	565	9
189(HCl)	Cl	3-F-1-pyrr	555	9
190(HCl)	Cl	1-pra	534	9
191(HCl)	Cl	5-Me-1-pra	547	9
192(HCl)	Cl	3-Et-1-pra	562	9
193(HCl)	Cl	3-iPr-1-pra	576	9
194(HCl)	Cl	3-cPr-1-pra	574	9
195(HCl)	Cl	3,5-diMe-1-pra	562	9
196	Cl	4-Br-1-pra	612, 614	9
197	Cl	3-phenyl-1-pra	610	9
198	Cl	3-(2-the)-1-pra	616	9
199(HCl)	Cl	3-Me-1-pipe	565	9
200(HCl)	Cl	3,5-diMe-1-pipe	579	9
201(HCl)	Cl	4-mor	553	9
202(HCl)	Cl	azepin-1-yl	565	13
203(HCl)	Cl	pyrrol-1-yl	533	9
204(HCl)	Cl	2,5-diMe-pyrrol-1-yl	561	9
205	Cl	2-Me-1-imid	548	9
206(HCl)	Cl	1-bimid	584	9
207(HCl)	Cl	indazol-1-yl	584	9
208(HCl)	CF3	1-pyrr	571	9
209(HCl)	Me	1-pyrr	517	9
Table 14
The number of sample (g)	Deputy RAnd	Deputy RIn	Deputy RWith	MS	The method of synthesis
210	-NH(CH2)2OH	Cl	1-pyrr	490	9
211	-NH(CH2)2OH	Cl	3-(R)-Me-1-pyrr	504	9
212	-NH(CH2)2OH	Cl	3-(S)-Me-1-pyrr	504	9
213	-NH(CH2)2OH	Cl	3,3-diMe-1-pyrr	518	9
214	-NH(CH2)2OH	CF3	1-pyrr	524	9
215	-NH(CH2) 2OH	CF3	3-(R)-Me-1-pyrr	538	9
216	-NH(CH2)2OH	CF3	3-(S)-Me-l-pyrr	538	9
217	-NH(CH2)2OH	CF3	3,3-diMe-1-pyrr	552	9
218	-NH(CH2)2OH	CF3	3,4-diMe-1-pyrr	552	9
219	-NH(CH2)2OH	CF3	4-Me-1-pra	535	9
220	-NHCH2CONH2	Cl	1-pyrr	503	9
221	-NHCH2CONH2	Cl	3-(R)-Me-1-pyrr	517	9
222	-NHCH2CONH2	Cl	3-(S)-Me-l-pyrr	517	9
223	-NHCH2CONH2	Cl	3,3-diMe-1-pyrr	531	9
224	-NHCH2CONH2	Cl	3-phenyl-1-pyrr	579	9
225	-NHCH2CONH2	Cl	3-Me-3-Et-1-pyrr	545	9
226	-NHCH2CONH2	CF3	1-pyrr	537	9
227	-NHCH2CONH2	CF3	3-(R)-Me-1-pyrr	551	9
228	-NHCH2CONH2	CF3	3-(S)-Me-1-pyrr	551	9
229	-NHCH2CONH2	CF3	3,3-diMe-1-pyrr	565	9
230	-NHCH2CONH2	CF3	3,4-diMe-1-pyrr	565	9
231	-NHCH2CONH2	CF3	3-F3C-1-pra	602	9
232	-NHCH2CONH2	CF3	4-Me-1-pra	548	9
233	-NHCH2CONH2	CF3	3-tBu-1-pra	590	9
234	-NHCH2CONH2	CF3	2,5-dihydropyr-rol-1-yl	535
Table 15
The number of sample (g)	Deputy RAnd	Deputy RIn	Deputy RWith	Deputy RD	MS	The method of synthesis
235	OMe	Cl	H	1-pyrr	461	1
236	OMe	Cl	3-Me-1-pra	F	490	1
237(HCl)	-NHCH2-(2-py)	Cl	H	1-pyrr	537	9
238	-NH2	Cl	3-Me-1-pra	F	474	9(8)
Table 16
The number of sample (g)	Deputy RAnd	Deputy RIn	Deputy RWith	MS	The method of synthesis
239	-NMe2	Cl	3-Me-1-pra	542	11
240	-NH(CH2)2OH	Cl	3-Me-1-pra	558	11
241	1-pyrr	Cl	3-Me-1-pra	568	11
242	1-pipe	Cl	3-Me-1-pra	582	11
243	2-HOCH2-1-pipe	Cl	3-Me-1-pra	612	11
244	3-HOCH2-1-pipe	Cl	3-Me-1-pra	612	11

These NMR of compounds, some examples are shown in table 17. The term "NMR " refers to δ(ppm) peaks for H-NMR obtained using DMSO-d₆as a solvent for measurement, unless otherwise specified, and (CH₃)₄Si as internal standard.

The structure of the compounds of the present invention are shown in table 18. These compounds can be easily synthesized by methods obvious to the average person skilled in the art, or modified methods.

Table 18
The connection number	R1	R2	R3	R4	R5
A1	-NH-(4-HO2C-Ph)	Cl	3-Me-pra	H	N
A2	-NH-(2-HO2C-Ph)	Cl	3-Me-pra	H	N
A3	-NH-(4-Me2N-Ph)	Cl	3-Me-pra	H	N
A4	-NH-(4-cyano-Phenyl)	Cl	3-Me-pra	H	N
A5	-NH-(3-F3C-Ph)	Cl	3-Me-pra	H	N
A6	-NH-(2-MeO-Ph)	Cl	3-Me-pra	H	N
A7	-NH-(2-F-Ph)	Cl	3-Me-pra	H	N
A8	-NHCH2-(2-H2NOC-Ph)	Cl	3-Me-pra	H	N
A9	-NH-(6-HO-3-py)	Cl	3-Me-pra	H	N
A10	-NH-(6-Cl-pyridazin-3-yl)	Cl	3-Me-pra	H	N
A11	-NH-(6-Me-2-py)	Cl	3-Me-pra	H	N
A12	-NH-(5-H2NOC-2-py)	Cl	3-Me-pra	H	N
A13	-NH-(2-thia)	Cl	3-Me-pra	H	N
A14	-NH-(1-Me-2-imid)	Cl	3-Me-pra	H	N
A15	-NH-(pyrazin-2-yl)	Cl	3-Me-pra	H	N/td>
A16	-N(Me)-(6-HO-3-py)	Cl	3-Me-pra	H	N
A17	-NHCH2To(4-H2NOC-2-py)	Cl	3-Me-pra	H	N
A18	-N(Me)CH2-(3-py)	Cl	3-Me-pra	H	N
A19	-NHCH2-(4-F-2-py)	Cl	3-Me-pra	H	N
A20	-NHCH2-(pyrimidin-2-yl)	Cl	3-Me-pra	H	N
A21	2-H2NOC-pyrr	Cl	3-Me-pra	H	N
A22	2-H2NOC-pipe	Cl	3-Me-pra	H	N
A23		Cl	3-Me-pra	H	N
A24		Cl	3-Me-pra	H	N
A25		Cl	3-Me-pra	H	N
A26		Cl	3-Me-pra	H	N
A27		Cl	3-Me-pra	H	N
A28		Cl	3-Me-pra	H	N
A29		Cl	3-Me-pra	H	N
A30		Cl	3-Me-pra	H	N
A31		Cl	3-Me-pra	H	N
A32		Cl	3-Me-pra	H	N
A33		Cl	3-Me-pra	H	N
A34		Cl	3-Me-pra	H	N
A35		Cl	3-Me-pra	H	N
A36		Cl	3-Me-pra		N
A37		Cl	3-Me-pra	H	N
A38		Cl	3-Me-pra	H	N
A39		Cl	3-Me-pra	H	N
A40		Cl	3-Me-pra	H	N
A41		Cl	3-Me-pra	H	N
A42		Cl	3-Me-pra-	H	H
A43		Cl	3-Me-pra-	H	H
A44	-NHCH2-(2-py)	Br	3-Me-pra-	H	H
A45	-NH(CH2)2OH	Br	3-Me-pra-	H	H
A46	-NHCH2CONH2	Br	3-Me-pra-	H	H
A47	-NH2	Br	3-Me-pra-	H	H
A48	-NHCH2-(2-py)	Me	3-Me-pra-	H	H
A49	-NH(CH2)2OH	Me	3-Me-pra-	H	H
A50	-NHCH2CONH2	Me	3-Me-pra-	H	H
A51	-NH2	Me	3-Me-pra-	H	H
A52	-NH(CH2)2OH	Me	pyrr-	H	H
A53	-NHCH2-(6-HO-2-py)	Me	Pyrr-	H	H
A54	-NHCH2-(2-py)	Me	pyrr-	H	H
A55	-N((CH2)2OH)2	Me	pyrr-	H	H
A56	-NH2	Me	pyrr-	H	H
A57	-NHCH2CONH2	Me	3-Me-pyrr-	H	H
A58	-NHCH2-(2-py)	Me	3-Me-pyrr-	H	H
A59	-NH2	Me	3-Me-pyrr-	H	H
A60	-NH(CH2)2OH	Me	3-Me-pyrr-	H	H
A61	-NHCH2CONH2	Me	3,3-diF-pyrr-	H	H
A62	-NHCH2CONH2	Me	3,4-diMe-pyrr-	H	H
A63	-NH2	Me	3,3-diF-pyrr-	H	H
A64	-NH2	Me	3,4-diMe-pyrr-	H	H
A65	-NHCH2-(6-HO-2-py)	CF3	3-Me-pra-	H	H
A66	-NHCH2-(6-Me-2-py)	CF3	3-Me-pra-	H	H
A67		CF3	3-Me-pra-	H	H
A68	-NHCH2-(6-HO-2-py)	CF3	3-Me-pra-	H	H
A69	-N((CH2)2OH)2		CF3	3-Me-pra-	H	H
A70	-NHCH2-(6-HO-2-py)	CF3	pyrr-	H	H
A71	-NHCH2-(2-py)	CF3	pyrr-	H	H
A72	-N((CH2)2OH)2	CF3	pyrr-	H	H
A73	-N((CH2)2OH)2	Cl	3-Me-pyrr-	H	H
A74	-NHCH2-(2-py)	Cl	2-H2NOC-pyrr-	H	H
A75	-NHCH2-(2-py)	Cl	3-HO-pipe-	H	H
A76	-NHCH2-(2-py)	CF3	3-HO-pipe-	H	H
A77	-NHCH2-(2-py)	Cl	3-MeO-pyrr-	H	H
A78	-NHCH2-(2-py)	CF3	3-MeO-pyrr-	H	H
A79	-NHCH2-(2-py)	Cl	4-NC-pipe-	H	H
A80	-NHCH2-(2-py)	Cl	3,4-diMe-pyrr-	H	H
A81	-NH(CH2)2OH	Cl	2,4-diMe-pyrr-	H	H
A82	-NHCH2-(2-py)	Cl		H	H
A83	-NH(CH2)2OH	Cl		H	H
A84	-NHCH2CONH2	Cl		H	H
A85	-NH(CH2)2OH	CF3		H	H
A86	-NHCH2-(2-py)	CF3		H	H
A87	-NHCH2-(2-py)	Cl	3-Me-pra-	H	7-Me
A88	-NHCH2-(2-py)	Cl	3-Me-pyrr-	H	7-Me
A89	-NHCH2-(2-py)	Cl	3-Me-pra-	H	7-C1
A90	-NHCH2-(2-py)	Cl	3-Me-pyrr-	H	7-C1
A91	-NHCH2-(2-py)	CF3	3-Me-pra	H	7-Me
A92	-NHCH2-(2-py)	CF3	3-Me-pyrr	H	7-Me
A93	-NHCH2-(2-py)	CF3	3-Me-pra	H	7-C1
A94	-NHCH2-(2-py)	CF3	3-Me-pyrr	H	7-C1
95	-NHCH2-(2-py)	Cl	3-Me-pra	H	8-Me
A96	-NHCH2-(2-py)	Cl	3-Me-pyrr	H	8-Me
A97	-NHCH2-(2-py)	Cl	3-Me-pra	H	8-C1
A98 motorway	-NHCH2-(2-py)	Cl	3-Me-pyrr	H	8-C1
A99	-NHCH2-(2-py)	CF3	3-Me-pra	H	8-Me
A100	-NHCH2-(2-py)	CF3	3-Me-pyrr	H	8-Me
A101	-NHCH2-(2-py)	CF3	3-Me-pra	H	8-C1
A102	-NHCH2-(2-py)	CF3	3-Me-pyrr	H	8-C1
A103	-NHCH2-(2-py)	Cl	H	3-Me-pra-	H
A104	-NHCH2-(2-py)	Cl	H	3-Me-pyrr-	H
A105	-NHCH2CONH2	Cl	H	3-Me-pyrr-	H
A106	-NHCH2-(2-py)	Cl	H	pyrr-	H
A107	-NHCH2-(2-py)	CF3	H	3-Me-pra-	H
A108	-NHCH2-(2-py)	CF3	H	3-Me-pyrr-	H
A109	-NHCH2CONH2	CF3	H	3-Me-pyrr-	H
A110	-NHCH2-(2-py)	CF3	H	pyrr-	H
A111	-NH(CH2)2OH	Cl	3,3-diF-pyrr	H	H
A112	-NHCH2CONH2	Cl	3,3-diF-pyrr	H	H
A113	-NH(CH2)2OH	CF3	3,3-diF-pyrr	H	H
A114	-NHCH2CONH2	CF3	3,3-diF-pyrr	H	H
A115	-NH(CH2)2OH	Cl	3-CF3-pyrr	H	H
A116	-NHCH2CONH2	Cl	3-CF3-pyrr	H	H
A117	-NH(CH2)2OH	CF3	3-CF3-pyrr	H	H
A118	-NHCH2CONH2	CF3	3-CF3-pyrr	H	H
A119	-NH(CH2)2OH	Cl	2,5-dihydro-pyrrol-1-yl	H	H
A120	-NHCH2CONH2	Cl	2,5-dihydropyrrol-1-yl	H	H
A121	-NH2	Cl	2,5-dihydro-pyrrol-1-l	H	H
A122	-NH(CH2)2/sub> OH	Cl	3,4-diMe-1-pyrr	H	H
A123	-NHCH2CONH2	Cl	3,4-diMe-1-pyrr	H	H
A124	-NH2	Cl	3,4-diMe-1-pyrr	H	H
A125	-NHCH2CONH2	Cl		H	H
A126	-NH2	Cl		H	H
A127	-NHCH2CONH2	Cl	3,4-diHO-1-pyrr	H	H
A128	-NH2	Cl	3,4-diHO-1-pyrr	H	H
A129	-NH-(3-HOCH2-(E)-CH=CH-Ph)	CF3	3-Me-pra	H	H
A130	-NH-(3-HO2C-(E)-CH=CH-Ph)	CF3	3-Me-pra	H	H
A131	-NH-(3-phenyl-(E)-CH=CH-Ph)	CF3	3-Me-pra	H	H
A132	-NH-2-(5-H2NOC-(E)-CH=CH-Py)	CF3	3-Me-pra	H	H
A133	OMe	CF3	H2N-(Ac)N-	H	H
A134	OEt	CF3	H2N-(Ac)N-	H	H
A135	OEt	CF3	H2N-(Boc) - N-	H	H
A136	OiPr	CF3	H2N-(Boc) - N-	H	H
A137	OEt	Cl	H2N-(Boc) - N-	H	H
A138	OiPr	Cl	H2N-(Boc) - N-	H	H
A139	OEt	CF3	H2N-HN-	H	H
A140	OiPr	CF3	H2N-HN-	H	H
A141	OEt	Cl	H2N-HN-	H	H
A142	OiPr	Cl	H2N-HN-	H	H
A143	-NHCH2CONH2	CF3	3-Me-pra	Me	H
A144	CF3	3-Me-pra	Me	H
A145	-NHCH2CONH2	CF3	3-Me-pra	F	H
A146	-NH2	CF3	3-Me-pra	F	H
A147	-NHCH2CONH2	CF3	3-Me-pyrr	F	H
A148	-NH2	CF3	3-Me-pyrr	F	H
A149	-NH2	CF3	3-Me-pyrr	Me	H
A150	-NH-(4-H2NOC-Ph)	CF3	3-Me-pra	H	H
A151	-NH-(3-H2NOC-Ph)	CF3	3-Me-pra	H	H
A152	-NH-(3-Me-Ph)	CF3	3-Me-pra	H	H
A153	-NH-(4-HOCH2-Ph)	CF3	3-Me-pra	H	H
A154	-NH-(3-HOCH2-Ph)	CF3	3-Me-pra	H	H
A155	-NH-(4-MeOCH2-Ph)	CF3	3-Me-pra	H	H
A156	-NHCH2To(4-H2NOC-Ph)	CF3	3-Me-pra	H	H
A157	-NH-(3-Ms-Ph)	CF3	3-Me-pra	H	H
A158	-NH-(3-Ac-Ph)	CF3	3-Me-pra	H	H
A159	-NHCH2To(4-H2NO2S-Ph)	CF3	3-Me-pra	H	H
A160	-NH-(2-HO-cHex)	CF3	3-Me-pra	H	H
A161	-NH-(3-H2NOCCH2-Ph)	CF3	3-Me-pra	H	H
A162	-NH-(3-H2NOC(CH2)2-Ph)	CF3	3-Me-pra	H	H
A163	-NH-(3-H2NOC-(E)-CH=CH-Ph)	CF3	3-Me-pra	H	H
A164	-NH-(3-AcNH-Ph)	CF3	3-Me-pra	H	H
A165	-NH-(4-H2NOC-Ph)	CF3	3-Me-pyrr	H	H
A166	-NH-(3-H2NOC-Ph	CF3	3-Me-pyrr	H	H
A167	-NH-(3-Me-Ph)	CF3	3-Me-pyrr	H	H
A168	-NH-(4-HOCH2-Ph)	CF3	3-Me-pyrr	H	H
A169	-NH-(3-HOCH2-Ph)	CF3	3-Me-pyrr	H	H
A170	-NH-(4-MeOCH2-Ph)	CF3	3-Me-pyrr	H	H
A171	-NH-(3-Ms-Ph)	CF3	3-Me-pyrr	H	H
A172	-NH-(3-Ac-Ph)	CF3	3-Me-pyrr	H	H
A173	-NHCH2To(4-H2NOS-Ph)	CF3	3-Me-pyrr	H	H
A174	-NH-(2-HO-cHex)	CF3	3-Me-pyrr	H	H
A175	-NH-(3-H2NOCCH2-Ph)	CF3	3-Me-pyrr	H	H
A176	-NH-3-H 2NOC(CH2)2-Ph)	CF3	3-Me-pyrr	H	H
A177	-NH-(3-H2NOC-(E)-CH=CH-Ph)	CF3	3-Me-pyrr	H	H
A178	-NH-(3-AcNH-Ph)	CF3	3-Me-pyrr	H	H
A179	-NH-(4-H2NOC-Ph)	Cl	3-Me-pyrr	H	H
A180	-NH-(3-H2NOC-Ph)	Cl	3-Me-pyrr	H	H
A181	-NH-(3-Me-Ph)	Cl	3-Me-pyrr	H	H
A182	-NH-(4-HOCH2-Ph)	Cl	3-Me-pyrr	H	H
A183	-NH-(3-HOCH2-Ph)	Cl	3-Me-pyrr	H	H
A184	-NH-(4-MeOCH2-Ph)	Cl	3-Me-pyrr	H	H
A185	-NH-(3-Ms-Ph)	Cl	3-Me-pyrr	H	H
A186	-NH-(3-Ac-Ph)	Cl	3-Me-pyrr	H	H
A187	-NHCH2To(4-H2NO2 S-Ph)	Cl	3-Me-pyrr	H	H
A188	-NH-(2-HO-cHex)	Cl	3-Me-pyrr	H	H
A189	-NH-(3-H2NOCCH2-Ph)	Cl	3-Me-pyrr	H	H
A190	-NH-(3-H2NOC(CH2)2-Ph)	Cl	3-Me-pyrr	H	H
A191	-NH-(3-H2NOC-(E)-CH=CH-Ph)	Cl	3-Me-pyrr	H	H
A192	-NH-(3-AcNH-Ph)	Cl	3-Me-pyrr	H	H

1. Derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the General formula (I)or its pharmaceutically acceptable salt

where R¹represents-OH, -O-lower alkyl or optionally substituted amino;

R²represents lower alkyl which may be substituted by one or more halogen atoms, or halogen;

R³, R⁴one is-H, lower alkyl or halogen and the other represents an optionally substituted nonaromatic cyclic amino or optionally substituted aromatic cyclic amino; and

R⁵is-H, lower alkyl, or halogen.

2. The compound according to claim 1, where R¹represents-OH, -O-lower alkyl, a group represented by the following General formula (II), or a group represented by the following General formula (III):

where a represents a simple bond, a lower alkylene or lowest alkylen-C(=O)-;

R¹¹represents lower alkyl which may be substituted by a group selected from the group consisting of-OH, -O-lower alkyl, -CO₂H, -CO₂is lower alkyl and carbamoyl, which may be substituted by one or two lower alkilani, or N;

R¹²is

(1) if a represents a simple bond or a lower alkylene, R¹²represents aryl, cycloalkyl, aromatic heterocycle or the non-aromatic heterocycle, each of which may be substituted, or-H, -OH, -O-lower alkyl, -CO₂H, -CO₂-lower alkyl, or carbarnoyl, which may be substituted by one or two lower alkilani; and

(2) if a is lowest alkylen-C(=O)-, R¹²represents a group represented by the General formula (III), or a group represented by the General formula (IV);

In represents a simple bond or a lower alkylene;

R¹³, R¹⁴are optionally substituted nonaromatic Ilichevsky amino, associated together with the neighboring nitrogen atom.

3. The compound according to claim 2, where R¹represents a group represented by the General formula (II), or a group represented by the General formula (III).

4. The compound according to claim 3, where R³is optionally substituted nonaromatic cyclic amino or optionally substituted aromatic cyclic amino; R⁴is-H, lower alkyl, or halogen and R⁵is N.

5. The compound according to claim 4, where R⁴is N.

6. The compound according to any one of claims 1 to 5, where the compound is chosen from the group consisting of

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(pyridine-2-ylmethyl)ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-[1-(2-chloro-4-pyrrolidin-1-aventyl)-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene]ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-(3-methyl-1H-pyrazole-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-debtor-1-[4-(3R)-3-methylpyrrolidine-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-[(3R)-3-methylpyrrolidine-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}-N-(2-hydroxyethyl)ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-debtor-1-[4-(3S)-3-methylpyrrolidine-1-yl]-2-(Tr is permitil)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-[(3-methyl-1H-pyrazole-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene] -N- (2-hydroxyethyl) ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3R)-3-methylpyrrolidine-1-yl]benzoyl}-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene)ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3S)-3-methylpyrrolidine-1-yl]benzoyl}-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene)ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[4-(4-methyl-1H-pyrazole-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{1-[4-(3,4-dimethylpiperidin-1-yl)-2-(trifluoromethyl)benzoyl]-4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide;

(2Z)-2-{4,4-debtor-1-[2-methyl-4-(3-methyl-1H-pyrazole-1-yl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ilidene}ndimethylacetamide

and their pharmaceutically acceptable salts.

7. Pharmaceutical composition, which represents the agonist receptor V₂arginine-vasopressin, comprising the compound according to claim 1 as an active ingredient.

8. The pharmaceutical composition according to claim 7, where the pharmaceutical composition is a medicine used to treat Central diabetes insipidus or nocturia.

9. Derivative of 4,4-debtor-1,2,3,4-tetrahydro-5H-1-benzazepine represented by the General formula (V)or its pharmaceutically acceptable salt:

where R²¹is lower alkyl;

R²²represents chlorine or trifluoromethyl and

R²³and R²⁴one is-H and the other is not necessarily secure hydratherapy.