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

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

 

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 V1aV1band V2. It is known that a major pharmaceutical action of AVP on the periphery are vasoconstriction, oposredstvovaniya V1Areceptor, 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).

RAndrepresents 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-RA, -O-aryl, -OCO-RA, oxo(=O);

(c) -SH, -S-RA, -S-aryl, -SO-RA, -SO-aryl, SO2-RAnd, -SO2-aryl, sulfamoyl, which may be substituted by one or two RA;

(d) amino which may be substituted by one or two RA,

-NHCO-RA, -NHCO-aryl, -NHSO2-RA, -NHSO2-aryl, nitro;

(e) -CHO, -CO-RA, -CO2H, -CO2-RA, carbarnoyl, which may be substituted by one or two RA, 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 RA;

(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 RA;

(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.

Table 1
Affinity to V2receptor
ConnectionKi(nm)ConnectionKi(nm)
Example 723,7 Example 584,8
Example 762,2Example 745,6
Example 1195,6Control68

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.

Table 2
Antidiuretic action (intravenous)
ConnectionThe rate of urinary tract (%)
After 1 hourAfter 2 hours
Group aExample 13501,1
GroupExample 201013,3
GroupDMSOto 49.958,4

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.

Table 3
Antidiuretic action (oral administration)
ConnectionED50(mg/kg)ConnectionED50(mg/kg)
Example 1390,14Example 1740,17
Example 760,22Example 1730,16
Example 1750,38

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.

Table 4
Effects of inhibition of CYP(3A4 and 2C9)
ConnectionIC50(µm)
CYP3A4CYP2C9
Example 8>2013
Example 190166,5
Example 2201011
Control<0,091<0,091

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)+);

Rb, Rc, Rdrepresent 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.

FAB-MS(M+H)+:302 Cltd align="center" namest="c3" nameend="c6"> 3,5-diMe-1-pra
Table 5
A number of comparative exampleDeputy RbDeputy

Rc
The results of mass-spectrometric studies
1Cl3-Me-1-praFAB-MS(M+H)+:251
2Cl1-pyrrFAB-MS(M+H)+:240
3Cl1-praFAB-MS(M+H)+:237
4Cl4-morEI-MS(M)+:255
5Cl3-phenyl-1-praFAB-MS(M+H)+:313
6Cl4-Br-1-praFAB-MS(M+H)+:315,317
7Cl3-(2-the)-1-praFAB-MS(M+H)+:319
8Clindazol-1-ylFAB-MS(M+H)+:287
9Cl3,5-diMe-1-praFAB-MS(M+H)+:265
10Cl2-Me-imidFAB-MS(M+H)+:251
11Cl1-bimidFAB-MS(M+H)+:287
12Cl5-Me-1-praFAB-MS(M+H)+:251
13Cl2-Me-1-pyrrFAB-MS(M+H)+:254
14Cl3-(R)-Me-1-pyrrFAB-MS(M+H)+:254
15Cl3-(S)-Me-1-pyrrFAB-MS(M+H)+:254
16Cl3,3-diMe-1-pyrrFAB-MS(M)+:267
17Cl3-F-1-pyrrFAB-MS(M+H)+:258
18Cl 3-phenyl-1-pyrrFAB-MS(M+H)+:316
19Cl3-Me-3-Et-1-pyrrFAB-MS(M+H)+:282
20Cl3,5-diMe-1-pipeFAB-MS(M+H)+:282
21Cl3-Me-1-pipeFAB-MS(M+H)+:268
22Cl3-Et-1-praFAB-MS(M+H)+:265
23Cl3-iPr-1-praFAB-MS(M+H)+:279
24Cl3-cPr-1-praFAB-MS(M+H)+:277
25CF31-pyrrFAB-MS(M+H)+:274
26CF33-Me-1-praFAB-MS(M+H)+:285
27CF33-(R)-Me-1-pyrrFAB-MS(M+H)+:288
28CF33-(S)-Me-1-pyrrFAB-MS(M+H)+:288
29CF33,4-diMe-1-pyrr
30CF33,3-diMe-1-pyrrFAB-MS(M)+:30
31CF32,5-dihydropyrrol-1-ylFAB-MS(M+H)+:272
32CF33-iPr-1-praFAB-MS(M+H)+:313
33CF33-F3C-1-praFAB-MS(M+H)+:339
34CF33,5-diMe-1-praFAB-MS(M+H)+:299
35CF34-Me-1-praFAB-MS(M+H)+:285
36CF33-tBu-1-praFAB-MS(M+H)+:327
37CF35-Me-1-praFAB-MS(M+H)+:285
39Cl1-pipeEI-MS(M)+:253
40Clazepin-1-ylEI-MS(M)+:267
41Clpyrrol-1-yl/td> FAB-MS(M+H)+:236
42Cl2,5-diMe-pyrrol-1-ylFAB-MS(M)+:263
43Methyl1-pyrrFAB-MS(M+H)+:220
Table 6
A number of comparative exampleDeputy RcDeputy RdThe results of mass-spectrometric studies
383-Me-1-praFFAB-MS(M+H)+:269
44H1-pyrrFAB-MS(M+H)+:240
Table 7
A number of comparative exampleDeputy RbDeputy RcThe results of mass-spectrometric studies
45Cl3-Me-1-praFAB-MS(M-H)+:235
46Cl 1-pyrrFAB-MS(M+H)+:226
47Cl1-praFAB-MS(M+H)+:223
48Cl4-morFAB-MS(M-H)+:241
49Cl3-phenyl-1-praFAB-MS(M-H)+:297
50Cl4-Br-1-praFAB-MS(M-H)+:299,301
51Cl3-(2-the)-1-praFAB-MS(M-H)+:303
52ClIndazol-1-ylFAB-MS(M-H)+:271
53Cl3,5-diMe-1-praFAB-MS(M-H)+:249
54ClPyrrol-1-ylFAB-MS(M-H)+:220
55Cl2-Me-1-imidFAB-MS(M+H)+:237
56Cl1-bimidFAB-MS(M+H)+:273
57Cl5-Me-1-praFAB-MS(M-H)+:235
582-Me-1-pyrrFAB-MS(M+H)+:240
59Cl3-(R)-Me-1-pyrrFAB-MS(M+H)+:240
60Cl3-(S)-Me-1-pyrrFAB-MS(M+H)+:240
61Cl3,3-diMe-1-pyrrFAB-MS(M+H)+:254
62Cl3-F-1-pyrrFAB-MS(M+H)+:244
63Cl3-phenyl-1-pyrrFAB-MS(M-H)+:300
64Cl3-Me-3-Et-1-pyrrFAB-MS(M+H)+:268
65Cl3,5-diMe-1-pipeFAB-MS(M-H)+:266
66Cl3-Me-1-pipeFAB-MS(M-H)+:252
67Cl3-Et-1-praFAB-MS(M+H)+:251
68Cl3-iPr-1-praFAB-MS(M+H)+:265
69Cl3-cPr-1-pra FAB-MS(M+H)+:263
70Cl2,5-diMe-pyrrol-1-ylFAB-MS(M-H)+;248
71CF31-pyrrFAB-MS(M+H)+:258
72CF33-Me-1-praFAB-MS(M+H)+:271
73CF33-(R)-Me-1-pyrrFAB-MS(M+H)+:274
74CF33-(S)-Me-1-pyrrFAB-MS(M-H)+;272
75CF33,4-diMe-1-pyrrFAB-MS(M+H)+:288
76CF33,3-diMe-1-pyrrFAB-MS(M+H)+:288
77CF32,5-dihydropyrrol-1-ylFAB-MS(M+H)+:258
78CF33-iPr-1-praFAB-MS(M+H)+:299
79CF33-F3C-1-praFAB-MS(M-H)+:323
80CF3FAB-MS(M+H)+:285
81CF34-Me-1-praFAB-MS(M+H)+:271
82CF33-tBu-1-praFAB-MS(M+H)+:313
83CF35-Me-1-praFAB-MS(M+H)+:271
84IU1-pyrrFAB-MS(M+H)+:206
85Cl1-pipeFAB-MS(M-H)+:238
86ClAzepin-1-ylFAB-MS(M-H)+:252
Table 8
A number of comparative exampleDeputy RcDeputy RdThe results of mass-spectrometric studies
873-Me-1-praFFAB-MS(M+H)+:255
88H1-pyrrFAB-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);

RA, RB, RWith, RD, R1Arepresent 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: -NHCH2-(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.)

Cltd align="center" namest="c0" nameend="c4"> 83 578 9
Table 9
The number of sample (g)Deputy RADeputy RBDeputy RCMCThe method of synthesis
1-OMeCl3-Me-1-pra4721
2-OMeMe-Br4522
3-OMeCF3-Br5043
4-OMeMe-N(Boc)NH25024
5-OMeMe3-Me-1-pra4525
6-OHCl3-Me-1-pra4586
7-NHCH2-(2-the)Cl3-Me-1-pra5537
8-NH2Cl3-Me-1-pra4578
9(HCl)-NHCH2-(2-py)Cl1-pyrr5389
10-NHCH2CO2HCl3-Me-1-pra51510
11-NHCH2CONHMeCl3-Me-1-pra52811
12-N(Me)CH2CONH2Cl3-Me-1-pra52812
13(HCl)-NHCH2-(2-py)Cl1-pipe55113
Table 10
The number of sample (g)Deputy RBDeputy RCMSThe method of synthesis
14Cl1-pyrr4611
15Cl2-Me-1-pyrr4751
16Cl3-Me-1-pyrr4751
17Cl3-(R)-Me-1-pyrrMM;4741
18Cl3-(S)-Me-1-pyrr4751
19Cl3,3-diMe-1-pyrr4891
20Cl3-Me-3-Et-1-pyrr 5031
21Cl3-F-1-pyrr4791
22Cl3-phenyl-1-pyrr5381
23CF31-pyrr4951
24CF33-(R)-Me-1-pyrr5091
25CF33-(S)-Me-1-pyrr5091
26CF33,4-diMe-1-pyrr5231
27CF33,3-diMe-pyrr5231
28Me1-pyrr441 1
29Cl1-pra4581
30Cl5-Me-1-pra4721
31Cl3-Et-l-pra4861
32Cl3-iPr-1-pra5001
33Cl3-cPr-1-pra4981
34Cl3,5-diMe-1-pra4861
35Cl4-Br-1-pra536,5381
36Cl3-phenyl-1-pra5341
37Cl3-(2-the)-1-pra5401
38CF33-Me-1-pra5061
39CF33-Me-1-pra5065
40CF34-Me-1-pra5061
41CF35-Me-1-pra5061
42CF33-iPr-1-pra5341
43CF33-F3C-1-pra5601
44CF33-tBu-1-pra5481
45CF33,5-diMe-1-pra5201
46Cl3-Me-1-pipe5651
47Cl3,5-diMe-1-pipe15791
48Cl4-mor4771
49Clpyrrol-1-yl4571
50Cl2,5-diMe-pyrrol-1-yl4851
51CF32,5-dihydro-1H-pyrrol-1-yl4931
52Cl2-Me-imidazol-1-yl4721
531-bimid5081
54Clindazol-1-yl5081
55CF3-N(Boc)NH25564
Table 11
The number of sample (g)Deputy RAndVice-tel RInMSThe method of synthesis
563-HO-1-pyrrCl5277
573-HO-1-pipeCl5417
583-H2NOC-1-pipeCl5687
59 4-H2NOC-1-pipeCl5687
602-HOCH2-1-pipeCl5557
613-HOCH2-1-pipeCl5557
62-NH-(2-HO-cHex)Cl5557
63-NHPhCl5337
64-NH-(2-HO-Ph)Cl5497
65-NH-(3-HO-Ph)Cl5497
66-NH-(4-HO-Ph)Cl5497
67-NH-(S-Ac-Ph Cl5757
68-NH-(3-HO2C-Ph)Cl5777
69-NH-(3-MeO2C-Ph)Cl5917
70-NH-(2-H2NOC-Ph)Cl5767
71-NH-(3-H2NOC-Ph)Cl5767
72-NH-(4-H2NOC-Ph)Cl5767
73-NH-(3-MeNHCO-Ph)Cl5907
74-NH-(3-Me-Ph)Cl5477
75 -NH-(2-HOCH2-Ph)Cl5637
76-NH-(3-HOCH2-Ph)Cl5637
77-NH-(4-HOCH2-Ph)Cl5637
78-NH-(3-HO(CH2)2-Ph)Cl5777
79-NH-(3-MeCH(OH)-Ph)Cl5777
80-NH-(2-HOCH2CH(OH)-Ph)Cl5937
81-NH-(4-HOCH2CH(OH)-Ph)Cl5937
82-NH-(3-MeOCH2-Ph)Cl5777
-NH-(3-H2NOCCH2-Ph)Cl5907
84-NH-(3-H2NOC(CH2)2-Ph)Cl6047
85-NH-(3-H2NOC-(E)-CH=CH-Ph)Cl6027
86-NH-(3-F-Ph)Cl5517
87-NH-(3-Ms-Ph)Cl6117
88-NH-(3-AcNH-Ph)Cl5907
89-NH-(3-the)Cl5397
90Cl540 7
91Cl5417
92Cl5577
93-NHCH2CO2MeCl5297
94-NHCH2CONH2Cl5147
95-NHCH2PhCl5477
96-NHCH2-(4-HO-Ph)Cl5637
97-NHCH2-(3-HO-Ph)Cl5637
98-NHCH2-(2-HO-Ph) Cl5637
99-NHCH2-(3,4-diHO-Ph)Cl5797
100-NHCH2-(4-MeO-Ph)Cl5777
101-NHCH2-(3,4-diMeO-Ph)Cl6077
102-NHCH2-(4-HO-3-MeO-Ph)Cl5937
103-NHCH2-(4-HO2C-Ph)Cl5917
104-NHCH2-(4-MeO2C-Ph)Cl6057
105-NHCH2To(4-H2NOC-Ph)Cl5907
106-NHCH2-(3-H2NOC-Ph)Cl5907
107-NHCH2-(3-HOCH2-Ph)Cl5777
108-NHCH2-(4-F-Ph)Cl5657
109-NHCH2To(4-H2NO2S-Ph)Cl6267
110(HCl)-NHCH2-(2-py)Cl5487
111-NHCH2-(6-HO-2-py)Cl5647
112-NHCH2-(5-MeO-2-py)Cl5787
113(HCl)-NHCH2-(6-MeO-2-py)Cl7
114-NHCH2-(6-iPrO-2-py)Cl6067
115-NHCH2-(6-H2NOC-2-py)Cl5917
116-NHCH2-(6-Me2NOC-2-py)Cl6197
117-NHCH2-(6-cyano-2-py)Cl5737
118-NHCH2-(5-Me-2-py)Cl5627
119(HCl)-NHCH2-(6-Me-2-py)Cl5627
120(HCl)-NHCH2-(6-HOCH2-2-py)Cl5787
121(HCl) -NHCH2-(6-H2N-2-Me-3-py)Cl5777
122(HCl)-NHCH2-(6-H2N-2-py)Cl5637
123-NHCH2-(6-Me2N-2-py)Cl5917
124-NHCH2-(6-F-2-py)Cl5667
125-NHCH2-(6-Cl-2-py)Cl5827
126(HCl)-NHCH2-(3-py)Cl5487
127-NHCH2-(3-the)Cl5537
128-NHCH2-(2-fur)Cl537 7
129-NHCH2-(2-thia)Cl5547
130-NHCH2-(4-thia)Cl5547
131(HCl)-NHCH2-(pyrazol-2-yl)Cl5497
132-NHCH2-(pyridazin-3-yl)Cl5497
133-NHCH2-(pyrimidin-4-yl)Cl5497
134-NHCH2-(pyridazin-4-yl)Cl5497
135(HCl)-NHCH2-(2-bimid)Cl5877
136(HCl)-NHCH2-(1-Me-2-bimid) Cl6017
137-NHCH2-(2-bthia)Cl6047
138-NHCH(CONH2)2Cl5577
139-NH(CH2)2OHCl5017
140-(R)-NHCH(Me)CH2OHCl5157
141-(S)-NHCH(Me)CH2OHCl5157
142-(R)-NHCH2CH(Me) - OHCl5157
143-(S)-NHCH2CH(Me) - OHCl5157
144 -NHC(Me)2CH2OHCl5297
145-NHCH2C(Me)2OHCl5297
146-NH(CH2)2OMeCl5157
147-NH(CH2)2CONH2Cl5287
148-NHCH(CO2Me)CH2OHCl5597
149-NHCH(CONH2)CH2OHCl5447
150-NHCH(Ph)CH2OHCl5777
151-NH(CH2)3OHCl 5157
152-NHCH2CH(OH)CH2OHCl5317
153-NHCH(CH2OH)2Cl5317
154-NH(CH2)4OHCl5297
155-NHnPenCl5277
156-NMe2Cl4857
157-N(Me)(CH2)2OHCl5157
158-N((CH2)2OH)2Cl5457
159-N(CH2 CONH2)((CH2)2OH)Cl5587
160-N(CH2-2-py)((CH2)2OH)Cl5927
161-N(CH2CONH2)2Cl5717
162-NH2CF34919(8)
163-NH(CH2)2OHCF35359
164-NHCH2CONH2CF35489
165(HCl)-NHCH2-(2-py)CF35829
166-NHCH2CONH2 Me4949
167-NH2Me4379(8)
Table 12
The number of sample (g)Deputy RInDeputy RWithMSThe method of synthesis
168Cl1-pyrr4469(8)
169Cl3,3-diMe-1-pyrr4749(8)
170Cl3-F-1-pyrr4649(8)
171Cl3-phenyl-1-pyrr5229(8)
172Cl3-Me-3-Et-1-prr 4889(8)
173Cl3-(S)-Me-1-pyrr4609(8)
174Cl3-(R)-Me-1-pyrr4609(8)
175CF31-pyrr4809(8)
176CF33-(R)-Me-1-pyrr4949(8)
177CF33-(S)-Me-1-pyrr4949(8)
178CF33,3-diMe-1-pyrr5089(8)
179CF33,4-diMe-1-pyrr5089(8)
180CF3 4-Me-1-pra4919(8)
181CF35-Me-1-pra4919(8)
182CF33-iPr-1-pra5199(8)
183CF33-tBu-1-pra5339(8)
184CF33-F3C-1-pra5459(8)
185CF33,5-diMe-1-pra5059(8)
Table 13
The number of sample (g)Deputy RInDeputy RWithMSThe method of synthesis
186(HCl)Cl2-Me-1-pyrr5519
187(HCl)Cl3-Me-1-pyrr5519
188(HCl)Cl3,3-diMe-1-pyrr5659
189(HCl)Cl3-F-1-pyrr5559
190(HCl)Cl1-pra5349
191(HCl)Cl5-Me-1-pra5479
192(HCl)Cl3-Et-1-pra5629
193(HCl)Cl3-iPr-1-pra5769
194(HCl) Cl3-cPr-1-pra5749
195(HCl)Cl3,5-diMe-1-pra5629
196Cl4-Br-1-pra612,

614
9
197Cl3-phenyl-1-pra6109
198Cl3-(2-the)-1-pra6169
199(HCl)Cl3-Me-1-pipe5659
200(HCl)Cl3,5-diMe-1-pipe5799
201(HCl)Cl4-mor5539
202(HCl)Cl azepin-1-yl56513
203(HCl)Clpyrrol-1-yl5339
204(HCl)Cl2,5-diMe-pyrrol-1-yl5619
205Cl2-Me-1-imid5489
206(HCl)Cl1-bimid5849
207(HCl)Clindazol-1-yl5849
208(HCl)CF31-pyrr5719
209(HCl)Me1-pyrr5179
Table 14
The number of sample (g)Deputy RAndDeputy RInDeputy RWithMSThe method of synthesis
210-NH(CH2)2OHCl1-pyrr4909
211-NH(CH2)2OHCl3-(R)-Me-1-pyrr5049
212-NH(CH2)2OHCl3-(S)-Me-1-pyrr5049
213-NH(CH2)2OHCl3,3-diMe-1-pyrr5189
214-NH(CH2)2OHCF31-pyrr5249
215-NH(CH2) 2OHCF33-(R)-Me-1-pyrr5389
216-NH(CH2)2OHCF33-(S)-Me-l-pyrr5389
217-NH(CH2)2OHCF33,3-diMe-1-pyrr5529
218-NH(CH2)2OHCF33,4-diMe-1-pyrr5529
219-NH(CH2)2OHCF34-Me-1-pra5359
220-NHCH2CONH2Cl1-pyrr5039
221-NHCH2CONH2Cl3-(R)-Me-1-pyrr517 9
222-NHCH2CONH2Cl3-(S)-Me-l-pyrr5179
223-NHCH2CONH2Cl3,3-diMe-1-pyrr5319
224-NHCH2CONH2Cl3-phenyl-1-pyrr5799
225-NHCH2CONH2Cl3-Me-3-Et-1-pyrr5459
226-NHCH2CONH2CF31-pyrr5379
227-NHCH2CONH2CF33-(R)-Me-1-pyrr5519
228-NHCH2CONH2 CF33-(S)-Me-1-pyrr5519
229-NHCH2CONH2CF33,3-diMe-1-pyrr5659
230-NHCH2CONH2CF33,4-diMe-1-pyrr5659
231-NHCH2CONH2CF33-F3C-1-pra6029
232-NHCH2CONH2CF34-Me-1-pra5489
233-NHCH2CONH2CF33-tBu-1-pra5909
234-NHCH2CONH2CF32,5-dihydropyr-rol-1-yl535
Table 15
The number of sample (g)Deputy RAndDeputy RInDeputy RWithDeputy RDMSThe method of synthesis
235OMeClH1-pyrr4611
236OMeCl3-Me-1-praF4901
237(HCl)-NHCH2-(2-py)ClH1-pyrr5379
238-NH2Cl3-Me-1-praF4749(8)
Table 16
The number of sample (g)Deputy RAndDeputy RInDeputy RWithMSThe method of synthesis
239-NMe2Cl3-Me-1-pra54211
240-NH(CH2)2OHCl3-Me-1-pra55811
2411-pyrrCl3-Me-1-pra56811
2421-pipeCl3-Me-1-pra58211
2432-HOCH2-1-pipeCl3-Me-1-pra61211
2443-HOCH2-1-pipeCl3-Me-1-pra61211

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.

Table 17
ExampleNMR
581,22-of 1.78 (3H,m), 1,86 is 2.01 (1H, m), 2,22 (3H, s), 2.26 and-to 2.42 (2H, m), 2,64-to 2.74( 2H, m), 3,02 of 3.28 (2H, m), 3,88 (1H, d, J=and 12.2 Hz), 4,42 (1H, d, J=and 12.2 Hz), 4,70-is 4.93 (1H, W), 6,32 (1H, d, J=2.4 Hz), of 6.65 (1H, s), 6,85-6,98 (1H, m), 7,00 for 7.12 (2H, m), 7,18 (1H, t, J=7.8 Hz), 7,22-7,29 (1H, m), 7,35 is 7.50 (2H, m), 7,54 to 7.62 (1H, m), 7,81 (1H, s)of 8.37 (1H, s).
621,12-of 1.32 (4H, m), 1.56 to 1,72 (2H, m), 1,83 is 1.96 (2H, m), 2,22 (3H, s), 2,36 at 2.45 (1H, W),2,54-and 2.79 (1H, W), 3.04 from is 3.23 (1H, W), 3,29-to 3.38 (1H, m), 3,44 is 3.57 (1H, W), to 4.52 (1H, d, J=4,Hz), 4,68-4,94 (1H, W), 6,33 (1H, d, J=2.5 Hz), 6,36 (1H, s), 6,93-to 7.09 (2H, m), 7,16 (1H, dt, J=1,2, 7,8 Hz), 7,25 (1H, t, J=7.8 Hz), 7,33 (1H, d, J=7.8 Hz), EUR 7.57 (1H, d, J=7.8 Hz), to 7.84 (1H, s), 8,09-8,18 (1H, W), scored 8.38 (1H, d, J=2,4 Hz).
672,22 (3H, s), 2,55-2,90 (1H, W), 2,60 (3H, s), 3,10-to 3.35 (1H, W), 3,50-the 3.65 (1H, W), 4,80-of 4.95 (1H, W), 6,34 (1H, d, J=2.4 Hz), of 6.65 (1H, s), 7,00-of 7.96 (10H, m), to 8.20 (1H,s), scored 8.38 (1H, d, J=2.6 Hz), 10,57 (1H, s).
712,22 (3H,s), 2,41-2,47 (1H, W), 2,60-2,78 (1H, W), 3,12 of 3.28 (1H, W), 4,69-to 4.98 (1H, W), 6,63 (1H, d, J=2.4 Hz), 6,63 (1H, s), 7,02 (1H, d, J=7.8 Hz), 7,05-7,14 (1H, W), then 7.20 (1H, dt, J=1.5 and 7.8 Hz), and 7.8 (1H, t, J=7.8 Hz), 7,34-7,41 (2H,m), 7,44 (1H, t, J=7.8 Hz), to 7.61 (2H, J=7.8 Hz), 7,83-7,88 (2H, m), 7,95 (1H, s), 8,07 (1H, s)of 8.37 (1H, d, J=2.4 Hz), of 10.47 (1H, s).
722,22 (3H, s), 2,28-2,39 (1H, W), 2,58-and 2.79 (1H, W), 3,22 is 3.40 (1H, W), 4,50 of 4.83 (1H, W), 6,33 (1H, d, J=2.4 Hz), of 6.65 (1H,s), 7,03 (1H, d, J=7.8 Hz), 7,06-7,13 (1H, W), 7,21 (1H, dt, J=1.5 and 7.8 Hz), 7.24 to 7,33 (2H, m), 7,37 (1H, d, J=7.8 Hz), to 7.59 (1H, d, J=8,3 Hz), 7,71 (2H, d, J=8,8 Hz), 7,83-to $ 7.91 (4H, m), with 8.33 (1H, d, J=2.4 Hz), 10,56 (1H, s).
73of 2.23 (3H, s), 2,34-2,47 (1H, W), 2,54-2,69 (1H, W), and 2.79 (3H, d, J=4.4 Hz), 3.00 and of 3.28 (1H,W), 4,71-of 4.90(1H, W), 6,34 (1H, d, J=2.4 Hz), 6,63 (1H, s), of 6.96-7,14 (2H, t), 7,21 (1H,t, J=7.8 Hz), 7,29 (1H, t, J=7.8 Hz), 7,37 (1H, d, J=7.8 Hz), was 7.45 (1H, t, J=7.8 Hz), 7,52-to 7.64 (2H, m), 8,07 (1H, s), scored 8.38 (1H, d, J=the 2.4 Hz), to 8.41-8,49 (1H, m), 10,50 (1H,s).
742,22 (3H, s), 2,31 (3H, s), 2,55-2,90 (1H, W), 3,10-to 3.35 (1H, W), 3,50-the 3.65 (1H, W), 4,80-of 4.95 (1H, W), 6,33 (1H, d, J=2.4 Hz), 6,60 (1H, s), 6.90 to-to 7.61 (10H, m), to 7.84 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 10,27 (1H, s).
762,22 (3H, s), 2,60-2,90 (1H, W), 3,05-to 3.35 (1H, W), 3,50-the 3.65 (1H, W), 4,51 (2H, d, J=5,1 Hz), 4,76-of 4.90 (1H, W), 5,23 (1H, t, J=5.6 Hz), 6,33 (1H, d, J=2.4 Hz), is 6.61 (1H, s), 6,98-7,39 (7H, m), 7,51-7,63 (3H, m), to 7.84 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 10,33 (1H, s).
772,22 (3H, s), 2,60-2,95 (1H, W), 3,00-3,30 (1H, W), 3,50-the 3.65 (1H,W), 4,47 (2H, d, J=5.5 Hz), 4.75 V-of 4.95 (1H, W), to 5.13 (1H, t, J=5.6 Hz), 6,33 (1H, d, J=2.4 Hz), is 6.61 (1H, s), 6,99-7,39 (7H, m), 7,56-to 7.61 (3H, m), to 7.84 (1H, s)of 8.37 (1H, d, J=2.4 Hz), 10,32 (1H, s).
782,22 (3H, s), of 2.72 (2H, t, J=7.0 Hz), 2,55-2,90 (1H, W), 3,10-to 3.35 (1H, W), 3,50-the 3.65 (1H, W), to 3.58-3,66 (2H, m), 4,6 (1H, t, J=5,2 Hz), 4.80 to of 4.95 (1H, W), 6,33 (1H, d, J=2.4 Hz), 6,60 (1H, s), 6,95-to 7.61 (10H, m), to 7.84 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 10,29 (1H, s).
79of 1.33 (3H, d, J=6.4 Hz), 2,22 (3H, s), 2,55-2,90 (1H, W), 3,05-3,30 (1H, W), 3,50-the 3.65 (1H, W), 4,67 was 4.76 (1H, m),4.75 V-4,90 (1H, W), 5,20 (1H, d, J=4.0 Hz), 6,33 (1H, d, J=2.4 Hz), 6,60 (1H, s), 7,00-7,39 (7H, m), 7,52-to 7.61 (3H, m), to 7.84 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 10,33 (1H, s).
812,22 (3H, s), 2,45 is 2.55 (1H, W), 2,70 is 2.80 (1H, W), 3,15-of 3.25 (1H, W), of 3.42 (2H, t, J=6,1 Hz), 4,51 (1H, q, J=5.4 Hz), 4,69 (1H, t, J=5,9 Hz), 4.75 V-of 4.95 (1H, W), by 5.18 (1H, d, J=3,9 Hz), 6,34 (1H, d, J=2.4 Hz), is 6.61 (1H, s), 7,01 (1H, d, J=7.8 Hz), 7.03 is-to 7.15 (1H, W), then 7.20 (1H, dt, J=1.5 and 7.8 Hz), 7,25-to 7.35 (3H, m), 7,38 (1H, DD, J=7,8, 1.5 Hz), 7,55-to 7.61 (3H, m), a 7.85 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), and 10.3 (1H, s).
822,22 (3H, s), 2,55-2,90 (1H, W), 3,10-to 3.35 (1H, W), of 3.32 (3H, s), 3,50-the 3.65 (1H, W), was 4.42 (2H, s), 4.80 to of 4.95 (1H, W), 6,34 (1H, d, J=2.4 Hz), is 6.61 (1H, s), 7,00-7,39 (7H, m), 7,55-to 7.64 (3H, m), a 7.85 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 10,37 (1H, s).
832,22 (3H,s), 2,42-2,48 (1H, W), 2,66-of 2.93 (1H, W), 3,09-of 3.27 (1H, W), to 3.38 (2H, s), 4,69-5,00 (1H, W), 6,33 (1H, d, J=2.4 Hz), 6,51 (1H, s)6,91 (1H, s), 7,02 (2H, d, J=7.8 Hz),? 7.04 baby mortality-to 7.15 (1H, W), then 7.20 (1H, t, J=7,8gts),7,24-7,33 (2H, m), 7,37 (1H, d, J=7.8 Hz), 7,46-7,63 (4H, m), to 7.84 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 10,35 (1H, s).
842,22 (3H, s), is 2.37 (2H, t, J=7.8 Hz), 2,43-2,48 (1H, W), 2,63-to 2.74 (1H, W), 2,80 (2H, t, J=7.8 Hz), 3,19-3,24 (1H, W), 4,75-4,94 (1H, W), 6,34 (1H, d, J=2.4 Hz), 6,60 (1H, s), 6,77 (1H, s), 6,97 (1H, d, J=7.8 Hz), 7,03 (1H, d, J=7.8 Hz), 7,06-7,14 (1H, W), 7,17-7,34 (5H, m), 7,37 (1H, DD, J=1,0, and 7.8 Hz),7,44-7,52 (1H, m), to 7.59 (1H, d, J=7.8 Hz), to 7.84 (1H, d), of 8.37 (1H, d, J=2.4 Hz), 10,31 (1H, s).
852,22 (3H, s), 2,42-2,48 (1H, W), 2,69-2,82 (1H, W), 3,22-3,29 (1H, W), 4,74-5,02 (1H, W), 6,34 (1H, d, J=2.4 Hz), 6,62 is 6.67 (2H, m), 7,03 (1H, d, J=7.8 Hz), 7,05-7,16 (2H, m), 7,22 (1H, dt, J=1,4, and 7.8 Hz), 7,27-7,33 (2H, m), of 7.36-7,44 (3H, m), 7,51-the 7.65 (3H, m), to 7.84 (1H, s), to 7.99 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 10,43( 1H, s).
862,22 (3H, s), 2,55-2,90 (1H, W), 3,10-to 3.35 (1H, W), 3,50-the 3.65 (1H, W), 4,80-of 4.95 (1H, W), 6,33 (1H, d, J=2.4 Hz), only 6.64 (1H, s), 6,91-7,66 (10H, m), to 7.84 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 10,57 (1H, s).
872,22 (3H, s), 2,55-2,90 (1H, W), 3,10-to 3.35 (1H, W), 3,24 (3H, s), 3,50-the 3.65 (1H, W),4,80-of 4.95 (1H, W), 6,34 (1H, d, J=2.4 Hz), of 6.66 (1H, s), 7,00-7,40 (5H, m), EUR 7.57-of 7.69 (3H, m), to 7.84 (1H, s), 7,95-8,00 (1H, m), compared to 8.26 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), is 10.75 (1H, s).
88is 2.05 (3H, s), 2,22 (3H, s), 2,32-2,47 (1H, W), 2,55-2,78 (1H, W), 2,99 of 3.28 (1H, W), 4,70-to 4.98(1H, W), 6,33 (1H, d, J=2.4 Hz), 6,60 (1H, s), 7,02 (1H, d, J=7.8 Hz),? 7.04 baby mortality-to 7.15 (1H, W), 7,17-7,39 (6H, m), 7,60 (1H,d, J=8,3 Hz), to 7.84 (1H, s), 7,98 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 9,99 (1H, s), 10,37 (1H, s).
901,77 is 1.91 (1H, m), 2,22 (3H, s), 2,32-2,47 (2H, m), 2,69-and 2.83 (1H, W), 3,19-of 3.27 (3H, m), 4,32-4,50 (1H, m), 4.75 V to 4.92 (1H, W), 6,33 (1H, d, J=2.4 Hz), 6.42 per (1H, s), 6,91-7,07 (2H, m), 7,17 (1H, dt, J=1.5 and 7.8 Hz), 7,24 (1H, t, J=7.8 Hz), 7,32 (1H, DD, J=1.5 and 7.8 Hz), to 7.59 (1H, d, J=8,3 Hz), to 7.84 (1H, s), to $ 7.91 (1H, s)of 8.37 (1H, d, J=2.4 Hz), 8,65-8,76 (1H, m).
912,22 (3H, s), 2,32-2,47 (1H, W), 2,62-2,90 (1H, W), 3,09 is 3.23 (1H, W), of 3.25 and 3.31 (2H, m),4,22-4,30 (1H, W), 4,37-of 4.44 (1H, m), br4.61-5,00 (2H, m), 6,33 (1H, d, J=2.4 Hz), of 6.45 (1H,s), 6,93-7,07 (2H, m), 7,18 (1H, dt, J=1,4, and 7.8 Hz), 7,25 (1H, t, J=7.8 Hz), 7,31 (1H, d, J=7,8gts), 7,58 (1H, d, J=7.8 Hz), 7,83 (1H, s)of 8.37 (1H, d, J=2.4 Hz), a total of 8.74-8,98 (1H, Shir.).
921,04 by 1.12 (1H, m), 2,07-2,19 (2H, m), 2,22 (3H,s), 2,34 at 2.45 (1H, W), to 2.57-of 2.93 (1H, W),3,02-of 3.27 (1H, W), 3,33-3,51 (1H, m), 4,62 is equal to 4.97 (2H, W), 6,33 (1H, d, J=2.4 Hz), of 6.45 (1H, s), 6.90 to-was 7.08 (2H, m), 7,16 (1H, t, J=7,3 Hz), 7,24 (1H, t, J=7,3 Hz), 7,31 (1H, d, J=7,3 Hz), to 7.59 (1H, d, J=7,3 Hz), to 7.84 (1H, s), scored 8.38 (1H, s), 8,71-8,83 (1H, Shir.).
1052,22 (3H, s), 2,55-2,90 (1H, W), 3,05-3,30 (1H, W), 3,50-the 3.65 (1H, W), of 4.45 (2H, d, J=5,9 Hz), 4.75 V-4,90 (1H, W), 6,33 (1H, d, J=2.4 Hz), 6,47 (1H, s), 6,95-7,58 (9H, m), 7,82-of 7.95 (4H, m), of 8.37 (1H, d, J=2.6 Hz), to 8.94 (1H, s).
1092,22 (3H, s), 2,41-2,47 (1H, W), 2,55-of 2.64 (1H, W), 3,09-3,26 (1H, W), to 4.46 (2H, d, J=4.9 Hz), 4,74-of 4.90 (1H, W), 6,33 (1H, d, J=2.4 Hz), of 6.49 (1H, s), 6,95-7,10 (2H, m), 7,17 (1H, dt, J=1.5 and 7.8 Hz), 7,25 (1H, dt, J=1.5 and 7.8 Hz), 7.29 trend was 7.36 (3H, m), of 7.48-of 7.60 (3H, m), to 7.77-to 7.84 (3H, m), of 8.37 (1H, d, J=2.4 Hz), of 9.00 (1H, ).
1102,22 (3H, s), 2.40 a-2,50 (1H, W), 2,67-2,89 (1H,W), 3,11 is 3.23 (1H, W), to 4.73 (2H, d, J=5.4 Hz), 4,76-of 4.90 (1H, W), 6,34 (1H, d, J=2.5 Hz), 6,41 (1H, s), of 6.99 (1H, d, J=7.8 Hz), 7,19 (1H, t, J=7.8 Hz), 7,26 (1H, t, J=7.8 Hz), 7,33 (1H, d, J=6.8 Hz), to 7.61 (1H, d, J=8,3 Hz),7,79-7,88 (3H, m), 8,35-to 8.45 (2H, m), 8,79 (1H, d, J=4,8 Hz), of 9.30 (1H, s).
1192,22 (3H,s), 2,35 is 2.55 (1H, W), 2,70 (3H, s), 2,70-to 2.85 (1H, W), 3,12-3,30 (1H, W), of 4.67 (2H, Sirs), 4,75-of 4.90 (1H, W),6,34 (1H, d, J=2.5 Hz), 6,53 (1H, s), of 6.99 (1H, d, J=7.8 Hz), 7,00 for 7.12 (1H, W), 7,19 (1H, TD, J=7,8, 1.5 Hz), 7,26 (1H, d, J=7.8 Hz), 7,33 (1H, d, J=7.8 Hz), 7,55-of 7.70 (3H, m), to 7.84 (1H, s), 8,23-of 8.33 (1H, W), 8,39 (1H, d, J=2.5 Hz), 9,23 (1H, Sirs).
144of 1.27 (6H, s), 2,22 (3H, what), 2,34 is 2.55 (1H, W), 2,55 is 2.80 (1H, W), 3,21 of 3.28 (1H, W), of 3.45 (2H, s), 4,70-4,96 (1H, W), a 4.86 (1H, t, J=5,9 Hz), 6,32 (1H, s), 6,33 (1H, d, J=2.5 Hz), 6.87 in-7,07 (1H, W), of 6.96 (1H, d, J=7.8 Hz), to 7.15 (1H, t, J=7,3 Hz), 7,22 (1H, t, J=7,3 Hz), 7,33 (1H, d, J=7,3 Hz), 7,56 (1H, d, J=8,8 Hz), 7,74 (1H, s), 7,83 (1H, s)of 8.37 (1H, d, J=3.5 Hz).
162of 2.24 (3H, s), 2,34 at 2.45 (1H, W), to 2.57-2,70 (1H, W), a 3.06-3,20 (1H, W), 4,69-4,99 (1H, W), 6,36 (1H, d, J=2.5 Hz), 6,46 (1H,s)6,76 (1H, d, J=7.8 Hz), 7,02 (1H, d, J=8,3 Hz), 7,16 (1H, dt, J=1.5 and 7.8 Hz), 7,24 (1H, dt, J=1.5 and 7.8 Hz), 7,32 (1H, DD, J=1.5 and 7.8 Hz), was 7.36 (1H, s), a 7.85 (1H, DD, J=of 1.5 and 8.3 Hz), to $ 7.91 (1H, s), of 8.09 (1H, d, J=1.5 Hz), 8,46 (1H, d, J=2.5 Hz).
1632,22 (3H, s), 2,37 at 2.45 (1H, W), 2,71-2,87 (1H, W), is 3.08 be 3.29 (3H, m), 3,49 (2H, t, J=6.4 Hz), 4,70 to 4.92 (1H, W), 6,36 (1H, d, J=2.5 Hz), 6.48 in (1H, s), 6,97 (1H, d, J=7.8 Hz),7,03 (1H, d, J=8,8 Hz), to 7.15 (1H, dt, J=1.5 and 7.8 Hz), 7,25 (1H, dt, J=1.5 and 7.8 Hz), 7,34 (1H, DD, J=1,8, 7,8 Hz), to 7.84 (1H, DD, J=1,5, 8,8 Hz), of 8.09 (1H, d, J=1.5 Hz), of 8.47 (1H, d, J=2.5 Hz), 8,51 (1H, t, J=at 5.3 Hz).
1672,22 (3H, s)to 2.41 (3H, s), 2,43 is 2.46 (1H, W), to 2.57-of 2.64 (1H, W), 3,00-is 3.21 (1H, W), 4,71-4,99 (1H, W), 6,24 of 6.31 (1H, W), 6,37 (1H, s), 6,57-6,87 (2H, m), to 7.09 (1H, t, J=7.8 Hz), to 7.15 (1H, t, J=7.8 Hz), 7,25-7,39 (3H, m), 7,58 (1H, s), to 7.84 (1H, s), of 8.27 (1H, s).
169the 1.04 (6H, s)to 1.70 (2H, t, J=6.3 Hz), 2,43-2,48 (1H, W), 2,53-to 2.57 (1H, W), 2,86-2,96 (2H, W), 3,17-3,26 (3H, m), 4,62-5,02 (1H, W), 6,12-to 6.19 (1H,m), and 6.25 (1H, s), 6,36-6,40 (1H, W), 6,64-6,72 (1H, W), 6,86-6,92 (1H, W), 7,13-to 7.35 (4H, m), 7,79 (1H,s).
1711,94-of 2.09 (1H, m), 2.26 and at 2.45 (2H, m), 2,53-by 2.73 (1H, W), 3.04 from-3,19 (3H, m), 3,28-3,51 (2H, m), 3,57-3,68 (1H, m), 4,57-5,04 (1H, W), 6,21-6,30 (2H, W is R.), 6,47 (1H, s), 6,65 to 6.75 (1H, m), 6,84-6,91 (1H, m), 7,12-7,37 (9H, m), 7,76-7,83 (1H, Shir.)
1720,86 (3H, t, J=7,3 Hz)to 0.97 (3H, s), 1,33-1,44 (2H, m), 1.60-to or 1.77 (2H, m), 2,33-2,47 (1H, W), 2,54-a 2.71 (1H, W), 2,85 are 2.98 (2H, m), 3,16-3,26 (3H, m), 4,72-to 5.03 (1H, W), 6,13-of 6.20 (1H, m), and 6.25 (1H, s), 6,33-6.42 per (1H, W), 6,60-6,72 (1H, W), for 6.81-6,92 (1H, W), 7,12-7,29 (3H, m), 7,33 (1H, s), 7,75-to 7.84 (1H, Shir.).
176of 1.03 (3H, d, J=6.3 Hz), 1,48 is 1.60 (1H, m), 1,99-2,10 (1H, m), 2,24-2,47 (2H, m), 2,54 is 2.80 (2H, m), 3,10-to 3.38 (4H, m), 4,72-is 4.93 (1H, W), 6.35mm (1H,s), 6,38-to 6.43 (1H, m), is 6.61 (1H, s), 6,64 to 6.75 (2H, m), 7,14 (1H, t, J=7.8 Hz), 7.23 percent (1H, t, J=7.8 Hz), 7,29 (1H, d, J=7.8 Hz), 7,35 (1H, s), a 7.85 (1H, s).
180to 2.06 (3H, s), 2,32 is 2.44 (1H, W), 2,61-and 2.79 (1H, W), 2,98-3,20 (1H, W), 4,78-4,99 (1H, W), of 6.45 (1H, s)6,70 (1H, d, J=7.8 Hz), 7,03 (1H, d, J=8,3 Hz), 7,16 (1H, dt, J=1,5, 7,8gts), 7,25 (1H, dt, J=1.5 and 7.8 Hz), 7,32 (1H, DD, J=1.5 and 7.8 Hz), 7,37 (1H, s), 7,60 (1H, s), to 7.84 (1H, DD, J=1,5, 8,3 Hz), a 7.92 (1H, s), of 8.09 (1H, d, J=1.5 Hz), at 8.36 (1H, s).
188of 1.07 (6H, s), 1,71 (2H, t, J=6.4 Hz), a 2.36-2,47 (1H, W), 2,55 of 2.68 (1H, W), 2,88-2,96 (2H, W), 3,02-and 3.16 (1H, W), 3,17 of 3.28 (2H, W), 4,63-4,82 (3H, m), 6,13 and 6.25 (1H, m), 6,33-6.42 per (1H, W), 6,47 (1H, s), 6,67-6,77 (1H, m), 6,83-6,94 (1H, m), 7,13-7,38 (3H, m), 7,79-7,80 (2H, m), to 8.41 (1H, t, J=7.8 Hz),8,79 (1H, d, J=4.9 Hz), 9,20-9,29 (1H, m).
213the 1.04 (6H, s), 1.69 in (2H, t, J=6.8 Hz), 2,42-2,48 (1H, W), 2,53-2,70 (1H, W), 2,87-2,95 (2H, W), 3,18-of 3.25 (5H, m),3.43 points-of 3.50 (2H, m), 4,71 (1H, t, J=5.4 Hz), 4,73-a 4.86 (1H, W), 6,10-to 6.19 (1H, m), 6,27 (1H, s), 6,34-6,40 (1H, W), 6,61-of 6.71 (1H, W), 6,80-6,92 (1H, W), 7,12-to 7.32 (3H, m),8,31 -8,40 (1H, Shir.).
215of 1.03 (3H, d, J=6.8 Hz), 1,47-1,60 (N, m)2,00-2,10 (1H, m), 2,25-2,47 (2H, m), 2.57 m-2,82 (2H, m), 3,14-3,50 (8H, m), to 4.73 (1H, t, J=5.4 Hz), 4,76 to 4.92 (1H, W), 6,34-6,44 (2H, m), 6,62 (1H, s),6,66-6,72 (2H, m), 7,16 (1H, t, J=7.8 Hz), 7,22 (1H, t, J=7.8 Hz), 7,32 (1H, d, J=7.8 Hz), 8,43 (1H, s).
216of 1.03 (3H, d, J=6.8 Hz), 1,50-1,60 (1H, m), 2.00 in was 2.05 (1H, m), 2,25-to 2.40 (2H, m), 2,41 is 2.55 (1H, m), 2.70 height is 2.80 (1H, m), 3,20-3,40 (7H, m), 3,47 (2H, q, J =5,9 Hz), 4.75 V-4,90 (1H, W), 6,37 (1H, s), 6,37-6.42 per (1H, m), 6,62 (1H,s), 6,63 to 6.75 (2H, m), 7,16 (1H, t, J=7,3 Hz), 7.23 percent (1H, t, J=7,3 Hz), 7,32 (1H, d, J=7,3 Hz), 8,42 (1H, s).
2201,81 is 1.96 (4H, m), 2,32-to 2.41 (1H, W), 2,54-to 2.67 (1H, W), 3,06-3,17 (4H, m), 3.27 to to 3.49 (1H, W), of 3.78 (2H, s), 4,62-free 5.01 (1H, W), 6,13-to 6.22 (1H, m), 6,34 (1H, s), 6,37-of 6.45 (1H, m), 6,62-of 6.73 (1H, m), 6,82-6,91 (1H, m), 7,10-to 7.35 (5H, m), 5,50-8,64 (11H, W).
221of 1.02 (3H, d, J=5,9 Hz), 1,45-1,55 (1H, m), 1,95-2,10 (1H, m), 2,25-2,50 (3H, m), 2,65 is 2.75 (2H, m), 3.00 and-to 3.35 (3H, m), 3,70-of 3.80 (2H, m), 4,70-of 4.95 (1H, m), 6,15-of 6.20 (1H, m), 6,34 (1H, s), to 6.39 (1H, s), 6,60-6,70 (1H, W), 6,80-of 6.90 (1H, W), 7,10-7,40 (5H,m), 8,50 at 8.60 (1H, Shir.).
222of 1.02 (3H, d, J=5,9 Hz), 1,45-1,55 (1H, m), 1,97-of 2.08 (1H, m), 2,25-2,60 (3H, m), 2,65 is 2.75 (2H, m), 3,05-to 3.35 (3H, m), 3,70-of 3.80 (2H, m), 4,65-4,80 (1H, m), 6,10-of 6.20 (1H, m), 6,34 (1H, s), to 6.39 (1H, s), 6,60-6,70 (1H, W), 6,80-of 6.90 (1H, W), 7,10-7,40 (5H, m), 8,50 at 8.60 (1H, Shir.).
223the 1.04 (6H, s), 1.69 in (2H, t, J=6.4 Hz), 2,44-2,47 (1H, W), 2,53-2,69 (1H, W), 2,87-2,95 (2H, W), 3,17-of 3.27 (3H, m), 3,71-of 3.77 (2H, m), 4,77-to 4.98 (1H, W), 6,11-to 6.19 (1H, m), 6,34 (1H, s), 6,35-6,41 (1H, W), 6,62-of 6.73 (1H, W), 6,83-6,92 (1H, W),7,10 and 7.36 (5H, m), 8,58 (1H, s).
2241,95-of 2.09 (1H, m), 2,27-of 2.36 (1H, m), 2,42-2,48 (1H, W), 2,52-of 2.58 (1H, W), 3,11-3,20 (1, m), 3,23-to 3.33 (2H, m), 3,35-3,51 (2H, m), to 3.58-3,66 (1H, m), 3,74 (2H, d, J=3,9 Hz), 4,48-5,11 (1H, W), 6,21-of 6.26 (1H, m), 6,34 (1H, s), 6,44-of 6.52 (1H, W), 6,65-6,76 (1H, W), 6,83-6,92 (1H, m), 7,12 (1H, s), 7,16-7,34 (9H, m), 8,54-8,63 (1H, Shir.).
2250,86 (3H, t, J=7,3 Hz)to 0.97 (3H, s), 1,34-of 1.44 (2H, m), 1,61 to 1.76 (2H, m), 2,42-2,48 (1H, W), 2,52-to 2.57 (1H, W), 2,85-of 2.97 (2H, m), 3,15-of 3.27 (3H, m), 3,74 (2H, d, J=4.4 Hz), 4,70-to 5.03 (1H, W), 6,11-of 6.20 (1H, m), 6,34 (1H, s), 6,36-of 6.45 (1H, W),6,62-6,74 (1H, W), 6,82-to 6.95 (1H, m), 7,10-7,34 (5H, m), 8,53-8,64 (1H, Shir.).
227of 1.03 (3H, d, J=5.8 Hz), 1,48 is 1.60 (1H, m), 1,99-2,10 (1H, m), 2,24-of 2.36 (2H, m), 2,70-of 2.81 (1H, m), 3.00 and-of 3.42 (5H, m), 3,69-of 3.80 (2H, W), 4,78-4,82 (1H, W), to 6.39 (1H, d, J=7.8 Hz), to 6.43 (1H, s), 6,62 (1H, s), 6,65-6,74 (2H, m), 7,10-7,29 (4H, m), 7,35 (1H, d, J=8,4 Hz), 8,65 (1H,s).
228of 1.03 (3H, d, J=6.3 Hz), 1,50-1,60 (1H, m), 1,95-2,10 (1H, m), 2,20-2,40 (2H, m), 2.70 height is 2.80 (1H, m), 3.00 and is 3.40 (5H, m), 3,70-of 3.80 (2H, W), 4,70-of 4.95 (1H, W), to 6.39 (1H, d, J=7.8 Hz), to 6.43 (1H, s), 6,62(1H, s), 6,65 to 6.75 (2H, m), 7,10-7,30 (4H, m), 7,35 (1H, d, J=8,4 Hz)8,64 (1H, s).
230of 0.90 (6H, d, J=5,9 Hz), 2,23-of 2.50 (4H, m), 2,55 is 2.75 (1H, W), 2,80-3,00 (2H, W), 3,01-3,20 (1H, W), 3,25 is 3.40 (1H, m), 3,70-of 3.80 (2H, W), 4,75-of 4.90 (1H, W), 6,30-6,40 (1H, m), to 6.43 (1H, s), 6,60 (1H, s), of 6.68 (1H, d, J=8,3 Hz), 6,72 (1H, d, J=6.8 Hz), 7,10-7,30 (4H, t), 7,35 (1H, d, J=7,4 Hz), 8,63 (1H, s).
238of 2.23 (3H, s), 2,33 is 2.46 (1H, W), 2,54-and 2.79 (1H, W), 2,98-of 3.27 (1H, W), 4,62 is equal to 4.97 (1H, W), 6,24 (1H, s), 6,37 (1H, d, J=2.4 Hz), 7,07-rate of 7.54 (6H, m), 7,75-a 7.92 (2H, m), with 8.05 (1H, s).
2431,20-of 1.85 (6H, m), 2,22 (3H, s), 2,25-2,90 (5H, m), 3.00 and is 4.35 (5H, m), 4,45-4,70 (1H, m), 4.75 V-4,90 (1H, W), 6,33 (1H, d, J=2.5 Hz), and 6.3 (1H, C)6,98 (1H, d, J=7.8 Hz), 7,00 for 7.12 (1H, W), 7,16 (1H, t, J=7,1 Hz), 7,25 (1H, t, J=7,3 Hz), 7,37 (1H, d, J=7,4 Hz), EUR 7.57 (1H, d, J=7.8 Hz), 7,83 (1H, s), scored 8.38 (1H, d, J=2.4 Hz), 8,40-8,55 (1H, m).
2441,20-of 1.75 (6H, m), 2,22 (3H, s), 2,30-of 2.50 (2H, m), 2,65-a 3.01 (3H, m), 3,20-3,40 (3H, m), 3,70-of 3.80 (1H, m), 4,07 (1H, s), 4,54 (0,5H, t, J=5.4 Hz), 4,63 (0,5H, t, J=5.4 Hz), 4,65-4,80 (1H, W), 6,33 (1H, d, J=2.5 Hz), 6,40 (1H, s), 6,98 (1H, d, J=7.8 Hz), 7,00-7,10 (1H, W), 7,17 (1H, dt, J=1.5 and 7.8 Hz), 7,25 (1H, dt, J=1,0, and 7.8 Hz), 7,37 (1H, d, J=7,3 Hz), EUR 7.57 (1H, d, J=7.8 Hz), 7,83 (1H, s), scored 8.38 (1H, d, J=2.5 Hz), of 8.47 at 8.60 (1H, Shir.).

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.

td align="center"> -NH2
Table 18
The connection numberR1R2R3R4R5
A1-NH-(4-HO2C-Ph)Cl3-Me-praHN
A2-NH-(2-HO2C-Ph)Cl3-Me-praHN
A3-NH-(4-Me2N-Ph)Cl3-Me-praHN
A4-NH-(4-cyano-Phenyl)Cl3-Me-praHN
A5-NH-(3-F3C-Ph)Cl3-Me-praHN
A6-NH-(2-MeO-Ph)Cl3-Me-praHN
A7-NH-(2-F-Ph)Cl3-Me-praHN
A8-NHCH2-(2-H2NOC-Ph)Cl3-Me-praHN
A9-NH-(6-HO-3-py)Cl3-Me-praHN
A10-NH-(6-Cl-pyridazin-3-yl)Cl3-Me-praHN
A11-NH-(6-Me-2-py)Cl3-Me-praHN
A12-NH-(5-H2NOC-2-py)Cl3-Me-praHN
A13-NH-(2-thia)Cl3-Me-praHN
A14-NH-(1-Me-2-imid)Cl3-Me-praHN
A15-NH-(pyrazin-2-yl)Cl3-Me-praHN/td>
A16-N(Me)-(6-HO-3-py)Cl3-Me-praHN
A17-NHCH2To(4-H2NOC-2-py)Cl3-Me-praHN
A18-N(Me)CH2-(3-py)Cl3-Me-praHN
A19-NHCH2-(4-F-2-py)Cl3-Me-praHN
A20-NHCH2-(pyrimidin-2-yl)Cl3-Me-praHN
A212-H2NOC-pyrrCl3-Me-praHN
A222-H2NOC-pipeCl3-Me-praHN
A23Cl3-Me-praHN
A24Cl3-Me-praHN
A25Cl3-Me-praHN
A26Cl3-Me-pra HN
A27Cl3-Me-praHN
A28Cl3-Me-praHN
A29Cl3-Me-praHN
A30Cl3-Me-praHN
A31Cl3-Me-praHN
A32Cl3-Me-praHN
A33Cl3-Me-praHN
A34Cl3-Me-praHN
A35Cl3-Me-praHN
A36Cl3-Me-pra N
A37Cl3-Me-praHN
A38Cl3-Me-praHN
A39Cl3-Me-praHN
A40Cl3-Me-praHN
A41Cl3-Me-praHN
A42Cl3-Me-pra-HH
A43Cl3-Me-pra-HH
A44-NHCH2-(2-py)Br3-Me-pra-HH
A45-NH(CH2)2OHBr3-Me-pra-HH
A46-NHCH2CONH2Br3-Me-pra-HH
A47 -NH2Br3-Me-pra-HH
A48-NHCH2-(2-py)Me3-Me-pra-HH
A49-NH(CH2)2OHMe3-Me-pra-HH
A50-NHCH2CONH2Me3-Me-pra-HH
A51-NH2Me3-Me-pra-HH
A52-NH(CH2)2OHMepyrr-HH
A53-NHCH2-(6-HO-2-py)MePyrr-HH
A54-NHCH2-(2-py)Mepyrr-HH
A55-N((CH2)2OH)2Mepyrr-HH
A56-NH2Mepyrr-HH
A57-NHCH2CONH2Me3-Me-pyrr-HH
A58-NHCH2-(2-py)Me 3-Me-pyrr-HH
A59-NH2Me3-Me-pyrr-HH
A60-NH(CH2)2OHMe3-Me-pyrr-HH
A61-NHCH2CONH2Me3,3-diF-pyrr-HH
A62-NHCH2CONH2Me3,4-diMe-pyrr-HH
A63-NH2Me3,3-diF-pyrr-HH
A64-NH2Me3,4-diMe-pyrr-HH
A65-NHCH2-(6-HO-2-py)CF33-Me-pra-HH
A66-NHCH2-(6-Me-2-py)CF33-Me-pra-HH
A67CF33-Me-pra-HH
A68-NHCH2-(6-HO-2-py)CF33-Me-pra-HH
A69-N((CH2)2OH)2 CF33-Me-pra-HH
A70-NHCH2-(6-HO-2-py)CF3pyrr-HH
A71-NHCH2-(2-py)CF3pyrr-HH
A72-N((CH2)2OH)2CF3pyrr-HH
A73-N((CH2)2OH)2Cl3-Me-pyrr-HH
A74-NHCH2-(2-py)Cl2-H2NOC-pyrr-HH
A75-NHCH2-(2-py)Cl3-HO-pipe-HH
A76-NHCH2-(2-py)CF33-HO-pipe-HH
A77-NHCH2-(2-py)Cl3-MeO-pyrr-HH
A78-NHCH2-(2-py)CF33-MeO-pyrr-HH
A79-NHCH2-(2-py)Cl4-NC-pipe-HH
A80 -NHCH2-(2-py)Cl3,4-diMe-pyrr-HH
A81-NH(CH2)2OHCl2,4-diMe-pyrr-HH
A82-NHCH2-(2-py)ClHH
A83-NH(CH2)2OHClHH
A84-NHCH2CONH2ClHH
A85-NH(CH2)2OHCF3HH
A86-NHCH2-(2-py)CF3HH
A87-NHCH2-(2-py)Cl3-Me-pra-H7-Me
A88-NHCH2-(2-py)Cl3-Me-pyrr-H7-Me
A89-NHCH2-(2-py)Cl3-Me-pra-H7-C1
A90 -NHCH2-(2-py)Cl3-Me-pyrr-H7-C1
A91-NHCH2-(2-py)CF33-Me-praH7-Me
A92-NHCH2-(2-py)CF33-Me-pyrrH7-Me
A93-NHCH2-(2-py)CF33-Me-praH7-C1
A94-NHCH2-(2-py)CF33-Me-pyrrH7-C1
95-NHCH2-(2-py)Cl3-Me-praH8-Me
A96-NHCH2-(2-py)Cl3-Me-pyrrH8-Me
A97-NHCH2-(2-py)Cl3-Me-praH8-C1
A98 motorway-NHCH2-(2-py)Cl3-Me-pyrrH8-C1
A99-NHCH2-(2-py)CF33-Me-praH8-Me
A100-NHCH2-(2-py)CF33-Me-pyrrH8-Me
A101 -NHCH2-(2-py)CF33-Me-praH8-C1
A102-NHCH2-(2-py)CF33-Me-pyrrH8-C1
A103-NHCH2-(2-py)ClH3-Me-pra-H
A104-NHCH2-(2-py)ClH3-Me-pyrr-H
A105-NHCH2CONH2ClH3-Me-pyrr-H
A106-NHCH2-(2-py)ClHpyrr-H
A107-NHCH2-(2-py)CF3H3-Me-pra-H
A108-NHCH2-(2-py)CF3H3-Me-pyrr-H
A109-NHCH2CONH2CF3H3-Me-pyrr-H
A110-NHCH2-(2-py)CF3Hpyrr-H
A111-NH(CH2)2OHCl3,3-diF-pyrrHH
A112 -NHCH2CONH2Cl3,3-diF-pyrrHH
A113-NH(CH2)2OHCF33,3-diF-pyrrHH
A114-NHCH2CONH2CF33,3-diF-pyrrHH
A115-NH(CH2)2OHCl3-CF3-pyrrHH
A116-NHCH2CONH2Cl3-CF3-pyrrHH
A117-NH(CH2)2OHCF33-CF3-pyrrHH
A118-NHCH2CONH2CF33-CF3-pyrrHH
A119-NH(CH2)2OHCl2,5-dihydro-pyrrol-1-ylHH
A120-NHCH2CONH2Cl2,5-dihydropyrrol-1-ylHH
A121-NH2Cl2,5-dihydro-pyrrol-1-lHH
A122-NH(CH2)2/sub> OHCl3,4-diMe-1-pyrrHH
A123-NHCH2CONH2Cl3,4-diMe-1-pyrrHH
A124-NH2Cl3,4-diMe-1-pyrrHH
A125-NHCH2CONH2ClHH
A126-NH2ClHH
A127-NHCH2CONH2Cl3,4-diHO-1-pyrrHH
A128-NH2Cl3,4-diHO-1-pyrrHH
A129-NH-(3-HOCH2-(E)-CH=CH-Ph)CF33-Me-praHH
A130-NH-(3-HO2C-(E)-CH=CH-Ph)CF33-Me-praHH
A131-NH-(3-phenyl-(E)-CH=CH-Ph)CF33-Me-praHH
A132-NH-2-(5-H2NOC-(E)-CH=CH-Py)CF33-Me-pra HH
A133OMeCF3H2N-(Ac)N-HH
A134OEtCF3H2N-(Ac)N-HH
A135OEtCF3H2N-(Boc) - N-HH
A136OiPrCF3H2N-(Boc) - N-HH
A137OEtClH2N-(Boc) - N-HH
A138OiPrClH2N-(Boc) - N-HH
A139OEtCF3H2N-HN-HH
A140OiPrCF3H2N-HN-HH
A141OEtClH2N-HN-HH
A142OiPrClH2N-HN-HH
A143-NHCH2CONH2CF33-Me-praMeH
A144CF33-Me-praMeH
A145-NHCH2CONH2CF33-Me-praFH
A146-NH2CF33-Me-praFH
A147-NHCH2CONH2CF33-Me-pyrrFH
A148-NH2CF33-Me-pyrrFH
A149-NH2CF33-Me-pyrrMeH
A150-NH-(4-H2NOC-Ph)CF33-Me-praHH
A151-NH-(3-H2NOC-Ph)CF33-Me-praHH
A152-NH-(3-Me-Ph)CF33-Me-praHH
A153-NH-(4-HOCH2-Ph)CF33-Me-praHH
A154-NH-(3-HOCH2-Ph)CF33-Me-praHH
A155-NH-(4-MeOCH2-Ph)CF33-Me-praHH
A156-NHCH2To(4-H2NOC-Ph)CF33-Me-praHH
A157-NH-(3-Ms-Ph)CF33-Me-praHH
A158-NH-(3-Ac-Ph)CF33-Me-praHH
A159-NHCH2To(4-H2NO2S-Ph)CF33-Me-praHH
A160-NH-(2-HO-cHex)CF33-Me-praHH
A161-NH-(3-H2NOCCH2-Ph)CF33-Me-praHH
A162-NH-(3-H2NOC(CH2)2-Ph)CF33-Me-praHH
A163-NH-(3-H2NOC-(E)-CH=CH-Ph)CF33-Me-praHH
A164-NH-(3-AcNH-Ph)CF33-Me-praHH
A165-NH-(4-H2NOC-Ph)CF3 3-Me-pyrrHH
A166-NH-(3-H2NOC-PhCF33-Me-pyrrHH
A167-NH-(3-Me-Ph)CF33-Me-pyrrHH
A168-NH-(4-HOCH2-Ph)CF33-Me-pyrrHH
A169-NH-(3-HOCH2-Ph)CF33-Me-pyrrHH
A170-NH-(4-MeOCH2-Ph)CF33-Me-pyrrHH
A171-NH-(3-Ms-Ph)CF33-Me-pyrrHH
A172-NH-(3-Ac-Ph)CF33-Me-pyrrHH
A173-NHCH2To(4-H2NOS-Ph)CF33-Me-pyrrHH
A174-NH-(2-HO-cHex)CF33-Me-pyrrHH
A175-NH-(3-H2NOCCH2-Ph)CF33-Me-pyrrHH
A176-NH-3-H 2NOC(CH2)2-Ph)CF33-Me-pyrrHH
A177-NH-(3-H2NOC-(E)-CH=CH-Ph)CF33-Me-pyrrHH
A178-NH-(3-AcNH-Ph)CF33-Me-pyrrHH
A179-NH-(4-H2NOC-Ph)Cl3-Me-pyrrHH
A180-NH-(3-H2NOC-Ph)Cl3-Me-pyrrHH
A181-NH-(3-Me-Ph)Cl3-Me-pyrrHH
A182-NH-(4-HOCH2-Ph)Cl3-Me-pyrrHH
A183-NH-(3-HOCH2-Ph)Cl3-Me-pyrrHH
A184-NH-(4-MeOCH2-Ph)Cl3-Me-pyrrHH
A185-NH-(3-Ms-Ph)Cl3-Me-pyrrHH
A186-NH-(3-Ac-Ph)Cl3-Me-pyrrHH
A187-NHCH2To(4-H2NO2 S-Ph)Cl3-Me-pyrrHH
A188-NH-(2-HO-cHex)Cl3-Me-pyrrHH
A189-NH-(3-H2NOCCH2-Ph)Cl3-Me-pyrrHH
A190-NH-(3-H2NOC(CH2)2-Ph)Cl3-Me-pyrrHH
A191-NH-(3-H2NOC-(E)-CH=CH-Ph)Cl3-Me-pyrrHH
A192-NH-(3-AcNH-Ph)Cl3-Me-pyrrHH

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.



 

Same patents:

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide of the formula: and to its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition inhibiting activity of protein-tyrosine kinases and comprising the indicated compound, a method for treatment of disorders associated with protein-tyrosine kinases, such as an immune disorder, and oncology disease, and a method for cancer treatment.

EFFECT: valuable biochemical and medicinal properties of compounds and composition.

5 cl, 2 tbl, 581 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of quinazoline of the formula (I):

wherein m = 0, 1, 2 or 3; each group R1 that can be similar or different is taken among halogen atom, trifluoromethyl, hydroxy-, amino-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-, (C2-C6)-alkynyloxy-, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino- and (C2-C6)-alkanoylamino-group, or among the group of the formula: Q1-X1- wherein X1 represents oxygen atom (O); Q1 represents aryl-(C1-C6)-alkyl, heteroaryl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl and wherein neighboring carbon atoms in any (C2-C6)-alkylene chain in substitute at R1 are separated optionally by insertion to the chain the group taken among oxygen atom (O) and N(R5) wherein R5 represents hydrogen atom or (C1-C6)-alkyl, or when the inserted group represents N(R5); R5 can represent also (C2-C6)-alkanoyl and wherein any group -CH2 or -CH3 in substitute R1 carries one or more substitutes in each indicated group -CH2 or -CH3 and wherein these substitutes are taken among halogen atom or (C1-C6)-alkyl, or substitute taken among hydroxy-, amino-group, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-, (C2-C6)-alkanoyloxy, (C2-C6)-alkanoylamino- and N-(C1-C6)-alktyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X3-Q3wherein X3 represents oxygen atom (O) and Q3 represents heteroaryl, and wherein any aryl, heteroaryl or heterocyclyl group in substitute at R1 carries optionally 1, 2 or 3 substitutes that can be similar or different and taken among halogen atom, trifluoromethyl, cyano-, hydroxy-, amino-group, carbamoyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy, (C2-C6)-alkynyloxy,(C1-C6)-alkylthio-group, (C1-C)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-group, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]carbamoyl, (C2-C6)-alkanoyl, (C2-C6)-alkanoyloxy-, (C2-C)-alkanoylamino- and N-(C1-C6)-alkyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X4-R8 wherein X4 represents a simple bond and R8 represents hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, cyano-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl or di-[(C1-C6)-alkyl]amino-(C1-C6)-alkyl, or among the group of the formula: -X5-Q4 wherein X5 represents a simple bond or -CO, and Q4 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that carries optionally 1 or 2 substitutes that can be similar or different and taken among halogen atom, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group and wherein any heterocyclyl group in substitute at R1 carries optionally 1 or 2 oxo-substitutes, and wherein any aryl group in the group R1 represents phenyl; any heteroaryl group in the group R1 is taken among pyrrolyl, imidazolyl, triazolyl and pyridyl, and any heterocyclyl group in the group R1 is taken among oxyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl; R2 represents hydrogen atom; n = 0, 1, 2 or 3; R3 represents halogen atom, trifluoromethyl, cyano-, hydroxy-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or (C1-C6)-alkoxy-group, or its pharmaceutically acceptable salt. Also, invention relates to methods for preparing compounds of the formula (1) and to pharmaceutical composition based on thereof for using as an anti-tumor agent. Invention provides preparing new derivatives of quinazoline possessing an anti-tumor activity.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 7 tbl, 7 ex

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