Derived benzazepine, pharmaceutical composition, derived differentation and derivative (substituted) aminobenzoylglutamate

 

(57) Abstract:

Describes derived benzazepine presented to the following General formula I, or its pharmaceutically acceptable salt, where R1, R2, R3, R4, R5, R6, R7indicated in paragraph 1 of the claims. Also described pharmaceutical composition based on compounds of formula I, manifesting as the above compounds antagonistic activity against Organisatorische. Describes intermediate products for the synthesis of compounds of formula I. 4 C. and 8 C.p. f-crystals. 6 table.

The technical field

The invention relates to new derivatives benzazepine, which are used as antagonists Organisatorische, to their pharmaceutically acceptable salts, to pharmaceutical compositions containing these compounds as active ingredients and intermediate products for the synthesis of these compounds.

Background of the invention

Organisatorisches (AVP) is a peptide consisting of 9 amino acid residues, which is synthesized and secreted in the hypothalamus-neurohypophyseal system. As antagonists Organisatorische by unexamined Japanese patent application (Kokai) N 2-32098 known as connection peptide type. On the other hand derivatives of 2,3,4,5-tetrahydro-1H-1-benzazepine presented to the following General formula are described in EP-A-0514667 and in published unexamined Japanese patent application (Kokai) N 5-132466 as antagonists of vasopressin ones type.

< / BR>
(B above formula, R4is..., lowest alkoxycarbonylmethyl alkylidene group, a (lower alkyl)-amino-lower alkylidene group, cyano (lower) alkylidene group, ...; for other characters see the above patent publication).

In addition, in international patent publication N 91/05549 describes a compound represented by following General formula, and known derivatives of 2,3,4,5-tetrahydro-1H-1-benzazepine described in published unexamined Japanese patent application (Kokai) N 4-154765.

< / BR>
(B above formula is Deputy .. . ; the replacement group is ... oxoprop, gidrokshikislotu, alkylidene group, ...; for other characters see the above patent publication).

In addition, the authors of the present invention have been previously detected antagonism to Organisatorische the next about the private unexamined Japanese patent application (Kokai) N 5-320135).

< / BR>
(In the above formula R represents ... one of R1and R2represents a hydrogen atom and the other represents a lower alkoxygroup, lower alkoxycarbonyl group or phenyl group to another; for other characters see the above patent publication).

Derivatives (substituted) methylidene-substituted benzazepine described in these patent publications, demonstrate isomerization of Exo-olefin to endo-olefin in acidic or basic environments. In particular, it is known that the connection with electroncapture group-position capable of isomerization. As a result, these compounds are not only difficult to synthesize due to isomerization, but they are also poor at handling or stability in vivo because of their low physical resistance.

Description of the invention

The applicants of the present invention have conducted extensive studies of compounds with antagonistic to Organisatorische, and made the present invention based on the discovery that a new derived benzazepine presented to the following General formula (I) unexpectedly shows persistent and strong antagonism to Organisatorische.

< / BR>
[symbols in the formula have the following meanings: one of R1and R2represents a hydrogen atom, and the other is a group represented by

where A1and A2may be the same or different from each other, and each represents a single bond, lower alkylenes group or lower alkynylamino group

m denotes 0 or 1,

In denotes a group represented by a formula (or the nitrogen atoms in these formulas may be oxidized),

p represents 0 or an integer from 1 to 3 (provided that, when p = 2 or 3, the groups denoted by the symbol B may be the same or different optional),

R8represents a hydrogen atom; a lower alkyl group; a lower alkenylphenol group; cycloalkyl group; a hydroxyl group; a lower alkoxygroup; carboxyl group; lower alkoxycarbonyl group; a cyano; aryl group which may be substituted; nitrogen-containing aromatic five - or six-membered heterocyclic group which may be substituted; nitrogen-containing saturated five-to eight-membered heterocyclic group which may have a bridge and which may be substituted by a lower alkyl group on the nitrogen atom of the ring;

and who or different from each other, and each represents an integer from 1 to 3 (provided that the total number of s and t is an integer from 3 to 5), and represents an integer from 2 to 7,

A3, A4and A5may be the same or different from each other, and each represents a single bond, lower alkylenes group or lower alkynylamino group (provided that when the neighboring group is attached to A3or A5through a nitrogen atom or an oxygen atom, A3or A5represents a group other than a single bond),

R9represents a hydrogen atom or a lower alkyl group, q and r may be the same or different from each other, and each represents an integer from 1 to 3 (provided that the sum of q and r is an integer from 3 to 5),

X represents a group represented by-O - or-S(O)w-, w represents 0, 1 or 2,

R3and R4may be the same or different from each other, and each represents a hydrogen atom; a halogen atom; a lower alkyl group; a lower alkoxygroup; or an amino group which may be substituted by a lower alkyl group;

R5and R6may be the same or different from each other, and each represents ATU with the formation of a saturated carbon ring with adjacent carbon atoms),

n represents 0 or 1, and

R7represents an aryl group which may be substituted, or an aromatic five - or six-membered heterocyclic group which may be substituted.

The present invention relates also to pharmaceutical compositions, in particular, to the agent, which is an antagonist of Organisatorische, which contains a compound represented by the above General formula (I) or its pharmaceutically acceptable salt, as an active ingredient.

The present invention relates to a derivative of differentiation presented to the following General formula (II) and (III), or their salts, which are used as intermediates to obtain compounds represented by the above General formula (I) or its pharmaceutically acceptable salt.

< / BR>
(In this formula, R3such as the one above, and R10represents a hydrogen atom or a protective group for amino group).

< / BR>
(In this formula, R3and R10such as described above.)

The chemical structure of the compounds according to the present invention is characterized by the fact that diveristy fragment attached to the atom permetrina group. Due to the presence of differentage fragment of the compound of the present invention does not undergo isomerization and shows sufficient stability and excellent duration of action in vivo. Moreover, it manifests a strong antagonism to Organisatorische. In particular, a strong antagonism to Organisatorische shows a connection in which mathildenhohe group substituted (substituted) aminocarbonyl group. In addition, the compound of the present invention is perfectly absorbed by periorale introduction.

Further, the compound of the present invention is described in more detail.

Illustrative examples of the heterocyclic group of the "aromatic five - or six-membered heterocyclic group which may be substituted" represented by the radical R7compounds of the present invention include nitrogen-containing aromatic five - or six-membered heterocyclic group which contains, as heteroatoms, at least one nitrogen atom and may have an oxygen atom or sulfur, such as pyrrolidine, pyrazolidine, imidazolidine, triazoline, tetrataenia, perederina, pyridazine, pyrimidinyl, personalabteilung heterocyclic group, containing as the heteroatom, an oxygen atom and/or sulfur atom, such as thienyl, furilla, Pernilla group or etc.

Heterocyclic group of the "nitrogen-containing aromatic five - or six-membered heterocyclic group which may be substituted" represented by the symbol R8represents a nitrogen-containing aromatic five - or six-membered heterocyclic group which contains, as heteroatoms, at least one nitrogen atom and may have an oxygen atom and/or sulfur atom, and its illustrative examples include those groups described above as illustrative examples of the nitrogen-containing five - or six-membered heterocyclic group.

Illustrative examples of the heterocyclic group of the "nitrogen-containing saturated five-to eight-membered heterocyclic group, which has a bridge and which may be substituted by a lower alkyl group on the nitrogen atom in the ring" represented by the symbol R8include monocyclic or bridged saturated heterocyclic group containing as a heteroatom a nitrogen atom, such as pyrrolidinyl, piperideine, piperazinilnom, pyrazolidinone, imidazolium (hinkleyville group), (2-azabicyclo[2.2.2]-aktiline group), etc.], azabicyclo[2.2.1]heptylene group, etc.,), azabicyclo[3.2.1]aktalnye group, etc.,), azabicyclo[3.3.1]monilinia group and so on ), and azabicyclo[3.2.2]monilinia group and so on ). In these cycles (H) means that in this position may be a hydrogen atom or a Deputy or binding chain, which will be described later.

In addition, examples of the aryl group of the "aryl group which may be substituted", represented by the symbols R7and R8include aryl groups with 6 to 14 carbon atoms, such as phenyl, diphenylene, naftalina, antenna, phenanthroline group, etc.

The deputies, who must be an aromatic five - or six-membered heterocyclic group, a nitrogen-containing aromatic five - or six-membered heterocyclic group or aryl ring of the above groups, R7and R8can be selected from those usually used in this field as Vice-aromatic heterocyclic and aryl rings. These rings may have 1 or 2 or more substituents, which are identical or different from each other.

Preferred examples of these substituents wklu a halogen atom or a hydroxyl group,

b) lower alkoxygroup, which may be substituted by halogen atom, cyano, hydroxyl, carboxyl, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyloxy, carbamoyl, lower alkylaminocarbonyl or phthalimido group; a hydroxyl group; mercaptopropyl or lower allylthiourea,

(C) a halogen atom, a cyano or a nitro-group,

d) carboxyl, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyloxy, carbamoyl or lower alkylaminocarbonyl group

e) an amino group which may be substituted by a lower alkyl group; a lower alkylamino; 1-pyrrolidino group; piperidino; morpholinopropan; or piperazinilnom, imidazolidinyl or homopiperazine group which may be substituted by a lower alkyl group on the nitrogen atom of the ring,

f) cycloalkyl group

g) a phenyl group which may be substituted by a lower alkyl group, lower alkenylphenol group, lower alkenylphenol group, a halogen atom, a lower alkoxygroup, amino group which may be substituted by a lower alkyl group, a hydroxyl group or a carboxyl group, and

h) imidazolidinyl, triazolyl the ü substituted lower alkyl, cycloalkyl or phenyl group.

Particularly preferred examples of the substituents of the aromatic five - or six-membered heterocyclic group, the nitrogen-containing aromatic five - or six-membered heterocyclic group or aryl group, the radical R8include a halogen atom, a lower alkyl group, lower alkoxygroup and the amino group which may be substituted by a lower alkyl group.

As for the substituent aryl groups of the radical R7then, when the aryl group is a phenyl, preferred substituents can be used, all of the above groups, and when the aryl group is naphthyl or etc., as the preferred substituent can be used a lower alkyl group.

Unless otherwise indicated, the term "lower" when used in the definition of the General formula compounds of the present invention means an unbranched or branched carbon chain having from 1 to 6 carbon atoms.

Illustrative examples of "lower alkyl group" include an unbranched or branched alkyl groups having each from 1 to 6 carbon atoms, such as methyl, ethyl propyl, from util, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl etc.

Illustrative examples of the "lower alkenylphenol group" include an unbranched or branched alkeneamine groups having each from 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methylallyl, 1-methyl-1-propenyl, 1-methylallyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1,1-dimethylallyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,1-dimethyl-1-butenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 1-methyl-1-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 4-methyl-1-pentenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl etc.

Illustrative examples of the "lower alkenylphenol groupcache as ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-PROPYNYL, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-1-butenyl, 2-methyl-3-butynyl, 1-methyl-2-butenyl, 1-methyl-3-butynyl, 1,1-dimethyl-2-PROPYNYL, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.

Illustrative examples of "cycloalkyl group" include cycloalkyl group, preferably having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.

Illustrative examples of "lower alkoxygroup include low alkoxygroup, having as their alkyl part of the above-mentioned alkyl group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentylamine, trypantyhose, neopentylene, 2-methylbutoxy, 1,2-DIMETHYLPROPANE, 1 ethylpropoxy, hexyloxy etc.

Illustrative examples of "lower ancilliary include low ancilliary having as the alkyl part of the above-mentioned alkyl group, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, pentylthio, isopentyl, hexylthio, sagacity etc.

The sludge is proizvodnye from saturated aliphatic carboxylic acids, such as formyl, acetyl, propionyl, butisol, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl etc.

Illustrative examples of "lower alkanoyloxy" include groups containing as alkanoyloxy part above the lower alkanoyloxy group, such as acetoxy, propionyloxy etc.

Examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

The term "amino group which may be substituted by lower alkyl group" means an amino group or an amino group, mono - or disubstituted by the above lower alkyl group, and its illustrative examples include mono(lower)alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentyl(amyl)amino, isopentylamine, neopentylene, tert-pentylamine, hexylamine etc., and symmetric or asymmetric di(lower)alkylamino, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamine, ethylmethylamino, methylpropylamine etc.

"Lower alkoxycarbonyl group" is a lower alkoxycarbonyl group, with the alkyl part is specified in the s, having from 1 to 6 carbon atoms, a carbonyl group, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol, tert-pentyloxybenzoyl, hexyloxybenzoyl or etc.

Similarly, "lower alkylaminocarbonyl group" is a lower alkylaminocarbonyl group having alkylamino part of the amino group, substituted by the above lower alkyl group.

The term "lower Allenova group" means an unbranched or branched divalent carbon chain having from 1 to 6 carbon atoms, and its illustrative examples include methylene, METROTILE, ethylene, trimethylene, tetramethylene, 2-metallisation, 1-ethylethylene, pentamethylene, 1,2-diethylethylene, hexamethylen etc.

The term "lower alkenylamine group" means an unbranched or branched divalent carbon chain having from 2 to 6 carbon atoms, and its illustrative examples include vinile, propylen, 2-propanole, 1-Mitilini-len, 2-methylvinyl, butylen, 2-butylen, 3-BU the Illustrative examples of the protective group for the amino group" include a protective group of the urethane type, such as benzyloxycarbonyl, tert-butoxycarbonyl, tert-aryloxyalkyl, etc. which may be substituted by a lower alkyl group, lower alkoxygroup, a halogen atom, a nitro-group, phenylisopropyl or p-phenylisopropyl; protective groups are acyl types such as formyl, acetyl, TRIFLUOROACETYL, benzoyl, etc.; protective group Arakelova type, such as benzyl, benzhydryl, trityl and so on; organic protective group sulfonylurea type, such as alkanesulfonyl (for example, methanesulfonyl, econsultancy and trifloromethyl) and aromatic sulfonyl (for example, benzazolyl and toluensulfonyl (in particular, p-toluensulfonyl)); and the protective silyl group such as trimethylsilyl, triisopropylsilyl and tert-butyldimethylsilyl.

Salt of the compounds of the present invention may be the salt of the accession of the acid with an inorganic or organic acid or a salt with an inorganic or organic base, and preferred is a pharmaceutically acceptable salt. Illustrative examples of such salts include a salt accession acid, formed with inorganic acid, such as hydrochloric, Hydrobromic, idiscovered the new, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, methansulfonate, econsultancy acid or so on; or acidic amino acid such as aspartic acid, glutamic acid or so on; and a salt with an inorganic base, such as sodium, potassium, magnesium, calcium, aluminum, or etc.; an organic base such as methylamine, ethylamine, ethanolamine, or so forth, or with basic amino acid such as lysine, ornithine or similar Suitable Quaternary ammonium salt. Illustrative examples of Quaternary ammonium salts include lower alkylhalogenide lowest alkyldiphenyl lowest alkyllithium, benzylchloride etc., preferably methyliodide, benzylchloride etc.

When the compound of the present invention has a tertiary amine, this amine can be oxidized, and this description covers all such oxide derivatives.

The compound of General formula (I) can form optical isomers due to the asymmetric carbon atom, geometrical isomers due to the presence of a double bond or a cyclohexane ring or endo - and Exo-stereoisomers due to the presence of a ring having a bridge connection. In byeeeeeee and optical isomers. The present invention also includes hydrates, various solvate, tautomers, etc. of compounds of General formula (1). All types of polymorphism compounds of the present invention is also included in the scope of the invention.

A preferred example of the compound (I) of the present invention is a compound or its pharmaceutically acceptable salt, where the group represented by a formula selected from

1) a single bond,

2) groups of the formula

3) lower alkalinous or lower alkynylamino group or

4) the group of formula (A1represents the lower alkylenes or lower alkynylamino group) and

R8represents a hydrogen atom; cyano; carboxyl group; lower alkoxycarbonyl group; a lower alkyl group; a lower alkenylphenol group; cycloalkyl group; a hydroxyl group; a lower alkoxy group; phenyl or naftalina group which may be substituted by a lower alkyl group, halogen atom, amino group which may be substituted by a lower alkyl group or lower alkoxy group; nitrogen-containing aromatic five - or six-membered heterocyclic group which is selected from peredelnoj, imidazolidine, personalni, pyramidellidae groups, and which may be substituted by a lower alkyl group, halogen atom, amino group which may be substituted by a lower alkyl group, or a lower alkoxygroup; nitrogen-containing saturated five-to eight-membered heterocyclic group which is selected from pyrrolidinyl, piperidino, piperazinilnom, imidazolidinyl, homopiperazine, pyrazolidinone, azabicyclo[2.2.2]octiles, azabicyclo[2.2.1]heptylene and azabicyclo[3.2.1]octiles groups can have the bridge and may be substituted by a lower alkyl group on the nitrogen atom in the ring; or a group represented by the formula (atom N in the formula may be oxidized) (where q and r are 1, 2 or 3, and q+r = 3 to 5, X represents O or S(O)wand w represents 0, 1 or 2), and

R7represents a phenyl group which may have 1 to 5 substituents; naftalina group which may be substituted by a lower alkyl group; or an aromatic five - or six-membered heterocyclic group which is selected from thienyl, furillo, pyrrolidino, peredelnoj, imidazolidine, personalni, pyrimidinyl, perenlei, pyridazinyl, pyrazolidine, tetrazolyl, triazoline, thiazolidine, isothiazolines, oxazolidines and isoxazol which may be substituted by a lower alkyl group, or lower alkoxygroup; each of the substituents for the phenyl group represented by the symbol R7chosen from:

a) lower alkyl, lower alkenylphenol or lower alkenylphenol group which may be substituted by a halogen atom or a hydroxyl group,

b) low alkoxygroup, which may be substituted by halogen atom, cyano, hydroxyl, carboxyl, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyloxy, carbamoyl, lower alkylaminocarbonyl or phthalimido group; a hydroxyl group; mercaptopropyl or lower ancilliary.

c) halogen atom, ceanography or nitro,

d) carboxyl, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyloxy, carbamoyl or lower alkylaminocarbonyl group,

(e) an amino group which may be substituted by a lower alkyl group, lower alkanolamines; 1-pyrrolidinyloxy group; piperidino; morpholinopropan; or piperazinilnom, imidazolidinyl or homopiperazine group which may be substituted by a lower alkyl group on the nitrogen atom in the ring,

f) cycloalkyl group,

g) phenyl group, which may be lower alkoxygroup, amino group which may be substituted by a lower alkyl group, a hydroxyl group or a carboxyl group, and

h) imidazolidine, triazoline, tetrazolyl, pyrrolidino, peredelnoj, personalni or pyrimidinyl group which may be substituted by lower alkyl, cycloalkyl or phenyl group. Another preferred compound is the compound or its pharmaceutically acceptable salt, where the group represented by a formula selected from

1) a single bond,

2) or

3) lower alkalinous or lower alkynylamino group, and

R8represents a hydrogen atom; cyano; carboxyl group: lower alkoxycarbonyl group; a lower alkyl group; a lower alkenylphenol group; cycloalkyl group; a hydroxyl group; a lower alkoxygroup; phenyl group which may be substituted by a lower alkyl group or a halogen atom; a nitrogen-containing aromatic five - or six-membered heterocyclic group which is selected from peredelnoj, imidazolidine, triazoline, thiazolidines and oxazoline groups, and which may be substituted by a lower alkyl group or amino group which may be substituted by lower al is pyrrolidinyloxy, piperidine, homopiperazine, azabicyclo[2.2.2]octiles and azabicyclo[3.2.1]octiles groups can have the bridge and may be substituted by a lower alkyl group on the nitrogen atom in the ring; or a group represented by the formula

(the N atom in the formula may be oxidized), (where q and r are 1, 2 or 3, and q+r=3 to 5, X represents O or S(O)ww represents 0, 1 or 2), and

R7represents a phenyl group which may have 1 to 5 substituents, naftalina group or an aromatic five - or six-membered heterocyclic group which is selected from thienyl, furillo, pyrrolidino, peredelnoj, imidazolidine, triazoline, thiazolidines and oxazolidinone groups and may be substituted by a lower alkyl group, and each of the substituents for the phenyl group represented by the symbol R7chosen from:

a) lower alkyl, lower alkenylphenol or lower alkenylphenol group which may be substituted by a halogen atom or a hydroxyl group,

b) low alkoxygroup, which may be substituted by hydroxyl, carboxyl or carbamoyl group, or lower allylthiourea,

c) halogen atom, or nitro,

(e) an amino group which may be substituted missiles group, which may be substituted by a lower alkyl group on the nitrogen atom in the ring,

g) a phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup, amino group which may be substituted by a lower alkyl group, or a hydroxyl group, and

h) imidazolidine, triazoline or pyrrolidino group which may be substituted by lower alkyl, cycloalkyl or phenyl group. The preferred compound is the compound or its pharmaceutically acceptable salt, where the group represented by formula represents

1) single bond, p = 0, and R8represents a cyano, a carboxyl group or a lower alkoxycarbonyl group, or

2)

3) lower alkylenes or lower alkynylamino group, p = 0, 1, or 2, and

R8represents a hydrogen atom; a lower alkyl group; a lower alkenylphenol group; a hydroxyl group; a lower alkoxygroup; cycloalkyl group; phenyl group which may be locked lower alkyl group or a halogen atom; a nitrogen-containing aromatic five - or six-membered heterocyclic group which is selected from peredelnoj, imidazolidine, triazoline is which may be substituted by a lower alkyl group; nitrogen-containing saturated five-to eight-membered heterocyclic group which is selected from pyrrolidinyl, piperidino, homopiperazine, azabicyclo[2.2.2]octiles and azabicyclo[3.2.1]octiles groups can have the bridge and may be substituted by a lower alkyl group on the nitrogen atom in the ring; or a group represented by the formula (atom N in the formula may be oxidized), (where q and r are 1, 2 or 3, and q+r = 3 to 5, X represents O or S(O)ww represents 0, 1 or 2), provided that when A2is p= 0, R8is and when A2is the lowest alkalinous group and p = 0, R8represents a hydroxyl group.

The most preferred compound is the compound or its pharmaceutically acceptable salt, where

1) when the group represented by the formula is a single bond, represents (1) -R8a (where R8a represents a cyano, a carboxyl group or a lower alkoxycarbonyl group),

2) when the group represented by the formula is the fact is

< / BR>
(where saand tarepresent 1, 2 or 3,

sa+ ta= 3-5,

A3arepresents a single bond or lower alkylenes group and
bare 4, 5 or 6,

A4aand A4brepresent each a single bond, and

R8crepresents a hydrogen atom),

< / BR>
(where ucis 4, 5 or 6,

A4cand A5arepresent each a single bond, and

R9aand R8dthe same or different from each other and each represents a lower alkyl group),

< / BR>
(where udis 4, 5 or 6,

A4drepresents a single bond, and

R8erepresents a hydrogen atom),

< / BR>
(where R9brepresents a hydrogen atom or a lower alkyl group,

A5brepresents a single bond or lower alkylenes group and

R8brepresents a hydrogen atom, cycloalkyl group, phenyl group, pyridyloxy group, piperidino group which may be substituted by a lower alkyl group on the nitrogen atom in the ring, hinkleyville group, hydroxyl group, lower alkoxygroup or a lower alkyl group),

< / BR>
(where A5crepresents the lower alkylenes group

A5drepresents a single bond,

R9cand R9dthe same or different from each other and each represents a hydrogen atom or a lower al represents a group represented by the formula

< / BR>
(where q and r are 1, 2 or 3, and q+r = 3 to 5, X represents O or S(O)wand w represents 0, 1 or 2), or

3) when the group represented by the formula is the lowest Allenova or lower alkenylamine group, it is

< / BR>
(where A1arepresents the lower alkylenes group

sband tbrepresent 1, 2 or 3,

sb+ tb= 3-5,

A3brepresents a single bond, and

R8irepresents a hydrogen atom or a lower alkyl group),

< / BR>
(where A1brepresents the lower alkylenes group

ucis 4, 5 or 6,

A4erepresents a single bond, and

R8jrepresents a hydrogen atom), or

< / BR>
(where A1crepresents the lower alkylenes group

R8kand R9erepresents a hydrogen atom or a lower alkyl group, and

A5erepresents a single bond), or (3-4) - A1d- R8l(where A1dis alkylenes group, and R8lrepresents a hydroxyl group).

Particularly preferred is a compound or its pharmaceutically acceptable salt, where R7represents a phenyl group which can be substituted by hydrogen atom, low alkoxygroup, which may be substituted carbamoyl group, halogen atom, piperidino, phenyl group which may be substituted by a lower alkyl group, imidazolidine, triazoline or pyrrolidino group which may be substituted, a lower alkyl group;

naftalina group, or thienyl, follow or pyrrolidino group which may be substituted by a lower alkyl group, and more preferably a compound in which the group represented by formula represents or its pharmaceutically acceptable salt, in particular its Z-form and its pharmaceutically acceptable salt.

The following are illustrative examples of particularly preferred compounds.

1) 4'-[[4,4-Debtor-5-(4-methyl-1-piperazinil)carbonylmethyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-phenylbenzene or its pharmaceutically acceptable salt (especially the Z-form).

2) 4'-[[4,4-Debtor-5-[(1-piperazinylcarbonyl)methylene] -2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-phenylbenzene or its pharmaceutically acceptable salt (especially the Z-form).

3) 4'-[[4,4-Debtor-5-[[(4-dimethylaminopyridine)carbonyl] - methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-2-heilhecker-1,4-diazepin-1 - yl)carbonylmethyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2 - phenylbenzene or its pharmaceutically acceptable salt (especially the Z-form).

5) 4'-[[5-[[(hexahydro-1,4-diazepin-1-yl)carbonyl]methylene]-4,4 - debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene or its pharmaceutically acceptable salt (especially the Z-form).

6) 4'-[[4,4-Debtor-5-[[N-methyl-N-(1-methyl-4-piperidyl)- carbamoyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]-carbonyl]-2 - fenbendazole or its pharmaceutically acceptable salt (especially the Z-form).

7) 4'-[[4,4-Debtor-5-[[N-(3-hinokitiol)carbarnoyl]methylene]-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-2-phenylbenzene or its pharmaceutically acceptable salt (especially the Z-form and its enantiomer).

8) N-[4-[[4,4-Debtor-5-[[(4-dimethylaminopyridine)carbonyl] methylene] - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] phenyl]-3-methylthiophene - 2-carboxamide or its pharmaceutically acceptable salt (especially the Z-form).

9) 4'-[[4,4-Debtor-5-(N-isopropylaminomethyl] -2,3,4,5 - tetrahydro-1H-1-benazepril-1-yl] carbonyl] -phenyl-benzanilide or its pharmaceutically acceptable salt (especially the Z-form).

10) 4'-[[4,4-Debtor-5-[N-(2-methoxyethyl)carbamoylmethyl] - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-phenylbenzene or its pharmaceutically acceptable salt (especially the Z-form).

11) 4'-[[4,4-Debtor-5-(N-isopropy who controls salt (in particular, its Z-form).

The method of obtaining

The compound of the present invention and salts thereof can be obtained by different methods of synthesis with the use of the distinctive features of their basic skeleton or type of substituents. In this case, it may be useful from the point of view of the method of obtaining to replace the carbonyl group of the intermediate compound or compounds of the present invention a suitable protecting group, namely, a functional group that can be easily converted into a carbonyl group. Can be used protecting groups are described, for example, Greene and Wutss in "Protective Groups in Organic Synthesis", 2nd ed, not necessarily in accordance with the reaction conditions. In addition to these groups, a functional group that can be converted into a carbonyl group, is also hydroxymethylene group (-CH(OH)-), and this functional group is also used as a carbonyl protective group.

Described below are typical examples of the method for obtaining compounds of the present invention.

The first method of obtaining

< / BR>
or its reactive derivative (III-a) or its salt

< / BR>
(In the above formulas, R1, R2, R3, R4 is (I) of the present invention receive, subjecting the carboxylic acid represented by the General formula (IV) or its reactive derivative and substituted aniline represented by the General formula (III-a) or its salt to the amidation and removal, if necessary, the protective group.

Examples of the reactive derivative of the compound (IV) include basic esters of carboxylic acids, such as methyl, ethyl, isobutyl, tert-butyl, etc.; halides such as acid chloride, bromohydrin etc. ; azides acids, active esters obtained by reacting with a phenolic compound such as 2,4-dinitrophenol, or N-hydroxylaminopurine, such as 1-hydroxysuccinimide, 1-hydroxybenzotriazole or similar; symmetric acid anhydrides; and mixed acid anhydrides, including mixed anhydrides with organic acids, obtained through collaboration with alkylamine esters halogencarbonic acids, such as halides alkylcarboxylic acids or pivaloyloxy, and mixed anhydrides based on phosphoric acid, obtained by the interaction with diphenylphosphinylchloride or N-methylmorpholine.

In addition, when the carboxylic acid is subjected to interaction in the form of free such as dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl, diethylphosphoramidite, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or etc.

In particular, in accordance with the present invention may be advisable to use chloranhydride method, a method in which the reaction is carried out in the joint presence of active tarifitsiruemih and condensing agent, or a method in which a conventional ester is treated with an amine, such as Metalli you can get a connection according to the present invention is simple and easy.

Although it varies depending on the reactive derivative, condensing agent, etc., usually the reaction can be performed in an inert organic solvent selected, for example, from halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., aromatic hydrocarbons such as benzene, toluene, xylene and so on, ethers such as diethyl ether, tetrahydrofuran, etc., esters such as ethyl acetate, etc.,, N,N-dimethylformamide and dimethyl sulfoxide, and the temperature of the cooling or at a temperature within the temperature ohlazhdeniya reactive derivative.

For a soft reaction can be convenient to use the substituted aniline (III-a) in excess, or to carry out the reaction in the presence of a base, such as N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, lutidine or so on the Pyridine can also be used as solvent. The second way of obtaining see the end of the description.

(In the above formulae, Ph represents a phenyl group, Y represents a halogen atom, R11represents a lower alkyl group and R1, R2, R3, R4, R5, R6, R7and n are such as defined above).

Thus, the compound (I) of the present invention can be obtained by interaction of the compounds represented by the General formula (V), with the salt of the phosphonium represented by the General formula (VIa), or a phosphonate represented by the General formula (VIb).

The reaction of the salt (VIa) of phosphonium not particularly limited, if it is executed under the conditions used for the synthesis of olefin in accordance with the Wittig reaction, and it can be carried out in a solvent such as diethyl ether, tetrahydrofuran, benzolamide desirable to add to the reaction system Foundation examples of such bases include inorganic bases such as sodium hydroxide, sodium carbonate, etc., alcoholate, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and etc., organic bases such as triethylamine, pyridine, etc., and ORGANOMETALLIC compounds such as n-utility, etc., halogen Atom represented by the symbol Y denotes a chlorine atom, bromine or etc.

Reaction with phosphonate (VIb) is also carried out in an inert solvent, such as methanol, ethanol, benzene, toluene, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide or etc., in the presence of a base such as sodium hydride, sodium amide, sodium methoxide, ethoxide sodium or so on the Third way of getting listed at the end of the description.

(In the above formulas, Rarepresents a lower alkyl group and R1, R2, R3, R4, R5, R6, R7, n, B, R8and p, such as described above).

By the third method of connection according to the present invention is converted into other claimed compounds. In the reaction "a" of the target compound (1a) in which R1or R2is ester, hydrolyzing to convert it to another target is unity (1b) is subjected to interaction with the amine to amide bond formation and thereby turning it into another target compound (1c), in which R1or R2is amide. In reaction c, the target compound (Ia) is subjected to interaction with the amine H-(-B-)p-R8to convert it into the target compound (1c) in which R1or R2is amide.

Response "b" and "c" is carried out in the same conditions as the amidation reaction in the first method of obtaining. In the reaction "a" hydrolysis is carried out in the solvent specified in the first method of obtaining, or in a mixed solvent of alcohol (e.g. methanol and ethanol) and water in the presence of a suitable acid or alkaline catalyst under cooling or at a temperature ranging from the temperature of cooling to room temperature, or from room temperature to high temperature.

In this connection, it is to say that the compounds (IIIa) and (V) as the parent compounds of these processes can be easily obtained by the method shown in the following reaction scheme (see. at the end of the description).

(In the above formulas, R1, R2, R3, R4, R5, R6, R7, R10and n are such as defined above, and R12represents lower alkyl or lower alkanoyloxy group).

Thus, when a researcher is real stepwise fluorination using a fluorinating agent, such as N-perbenzoic and triftorbyenzola N-torpedine, (VII) ---> (VIII) ---> ((II)), or first exposing its enol esterification in alkaline or acidic conditions to obtain the compound (IX) and then directly through diflorasone intermediate product using the same fluorinating agent(VII) ---> (IX) ---> ((II)). When the initial substance use derived tetrahydroquinolin-4-it (X), the compound (II) obtained by a method described in Chem. Pharm. Bull., 27 (12), 3123 (1979), in which the substance is subjected enol esterification as described above, for the formation of three-membered rings divorcement or etc., obtained from chlorodifluoroacetate sodium, with subsequent expansion of the ring in the presence of a base such as lithium hydroxide, or an acidic environment ((X) ---> (XI) ---> (XII) ---> ((II)).

Further, the compound (V) obtained by converting the substituent R10obtained in the manner described above, the compound (II) in the hydrogen atom and then amidation replaced by carbonemitting acid (XIII) or its reactive derivative in the same way as in the first method, or, alternatively, it is possible to obtain the compound (III-a) by removing protection from compounds (II) and is described in the first method of obtaining obtaining a derivative of 4,4-debtor-1-(p-nitrobenzoyl)benzdiazepine (XV), which is sequentially subjected to the restoration of obtaining the derived p-aminobenzoylamino (XVI), and then interact the latter derived from the compound (VIa) or (Vlb) as described in the second method of obtaining. Another intermediate compound (III) can be obtained by introducing a protective group into the p-aminobenzoylamino derivative of compound (III-a).

The compound (V) can be obtained when the compound (XVI) is subjected to amidation with compound (IV) or its reactive derivative as described in the first method of obtaining.

These reactions are obtaining can be carried out with the use of commonly used methods.

(Other ways to get)

In addition to the above methods of preparation, the compound (I) of the present invention can also be obtained by conversion of different substituents.

For example, a connection that is not amidon and is Deputy-based amine may be obtained by conventional N-alkylation, in which the corresponding halide or sulfonate subjected to interaction with the appropriate amine, in a way which is suitable is the same 5-ethylidene-5-hydroxybenzamide, obtained by interaction of the compound (V) with the Grignard reagent derived from vinylchloride, treated with the appropriate amine in the presence of a catalyst. In this regard, such halides and sulfonates can be obtained by processing hydroxycodone obtained by the second method of obtaining (obtained by recovery of ester, carboxylic acid or aldehyde obtained by the third method), halogen or a sulfonic acids in the usual way. Such methods of obtaining particularly suitable for producing compounds in which A1or A2represents the lower alkylenes or lower alkynylamino group (for example, allylamine).

N-oxide compound can also be obtained in the traditional way of oxidation, for example, by treating the corresponding derivative of the tertiary amine organic nagkalat or hydrogen peroxide.

In addition, aromatic aminosilane can be obtained by recovering the corresponding nitro compounds in the usual way. So same connection, substituted lower alkyl group, can be obtained by the above-mentioned conventional reactions of N-alkylation, and the implementation of the above-mentioned conventional reactions of N-alkylation.

The compound of the present invention obtained in the manner described above, is isolated and purified as a free compound or its salt, hydrate or solvate, such as a solvate with ethanol, or in the form of polymorphic compounds. Pharmaceutically acceptable salts of compound (I) can be obtained, subjected to this connection to conventional salt formation reactions.

Isolation and purification is carried out by performing common chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, etc.

Different types of isomers can be separated using differences in their physicochemical properties.

Each optical isomer can be obtained in the form of pure stereochemical isomer by using appropriate starting compound or by racemic separation of racemic compounds (for example, transforming them into diastereomer salts with conventional optically active acid or base and then putting salt optical separation).

Industrial applicability

Compounds of the present invention and their salts have a strong antagonism to organisatorisches V1and/or V2agonism and V1and V2receptors, a compound that exhibits strong antagonism selectively to V1receptor, and the compound, which exhibits strong antagonism selectively to V2the receptor.

Particularly preferred is a compound exhibiting a strong antagonism to the V1and V2the receptors.

Compounds of the present invention exhibit high absorption by oral administration and long-term effect due to their resistance to metabolism in vivo.

Therefore, based on these functions, the compounds according to the invention render action: water diuretic, increasing urine output, inhibition of secretion of factor VIII, the blood vessels to dilate, the acceleration of cardiac activity, inhibition of reduction mesangial cells, inhibition of proliferation mesangial cells, inhibition of gluconeogenesis in the liver, inhibition of platelet aggregation, inhibition of the secretion of aldosterone, oppression production endothelin, regulation of blood pressure, regulation of renin secretion, regulation of memory, thermoregulation, regulation of the production of prostaglandins, etc., and is used as a characteristic of water deurle the treatment of cardiac and renal failure and inhibitors of blood coagulation, and effective for the prevention and/or treatment of cardiac insufficiency, hyponatremia, syndrome of abnormal secretion of antidiuretic hormone (SIADH), hypertension, kidney disease (nephrosis, nephritis, diabetic nephropathy, chronic or acute renal failure), hydrocephalus, cerebral edema, ascites, cirrhosis, hypokalemia, disorders of water metabolism, diabetes, various ischemic diseases, diseases of the brain vessels, cyclothymic disorder, stomach ulcers, nausea, vomiting, fainting, disorder of the kidneys, etc., and for mitigating the consequences of cerebral infarction, intracerebral hemorrhage, etc.

In addition, compound (II) and (III) of the present invention are used as a convenient intermediate products for use in obtaining the compound (I) of the present invention and its pharmaceutically acceptable salts. The reaction path of obtaining the compound (I) or its pharmaceutically acceptable salt based on the compound (II), (III) or their salts is the same as described above.

The applicability of the compounds of the present invention was confirmed by the following tests.

1) Test the binding of V1receptors

On metodyka activity = 75,8 cubic inches/mmol), 70 mg of the sample membranes and each test drug from 10-8up to 10-4M) were incubated at 30oC for 30 minutes in 250 μl of 100 mm Tris-HCI buffer (pH 8.0) containing 5 mm magnesium chloride, 1 mm ethylendiaminetetraacetic acid (EDTA) and 0.1% bovine serum albumin (BSA). After that he sucked out the incubation solution, using a cell harvester, and the free ligand and excess buffer was removed, passing the reaction mixture through a glass filter (GF/B), catching on the filter associated with the labeled receptor ligand. The glass filter was removed, thoroughly dried and then mixed with liquid scintillation cocktail, and the number associated with the membrane [3H]-vasopressin was measured using liquid acquired scintillation counter to calculate the coefficient of inhibition according to the following formula:

The ratio of inhibition

< / BR>
where C1- the number of [3H]-vasopressin, is associated with the membrane, while the presence of a known amount of each of the test drugs and [3H]-vasopressin,

C0- the number of [3H]-vasopressin, is associated with the membrane when the test drug is not probabl is opressing (10-6M).

The concentration of the test drug, which leads to 50% increase inhibition refers to as IC50and used the following formula to calculate the binding affinity of non-radioactive ligand, namely, dissociation constants (Ki).

< / BR>
where [L] is the concentration of radioactive ligand,

KD is the dissociation constant calculated from the graph of Scatchard.

The negative logarithm of the calculated values thus used as the value of the pKi. The results are shown in table 1.

2) Test the binding of V2receptor

According to the method of Campbell et al (J. Biol. Chem., 247, 6167, 1972)) was prepared with the sample membrane medulla kidney rabbit, and [3H]-Arg-vasopressin (2 nm, specific activity = 75,8 Ci/mmol (cubic inches/mmol), 100 µg of sample membrane and each test drug (10-8-10-4M) was subjected to investigation as well as in the case described above studies linking with V1receptor, the pKi values were calculated in the same way. The results are shown in table. 1.

Compounds of the present invention exhibit a strong antagonism to Organisatorische. For example, the compounds of the example is inim even in comparison with the antagonist V2receptor compound OPC-31260 and antagonist V1receptor, compound OPC-21268, which are being developed as antagonists Organisatorische. It was also confirmed that the compounds of examples 42, 103, 104, 105 and 113 show significantly stronger antagonism to the V1receptors than OPC-21268, and excellent at V1selectivity (see table. 1-6 at the end of the description).

Effect on water diuresis in in consciousness rats (oral administration)

Each test compound suspended in 0.5% aqueous solution of methylcellulose and administered orally in phase 3 mg/kg male Wister rats (weighing 270-300 g) deprived of water before in the course of 16-20 hours. Using the camera for metabolism studies, collected urine sample immediately after the introduction of each test sample and up to 4 hours after the administration to measure the amount of urine.

The tested group, which was administered to each of the compounds of examples 11, 13, 15, 24 and 84, the amount of urine collected during the period from the time immediately after the introduction of up to 2 hours after administration was 55-85 times more than the group that was administered the solvent, and the amount of urine collected during the period from 2 to 4 hours after the injection,I water diuresis. On the other hand, the group which introduced the OPC-31260, the amount of urine collected during the period from the time immediately after the introduction of up to 2 hours after administration was 11 times higher than in the group that was administered the solvent, and the amount of urine collected over a period of 2 to 4 hours after injection, was almost the same as in the group that was administered the solvent, indicating that the disappearance of the enhancement effect of water diuresis.

The above results confirmed that enhance water diuresis action of the compounds according to the present invention when oral administration in conscious rats appeared to be more severe and prolonged compared with the connection of OPC-31260.

V1Antagonism of conscious rats (oral administration)

V1Antagonism was studied on male Wister rats (weighing 300-320 g), each of which was entered (2-3 days before the test) cannula into the left carotid artery for measuring blood pressure in the left jugular vein for injection of Organisatorische (WUAs). Blood pressure was measured without anesthesia by means of the pressure sensor through a cannula in the carotid artery. Each test compound suspended in 0.5% solution of methylcellulose and enter evendim the introduction of 30 mIU/kg WUA before the introduction of the test compound, took over 100%, and measured the increase in pressure caused by the intravenous injection of 30 mIU/kg WUAs, periodically during the period from 30 minutes after administration of the test compound to 8 hours after administration of the test compound to calculate the coefficient of inhibition increasing pressure test connection, i.e., V1antagonism of the test compounds.

Caused by WUAs pressure increase was suppressed to 50% or below during the period from 30 minutes after injection of the sample for testing up to 6 hours after administration of 1 mg/kg of each of the compounds of examples 11, 13 and 24, which indicates prolonged V1antagonism. On the other hand, for the suppression caused by the WUA increase the pressure to 50% or lower oral introduced compound OPC-21268 at the dose of 10 mg/kg, ten times higher than the dose of these compounds of the present invention, but during the period of from 30 minutes to 1 hour after injection, and the pressure increase caused by the WUAs, and returned to 100% at 4 hours after injection, indicating that the disappearance of the V1-antagonism.

On the basis of the above results confirmed that the V1antagonism of the compounds of the present invention when they are rst oral">

Pharmaceutical composition comprising as an active ingredient one or more compounds of General formula (I) and their pharmaceutically acceptable salts, are produced in the form of various dosage forms such as tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, plasters, etc. using commonly used pharmaceutical wearing lei, fillers and other additives and administered orally or parenterally.

Clinical dose of the compound of the present invention for a person may not necessarily be assigned with consideration of symptoms, body weight, age, sex, etc. of each patient, but usually it can be from 0.1 to 500 mg per adult person per day in the case of oral administration, and the daily dose can be used in one piece or separate portions. Because the dose varies depending on various conditions, sufficient effects can be obtained in some cases with less than the specified limits, the dose.

As solid compositions for oral administration according to the present invention can be used in tablets, powders, granules, etc. In such a t is th diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, fine crystalline cellulose, starch, polyvinylpyrrolidone or manuallyenteredvehicl. Typically, the composition may contain other inert diluent, additive, which include lubricating substance, such as magnesium stearate, loosening the substance, such as fibrous calcipala, a stabilizing agent, such as lactose, and solubilizers agent or facilitate solubilization agent such as glutamic or aspartic acid. If necessary, tablets or pills may be coated with a film of soluble in the stomach or in the intestine of a substance, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose or etc.

The liquid composition used for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elexir, etc. that contain a generally used inert diluent such as purified water and ethanol. Besides inert diluents such compositions may also contain auxiliary agents, such as solubilizers agent or facilitate solubilization agent, moisturize antisepticise agent.

Injections are used for parenteral administration include aseptic aqueous and non-aqueous solutions, suspensions and emulsions. Examples of the diluent for use in aqueous solutions and suspensions include distilled water for injection use and saline. Examples of the diluent for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil), alcohols (e.g. ethanol) and Polysorbate 80 (trade name). Such compositions may also contain additives such as a toning agent, an antiseptic agent, wetting agent, emulsifying agent, dispersing agent, stabilizing agent (e.g., lactose), solubilizers agent that promotes solubilization agent, etc., These compositions are sterilized by bacterial filtration through inhibiting bacteria filter, germicidal mixing or exposure. Alternatively, you can use aseptically manufactured solid composition, dissolved before use in sterile water or sterile injecting the solvent.

The best way of carrying out the invention

Thus, described with the detail with reference to the following examples. However, these examples do not limit the present invention. In this regard, it should be said that examples of ways to obtain the intermediate compounds of the present invention and other used here, the source compounds are presented as reference examples.

In the following examples IR,1H-NMR and MS denote the spectrum of infrared absorption spectrum, nuclear magnetic resonance data and mass spectrometry, respectively.

In the following examples, the words and abbreviations used in the analytical part of the examples, indicate the following:

total - total

IR - IR

MS - MC

S, d, t, q, m, respectively s (singlet), d (doublet), t (triplet), q (Quartet), m (multiplet). Scheme 2 shows at the end of the description. (In the above formulas, Ts means p-toluensulfonyl group (tonilou group), Me means methyl group, and Ac means acetyl group).

(Reference example 1

(Method A-1 fluoridation)

1) In 10 ml of dimethylformamide suspended 165 mg of 60% sodium hydride and the resulting suspension was added under ice cooling 1.0 g 1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it is then cooled for 1 hour in an ice bath. To the resulting mixture dobu aqueous solution of ammonium chloride and subsequent evaporation of the solvent thus obtained residue was treated with chloroform and water for the implementation of phase separation and the organic layer was dried over anhydrous magnesium sulfate. The solvent evaporated and the obtained residue was subjected to column chromatography with elution with a mixture (4:1, vol/vol) hexane-ethyl acetate to obtain the result 621 mg of 5-methoxy-1-tosyl-2,3-dihydro-1H-1-benzazepine.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,09 (2H, m), 2.38 (3H, s), 3.21 (3H, s), was 4.02 (2H, m), 4,60 (1H, t), 7,20-7,60 (total 8H)

MC m/z (E1): 329 (M+)

2) In 6 ml of dichloroethane suspended 213 mg of 5-methoxy-1-tosyl-2,3-dihydro-1H-1-benzazepin and 480 mg triftoratsetata N-herperidin and suspension during the night was heated under reflux. Added water to separate the organic layer, which is then sequentially washed with a saturated aqueous solution of sodium and dried over anhydrous magnesium sulfate. The solvent evaporated and the obtained residue was subjected to column chromatography with elution with a mixture (4:1, vol/about.) hexane-ethyl acetate to obtain 621 mg of 4,4-debtor-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

(Reference example 2)

(Method A-2 fluoridation)

1) in 150 ml of tetrahydrofuran was dissolved 3.55 ml Diisopropylamine and added dropwise 14.9 ml n-utility under stirring at -78oC in argon atmosphere. After 30 minutes of stirring under ice cooling is terasawa to 6.39 g of 1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-she then the resulting mixture was stirred for 30 minutes. Then was added dropwise 90 ml tertrahydrofuran ring solution containing 8.94 g of N-forbindelseshastighed, and the resulting mixture was stirred for 1 hour while gradually raising the temperature to 0oC. Adding to the reaction solution, a saturated aqueous solution of ammonium chloride, the mixture was concentrated under reduced pressure. Added ethyl acetate to separate the aqueous layer and the organic layer was washed saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, in that order. Then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography with elution by chloroform and receiving 5.31g 4-fluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

Elemental analysis data (C17H16NO3SF)

WITH% H% N% S% F%

calc.: 61,25 4,84 4,20 9,62 5,70

found: 61,07 4,80 4,16 10,01 by 5.87

IR (KBr, cm-1): 1706

1H-NMR ( M. D. in CDCl3, internal standard TMS): a 2.13 (1H, m), 2.44 (3H, s), 2,69 (1H, m) to 3.64 (1H, m), 4,30 (1H, m), is 5.06 (1H, DDD), 7,30 (2H, d), of 7.36 (1H, m), 7,53 (1H, m), 7,56 (1H, m), 7,73 (2H, lamina and only 2.91 g of tert-butoxide potassium, was added dropwise and 16.2 ml of a 1.6 n solution of n-utility in n-hexane at -78oC and then 30 min stirring at -78oC. To this reaction solution was added 70 ml of tertrahydrofuran ring solution containing 7.2 g of 4-fluoro-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it, followed by stirring for 1 hour at -78oC. the Reaction solution was mixed with 70 ml of tertrahydrofuran ring solution containing 10,22 g N forbindelseshastighed, and the resulting mixture was stirred 2 hours at -78oC and then for 1 hour at room temperature. Mixed reaction solution with 500 ml of 0.1 G. of an aqueous solution of hydrochloric acid and the mixture was extracted with ethyl acetate. The obtained organic layer is washed with 10% sodium thiosulfate, 1 N. sodium hydroxide and saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, then the solvent evaporated. The obtained residue was subjected to column chromatography on silica gel with elution mixed solvent (4:1, vol/vol) n-hexane-ethyl acetate and receiving 2,31 g 4,4-debtor-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

(Method A-2 fluoridation, alternative)

3) Trimethylsilyltriflate is etrahydro-1H-1-benzazepin-5-she 4.52 ml of triethylamine, under ice cooling and the resulting mixture was stirred for 1 hour at room temperature. The reaction solution was diluted with ether and washed with saturated aqueous sodium bicarbonate, cooled on ice, 1 N. aqueous solution of hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, in that order. After drying over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure to obtain silyl derivative enol ether. Silyl enol ether and 2.67 g triftoratsetata N-torpedine was dissolved in 20 ml of dichloroethane and heated under reflux for 2 hours. Was added to the reaction solution, chloroform and the resulting mixture was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, followed by evaporation of the solvent under reduced pressure. The obtained residue was subjected to column chromatography on silica gel with elution mixed solvent of ethyl acetate-hexane 3:7, vol/vol) and obtain 1.78 g of 4,4-debtor-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

IR (KBr, cm-1): 1724

1H-NMR ( N. D. in CDCI3,
(Reference example 3)

(Method B fluoridation)

1) in 30 ml isopropylalcohol ester of acetic acid was dissolved 1,2,3,4-tetrahydroquinolin-4-one (2.00 g) and 114 mg p-toluensulfonate acid and the solution was heated under reflux for 2 days with simultaneous evaporation of acetic acid. Then was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate with subsequent drying over anhydrous magnesium sulfate. After vyparivaya solvent, the obtained residue was led from chloroform diethyl ether-hexane to obtain 518 mg of 4-acetoxy-1-tosyl-1,2-dihydroquinoline.

1H-NMR ( M. D. in CDCl3, internal standard TMS): of 2.16 (3H, s) to 2.35 (3H, s), 4,60 (2H, d), 5,43 (1H, t), 7,05 (1H, d), 7,11 (2H, d), 7,19 (1H, t), 7,32 (1H, t), 7,39 (2H, d), 7,74 (1H, d)

MS m/z (EI): 343 (M+)

2) 4-Acetoxy-1-tosyl-1,2-dihydroquinoline (518 g) was dissolved in 5 ml of diglyme and was heated under reflux, after which was added dropwise digimobil solution containing 2,62 g chlorodifluoroacetate sodium. After cooling, was added ethyl acetate and the mixture washed with water and then dried over anhydrous magnesium sulfate. The solvent evaporated and the obtained residue was subjected to column chromatography and elwira is 3,4-tetrahydroquinoline.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 1,99 (3H, s), 2,10 (1H, m), is 2.41 (3H, s), Android 4.04 (1H, DD), 4,25 (1H, DD), 7,21 (1H, d), 7,28 (2H, d), 7,33 (1H, t), of 7.55 (1H, d), 7,60 (1H, d), a 7.62 (2H, d)

MC m/z (E1): 393 (M+)

3) 7b-Acetoxy-1,1-debtor-3-totallycrap[s]-1,2,3,4-tetrahydroquinolin (40 mg) was dissolved in 2 ml methanol and 2 ml of tetrahydrofuran, the resulting solution was added dropwise 1 ml of an aqueous solution of 7 mg of lithium hydroxide and the resulting mixture was stirred 2 days at room temperature. After evaporation of solvent was added water and the resulting mixture was extracted with ethyl acetate. Then the obtained organic layer was washed with water and dried over anhydrous magnesium sulfate. After that, the solvent evaporated and the obtained residue was subjected to column chromatography with elution by the mixture hexane-ethyl acetate (4: 1, volume/volume ) and obtain 27 mg of 1-tosyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

(Reference example 4)

4,4-Debtor-1-tosyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-Oh (3.00 g) was dissolved in 14 ml of acetic acid, to the solution was added 7 ml of concentrated sulfuric acid and then the resulting mixture was heated at 60oC for 10 hours. The reaction solution was cooled with ice, was podslushivaet potassium hydroxide and extalia. Evaporation of the reaction solvent received 4.4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it. This product was used in subsequent reactions without purification.

To 20 ml methylenchloride solution containing the newly received ketone and 1.55 ml of triethylamine were added to 1.9 g of 4-nitrobenzylamine under ice cooling, followed by stirring for 12 hours at room temperature. The reaction solution was diluted with ethyl acetate and washed with 1 N. aqueous solution of hydrochloric acid, 1 N. aqueous sodium hydroxide solution and saturated aqueous sodium chloride, in that order. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, the solvent and then the resulting residue was recrystallized from a mixture of chloroform-diethyl ether to obtain 1.65 g of 4,4-debtor-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-braaaain-5-it. The mother liquor was evaporated under reduced pressure, the obtained residue was subjected to column chromatography on silica gel with elution by chloroform and still getting 649 mg of 4,4-debtor-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

Melting point 192-195 (in Russian)oC

Data element analisa

IR (KBr, cm-1): 1716, 1656

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,73 (2H, m), 4,35 (2H, m), 6,62 (1H, m), 7,25 (1H, m), 7,33 (1H, m), of 7.48 (2H, m), 8,00 (1H, m), 8,10 (2H, m)

MS (EI): 346 (M+)

(Reference example 5)

4,4-Debtor-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-he (940 mg) was dissolved in 20 ml of acetic acid was added to a solution of 3.07 g of tin chloride (2) at room temperature and then the mixture was heated under reflux for 5 hours. The reaction solution was cooled with ice and podslushivaet using 1 n sodium hydroxide. Then, after separation of the organic layer, the aqueous layer was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous potassium carbonate and evaporated under reduced pressure the solvent. The resulting residue was recrystallized from a mixture of chloroform-hexane to obtain 711 mg of 1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

IR (KBr, cm-1): 1712, 1628

1H-NMR ( M. D. in CDCl3internal standard TMS): 1,59 (2H, m) to 2.66 (2H, m) to 3.33 (1H, m), 4,24 (1H, m), 6,45 (2H, m), 6,76 (1H,m), 7,17 (2H, d), from 7.24 (2H, m), 7,95 (1H, m)

MS (EI): 316 (M+)

(Reference example 6)

In 10 ml of tetrahydrofuran suspended 60% hydride natively at room temperature for 30 minutes. Was added dropwise at -78oC 20 ml tertrahydrofuran ring of a solution containing 600 mg of 1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it, followed by raising the temperature to 0oC for 10 hours. Was added a saturated aqueous solution of ammonium chloride and water and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure, the solvent and then the resulting residue was subjected to column chromatography on silica gel with elution mixed solvent of ethyl acetate-hexane (4,5:5,5, volume/volume) and the receipt of the original 170 mg of methyl (E)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,40 (2H, m), 3,18 (1H, m), 3,71 (3H, s), of 3.78 (2H, m) 5,08 (1H, m), 6.42 per (2H, d), 6,59 (1H, s), of 6.73 (1H, d), 7,14 (1H, m), 7,20 (1H, m), 7,29 (3H, m)

MS (EI): 372 (M+)

Continuing further elution, got 536 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,50 (2H, m), 3,20 (1H, m), of 3.78 (2H, m), 3,82 (3H, s), of 5.05 (1H, m), 6,18 (1H, s), to 6.39 (2H, d), of 6.73 (1H, d), 6,97 (2H, d), 7,12 (1H, m), 7.23 percent (1H, m), 7,37 (1H, m)

MS (E1): 372 (M)

(Sukladni ice triethylphosphate (4.12 g) and the mixture was stirred for 30 minutes under ice cooling. To the reaction solution was added to 1.16 g of 1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benazepril-5-it, followed by stirring for 3 hours at room temperature. The reaction solution was poured into ice water and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, then the solvent evaporated from the receipt of 1.41 g of a mixture of (E)- and (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benazepril - 5-ilidene]acetate.

MS (FAB): 387 (M++ 1)

(Reference example 8)

In 5 ml of methylene chloride was dissolved on-phenylbenzene acid (163 mg) and to the solution was added dropwise a catalytically effective amount of N,N-dimethylformamide and 0.165 ml oxalicacid. After 3 hours stirring at room temperature was added benzene and viparis solvent, got chloride o-vinylbenzoic acid.

In 10 ml of methylene chloride was dissolved 1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-Oh (200 mg) and 5 ml of pyridine and to the solution was added dropwise under ice cooling 10 ml of a solution of the obtained chloride o-vinylbenzoic acid in methylene chloride. After 1 hour stirring at room temperature mawali saturated aqueous sodium carbonate, 1 N. aqueous solution of hydrochloric acid and saturated aqueous sodium chloride, in that order. After drying over anhydrous magnesium sulfate and subsequent evaporation under reduced pressure of the solvent, the obtained residue was subjected to column chromatography with elution mixed solvent of ethyl acetate-hexane (2: 3, vol/vol) and obtain 283 mg of 4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] -2,3,4,5-tetrahydro - 1H-1-benzazepin-5-it. This product was recrystallized from a mixture of ethyl acetate-hexane.

Melting point 201-203oC

1H-NMR ( M. D. in CDCI3, internal standard TMS): to 2.67 (2H, m), 3,30 (1H, m), is 4.21 (1H, m), of 6.65 (2H, m), to 6.88 (1H, s), 6,97 (2H, m), 7,19 (2H, m), 7,24 (1H, m), 7,32-7,47 (total 7H), 7,55 (1H, m), 7,88 (1H, m), of 7.96 (1H, m)

MS (EI): 496 (M+)

(Reference example 9)

Using 2-(4-were)benzoic acid and (Z)-1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-he repeated the procedure similar to that described in reference example 8, to obtain 4,4-debtor-1-[4-[2-(4-were)benzoylamine] benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,35 (3H, s) to 2.67 (2H, m), 3,50-4,80 (total 2H), 6,66 (1H, m) 6,94 (1H, s), of 6.99 (2H, m), 7.18 in-7,32 (total 8H), what ventino acid, 0,290 ml oxalicacid and 620 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in reference example 8, to obtain 878 mg of methyl (Z)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,30-2,80 (total 2H), 3,21 (1H, m), 3,83 (3H, s), of 5.03 (1H, m), 6,17 (1H, s), 6,66 (1H, m) 6,91 (3H, m), 7,01 (2H, m), to 7.09 (1H, t), from 7.24 (1H, t), 7,33-7,45 (total 7H), 7,52 (1H, t), 7,56 (1H, t), 7,83 (1H, d),

MS (E1): 522 (M+)

(Example 2)

Using 127 mg on-vinylbenzoic acid, 0,141 ml oxalicacid and 200 mg of methyl (E)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in reference example 8, with the receipt of 287 mg of methyl (E)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] - 2, 3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,20-2,70 (total 2H), 3,30 (1H, m) to 3.67 (3H, s), to 4.98 (1H, m), 6,55-6,74 (total 2H), 6,85-7,70 (total 15H), to 7.84 (1H, m), MS (EI): 553 (M++ 1)

(Example 3)

Using 630 mg of 2-(4-were)benzoic acid, 0,389 ml oxalicacid and 670 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]�1-[4-[2-(4-were)benzoylamine] benzoyl] -2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): a 2.36 (3H, s), is 2.40 (1H, m), 2,62 (1H, m), 3,21 (1H, m), 3,83 (3H, s), 5,04 (1H, m), 6,17 (1H, s), to 6.67 (1H, d), of 6.90 (1H, s) 6,94 (2H, d), 7,02 (2H, d), 7,10 (1H, t), 7,18 (2H, d), 7,22 (1H, t), 7,29 (2H, d), 7,37 (2H, m), 7,44 (1H, m), 7,52 (1H, m), 7,82 (1H, d)

MS (E1): 566 (M++ 1)

(Example 4)

Using 277 mg of 2-(3-were)benzoic acid, to 0.127 ml oxalicacid and 180 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] acetate, repeated the procedure similar to that described in reference example 8, with the receipt of 249 mg of methyl (Z)-[4,4-debtor-1-[4-[2-(3-were) benzoylamine] benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): to 2.29 (3H, s) to 2.41 (1H, m), 2,65 (1H, m), 3,21 (1H, m), 3,83 (3H, s), of 5.03 (1H, m), 6,18 (1H, s), 6,66 (1H, m), 6,85-7,60 (total 15H), a 7.85 (1H, d)

MS (E1): 566 (M+)

(Example 5)

Using 230 mg of 4,4-debtor-[4-(2-phenylendiamine)-benzoyl]-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-she repeated the procedure similar to that described in reference example 6, to obtain 100 mg of methyl (Z)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] -2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetate.

(Example 6)

In 15 ml of methylene chloride containing one drop of dimethylformamide, was dissolved 2-(4-methylp is at room temperature for 3 hours. To the reaction solution was added dropwise a solution in a mixture of 10 ml of pyridine and 10 ml of methylene chloride containing 1.4 g of a mixture of ethyl (E)- and (Z)-11-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] acetate, followed by stirring for 13 hours at room temperature. Was added to the reaction solution, water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed 1 N. aqueous solution of hydrochloric acid, 1 N. aqueous sodium hydroxide solution and saturated aqueous sodium chloride, in that order, and dried over anhydrous magnesium sulfate, then the solvent evaporated. The obtained residue was purified by column chromatography on silica gel with elution mixed solvent of n-hexane-ethyl acetate (2:1, vol/vol) and obtain 260 mg, 290 mg of ethyl (Z)- and (S)-[4,4-debtor-1-[4-[2-(4-methyl)-phenyl] benzoylamine] benzoyl - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

Compound 6 (a)

(Z)-form

1H-NMR (( M. D. in CDCI3, internal standard TMS): of 1.34 (3H, t), 2,39 (3H, s), is 2.40 (2H, m), 3,10-3,30 (1H, m), the 4.29 (2H, q), 4,90-5,10 (1H, m), 6,17 (1H, s), of 6.66 (1H, d), 6,80-7,60 (total 14H), of 7.82 (1H, d)

MS (FAB): 581 (M++ 1)

Compound 6 (b)

(E)-form

1H-NMR ( M. D. in CDCl), of 7.82 (1H, d)

MS (FAB): 581 (M++ 1)

(Example 7)

In 10 ml of methanol was dissolved methyl (Z)-[4,4-debtor-1-[4-(2 - phenylendiamine)benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate (857 mg), to the resulting solution was added dropwise under ice cooling, 2 ml of an aqueous solution containing 195 mg of the monohydrate of lithium hydroxide, and the mixture was stirred at room temperature for 7 hours. After evaporation under reduced pressure of the solvent was added 1 N. aqueous solution of hydrochloric acid and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. Viparis under reduced pressure, the solvent, the obtained residue was recrystallized from a mixture of ethyl acetate-hexane obtaining 633 mg (Z)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl]-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene)acetic acid.

Melting point 224-226oC

1H-NMR ( M. D., CDCl3, internal standard TMS): 2,41 (1H, m) to 2.67 (1H, m), 3,24 (1H, m), 3,68 (1H, m) 5,00 (1H, m), to 6.19 (1H, s), to 6.67 (1H, m), 6,92 (2H, m), 6,98 (3H, m), 7,10 (1H, m), 7,24 (1H, d), 7,30-7,50 (total 8H), 7,53 (1H, m), 7,80 (1H, m)

MS (E1): 538 (M+)

(Example 8)

Using 280 mg of methyl (E)-[4,4-debtor-1-[4-(2-phenyl-benzoylamine) benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]ACET is Ino)benzoyl] -2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene acetic acid.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,41 (1H, m), 3,10-3,50 (total 2H), 4,99 (1H, m), 6,59 (1H, s), to 6.67 (1H, m), 6.89 in (2H, m), was 7.08 (2H, m), 7,17 (1H, m), 7.24 to of 7.48 (total 8H), 7,52 (1H, m), 7,73 (1H, m)

MS (E1): 538 (M+)

(Example 9)

Using 527 mg of methyl (Z)-[4,4-debtor-1-[4-12-(4-were) benzoylamine)benzoin]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, to obtain 460 mg of (Z)-[4,4-debtor-1-[4-[2-(4-were)benzoylamine] benzoyl] - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,35 (3H, s), 2,50-3,80 (total 4H), 5,02 (1H, m), of 6.20 (1H, s), 6,69 (1H, m), 6.90 to-of 7.48 (total 14H), 7,52 (1H, m), 7,80 (1H, d)

MS (E1): 552 (M+)

(Example 10)

Using 240 mg of methyl (Z)-[4,4-debtor-1-[4-[2-(3-were) benzoylamine]benzoyl]-2,3,4,5-tetrahydro-1H-1-benzamin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, to obtain 210 mg of (Z)-[4,4-debtor-1-[4-[2-(3-were)benzoylamine] benzoyl] - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,35 (3H, s), 2,35-2,80 (total 3H), 3,20 (1H, m), 5,02 (1H, m), to 6.19 (1H, s), 6,69 (1H, m), 6,85-7,60 (total 15H), 7,81 (1H, m)

MS (E1): 552 (M+)

(Example 11)

Mixed is amino) benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid (318 mg) and 96 mg of 1-hydroxybenzotriazole was added dropwise under ice cooling 10 ml methylenechloride solution, containing 136 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide. Then added 0,079 ml of N-methylpiperazine and stirred the mixture overnight at room temperature. Then added 1 N. aqueous sodium hydroxide solution and the mixture was extracted with chloroform and dried over anhydrous potassium carbonate. The solvent evaporated and the obtained residue was subjected to column chromatography on silica gel with elution mixed solvent of chloroform-methanol (95: 5, vol/vol), and obtain 308 mg of free base. This product was dissolved in ethanol and converted into the hydrochloride by adding 4 n hydrochloric acid in ethyl acetate, and then evaporated under reduced pressure the solvent. By recrystallization of the resulting residue from a mixture of metonymically broadcast received 185 mg of (Z)-4'-[[4,4-debtor-5-(4 - methyl-1-piperazinil)carbonylmethyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl]carbonyl]-2-phenylbenzimidazole.

Melting point 194-197oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,42 (2H, m), of 2.81 (3H, s), 2,82 of 3.28 (total 4H), 3,36-3,70 (total 3H), 4.09 to (1H, m), 4,43 (1H, m), a 4.86 (1H, m), 6,77 (1H, s), PC 6.82 (1H, m), 7,01 (2H, m), 7,20 (1H, t), 7,25-7,41 (total 8H), 7,47 (2H, m), 7,56 (3H, m), 10,35 (1H, whom) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]-acetic acid and 90 mg of piperazine, repeated the procedure similar to that described in example 11, to obtain 70 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[(1-piperazinylcarbonyl)methylene]-2,3,4,5 - tetrahydro-1H-benzazepin-1-yl]carbonyl]-2-phenylbenzene in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,42 (2H, m), 3,02-3,22 (total 5H), 3,60-to 3.92 (total 4H), to 4.87 (1H, m), 6,77 (1H, s), PC 6.82 (1H, m), 7,01 (2H, m), 7,20 (1H, m), 7,25-7,41 (total 8H), 7,47 (2H, m), 7.51-7,62 (total 3H), of 9.30 (1H, m), 10,34 (1H, s)< / BR>
MS (E1): 606 (M+)

(Example 13)

Using 196 mg (Z)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]-acetic acid and 56 mg of 4-dimethylaminopyridine, repeating the method of synthesis, similar to that described in example 11, and the product was recrystallized from a mixture of chloroform-ether to obtain 160 mg of (Z)-4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine)carbonyl]methylene] - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2 - phenylbenzimidazole.

Melting point: decomposition at 230oC or higher.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,39-1,80 (total 2H), 2,07 (2H, m), is 2.41 (2H, m) to 2.66 (1H, m), of 2.72 (6H, s), 2.95 and-3,20 (total 2H), 3,43 (1H, m), Android 4.04 (1H, m) to 4.52 (1H, m), a 4.86 (1H, m), 6,78 (1H, s), for 6.81 (1H, m), 7,01 (2H, m), 7,19 (1H, m), 7,26-7,43 (total 8H), 7,44-7,60 (about what solumina) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid and 0,063 ml of 2-aminomethylpyridine, repeated the procedure similar to that described in example 11, to obtain 190 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[N-(2-pyridylmethyl)-carbonylmethyl] -2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl]-carbonyl]-2-phenylbenzene in the form of colorless amorphous solid.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,32 (1H, m), 2,73 (1H, m), 3,20 (1H, m), 4,89 (3H, m), 6,41 (1H, m), 6,59 (1H, m), 6,85-7,10 (total 6H), 7.23 (1H, m), 7,30-7,50 (total 7H), 7,53 (1H, m), of 7.70 (1H, m), 7,80 (1H, m), 7,89 (1H, m), 8,23 (1H, m), to 8.45 (1H, m), 8,58 (1H, m)

MC (E1): 629 (M++ 1)

(Example 15)

Using 250 mg of (Z)-[4,4-debtor-1-[4-(2-phenylendiamine) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-6-ilidene] acetic acid and 76 mg of N,N, N'-trimethylethylenediamine, repeated the procedure similar to that described in example 11, and the product was recrystallized from a mixture of ethanol-diisopropyl ether, to obtain 190 mg of (Z)-4'-[4,4-debtor-5-[[N-(2-dimethylaminoethyl)-N-methylcarbamoylmethyl] - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2 - phenylbenzimidazole.

Melting point 157-160oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): to 2.41 (2H, m), 2,80 (bn, m) is 3.08 (3H, s) of 3.25 (2H, m), 3,55-4,00 (total 3H), a 4.86 (1H, m), 6,79 (2H, m), 7,00 (2H, m), 7,19 (1H, m), 7.24 to 7,41 (total 8H), 7,46 (3H, m), 7,54 (5H, m), 10,34 (1H, s), at 10.64 (1H, m)

MS (E1): 622 (M+

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,23-2,45 (total 2H), 2,70-3,25 (total 7H), 3,35-3,80 (total 3H), 4,08 (1H, m), 4,36 (1H, m), 4,91 (1H, m), 6,72 (1H, m), 6,97-to 7.59 (total 17H), 10,36 (1H, m), of 10.72 (1H, m)

MS (E1): 620 (M++ 1)

(Example 17)

Using 226 mg (Z)-[4,4-debtor-1-[2-[(4-were)benzoylamine] benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid and 0,054 ml of N-methylpiperazine, repeated the procedure similar to that described in example 11, to obtain 160 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-(4-methyl-1-piperazinil)carbonylmethyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl]carbonyl] -2-(4-were)benzanilide in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,28(3H, s), a 2.45 (2H, m), 2,82 (3H, m), 2,83-3,25 (total 4H), 3,36-3,65 (total 3H), 4.09 to (1H, m), of 4.45 (1H, m), a 4.86 (1H, m), 6,77 (1H, s), 6,83 (1H, m), 7,02 (2H, m), 7,13 (2H, d), 7,20 (1H, t), 7,27 (2H, d), 7,32 (1H, t), of 7.36-7,47 (4H, m), of 7.48-to 7.59 (3H, m), 10,36 (1H, m), 10,90 (1H, m)

MS (E1): 634 (M+)

(Example 18)

Using 203 mg (Z)-[4,4-debtor-1-[4-[2 is of terpyridine, repeated the procedure similar to that described in example 11 to give 150 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[N-(2-pyridylmethyl)carbonylmethyl] -2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-(3-were)benzanilide in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): of 2.27 (3H, s), of 2.38 (1H, m) to 2.67 (1H, m), of 3.07 (1H, m) and 4.65 (2H, m), to 4.87 (1H, m), 6,63 (1H, s), 6,77 (1H, m), 7,03 (2H, m), 7,10-7,20 (total 3H), 7.24 to 7,34 (total 3H), 7,35-to 7.59 (total 7H), of 7.75 (2H, m), 8,30 (1H, m), is 8.75 (1H, m), 9,17 (1H, m), 10,33 (1H, s)

MS (E1): 642 (M+)

(Example 19)

Using 210 mg of (Z)-[4,4-debtor-1-[4-[2-(3-were)-benzoylamine] benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid and by 0.055 ml of N-methylpiperazine, repeated the procedure similar to that described in example 11, to obtain 140 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-(4-methyl-1-piperazinil)carbonylmethyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-(3-were)benzanilide in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): of 2.21 (3H, s), a 2.45 (2H, m), and 2.83 (3H, s), 2,84-3,20 (total 4H), 3,38 at 3.69 (total 3H), 4,10 (1H, m), of 4.44 (1H, m), a 4.86 (1H, m), 6,77 (1H, s), PC 6.82 (1H, m), 7,01 (2H, m), to 7.09 (1H, m), 7,19 (4H, m), 7,26-7,41 (3H, m), 7,45 (2H, m), 7,50-of 7.60 (3H, m), 10,34 (1H, m), 10,71 (1H, m)

MS (E1): 634 (M+)o
C in a sealed tube. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution mixed solvent of chloroform-methanol (40:1, volume/volume) and receiving 150 mg of (Z)-4'-[[4,4-debtor-5-(N-methylcarbamoylmethyl)-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-(4-were)benzanilide.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): of 2.27 (3H, s) to 2.35 (2H, m) of 2.64 (3H, d), of 3.00 (1H, m), the 4.90 (1H, m), 6.48 in (1H, s), of 6.75 (1H, d), 7,03 (1H, d), 7,12 (2H, d), 7,20-7,60 (total 11H), 8,23 (1H, d), 10,30 (1H, s)

MS (FAB): 566 (M++ 1)

(Example 21)

Using 200 mg of ethyl (E)-[1-[4-[2-(4-were)benzoylamine] benzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate as a starting material, repeating the procedure similar to that described in example 20 to obtain 180 mg of (E)-4'-[[4,4-debtor-5-(N - methylcarbamoylmethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] - 2-(4-were)benzanilide.

Melting point 256-258oC.

1H-NMR ( m l in DMSO-d6, internal standard TMS): 2,28 (3H, s), is 2.40 (2H, m), 2,62 (3H, d), 3,06 (1H, m), 4,82 (1H, m), of 6.68 (1H, s) of 6.71 (1H, d), 7,10-7,60 (total 15H), to 8.41 (1H, d), 10,29 (1H, s)

MS (FAB): 566 (M++ 1)

(Example 22)

To 20 ml of a suspension of 70 mg of 60% sodium hydride in theregional. To the reaction solution was added 4'-[(4,4-debtor-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin - 1-yl)carbonyl]-2-(4-were)benzanilide (220 mg) and the mixture was stirred for 3 hours under ice cooling and then for 1 hour at room temperature. Pouring the reaction solution into ice-cold water and extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, then the solvent evaporated. The obtained residue was purified by column chromatography on silica gel with elution with a mixture of n-hexane-ethyl acetate to change the ratio between its components from 4:1 to 3:1 by volume and the residue obtained from the eluate, recrystallized from a mixture of chloroform-n-hexane to obtain 100 mg of (Z)- and (E)-4'-[(5-cyanomethylene-4,4-debtor-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl]-2-(4-were)benzanilide.

Compound 22 (a)

(Z)-form

The melting point of 133-135oC

1H-NMR ( M. D. in CDCI3, internal standard TMS): a 2.36 (3H, s) of 2.50 (2H, m) of 3.25 (1H, m), of 5.05 (1H, m), 5,79 (1H, s), 6,72 (1H, d), 6.90 to-7,60 (total 14H), 7,74 (1H, d)

MS (FAB): 534 (M++ 1)

Compound 22 (b)

(E)-form

Melting point 202-205 areoC

1H-NMR ( M. D. in CDCI3internal mill
(Example 23)

In 10 ml of methylene chloride and 5 ml of acetonitrile was dissolved (Z)-4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] -2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene]acetic acid (250 mg) and 75 mg of 1-hydroxybenzotriazole and to the solution was added under cooling 107 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimides. Then added 0,088 ml of N-ethylpiperazine and the mixture was stirred over night at room temperature. Then to the reaction solution was added 1 N. aqueous sodium hydroxide solution and the mixture was extracted with chloroform and dried over anhydrous potassium carbonate. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of chloroform-methanol (97: 3, vol/vol), with 293 mg of the free base. Next, this product was dissolved in methanol and converted into the hydrochloride by adding 4 n hydrochloric acid in ethyl acetate, and then evaporated under reduced pressure the solvent. The obtained residue was recrystallized from a mixture of ethanol-diethyl ether to obtain 221 mg (Z)-4'-[[5-[(4-ethyl-1-piperazinil)carbonylmethyl] - 4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2 - phenylbenzene HART TMS): of 1.27 (3H, t) to 2.41 (2H, m), 2,78-3,30 (total 6H), 3,52 (2H, m) to 3.64 (1H, m), 4,10 (1H, m), 4,46 (1H, m), a 4.86 (1H, m), 6,77 (1H, s), 6.82 (1H, m), 7,01 (2H, m), 7,20 (1H, m), 7.24 to 7,41 (total 8H), 7,43-7,51 (total 2H), 7,52-7,58 (total 3H), 10,34 (1H, s), of 11.15 (1H, m)

MC (FAB): 635 (M++ 1)

(Example 24)

In 10 ml of methylene chloride and 5 ml of acetonitrile was dissolved (Z)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] -2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene]acetic acid (250 mg) and 75 mg of 1-hydroxybenzotriazole and to the solution was added under cooling 107 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimides. Then added 0,088 ml of N-methylhomopiperazine and the mixture was stirred overnight at room temperature. Then to the reaction solution was added 1 N. aqueous sodium hydroxide solution and the mixture was extracted with chloroform and dried over anhydrous potassium carbonate. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of chloroform-methanol (90: 10, vol/vol), and obtain 240 mg of the free base. Paley this product was dissolved in methanol and converted into the hydrochloride by adding 4 n hydrochloric acid in ethyl acetate, and then evaporated under reduced pressure the solvent. The obtained residue was mixed with a mixture of ethanol di is etrahydro-1H-1-benzazepin-1-yl]carbonyl]-2 - phenylbenzimidazole in the form of colorless amorphous solid.

Elemental analysis data (C38H36N4O3F20,4 H2O)

With% H% N% Cl% F%

calc.: 67,28 5,62 compared to 8.26 5,23 ceiling of 5.60

found: 67,27 5,55 8,32 are 5.36 5,59

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,05-2,34 (total 2H), 2,35 is 2.55 (total 2H), and 2.79 (3H, s), 2,92-4,08 (total 9H), a 4.86 (1H, m), 6,74-6,89 (total 2H), 7,01 (2H, m), 7,19 (1H, m), 7,25-7,41 (total 8H), 7,42-7,52 (total 2H), 7,53-7,60 (total 3H), 10,35 (1H, s), 10,84 (1H, m)

MS (FAB): 635 (M++ 1)

(Example 25)

In 10 ml of methylene chloride and 5 ml of acetonitrile was dissolved (Z)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] -2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid (250 mg) and 75 mg of 1-hydroxybenzotriazole and to the solution was added under cooling 107 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide. Then added 0,074 ml of N,N-dimethylethylenediamine and the mixture was stirred over night at room temperature. Then to the reaction solution was added 1 N. aqueous sodium hydroxide solution and the mixture was extracted with chloroform and dried over anhydrous potassium carbonate. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of chloroform-methanol (94: 6, vol/vol), with the result 261 mg of free base. Then this platy in ethyl acetate, then evaporated under reduced pressure the solvent. To the obtained residue was added a mixture of chloroform-diethyl ether, resulting in the received 200 mg of (Z)-4'-[[4,4-debtor-5-[[N-(2-dimethylaminoethyl)carbarnoyl] methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2 - phenylbenzimidazole in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,39 (1H, m), 2,65 (1H, m), of 2.81 (6H, s) to 3.09 (1H, m), and 3.16 (2H, m), 3,49 (2H, m), 4,88 (1H, m), 6,53 (1H, s), 6,77 (1H, m), 7,02 (2H, m), 7,17 (1H, m), 7.24 to 7,41 (total 9H), 7,42-7,51 (total 2H), 7,52-7,60 (total 2H), at 8.60 (1H, t), 9,99 (1H, m), 10,31 (1H, s)

MC (FAB): 609 (M++ 1)

(Example 26)

Using 250 mg of (Z)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] -acetic acid and 0,097 ml of N-benzylpiperazine, repeated the procedure similar to that described in example 23, and the product was recrystallized from a mixture of acetonitrile-ether to obtain 200 mg (Z)-4'-[[5-[(4-benzyl-1-piperazinyl)-carbonylmethyl] - 4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2 - phenylbenzimidazole.

Melting point 164-169oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): to 2.41 (2H, m), 2,84-3,25 (total 4H), 3,30-of 3.46 (total 2H), 3,63 (1H, m), was 4.02 (1H, m), 4,33-4,51 (3H, m), 4 1)

(Example 27)

Using 250 mg of (Z)-[4,4-debtor-1-[4-(2-phenylendiamine) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] -acetic acid and 0,089 ml of N, N-dimethyl-1,3-propandiamine, repeated the procedure similar to that described in example 24 to obtain 245 mg of (Z)-4'-[[4,4-debtor-5-[[N-(3-dimethylaminopropyl)carbarnoyl] methylene] - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl] -2 - phenylbenzimidazole in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,81-1,92 (total 2H), 2,39 (1H, m) to 2.67 (1H, m), 2,73 (6H, s), 2,96-3,30 (total 5H), 4,88 (1H, m), of 6.52 (1H, s) 6,76 (1H, m), 7,02 (2H, m), 7,12-7,41 (total 9H), 7,42-7,51 (total 3H), 7,52-7,60 (total 2H), 8,51 (1H, t), 10,32 (1H, s), 10,59 (1H, m)

MS (FAB): 623 (M++ 1)

(Example 28)

Using 220 mg of (Z)-[4,4-debtor-1-[4-(2-phenylendiamine)benzoyl] - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]-acetic acid and 205 mg homopiperazine, repeated the procedure similar to that described in example 24 to obtain 220 mg (Z)-4'-[[5-[(1,4-diazepin-1-yl)carbonylmethyl]- 4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2 - phenylbenzimidazole in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,97-2,10 (total 2H), 2,41 (2H, m), and 3.16 (5H, m), 3,50-to 3.92 (total 5H), to 4.87 (1H, whom Rymer 29)

Using 427 mg of 2-(2-were)benzoic acid, 0,233 ml oxalicacid and 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]-acetate, repeated the procedure, analogic) described in example 8, to obtain 603 mg of methyl (Z)-[4,4-debtor-1-[4-[2-(2-were) benzoyl] amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): to 2.06 (3H, s), 2,27-2,75 (total 2H), 3,24 (1H, m), 3,83 (3H, s), free 5.01 (1H, m), 6,17 (1H, s), of 6.65 (1H, m), at 6.84 (2H, d), of 6.99 (2H, d), 7,07 (1H, t), to 7.09 (1H, s), 7,20-7,39 (total 7H), to 7.50 (1H, t), 7,56 (1H, t), 8,07 (1H, d)

MS (FAB): 567 (M++ 1)

(Example 30)

In 5 ml of methylene chloride was dissolved methyl (Z)-[1-(4-aminobenzoyl)- 4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate (500 mg) and 0,373 ml of triethylamine, the resulting solution was added dropwise under ice cooling 0,210 ml of 2-methylbenzylamine and then the mixture was stirred at room temperature for 2 hours. Was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with methylene chloride. The obtained organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The obtained residue was subjected to column chromatography with elution of sexanimated)amino] -benzoyl] -2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene]acetate.

Elemental analysis data (C28H24N2O4F2)

WITH% H% N% F%

calc.: 68,56 4,93 5,71 7,75

found: 68,33 4,95 5,71 7,73

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,02-2,82 (total 2H), 2,47 (3H, s), 3,21 (1H, m), 3,83 (3H, s), is 5.06 (1H, m), 6,21 (1H, s), of 6.73 (1H, d), 7,12-7,50 (total 12H)

MS (E1): 490 (M+)

(Example 31)

Using 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 0,210 ml of 2-methoxybenzylamine, repeated the procedure similar to that described in example 30, with getting 644 mg of methyl (Z)-[4,4-debtor-1-[4-(2-metacresol)amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl3, internal standard TMS): and 2.26-2,84 (total 2H), 3,26 (1H, m), 3,83 (3H, s), a 4.03 (3H, s), of 5.03 (1H, m), 6,21 (1H, s), 6.73 x (1H, m), 7,02 (1H, d), 7,09-7,28 (total 5H), 7,37 (1H, d), to 7.50 (3H, m), 8,23 (1H, m), 9,84 (1H, m)< / BR>
MS (E1): 506 (M++ 1)

(Example 32)

Using 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 245 mg of 2-ethoxybenzoyl acid, repeated the procedure similar to that described in example 8, to obtain 697 mg of methyl (Z)-[1-[4-(2-ethoxybenzoyl)amino]benzoyl-4,4-debtor-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl37,18 (Gen. 4H), from 7.24 (1H, t), 7,37 (1H, d), 7,47 (3H, m), 8,24 (1H, m), 10,12 (1H, m)

MS (EI): 521 (M++ 1)

(Example 33)

Using 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 264 mg of 2-isopropoxybenzoic acid, repeated the procedure similar to that described in reference example 8, to obtain 693 mg of methyl (Z)-[4,4-debtor-1-[4-(2-isopropoxybenzoic)amino)benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 1,50 (6H, d), 2,35-2,82 (total 2H), 3,23 (1H, m), of 3.84 (3H, s), 4,82 (1H, m), 5,07 (1H, m), from 6.22 (1H, s), 6.73 x (1H, m), 7,00 (1H, d), 7,08-7,18 (total 4H) of 7.24 (1H, t), 7,38 (1H, d), 7,47 (3H, m), 8,24 (1H, m), of 10.25 (1H, m)

MS (EI): 521 (M++ 1)

(Example 34)

Using 600 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 0,238 ml 3-methoxybenzylamine, repeated the procedure similar to that described in example 30, with getting 787 mg of methyl (Z)-[4,4-debtor-1-[4-(3-methoxybenzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,30-2,82 (total 2H), 3,26 (1H, m), of 3.84 (3H, s), 3,85 (3H, s), of 5.05 (1H, m), 6,21 (1H, s), 6,72 (1H, m), 7,02 (1H, d), 7,06-7,19 (total 4H), from 7.24 (1H, t), 7,31-7,40 (total 4H), 7,46 (2H, d), cent to 8.85 (1H, s)< / BR>
MS (EI): 506 (M++ 1)

(Example 35)

benzoylchloride, repeated the procedure similar to that described in example 30 to obtain 820 mg of methyl (Z)-[1-[4-(2-chlorobenzoyl)amino] benzoyl - 4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,27-2,82 (total 2H), 3,26 (1H, m), 3,83 (3H, s), 5,04 (1H, m), 6,21 (1H, s), 6.73 x (1H, m), 7,10-7,20 (total 3H), 7,26 (1H, t), 7,34-7,50 (total 6H), 7,72 (1H, d), 7,88 (1H, s)

MS (EI): 510, 512 (M+)

(Example 36)

Using 600 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate and 0,214 ml 3-chlorobenzylchloride, repeated the procedure similar to that described in example 30 to obtain 820 mg of methyl (Z)-[1-[4-(3-chlorobenzoyl)amino] benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,27-2,82 (total 2H), 3,26 (1H, m), of 3.84 (3H, s), is 5.06 (1H, m), 6,21 (1H, s) of 6.71 (1H, m), 7,07-7,17 (both. 3H), from 7.24 (1H, t), of 7.36-7,47 (total 4H), 7,71 (1H, d), of 7.82 (1H, s), 7,94 (1H, s)

MS (EI): 510, 512 (M+)

(Example 37)

Using 3.00 g of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 0,214 ml of 2-nitrobenzoic acid, repeated the procedure similar to that described in reference example 8, to obtain 3.75 g of methyl (Z)-[4,4-debtor-1-[4-(2-nitrobenzoyl)-amino]benzoyl-2,3,4,5 - tetrahydro-1H-1-benzie, ,24 (1H, m), 3,83 (3H, s), 5,04 (1H, m), 6,24 (1H, s), of 6.75 (1H, m), 7,10-7,20 (total 3H), 7,14 (1H, t), 7,38 (1H, m), 7,52 (2H, d), EUR 7.57-to 7.67 (total 2H), 7.72 (1H, t), 8.08 (1H, d), of 10.09 (1H, s)

MS (FAB): 522 (M++ 1)

(Example 38)

Methyl (Z)-[4,4-debtor-[1-[4-(2-nitrobenzoyl)amino]benzoyl - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate (4,00 g) suspended in 100 ml of ethyl acetate, the suspension was added 10.4 g of monohydrate chloride tin (2) and the mixture was heated under reflux for 3 hours. Was added to the reaction solution while cooling with ice, saturated aqueous sodium bicarbonate solution, and precipitated in the sediment insoluble material was removed by filtration using celite, the filtrate was separated. The organic layer was dried over anhydrous magnesium sulfate and then the solvent evaporated. By crystallization of the resulting residue in a mixture of ethanol-diethyl ether got to 1.79 g of methyl (Z)-[1-[4-(2-aminobenzoyl)amino]benzoyl-4,4-debtor-2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene]acetate as a colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,39-2,56 (total 2H), 3,12 (1H, m), 3,76 (3H, s), to 4.87 (1H, m), 6,28 (2H, s), 6,56 (1H, t), of 6.73 (1H, d), 6,76 (1H, s), 6,85 (1H, m), 7,05 (2H, d), 7,17-7.23 percent (total 2H), 7,31 (1H, t), 7,41 (1H, d), 7,53-7,62 (total 3H), of 10.09 (1H, s)

MS (FAB): 492 (M++ 1)

tat (1.10 g) was dissolved in 10 ml of acetic acid, the solution was mixed with 511 mg of acetonylacetone and the mixture was heated under reflux for 2 hours. The solvent evaporated, to the residue was added water and the mixture was extracted with a mixed solvent of chloroform-methanol. After evaporation of the organic layer obtained residue was subjected to column chromatography on silica gel with elution with a mixture of chloroform-methanol (97:3), volume/volume) and obtained by elution connection was led from ethyl acetate and hexane to obtain 500 mg of methyl (Z)-[4,4-debtor-1-[4-[2-(2,5-dimethylpyrrole-1-yl)benzoyl]amino]benzoyl - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. L. in CDCI3, internal standard TMS): 2,28-2,80 (total 2H), up 3.22 (1H, m), 3,83 (3H, s), 5,02 (1H, m), 6.20 (1H, s) 6,70 (1H, m), 7,08-7,16 (total 3H), 7.24 to 7,31 (total 3H), 7,38 (1H, d), 7,44 (1H, d), EUR 7.57-7,66 (total 2H), 7,82 (1H, m), of 8.09 (1H, s), to 8.20 (1H, s), a 8.34 (1H, s)

MS (EI): 569 (M+)

(Example 40)

Using 948 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 530 mg of 2-(1H-1,2,4-triazole-1-yl)benzoic acid, repeated the procedure similar to that described in reference example 8, to obtain 1.23 g of methyl (Z)-[4,4-debtor-1-[4-[2-(1H-1,2,4-triazole-1-yl)benzoyl] amino] benzoyl - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]ACET 5,04 (1H, m), between 6.08 (2H, s), of 6.20 (1H, s), 6,64-6,74 (total 2H), of 6.96-7,30 (total 7H), 7,37 (1H, d), 7,56-7,68 (total 2H), of 8.37 (1H, d)

MS (FAB): 544 (M++ 1)

(Example 41)

In 10 ml of methylene chloride was dissolved 2-(1H-imidazol-1-yl)-benzoic acid (222 mg) and 160 mg of 1-hydroxybenzotriazole was added dropwise under ice cooling 10 ml methylenechloride solution containing 227 mg of the hydrochloride of 1-ethyl-3-(dimethylaminopropyl)carbodiimide. Then added 400 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and the mixture was stirred at room temperature for 3 days. Then to the reaction solution was added 1 n sodium hydroxide and the mixture was extracted with chloroform and dried over anhydrous potassium carbonate. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of chloroform - methanol (95:5, vol/vol) and obtained 270 mg of methyl (Z)-[4,4-debtor-1-[4-[2-(1H-imidazol-1-yl)benzoyl] amino] benzoyl - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl3internal standard TMS): 2,28-2,82 (total 2H), up 3.22 (1H, m), 3,83 (3H, s), of 5.03 (1H, m), of 6.20 (1H, s), 6,69 (1H, m), 7.03 is-7,41 (total 11H), 7,53-to 7.64 (total 2H), 7,66 (1H, s), 7,83 (1H, d),

MS (FAB): 543 (M++ 1)

(Example 42 is-1H-imidazol-1-yl)benzoic acid, repeated the procedure similar to that described in reference example 8, and the result was 5.0 g of methyl (Z)-[1-[4-[2-(2-ethyl-1H-imidazol-1-yl)benzoyl] amino] benzoyl - 4,4-debtor-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

The melting point of 230-231oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,04 (2H, t), is 2.40 (2H, q), 3,11 (1H, W), 3,74 (3H, s), a 4.86 (1H, W), 6,70-6,85 (total 3H), of 10.4 (1H, s)

MS (FAB): 571 (M++ 1)

(Example 43)

Using 600 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 266 mg on-tolyloxy acid, repeated the procedure similar to that described in reference example 8, to obtain 683 mg of methyl (Z)-[4,4-debtor-1-[4-(2-were)acetylamino]benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl3internal standard TMS): to 2.29 (3H, s), 2,35-2,80 (total 2H), 3,23 (1H, m), 3,70 (2H, s), 3,82 (3H, s), 5,04 (1H, m), x 6.15 (1H, s), to 6.67 (1H, m), 6,93 (1H, s), 7,06-7,14 (total 3H), 7.17-7.29 trend (total 6H), was 7.36 (1H, d)

MS (FAB): 505 (M++ 1)

(Example 44)

Using 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 245 mg of 2-methoxyphenylacetic acid, repeated the procedure similar to that described in reference example 8, to obtain 665 CLASS="ptx2">

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2.26 and is 2.80 (total 2H), 3,23 (1H, m) to 3.67 (2H, s), 3,82 (3H, s), 3,91 (3H, s), 5,04 (1H, m), 6,17 (1H, s), to 6.67 (1H, m), 6,93-7,01 (total 2H),? 7.04 baby mortality-7,13 (total 3H), 7,19-7,38 (total 6H), 7,76 (1H, s)

MS (FAB): 521 (M++ 1)

(Example 45)

Using 600 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and 0,261 ml of 2-triftormetilfullerenov, repeated the procedure similar to that described in example 30 with getting 861 mg of methyl (Z)-[4,4-debtor-1-[4-(2-trifloromethyl)-amino]benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]-acetate.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,30-2,82 (total 2H), 3,24 (1H, m), 3,83 (3H, s), 5,04 (1H, m), 6,21 (1H, s), 6.73 x (1H, m), 7,09-7,19 (total 3H), 7,26 (1H, t), of 7.36-7,44 (total 3H), 7,53-7,66 (total 4H), 7,74 (1H, d)

MS (E1): 544 (M+)

(Example 46)

Using 600 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate and of 0.337 ml of 1-nafolklore, repeated the procedure similar to that described in example 30, to obtain 860 mg of methyl (Z)-[4,4-debtor-1-[4-(1-afterburner)amino] benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,25-2,81 (total 2H), 3,29 (1H, m), of 3.84 (3H, s), of 5.03 (1H, m), from 6.22 (1H, s), 6,74 (1H, m), 7,13-7,21 (total 3H), 7,27 (1HR>
Using 600 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate and 222 mg of 1-methyl-2-terracarbon acid, repeated the procedure similar to that described in reference example 8, to obtain 480 mg of methyl (Z)-[4,4-debtor-1-[4-(1-methyl-2-pyrrolyl)carbylamine] benzoyl - 2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,28-2,82 (total 2H), 3,24 (1H, m), 3,83 (3H, s), 3,93 (3H,s), 5,04 (1H, m), 6,11 (1H, m), to 6.19 (1H, s), 6,66 (1H, m), 6,72 (1H, m), 6,77 (1H, m), 7,08-7,18 (total 3H), of 7.23 (1H, t), of 7.36-7,40 (total 3H), the 7.65 (1H, s)

MS (EI): 479 (M+)

(Example 48)

Using 600 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzamin-5-ilidene] acetate and 252 mg of 3-methyl-2-thiophencarboxylic acid, repeated the procedure similar to that described in reference example 8, to obtain the 722 mg of methyl (Z)-[4,4-debtor-1-[4-(3-methyl-2-thienyl)carbylamine] benzoyl-2, 3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,42 (1H, m) to 2.55 (3H, s), 2,68 (1H, m), 3,26 (1H, m), 3,83 (3H, s), of 5.05 (1H, m), to 6.19 (1H, s), 6,72 (1H, m), 6,93 (1H, d), 7,11 (1H, t), 7,16 (2H, d), 7.24 (1H, t), 7,32 (1H, d), of 7.36 (1H, d), 7,40 (2H, d), 7,49 (1H, d)

MS (FAB): 497 (M++ 1)

(Example 49)

Using 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-is eduru similar to that described in reference example 8, obtaining 414 mg of methyl (Z)-[4,4-debtor-1-[4-(3-methyl-2-furyl)carbylamine] benzoyl-2, 3, 4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,22-2,80 (total 2H), 2,41 (3H, s, of 3.23 (1H, m), 3,83 (3H, s), of 5.05 (1H, m), to 6.19 (1H, s) 6,38 (1H, s), 6.71 (1H, m), 7,10 (1H, t), 7.15 (2H, d), of 7.23 (1H, t), 7,32-7,40 (total 2H), 7,45 (1H, d), 8.02 (1H, s)

MS (FAB: 481 (M++ 1)

(Example 50)

Using 269 mg of 2,3-dimethoxybenzoic acid and 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene] acetate repeated the procedure similar to that described in reference example 8, to obtain 711 mg of methyl (Z)-[1-[4-(2,3-dimethoxybenzoyl)amino]benzoyl-4,4 - debtor-2,3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,27-2,80 (total 2H), with 3.27 (1H, m), of 3.84 (3H, s) to 3.92 (3H, s), of 3.96 (3H, s), 5,07 (1H, m), from 6.22 (1H, s), 6.73 x (1H, m), 7,08-7,26 (total 6H), 7,38 (1H, d), 7,49 (2H, d), 7,74 (1H, d), 10,07 (1H, s)< / BR>
MS (FAB): 537 (M++ 1)

(Example 51)

Using 296 mg chloride 2,6-dimethoxybenzoic acid and 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H - 1-benzazepin-5-ilidene] acetate repeated the procedure similar to that described in example 30, with getting 677 mg of methyl (Z)-[1-[4- (2,6-dimethoxybenzoyl)amino]-benzoyl-4,4-debtor-2,3,4,5 - Tetra the Society. 2H), 3,24 (1H, m), 3,81 (6H, s), 3,83 (3H, s), 5,07 (1H, m), of 6.20 (1H, s), to 6.58 (2H, d), 6,74 (1H, d), 7,11-7,18 (total 3H), 7,26 (1H, d), 7,31 (1H, t), 7,38 (1H,d), 7,40-7,52 (total 4H)

MC (FAB): 537 (M++ 1)

(Example 52)

Using 280 mg of 1 - phenylcyclopropane acid and 500 mg of methyl (Z)-[1-(4 - aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] acetate repeated the procedure similar to that described in reference example 8, with the receipt of 533 mg of methyl (Z)-[4,4-debtor - 1-[4-(1-phenylcyclopropane)amino] benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene] acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 1,71 (2H, m), of 1.85 (2H, m) 2,07 (2H, m), 2,20-2,80 (total 4H), 3,21 (1H, m), 3,81 (3H, s), of 5.03 (1H, m), 6,13 (1H, s), to 6.67 (1H, d), is 6.78 (1H, s), 7,05 (2H, d), to 7.09 (1H, t), 7,14 (2H, d), 7,22 (1H, t), 7,26-7,41 (total 6H)

MC (FAB): 545 (M++ 1)

(Example 53)

Using 302 mg 2-piperidinemethanol acid and 500 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-debtor-2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene] acetate repeated the procedure similar to that described in reference example 8, to obtain 711 mg of methyl (Z)- [4,4-debtor-1-[4-(2-piperidinoethyl)-amino] -benzoyl-2,3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene]-acetate.

1H-NMR ( M. D. in CDCI3, internal standard TMS): of 1.65 (2H, m), 1.77 in (4H, m), 2,24-2,80 (total 2H), 2,97 (4H, m) of 3.25 (1H, m), of 3.84 (3H, s) 5,07 (1H, m), 6+ 1)

(Example 54)

Using 600 mg of methyl (Z)-[4, 4-diftar-1-[4-12-(2-were)benzoyl] amino] benzoyl-2,3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, to obtain 500 mg of (Z)-[4,4-debtor-1-[4-[2-(2-were)benzoyl] amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCl3-DMSO-d6, internal standard TMS): 2,07 (3H, s), 2,23-2,84 (total 2H), 3,21 (1H, m) 5,00 (1H, m), of 6.20 (1H, s), only 6.64 (1H, m), of 6.68 (2H, d), of 7.00 (2H, d), 7,15-7,39 (total 9H), 7,47-to 7.59 (total 2H), 8,02 (1H, d)

MS (FAB): 553 (M1+ 1)

(Example 55)

Using 650 mg of methyl (Z)-[4,4-debtor-1-[4-(2-methyl-benzoyl) amines benzoyl-2,3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7 with getting 566 mg (Z)-04,4-debtor-1-(4-(2-methylbenzoyl)amino] benzoyl-2,3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,15-3,00 (total 2H), 2,43 (3H, s) to 3.35 (1H, m), 5,02 (1H, m), 6.20 (1H, s), of 6.75 (1H, m), 7,08-7,49 (total 12H), to 7.67 (1H, Shir)

MC (E1): 476 (M+)

(Example 56)

Using 650 mg of methyl (Z)-1-[4,4-debtor-1-[4-(2-methoxybenzoyl)amino] benzoyl-2, 3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in the EN]acetic acid.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,2-2,8 (total 2H), 3,26 (1H, m), a 4.03 (3H, s), of 5.03 (1H, m), 6,21 (1H, s), 6.73 (1H, m), 7,02 (1H, d), 7,09-7,28 (total 5H), 7,37 (1H, d), to 7.50 (3H, m), 8,23 (1H, m), 9,84 (1H, m)

MS (E1): 493 (M++ 1)

(Example 57)

Using 695 mg of methyl (Z)-[1-[4- (2-ethoxybenzoyl)-amino]benzoyl-4,4-debtor-2,3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, to obtain 670 mg of (Z)-[1-[4-(2-ethoxy-benzoyl)amino] benzoyl-4, 4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 1,59 (3H, t), 2,28-2,90 (total 2H), or 3.28 (1H, m), 4,22 (2H, HF), to 5.03 (1H, m), 6,27 (1H, s), 6.73 x (1H, m), 6,93 (1H, d), 7,06-7,18 (total 4H), from 7.24 (1H, t), 7,26-7,30 (total 4H), by 8.22 (1H, d), 10,16 (1H, m)< / BR>
MC (FAB): 507 (M++1)

(Example 58)

Using 683 mg of methyl (Z)-[4,4-debtor-1-[4-(2-isopropoxybenzoic) amines benzoyl-2,3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, with getting 499 mg (Z)-[4,4-debtor-1- 1-[4-(2-isopropoxybenzoic)aminobenzoyl-2,3,4,5-tetrahydro-1H - 1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCl3, internal standard TMS): to 1.47 (6H, d), 2,28-2,86 (total 2H), or 3.28 (1H, m), 4,79 (1H, m), 5,07 (1H, m), 6,27 (1H, s), 6.73 x (1H, m), 6,98 (1H, d), 7,06-7,20 (total 4H), 7,24 (1H, l (Z)-[4,4-debtor-1-[4-(3 - methoxybenzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene] acetate, repeated the procedure similar to that described in example 7, with getting 673 mg (Z)-[4,4-debtor-1-[4-(3 - methoxybenzoyl)amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCl3-DMSO-d6, internal standard TMS): 2,25-2,92 (total 2H), up 3.22 (1H, m), 3,86 (3H, s), 5,04 (1H, m), 6,24 (1H, s) of 6.71 (1H, m), 7.03 is-7,13 (total 2H), 7,15 (1H, d), 7,22 (1H, t), 7,34-7,40 (total 2H), 7,44-of 7.48 (total 2H), 7,60 (2H, d), 9,34 (1H, s)< / BR>
MS (FAB): 493 (M++ 1)

(Example 60)

Using 788 mg of methyl (Z)-[1-[4-(2- chlorobenzoyl)amino]benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, with getting 668 mg (Z)-[1-[4-(2- chlorobenzoyl)amino] benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H - 1-benzazepin-3-ilidene]acetic acid.

1H-NMR ( M. D. , CDCl3-DMSO-d6, internal standard TMS) 2,15-2,82 (total 2H), up 3.22 (1H, m), of 5.03 (1H, m), 6,24 (1H, s), 6,72 (1H, m), 7,09-7,20 (total 3H), 7,25 (1H, t), 7,32-of 7.48 (total 4H), 7,50-7,65 (total 3H), 9,85 (1H, s)

MS (FAB): 497, 499 (M++ 1)

(Example 61)

Using 782 mg of methyl (Z)-[1-[4-(3-chlorobenzoyl) amino]benzoyl-4,4-debtor-2,3,4, 5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, to obtain 631 mg (Z)-[l-[4-(3-chlorobenzoyl)amino] benzoyl-4,4-debtor-2,3,4, 5-tetrahydro tandard TMS): 2,43 (1H, m), 2,69 (1H, m), 3,24 (1H, m), of 5.03 (1H, m), 6,24 (1H, s) of 6.71 (1H, m), to 7.09 (1H, t), 7,14 (2H, d), 7,22 (1H, t), 7,34-7,43 (total 2H), of 7.48 (1H, d), to 7.59 (2H, d), 7,81 (1H, d), to 7.93 (1H, s), at 9.53 (1H, C)

MS (FAB): 497, 499 (M++ 1)

(Example 62)

Using 730 mg of methyl (Z)-[4,4-debtor-1-(14- (2-nitro-benzoyl)amino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, with the receipt of 389 mg (Z)-[4,4-debtor-1- 1[4-(2-nitrobenzoyl)amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene]acetic acid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): the 2.46 (2H, m), 3,11 (1H, m), 4,88 (1H, m), of 6.68 (1H, s), at 6.84 (1H, m), to 7.09 (2H, d), 7,21 (1H, t), 7,31 (1H, t), 7,38 (1H, d), to 7.50 (2H, d), 7,74-7,80 (total 2H), 7,86 (1H, t) to 8.14 (1H, d), a 10.74 (1H, s), of 13.18 (1H, W)

MS (FAB): 478 (M++ 1)

(Example 63)

Using 600 mg of methyl (Z)-[1-[4 - aminobenzoyl)amino]benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H - 1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7 to obtain 370 mg (Z)-[1-[4-(2- aminobenzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): the 2.46 (2H, m), 3,11 (1H, m) to 3.33 (2H, Shir), to 4.87 (1H, m), 6,56 (1H, s), of 6.65 (1H, s) 6,76 (1H, d), 6,83 (1H, m), 7,06 (2H, d), 7,14-7,24 (total 2H), 7,30 (1H, t), 7,38 (1H, d), 7,56 (2H, d), 10,04 (1H, s), 13,20 (1H, W)

MS (the Mino] benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, to obtain 500 mg of (Z)-[4,4 - debtor-1-1-[4-[2-(2,5-dimethylpyrrole-1-yl)benzoyl]amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 1,95 (6H, m), 2,24-2,84 (total 2H), 3,24 (1H, m), 5,04 (1H, m), between 6.08 (2H, s), and 6.25 (1H, s), 6,68-6,80 (total 2H), 7.03 is-7,30 (total 7H), 7,38 (1H, d), EUR 7.57-to 7.67 (total 2H), 8,35 (1H, d)

MS (FAB): 555 (M+)

(Example 65)

Using 960 mg of methyl (Z)-[4,4-debtor-1-[4- [2-(1H-1, 2, 4-triazole-1-yl)benzoyl]amino]benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene acetate, repeated the procedure similar to that described in example 7, to obtain the 767 mg (Z)-[ 4,4-debtor-1-[4-[2-(1H-1,2,4-triazole-1-yl)benzoyl] amino]- benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,44 (1H, m), 3,10 (1H, m), a 4.86 (1H, m), of 6.66 (1H, s), PC 6.82 (1H, m), 7,03 (2H, d), 7,19 (1H, t), 7,30 (1H, t), 7,34-7.46 (total 3H), 7,58-7,74 (total 4H), 8,07 (1H, s), 8,88 (1H, s), of 10.47 (1H, s), 10,19 (1H, m)

MS (FAB): 530 (M++ 1)

(Example 66)

Using 270 mg of methyl (Z)-[4,4-debtor-1-[4-[2- (1H-imidazol-1-yl)benzoyl]amino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, to obtain 115 mg of (Z )-[4,4-debtor-1- [4-[2-(1H-imidazol-1-yl)b the CDCl3, internal standard TMS): 2,44 (2H, m) to 3.09 (1H, m) a 4.86 (1H, m), of 6.66 (1H, s), PC 6.82 (1H, m), 6,97 (H1, C),? 7.04 baby mortality (2H, 1), 7,19 (1H, t), 7.23 percent-7,43 (total 5H), 7,52-7,70 (total 4H), 7,78 (1H, s), 10,49 (1H, t), 13,19 (1H, Shir)< / BR>
MC (FAB): 529 (M++ 1)

(Example 67)

Using 4,96 g of methyl (Z)-[4,4-debtor-1-[4-[2-(2-ethyl-1H-imidazol - 1-yl)benzoyl] amino]benzoyl-2,3,4,3-tetrahydro- -1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, to obtain 4,50 g (Z)- [4,4-debtor-1-[4-[2-(2-ethyl-1H-imidazol-1-yl)benzoyl] -amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]-acetic acid.

1H-NMR ( M. D. in CDCl3, internal standard TMS): the 1.04 (3H, t), is 2.41 (2H, q), is 3.08 (1H, Shir), a 4.86 (1H, Shir), 6,03 (1H, s), 10,42 (1H, s)

MC (FAB): 529 (M++ 1)

(Example 68)

Using 647 mg of methyl (Z)-[4,4-debtor-1-[4-[2-(2- were)acetylamino] benzoyl-2,3,4,3-tetrahydro-1H-benzazepin - 5-ilidene]acetate, repeated the procedure similar to that described in example 7, to obtain 517 mg (Z)-4,4-debtor-1-[4- (2-were)acetylamino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene]acetic acid.

1H-NMR: ( M. D. in CDCl3-DMSO-d6, internal standard TMS): 2,32 (3H, s), 2,35-2,82 (total 2H), up 3.22 (1H, m), 3,68 (2H, s), 5,02 (1H, m), of 6.20 (1H, s), to 6.67 (1H, m), 7,05-7,13 (total, 3H), 7,14-7,26 (total 5H), 7,34-7,39 (total 3H), 8,53 (1H, s)

MC (FAB): 491 (M++ 1)
1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, with the receipt of 596 mg (Z)-[4,4-debtor-1-[4-(2-methoxyphenyl) acetylamino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid]acid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,44 (2H, m), 3,10 (1H, m), of 3.60 (2H, s), of 3.73 (3H, s), a 4.86 (1H, m), 6,63 (1H, s), to 6.80 (1H, m), to 6.88 (1H, t), to 6.95 (1H, d), 7,02 (1H, d), 7,12-7,50 (General, 8H), 10,16 (1H, s), 13,20 (1H, Shir)< / BR>
MC (FAB): 507 (M++ 1)

(Example 70)

Using 830 mg of methyl (Z)-[4,4-debtor-1-[4-(2 - trifloromethyl)amino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, with the receipt of 751 mg (Z)-[4,4-debtor-1- [4-(2-trifloromethyl)amino] benzoyl-2,3,4,5-tetrahydro-1H - 1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): the 2.46 (2H, m), 3,11 (1H, m), 4,89 (1H, m), of 6.68 (1H, s), 6,85 (1H, m), to 7.09 (2H, m), 7,20 (1H, t), 7,31 (1H, t), 7,47-to 7.59 (total 2H), to 7.67-7,74 (total 2H), 7,78 (1H, t), to 7.84 (1H, d), as 10.63 (1H, s), 13,17 (1H, W)

MC (FAB): 531 (M++ 1)

(Example 71)

Using 760 mg of methyl (Z)-[4,4-debtor-1-[4-(1 - afterburner)amino] benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, to obtain 555 mg (Z)-[4,4-debtor-1-[4- (1-afterburner)amino] benzoy the/SUB>, internal standard TMS): 2,24-2,90 (total 2H), 3,23 (1H, m), 5,04 (1H, m), and 6.25 (1H, s), 6,74 (1H, m), 7,13-7,21 (total 3H), 7,25 (1H, t), 7,39 (1H, d), 7,47-EUR 7.57 (total 3H), 7,62 - 7,71 (total 3H), 7,89 (1H, m), 7,94 (1H, d), 8,29 (1H, m), for 9.95 (1H, s)

MC (FAB): 513 (M++ 1)

(Example 72)

Using 445 methyl (Z)-4,4-debtor-1-[4-(1-methylpropyl) amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] acetate, repeated the procedure similar to that described to 2.46 (2H, m), 3,11 (1H, m), 4,89 (1H, m), of 6.68 (1H, s), 6,85 (1H, m), to 7.09 (2H, m), 7,30 (1H, t), 7,31 (1H, t), 7,47-to 7.59 (total 2H), to 7.67-7,74 (total 2H), 7,78 (1H, t), to 7.84 (1H, d), as 10.63 (1H, s), 13,17 (1H, W)

MS (FAB): 531 (M++ 1) (1H, C)

(Example 73)

Using 700 mg of methyl (Z)-[4, 4-diftar-1-[4-(3-methyl-2-thienyl)carbylamine]benzoyl-2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, to obtain 656 mg of (Z)-[4,4-debtor-1-[4-(3-methyl-2-thienyl)carbylamine] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid.

1H-NMR ( M. D. in CDCl3-DMSO-d6, internal standard TMS): 2,25-2,89 (total 2H), 2,53 (3H, s), 3,24 (1H, m), 5,04 (1H, m), 6,23 (1H, s) of 6.71 (1H, m), 6,92 (1H, d), 7,12 (1H, t), to 7.15 (2H, d), of 7.23 (1H, t), 7,33 (1H, d), 7,38 (1H, d), 7,47 (2H, d), 8,40, (1H, s)

MS (FAB): 483 (M++ 1)

(Example 74)

Using 404 mg of methyl (Z)-[4,4-debtor-1-[4-(3-methyl-2-furyl)carbylamine] benzoyl-2,3,4,5-tetrahydro-1H-1-Ben is R-1-[4-(3-methyl-2-furyl)carbylamine] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene) acetic acid.

1H-NMR ( M. D. in CDCl3-DMSO-d6, internal standard TMS): 2,28-2,84 (total 2H), 2,41 (3H, s), 3,23 (1H, m), is 5.06 (1H, m), 6,23 (1H, s), to 6.39 (1H, s) 6,70 (1H, m), 7,07 (1H, t), to 7.15 (2H, d), 7,22 (1H, t), 7,37 (2H, m), 7,49 (1H, d), with 8.33 (1H, s)< / BR>
MC (FAB): 467 (M++ 1)

(Example 75)

Using 770 mg of methyl (Z)-[1-[4-(2,3-dimethoxybenzoyl)-amino] benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, to obtain 770 mg (Z)-[1-[4-(2,3-dimethoxybenzoyl)amino] benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS); of 2.45 (2H, m), 3,11 (1H, m), 3,76 (3H, s), of 3.84 (3H, c), to 4.87 (1H, m), of 6.66 (1H, s), at 6.84 (1H, m), 7.03 is-7.23 percent (total 6H), 7,30 (1H, t), 7,38 (1H, d), at 7.55 (2H, d), 10,31 (1H, s), 13,17 (1H, s)< / BR>
MS (FAB) : 523 (M++ 1)

(Example 76)

Using 660 mg of methyl (Z) -[1-[4-(2,5-dimethoxybenzoyl)-amino]benzoyl-4,4-debtor-2,3, 4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetate, repeated the procedure similar to that described in example 7, to obtain 512 mg (Z)-[1-[4-(2,6-dimethoxybenzoyl)amino] benzoyl-4, 4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,50 (2H, m), 3,10 (1H, m), of 3.73 (6H, s), 4,89 (1H, m), of 6.66 (1H, s) of 6.71 (2H, d), 6,83 (1H, m),? 7.04 baby mortality (2H, d), 7, methyl (Z)-[4,4-debtor-1-[4-(1-phenylcyclopropane)amino] benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, to obtain 459 mg (Z)-[4,4-debtor-1-[4-(1-phenylcyclopropane)amino] benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,53-1,73 (total 4H), of 1.88 (2H, m), 2,43 (2H, m) 2,60 (2H, m), is 3.08 (1H, m), 4,84 (1H, m), 6,56 (1H, s), 6,77 (1H, d), 6,98 (2H, d), 7,14 (1H, t), 7,16-7,50 (total 9H), 9,23 (1H, s), 13,24 (1H, m)< / BR>
MC (FAB): 531 (M++ 1)

(Example 78)

Using 700 mg of methyl (Z)-[4,4-debtor-1-[4-(2-piperidinoethyl) amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 7, to obtain 403 mg of (Z)-[4,4-debtor-1-[4-(2-piperidinoethyl)amines benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 1,64 (211, m), 1.77 in (4H, m), 2,24-3,85 (total 2H), 2,96 (4H, m) of 3.25 (1H, m), is 5.06 (1H, m), 6,28 (1H, s), 6,74 (1H, m), 7,11-7,34 (total 6H), 7,39 (1H, d), 7,47 (1H, t), EUR 7.57 (2H, m), by 8.22 (1H, d), of 12.73 (1H, s)

MS (FAB): 546 (M++ 1)

(Example 79)

In 10 ml of methylene chloride and 10 ml of acetonitrile was dissolved (Z) [4,4-debtor-1-[4-(2-phenylbenzyl)amino] benzoyl-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-ilidene]acetic acid (1,153 g) was added dropwise under ice cooling 10 ml methylenchloride of ristorazione and the mixture was stirred overnight at room temperature. Was added to the reaction solution, water, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of ethyl acetate-hexane (1:1, volume/volume) and received as a result of 1.27 g of the active complex ether.

of 2.56 (2H, m), is 2.88 (4H, W), 3,29 (1H, m), to 4.98 (1H, m), 6,38 (1H, s), 6,69 (1H, m), for 6.81-7,06 (total 5H), to 7.15 (1H, m), 7,25 - 7,58 (total 10H), a 7.85 (1H, m)

MS m/z (FAB): 636 (M++ 1)

Part (835 mg) obtained active complex ester was dissolved in 20 ml of tetrahydrofuran, the solution was mixed with 99 mg of sodium borohydride and the mixture was stirred 2 days at room temperature. Was added to the reaction solution, water, and the mixture was extracted with chloroform and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of ethyl acetate-hexane (1:1, volume/volume) and has obtained 538 mg (Z)-2- [1-[4-(2-diphenylcarbonate)benzoyl] - 4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]ethanol.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 1,83 (1H, m), 2,12-2,50 (total 2H), and 3.31 (1H, m), 4,60-4,8 O (total 3H), 6,14 (1H, m), 6,62 (1H, m), 6,82-7,16 (the benzoyl] -4,4 - debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene]ethanol (215 mg) and About; 114 ml of triethylamine were dissolved in 20 ml of methylene chloride was added dropwise under ice cooling 0,0349 ml methanesulfonanilide. Then, after 30 minutes, was added 10 ml of N, N-dimethylformamide, evaporated low-boiling solvent, was added 0,455 ml of N-methylpiperazine and then was stirred overnight at 90oC. After evaporation of the solvent, the obtained residue was mixed with 1 N. aqueous sodium hydroxide solution, was extracted with chloroform and the mixture is then dried over anhydrous potassium carbonate. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of chloroform-methanol (95:5, vol/vol) and received in the 176 mg of free base. Then this product was dissolved in methanol and converted into the hydrochloride by adding 4 in a solution of hydrochloric acid in ethyl acetate, after which the solvent evaporated under reduced pressure. Next, the resulting residue was recrystallized from a mixture of benzene-diethyl ether to obtain 143 mg of the dihydrochloride of (Z)-4'- -[4,4-debtor-5-[2-(4-methyl-1-piperazinil)ethylidene] -2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-2-phenylbenzene.

Melting point 159-162oC

1H-NMR ( M. D. in DMSO-, ,31 (1H, m), 7,34-7,60 (total 13H), 10,34 (1H, s), for 11.55 (1H, m)

MS m/z (FAB): 607 (M++ 1)

(Example 81)

(Z)-2-[1-[4-(2-Diphenylcarbonate)benzoyl]-4,4 - debtor-2,3, 4,5-tetrahydro-1H-1-benzazepin-5-ilidene]ethanol (220 mg) and 0,117 ml of triethylamine were dissolved in 10 ml of methylene-chloride and added dropwise under ice cooling 0.036 ml methanesulfonanilide. Then, after 30 minutes, was added 10 ml of N, N-dimethylformamide, evaporated low-boiling solvent, was added 0,350 ml pyrrolidine and then the mixture was stirred overnight at 90oC. After evaporation of the solvent, the obtained residue was mixed with 1 N. aqueous sodium hydroxide solution, the mixture was extracted with chloroform and then dried over anhydrous potassium carbonate, After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of chloroform-methanol (95: 5, vol/vol) and received in the 158 mg of the free base. Then this product was dissolved in methanol and converted into the hydrochloride by adding 4 n hydrochloric acid in ethyl acetate, after which the solvent evaporated under reduced pressure. Paley obtained residue was recrystallized from a mixture of acetonitrile-diethyl ether to obtain 61 mg of the guide is anilide in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,82-2,12 (total 4H), 3,15-2,70 (2H, s). 3,05-3,75 (total 7H), 4,25 - 4,70 (1H, m), 6,27 (1H, m), 6,70-of 6.90 (1H, m), 6,97-7,60 (agg 14N), 10,20-10,50 (total 2H)

MC m/z (FAB): 57S (M++ 1)

(Reference example 10)

In 30 ml of toluene suspended [(3-dimethylamine)propyl]- triphenylphosphonium (2, 11 g) was added dropwise 9,85 ml of 0.5 n solution hexamethyldisilazide potassium in toluene, followed by stirring for 1 hour at room temperature. Then was added dropwise 30 ml of a mixed solvent of toluene-dimethoxyethane containing 624 mg of 1-(4-aminobenzoyl)-4, 4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it, followed by stirring for 10 hours. Was added to the reaction solution, water, and the mixture was extracted with ethyl acetate, then the organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the obtained residue was subjected to column chromatography on silica gel with elution with a mixture of chloroform-methanol (87:3, vol/vol) and getting 697 mg (E)-4'- [[5-(3-dimethylaminopropyl)-4,4-debtor-2,3,4,5-tetrahydro-1H - 1-benzazepine.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 1,89-2,50 (total 6H), of 2.16 (5H, s), 2,24 (3H, s), 3,24 (1H, m), of 3.78 (1H, whom 82)

Using 690 mg (E)-1-(4-aminobenzoyl)-5-(3-dimethyl - aminopropylene)-4,4-debtor-2,3,4,5-tetrahydro-1H-1 - benzazepine and 430 mg on-vinylbenzoic acid, synthesized 520 mg of the free base as described in reference example 8. Then 340 mg of the free base was dissolved in chloroform and the resulting solution was mixed with 4 N. a solution of hydrochloric acid in ethyl acetate, after which the solvent evaporated. Then the obtained residue was mixed with hexane to obtain 111 mg of the hydrochloride of (E)-4'-[[4,4-debtor-5-(3-dimethylaminopropyl)- 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-phenylbenzene in the form of colorless amorphous solid.

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,29 of 3.28 (total 12H), is 4.93 (1H, m), to 6.19 (1H, m), 6,79-7,58 (total 17H), 7,78 (1 H, m), 12,82 (1H, m)

MC m/z (FAB): 566 (M++ 1)

(Example 83)

Using 300 mg of (Z)-[4,4-debtor-1-[4-(2 - phenylbenzyl)-amino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene]acetic acid and 79 mg of 4-piperidinylidene, repeated the procedure similar to that described in example 11, was received hydrochloride. It was recrystallized from a mixture of ethanol-ethyl acetate to obtain 212 mg of the hydrochloride of (Z)- 4'-[[4,4-debtor-5-[[(4-piperidinylidene)carbonyl] methylene]-2,3,4,5-Tetra the program 230oC or higher.

Elemental analysis data (C42H42N4O3F21,5 H2O)

With% H% N% Cl% F%

calc.: 67,06 6,16 7,45 4,17 of 5.05

found: 67,14 6,15 7,41 4,65 4,84

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,32-1,94 (total 7H), of 2.16 (2H, m), is 2.41 (2H, m) to 2.66 (1H, m), 2.91 in (2H, m), 2,98-of 3.46 (total 6H), is 4.03 (1H, m) to 4.52 (1H, m), 4,84 (1H, m), 6,77 (1H, s), for 6.81 (1H, m), 7,01 (2H, m), 7,16-to 7.59 (total 14H), 10,34 (1H, s), 10,53 (1H, m)

MS m/z (FAB): 689 (M++ 1)

(Example 84)

Using 193 mg (Z)-[4,4-debtor-1-[4-(2-phenylbenzyl)-amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid and 0,078 ml of 1-methyl-(4-methylamino)of piperidine, and repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-diethyl ether to obtain 80 mg of the hydrochloride of (Z)-4'-[[4,4 - debtor-5-[[N-methyl-N-(1-methyl-4-piperidyl)carbarnoyl] methylene]-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl-2 - phenylbenzene in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2,65-3,54 (total 11H), 2,65 (1,2 H W), 2,74 (1,2 H, W), 2,75 (1,2 H, s), 2.91 in (1,2 H, C) 3,94 (0,4 H, m), 4,49 (0,6 H, m), a 4.83 (1H, m), 6,77-6,90 (total 2H), 7,02 (2H, m), 7,16-7,62 (total 14H), 10,19 (0,4 H, s), 10.30 a.m.-10,42 (1,6, m).

MS m/z (FAB): 648 (M++ 1)

(Example 85)

1H-NMR ( M. D. in DMSO-d6, internal standard TMS) of 1.75 (1H, m), 1,89 (1H, m), 1,98-2,15 (total 2H), 2,27-2,70 (total 2H), 2.95 and is-3.45 (total 6H), to 3.64 (1H, m), 4,18 (1H, m), a 4.86 (1H, m), to 6.58 (1H, s), 6,77 (1H, m), 7,01 (2H, m), 7,17 (1H, m), 7,25-7,60 (total 13H), to 8.70 (1H, m), 10,12 (1H, m), 10,31 (1H, m)

MS m/z (FAB): 647 (M++ 1)

(Example 86)

Using 300 mg of (Z)-[4,4-debtor-1-[4-2-(2 - were-benzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-3-ilidene] acetic acid, repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-diethyl ether to obtain 264 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[(4-dimethylaminopyridine)carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl]carbonyl]-2-(2-were)benzanilide in the form of colorless crystals.

Melting point 210oC or higher.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,38-1,78 ( 7,06- 7,41 (Gen. 9H), 7,43-7,62 (total 4H), 10,23 (1H, s), 10,66 (1H, m)

MS (FAB): 663 (M++ 1)

(Example 87)

Using 230 mg of (Z)-[4,4-debtor-1-[4-2-(2 - were-benzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 0,083 ml 4 - dimethylaminopyridine, repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-diisopropyl ether to obtain 187 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine) carbonyl]methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-methylbenzamide in the form of colorless crystals,

Melting point 204-206oC

Elemental analysis data (C34H36N1O5F22H2O)

C% H% N% Cl% F%

calc.: of 61.95 6,27 8,50 5,38 5,78

found: 61,99 6,34 8,21 of 5.40 5,68

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,80 (total 2H), 2,09 (2H, m), 2,42 (2H, m) to 2.67 (1H, m), 2,71 (6H, s), 2,98-3,21 (total 2H), 4, 4,06 (1H, d), a 4.53 (1H, d), 4,89 (1H, m), for 6.81 (1H, s), 6,85 (1H, d), to 7.09 (2H, d), 7,20 (1H, t), 7,25-7,44 (total 5H), 7,52 (1H, d), 7,58 (2H, d), accounted for 10.39 (1H, s), of 10.72 (1H, m)

MS m/z (E1) 587 (M++ 1)

(Example 88)

Using 230 mg of (Z)-[4,4-debtor-1-[4-[2-(2- were)-benzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 97.5 ml of 4-piperidinophenyl from a mixture of ethanol-ethyl acetate-diethyl ether to obtain 166 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[[(4 - piperidinylidene)-carbonyl] methylene]-2,3,4,5 - tetrahydro-1H-benzazepin-1-yl] -carbonyl-2-methylbenzamide in the form of colorless crystals.

Melting point 194-196oC

Elemental analysis data (C37H40N4O3F28H2O)

C% H% N% Cl% F%

calc.: 63,89 6,46 8,05 5,10 5,46

found: 63,82 6,53 7,87 5,26 lower than the 5.37

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,32-1,94 (total 7H), of 2.15 (2H, m), of 2.34 (3H, s), 2,43 (2H, m) to 2.67 (1H, m), of 2.92 (2H, m), 3,02-3,49 (total 6H), of 4.05 (1H, m), a 4.53 (1H, m), to 4.87 (1H, m), to 6.80 (1H, s), 6,85 (1H, m), to 7.09 (2H, m), then 7.20 (1H, m), 7,25-7,34 (total 3H), 7,35 (1H, d), 7,42 (1H, d), 7,52 (1H, d), 7,58 (2H, d), accounted for 10.39 (2H, m)

MC m/z (FAB): 627 (M++ 1)

(Example 89)

Using 300 mg of (Z)-[4,4-debtor-1-[4-(2 - methoxybenzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid, repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-diisopropyl ether to obtain 270 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[[(4-dimethylamino-piperidino)carbonyl] methylene] -2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-2-methoxybenzanilide in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,42-1,78 (total 2H), 2,08 (2H, m), 2,42 (2H, m) to 2.67 (1H, m), of 2.72 (6H, s), 2,99-3,22 (total 2H), 3,43 (1H, m), 3,85 (3H, s), Android 4.04 (1H, m) to 4.52 (1H, m), a 4.83 (1H, m), 6,79 (1H, s), 6,83 (1H, m), 7,02-7,21 (total 5H), 7,31 (1H, t), 7,44-7,62 (total 5H), 10,19 (1H, s), 10,56 (1H, m)2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] -acetic acid, repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-diethyl ether to obtain 199 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine) carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] - carbonyl]-2-ethoxybenzonitrile in the form of colorless amorphous solid.

Melting point 181-186oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,35 (3H, s), of 1.40 and 1.80 (total 2H), 2,09 (2H, m), 2,47 (2H, m), 2,68 (1H, m), 2,70 (3H, s), a 2.71 (3H, s), 2.95 and-3,54 (total 3H), 4,06 (1H, m), is 4.15 (2H, q), a 4.53 (1H, m), a 4.86 (1H, m), for 6.81 (1H, s), at 6.84 (1H, m), 7,02-7,21 (total 4H), 7,31 (1H, t), 7,44-7,62 (total 4H), and 10.20 (1H, s), of 10.76 (1H, m)

MC (FAB): 617 (M++ 1)

(Example 91)

Using 300 mg of (Z)-[1-[4-(2-ethoxybenzoyl)amino] - benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] - acetic acid, repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-diethyl ether to obtain the result 157 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[[N-2-dimethylaminoethyl carbarnoyl] methylene] -2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl]carbonyl]-2-ethoxybenzonitrile in the form of colorless amorphous solid.

Melting point 140-144o (2H, m) to 4.15 (2H, q), 4,89 (1H, m), 6,56 (1H, s), to 6.80 (1H, m), 7,02-7,21 (total 5H), 7,29 (1H, t), 7,37 (1H, d), of 7.48 (1H, t), of 7.55 (2H, d), 7,63 (1H, d), 8,69 (1H, t), 10,19 (1H, s), 10,61 (1H, m)

MC (FAB): 577 (M++ 1)

(Example 92)

Using 240 mg of methyl (Z)-[[4,4-debtor-1-[4-(2-isopropoxybenzoic)amino] benzoyl-2, 3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetate, repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-diisopropyl ether to obtain 191 mg of the hydrochloride of (Z)-4' -[[4,4-debtor-5-[[(4-dimethylaminopyridine)carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]- 2-isopropoxybenzonitrile in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): is 1.31 (6H, d), of 1.40 and 1.80 (total 2H), 2,08 (2H, m), 2,42 (2H, m) to 2.67 (1H, m), of 2.72 (6H, s), 2,99-3,22 (total 2H), 3,43 (1H, m), 3,85 (3H, s), Android 4.04 (1H, m), a 4.53 (1H, m), to 4.73 (1H, m), a 4.86 (1H, m), for 6.81 (1H, s), at 6.84 (1H, m), 6,98 and 7.36 (total 5H), 7,31 (1H, m), 7,42-7,70 (total 5H), 10,19 (1H, s), 10,77 (1H, m)

MC (FAB): 631 (M++ 1)

(Example 93)

Using 240 mg of (Z)-[4,4-debtor-1-[4-(2-isopropoxybenzoic)amines benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid, repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-visapro is ahydro-1H-1 - benzazepin-1-yl]carbonyl]-2-isopropoxybenzonitrile in the form of a colorless amorphous solid,

1H-NMR ( M. D. in DMSO-d6internal standard tees): to 1.32 (6H, d), 2,24-2,80 (total 2H), 2,80 (3H, s), of 2.81 (3H, s), 2.95 and-3,24 (total 3H), 3,52 (2H, m), to 4.73 (1H, m), 4,91 (1H, m), to 6.58 (1H, s), to 6.80 (1H, m), 7,01-7,41 (total 7H), 7,42-7,58 (total 3H), of 7.65 (1H, d), 8,66 (1H, t), 10,18 (1H, s), 10,36 (1H, m)

MS (FAB): 591 (M++ 1)

(Example 94)

Using 300 mg of (Z)-[4,4-debtor-1-[4-(3-methoxybenzoyl) amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid and 0,134 ml 4-dimethylaminopyridine, repeated the procedure similar to that described in example 11, and received hydrochloride. It was recrystallized from a mixture of ethanol-diisopropanol-diisopropyl ether, to obtain 270 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine)carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-3-methoxybenzanilide.

Melting point 178-182oC

1H-NMR ( M. D. in DMSO-d6internal standard TMC): 1,38-1,80 (total 2H), 2,10 (2H, m), 2,43 (2H, m), 2,68 (1H, m), 2,71 (6H, s), 2,98 is 3.23 (total 2H), 5,44 (1H, m), 3,88 (3H, s) 4,06 (1H, m), a 4.53 (1H, m), 4,88 (1H, m), to 6.80 (1H, s), at 6.84 (1H, m), 7,06-7,24 (total 4H), 7,31 (1H, t), 7,38-7,56 (total 4H), 7,63 (2H, m), 10,33 (1H, s), 10,81 (1H, m)

MS (FAB): 603 (M++ 1)

(Example 95)

Using 788 mg (Z)-[1-[4-(2-chlorobenzoyl)amino benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] -acetic acid and 0,134 ml 4-dilatatum was led from a mixture of ethanol-diethyl ether obtained with 172 ml of hydrochloride of (Z)-2-chloro - 4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine)carbonyl] - the methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]- benzanilide.

Melting point 181-186oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,80 (total 2H), 2,09 (1H, m), 2,43 (2H, m) to 2.67 (1H, m), 2,71 (6H, s), 2.95 and-3,22 (total 2H), 3,43 (1H, m) 4,06 (1H, m), a 4.53 (1H, m), to 4.87 (1H, m), PC 6.82 (1H, s), 6,85 (1H, m), 7,10 (2H, m), then 7.20 (1H, t), 7,31 (1H, t), 7,41-7,63 (total 7H), 10,61 (1H, m)

MC (FAB): 607, 609 (M++ 1)

(Example 96)

Using 300 mg of (Z)-[1-[4-(3- chlorobenzoyl)amino]benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] -acetic acid and 0,134 ml 4 - dimethylaminopyridine, repeated the procedure similar to that described in example 11 and received hydrochloride, which was then led from a mixture of ethanol-diethyl ether to obtain 140 mg of the hydrochloride (Z)-3-chloro-4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine) carbonyl] -methylene)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -benzanilide in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,80 (total 2H), 2,08 (2H, m), 2,43 (2H, m) to 2.67 (1H, m), by 2.73 (3H, s), is 2.74 (3H, s), 3,02-3,22 (total 2H), 3,44 (1H, m) 4,06 (1H, m), of 4.54 (1H, m), to 4.87 (1H, m), to 6.80 (1H, s), at 6.84 (1H, m), 7,06-7,22 (total 3H), 7,31 (1H, t), of 7.48-7,69 (total 5H), 7,86 (1H, d), 7,95 (1H, s), 10,22 (1H, m), 10,43 (1H, s)

MS (FAB): 607, 609 (M++ 1)

(Example 97)

Using 350 is realy procedure similar to that described in example 11, and has obtained the hydrochloride, which was then led from a mixture of ethanol-diethyl ether to obtain 188 mg of the hydrochloride of (Z)-4' -[[4,4-debtor-5-[[(4-dimethylaminopyridine)carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-nitrobenzamide in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,80 (total 2H), 2,10 (2H, m), 2,43 (2H, m) to 2.67 (1H, m), 2,70 (3H, s), a 2.71 (3H, s), 3,02-3,24 (total 2H), 3,40 (1H, m), of 4.05 (2H, m), a 4.53 (1H, m), 4,88 (1H, m), 6,83 (1H, s) 6,86 (1H, m), 7,11 (2H, m), 7,22 (1H, m), 7,32 (1H, t), 7,52 (2H, m), 7,74 for 7.78 (total 2H), 7,86 (1H, t) to 8.14 (1H, DD), of 10.76 (1H, m), 10,80 (1H, s)

MS (FAB): 618 (M++ 1)

(Example 98)

Using 340 mg of (Z)-[1-[4-(2- aminobenzoyl)amino]benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] - acetic acid, repeated the procedure similar to that described in example 11, and received 372 mg (Z)-2-amino-4'- [[4,4-debtor-5-[[(4-dimethylaminopyridine)carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl] benzanilide.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,39-1,57 (total 2H), to 1.86 (2H, m) to 2.29 (6H, s), 2,10-2,80 (total 4H), 3.00 and-3,42 (total 2H), 3,97 (1H, m), free 5.01 (1H, m), vs. 5.47 (1H, s), 6,32 (1H, s), 6,66-6,77 (total 3H), 7,06-7,70 (total 5H), 7,35-7,50 (total 4H), 8,01 (1H, m)

MC (FAB): 588 (M++ 1)

(1-benzazepin-5-ilidene] acetic acid, repeated the procedure similar to that described in example 11, and received, 309 mg (Z)- 4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine)-carbonyl] methylene] - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2- (2,5-dimethylpyrrole-1-yl)benzanilide.

1H-NMR ( M. D. in CDCl3, internal standard TMS): 1,42-1,59 (total 2H), 1.91 a (2H, m), 2,18-2,80 (total 2H), to 2.29 (6H, s), 2,39 (1H, m), is 2.74 (1H, m), of 3.97 (1H, m), to 4.62 (1H, m), between 6.08 (1H, s) 6,34 (1H, s) 6,70 (2H, m), 7,06-7,18 (total 4H), 7,22 (1H, t), 7,38 (1H, d), 7,55-7,66 (total 2H), 8,35 (1H, DD)

MC (FAB): 666 (M++ 1)

(Example 100)

Using 300 mg of (Z)-[4,4-debtor-1-[4-[2-(1H-1,2,4 - triazole-1-yl)benzoyl] amino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene]acetic acid and 0,156 ml 4-dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which was then led from a mixture of ethanol-diethyl ether to obtain 243 mg hydrochloride (Z)-4'-[[4,4-debtor-5-[[(4 - dimethylaminopyridine)carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl] carbonyl]-2-(1H-1,2,4-triazole-1-yl)benzanilide,

Melting point 190-193oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS); 1,38-1,80 (total 2H), 2,09 (2H, m), 2,42 (2H, m) to 2.67 (1H, m), 2,70 (3H,s), a 2.71 (3H, s), 2,96-3,21 (total 2H), 3,44 (1H, m), 4.04 the(] H, m) to 4.52(1H, m), a 4.86(1H, m), of 6.75(1H,s), 6,83 (1H, m), 7,05 (2H,m), 7,20 (1H, t), 7,29 (1H, t
Using 300 mg of (Z)-[4,4-debtor-1-[4-2-(1H-1,2,4 - triazole-1-yl)benzoyl] amino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 115 mg of methylaminopropane, repeating the reaction of example 11 and the product was led from a mixture of ethanol-diethyl ether to obtain 190 mg (Z)-4'-[[4, 4-debtor-5-(N-methylcarbamoylmethyl)-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl]carbonyl]-2-(1H-1,2,4-triazole-1-yl) benzanilide.

Melting point 210oC or higher

1H-NMR ( M. D. in CDCI3, internal standard TMS): 2,41 (1H, m), equal to 2.94 and 2.95 (total 3H, each s), 2,96 (1H, m), 3,23 (1H, m), 4,96 (1H, m), 6,36 (1H, s), to 6.57 (1H, 2), 6,70 (2H, m), 7,00-7,16 (total 4H), 7,22-7,32 (total 2H), 7,35-7,70 (total 4H), 8,02 (1H, s), 8,31 (1H, s), 9,78 (1H, m)

MC (FAB): 543 (M++ 1)

(Example 102)

Using 100 mg of (Z)-[4,4-debtor-1-[4-[2-(1H-imidazol-1-yl)benzoyl]amino] benzoyl-2, 3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid and 56 mg of Isopropylamine, repeated the procedure similar to that described in example 11, and received 233 mg of (Z)-4'-[[4,4-debtor-5-(N - isopropylcarbamate)-2,3,4,5-tetrahydro-1H-1-benzazepin-1 - yl]-carbonyl]-2-(1H-imidazol-1-yl)benzanilide,

1H-NMR ( M. D. in CDCI3, internal standard TMS): 1,22 (6H, d), 2,15-2,70 (total 2H), 3,29 (1H, m), 4,17 (1H, m), 4,80 (1H, m), 6,01 (1H, m), 6,30 (1H, s), 6,66 (1H, m), 7,00-7,38 (total 10H), 7,40-7,62 (total 3H), of 7.69 (1H, s), 7,79 ] benzoyl] -4,4-debtor-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 5 ml of aqueous ammonia, repeated the procedure similar to that described in example 11, and received 683 mg of (Z)-4'-[(5-carbamoylmethyl-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-(2-ethyl-1H - imidazol-1-yl)benzanilide.

The melting point of 290oC or higher

Elemental analysis data (C31H27N5O3F2memorial plaques in DMSO-d6, internal standard TMS); the 1.04 (3H, t), is 2.40 (2H, q), 3,06 (1H, W), to 4.87 (1H, W), 6,48 (1H, s), accounted for 10.39 (1H, d)

MS (FAB): 556 (M++ 1)

(Example 104)

Using 0.5 g (Z)-1-[4-[2-(2-ethyl-1H-imidazol-1-yl)benzoylamine] benzoyl]-4,4-debtor-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 40% aqueous solution of methylamine, and repeated the procedure similar to that described in example 11, and received 425 mg of (Z) -2-(2-ethyl-1H-imidazol-1-yl)-4'-[[ 4,4-debtor-5-N-methylcarbamoyl)methylene]-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl]carbonyl]benzanilide.

The melting point of 290oC or higher

Elemental analysis data (C32H29N5O3F2)

C% H% N% F%

calc.: 67,48 5,13 12,30 6,67

found: 67,19 5,30 12,32 6,61

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,04 (3H, s), of 2.38 (2H, HF), 2,65 (1H, W), totaling 3.04 (1H, W), 4,88 (1H, W), of 6.50 (1H, s), to 8.20 (1H, m), 10,38 (1H, s)

MS (FAB): 570 (M++ 1)

(PR is saseen-5-ilidene]acetic acid and 0,074 ml cyclopropylamine, repeated the procedure similar to that described in example 11, and received 325 mg of (Z)-4'-[[5-[(N-cyclopropanecarbonyl) methylene] -4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-2-(2-ethyl-1H-imidazol-1-yl of benzanilide.

Melting point 260oC or higher

Elemental analysis data (C34H31N5O3F2)

C% H% N% F%

calc.: 68,56 5,25 11,76 6,38

found: 68,48 5,35 11,80 6,35

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 0,46 (2H, m) to 0.67 (2H, m), was 1.04 (3H, t), is 2.40 (2H, q), totaling 3.04 (1H, W), to 4.87 (1H, W), 6,48 (1H, s), 8,35 (1H, d), 10,38 (1H, s)

MS (FAB): 570 (M++ 1)

(Example 106)

Using 280 mg of (Z)-1-[4,4-debtor-1-[4-(2 - were)-acetylamino] benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 0,152 ml 4 - dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which was then led from a mixture of ethanol-diethyl ether to obtain 173 mg of the hydrochloride of (Z)-N-4'-[4'-[[4,4-debtor-5-[[(4 - dimethylaminopyridine)-carbonyl] methylene] -2,3,4,5-tetrahydro-1H - 1-benzazepin-1-yl-carbonyl] phenyl-2-methoxyphenylacetamide.

Melting point 186-191oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS); 1,39-1,77 (total 2H), 2,07 (2H, m), 2), ? 7.04 baby mortality (2H, m), 7,08-7,25 (total 5H), 7,28 (1H, t), 7,44 (2H, m), 7,56 (1H, m), 10,33 (1H, s), 10,48 (1H, m)

M (FAB): 601 (M++ 1)

(Example 107)

Using 280 mg of (Z)-[4,4-debtor-1-[4-(2 - methoxyphenyl)-acetylamino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 0,152 ml 4 - dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which was then led from a mixture of ethanol-diethyl ether to obtain 230 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[[(4 - dimethylaminopyridine)-carbonyl] -methylene]-2,3,4,5-tetrahydro - 1H-1-benzazepin-1-yl]-carbonyl]-3-methylpyrrole-2-carboxamide.

Melting point 183-188oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,80 (total 2H), 2,09 (2H, m), is 2.41 (2H, m) to 2.66 (1H, m), 2,70 (6H, s), 2,98-3,21 (total 2H), 3,43 (1H, m), of 3.60 (2H, s), of 3.73 (3H, s), of 4.05 (1H, m) to 4.52 (1H, m), to 4.87 (1H, m), 6,77 (1H, s), for 6.81 (1H, m), to 6.88 (1H, t), of 6.96 (1H, d), 7,03 (2H, m), 7,13-7,32 (total 5H), 7,42-7,51 (total 3H), of 10.21 (1H, c), of 10.73 (1H, m)

MC (FAB): 617 (M++ 1)

(Example 108)

Using 300 mg of (Z)-[4,4-debtor-1-[4-(2-trifluoromethyl-benzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid and 0,124 ml 4-dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which was then led iridine)carbonyl] methylene - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-2-triptoreline in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,85 (total 2H), 2,10 (2H, m), of 2.45 (2H, m) to 2.66 (1H, m), 2,70 (6H, s), 2.95 and-3,22 (total 2H), 3,43 (1H, m) 4,06 (1H, m), a 4.53 (1H, m), 4,88 (1H, m), PC 6.82 (1H, s) 6,86 (1H, m), 7,11 (2H, m), 7,21 (1H, t), 7,32 (1H, t), 7,53 (3H, m), 7,66-7,80 (total 3H), 7,83 (1H, d), is 10.68 (1H, s), 10,85 (1H, m)

MC (FAB): 641 (M++ 1)

(Example 109)

Using 260 mg of (Z) -[4,4-debtor-1-[4-(1-afterburner)amino]benzoyl-2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene] acetic acid and 0,112 ml 4-dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which was then led from a mixture of ethanol-diethyl ether to obtain 180 mg of the hydrochloride of (Z)-N-4'-[[4, 4-debtor-5-[[(4-dimethylaminopyridine)-carbonyl] methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]-carbonyl] phenylnaphthalene-1-carboxamide.

Melting point 196-201oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,36-1,81 (total 2H), 2,10 (2H, m) 2,44 (2H, m), 2,68 (1H, m), 2,71 (6H, s), 3.04 from-3,22 (total 2H), 3,44 (1H, m), 4,07 (1H, s), of 4.54 (1H, m), 4,89 (1H, m), 6,83 (1H, s), to 6.88 (1H, m), 7,13 (2H, m), 7,22 (1H, t), 7,33 (1H, t), 7,50-7,76 (total 7H), 8,00-8,16 (total 3H), is 10.68 (1H, s), of 10.76 (1H, m)

MC (FAB): 623 (M++ 1)

(Example 110)

Using 300 mg of (Z)-[4,4-debtor-1-[4-(1 - methylpyrrole) amines benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene]-acetic acid hydrochloride, which then led from a mixture of ethanol-diethyl ether to obtain 233 mg of the hydrochloride of (Z)- N-[4-[[4,4-debtor-5-[[(4-dimethylaminopyridine)carbonyl] methylidene - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]phenyl-1-methylpyrrole-2-carboxamide.

Melting point 195-198oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,80 (total 2H), 2,42 (2H, m) to 2.67 (1H, m), of 2.72 (6H, s), 2,96-3,23 (total 2H), 3,43 (1H, m), 3,83 (3H, s) 4,06 (1H, m), a 4.53 (1H, m), to 4.87 (1H, m), 6,07 (1H, t), 6,79 (1H, s), 6,83 (1H, m), of 7.00 (2H, d), 7,06 (2H, m), 7,18 (1H, t), 7,30 (1H, t), 7,51 (1H, d), 7,55 (2H, m), 9,82 (1H, s), 10,42 (1H, m)

MC (FAB): 576 (M++ 1)

(Example 111)

Using 300 mg of (Z)-[4,4-debtor-1-[4-2-(3 - methyl-2-thienyl)amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene] acetic acid and 0.137 ml 4-dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which was then led from a mixture of ethanol-diethyl ether to obtain 237 mg hydrochloride (Z)- [4-[[4,4-debtor-5-[[(4-dimethylaminopyridine)-carbonyl] methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] phenyl] -3-methylthiophene-2-carboxamide in the form of colorless amorphous solid.

1H-NMR( M. D. in DMSO-d6, internal standard TMS): 1,38-1,79 (total 2H), 2,10 (2H, m), is 2.40 (3H, s), 2,42 (19 (1H, t), 7,31 (1H, t), 7,53 (3H, m), 7,66 (1H, d), 10,07 (1H, s), 10,81 (1H, m)

MC (FAB): 593 (M++ 1)

(Example 112)

Using 250 mg of methyl (Z)-[4,4-debtor-1-[4- (3-methyl-2-thienyl]amino] benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetate and 175 mg of methylaminopropane, was collected during the reaction, the crystals were washed with water and dichloromethane to obtain 113 mg of the hydrochloride (Z)-N-[4-[[4,4-debtor-5-(N - methylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]phenyl]-3-methylthiophene-2-carboxamide.

Melting point 277-279oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): is 2.37 (1H, m), the 2.46 (3H, s) to 2.66 (3H, d), a 2.75 (1H, m), of 3.07 (1H, m), 4,89 (1H, m), 6.48 in (1H, s) 6,76 (1H, m), 7,01 (1H, d), 7,05-7,20 (total 3H), 7,27 (1H, t), 7,34 (1H, d), to 7.50 (2H, d), 7,66 (1H, d), 8,24 (1H, s), 10,00 (1H, s)

MC (FAB): 496 (M++ 1)

(Example 113)

Using 320 mg of (Z)-[4,4-debtor-1-[4-(3-methyl-2-furyl)-amino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 0,188 ml 4 - dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which is then recrystallized ethanol to obtain 176 mg of the hydrochloride of (Z) -N-[4-[[4,4-debtor-5-[[(4-dimethylaminopyridine) the carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-phenyl]-C-mate the internal standard TMS); 1,42-1,82 (total 2H), 2,10 (2H, m), 2,42 (2H, m) to 2.67 (1H, m), 2,70 (3H, d), 2,98-3,30 (total 2H), 3,44 (1H, m) 4,06 (1H, m), a 4.53 (1H, m), to 4.87 (1H, m), to 6.58 (1H, d), 6,79 (1H, s), at 6.84 (1H, m), 7,07 (2H, m), to 7.18 (1H, t), 7,28 (1H, t), 7,52 (2H, d), at 7.55 (2H, d), 7,78 (1H, d), 10,13 (1H, s) 11,00 (1H, m)

MC (FAB): 577 (M++ 1)

(Example 114)

Using 300 mg of (Z)- [4,4-debtor-1-[4-(2,3 - dimethoxy-benzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid, 0,158 ml 4 - dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which was then led from a mixture of isopropanol-diisopropyl ether to obtain 252 mg of the hydrochloride of (Z)-4'-[[4,4-debtor-5-[[(4 - dimethylaminopyridine)the carbonyl] methylene] -2,3,4,5-tetrahydro-1H - 1-benzazepin-1-yl] carbonyl] -2,3-dimethoxyphenylethylamine in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS); of 1.40 and 1.80 (total 2H), 2,09 (2H, m), 2,42 (2H, m) to 2.67 (1H, m), 2,71 (3H, s), 2,73 (3H, s), 3,06-3,22 (total 2H), 3,44 (1H, m), 3,76 (3H, s), of 3.84 (3H, s) 4,06 (1H, m), a 4.53 (1H, m), to 4.87 (1H, m), for 6.81 (1H, s), 6,85 (1H, m),? 7.04 baby mortality-7.23 percent (total m), 7,31 (1H, t), 7,51-7,60 (total 3H), 10,33 (1H, s), 10,48 (1H, m)

MC (FAB): 633 (M++ 1)

(Example 115)

Using 280 mg of (Z)-[4,4-DPTR-1-[4-(2,3-dimethoxy benzoyl)amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene]acetic acid and 181 mg was methylimidazole from ethanol to obtain 215 mg of (Z)-4'-[[4,4-debtor-5-(N-methylcarbamoylmethyl)-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2,3 - dimethoxybenzamide.

Melting point 242-243oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): a 2.36 (1H, m) to 2.66 (3H, d), 3,06 (1H, m), 3,76 (3H, s), of 3.84 (3H, s), the 4.90 (1H, m), 6,50 (1H, s), 6,78 (1H, m), 7.03 is-7,21 (total 6H), 7,27 (1H, t), 7,35 (1H, d), 7,54 (2H, d), of 8.25 (1H, m), 10,30 (1H, s)

MS (FAB): 536 (M++ 1)

(Example 116)

Using 250 mg of (Z)- [4,4-debtor-1-[4-(2,6-dimethoxy-benzoyl)amino] benzoyl - 2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 0,131 ml 4-dimethylaminopyridine, repeated the procedure similar to that described in example 11, and received hydrochloride. It was then led from a mixture of ethanol-diisopropyl ether to obtain 181 mg of the hydrochloride of (Z)-4' -[[4,4-debtor-5-[[(4-dimethylaminopyridine)-carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] -carbonyl]- 2,6-dimethoxyphenylethylamine in the form of colorless amorphous solid.

1H-NMR ( memorial plaques in DNA-d6, internal standard TMS): 1,40-1,80 (total 2H), 2,10 (2H, m), 2,43 (2H, m), 2,68 (1H, m), 2,70 (3H, s), a 2.71 (3H, s), 2.95 and is 3.23 (total 2H), of 3.45 (1H,m), of 3.73 (6H, s), of 4.05 (1H, m), a 4.53 (1H, m), to 4.87 (1H, m), of 6.71 (2H, d), to 6.80 (1H, s), at 6.84 (1H, m), 7,06 (1H, m), 7,21 (1H, m), of 7.36-7,38 (total 2H), 7,53 (3H, m), 10,31 (1H,c), 10,83 (1H, m)

MC (FAB): 633 (M++ 1)

(Example 117)

Using 280 mg of (Z) -[4,4-debtor-1-[4-(1-vinylcyclopentane] amino] benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin the least 11, and obtained the hydrochloride, which was led from a mixture of ethanol-diethyl ether to obtain 280 mg of the hydrochloride of (Z)-N-[4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine) carbonyl] methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] phenyl-1-phenylcyclohexanecarboxylic.

Melting point 210oC or higher

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,74 (total 6H), of 1.88 (2H, m), is 2.09 (2H, m), 2,39 (1H, m), 2,59 (2H, m) to 2.66 (1H, m), 2,70 (1H, s), 2,99-3,23 (total 2H), 3,42 (1H, m), was 4.02 (1H, m) to 4.52 (1H, m), a 4.83 (1H, m), 6,74 (1H, s), 6,79 (1H, m), 7,00 (2H, m), 7,12-7,46 (total 9H), 7,49 (1H, d), a 9.25 (1H, s), of 10.76 (1H, m)

MS (FAB): 641 (M++ 1)

(Example 118)

Using 318 mg (Z)-[4,4-debtor-1-[4-(1 - vinylcyclopentane] amino]benzoyl-2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene] acetic acid and 202 mg of methylaminopropane, repeated the procedure similar to that described in example 11, and the resulting product was led from a mixture of ethanol-diethyl ether to obtain 145 mg of (Z)-N-[4- [[4,4-debtor-5-(N-methylcarbamoylmethyl) -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl] phenyl-1-phenylcyclohexanecarboxylic.

Melting point 228-230oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS); 1,50-1,70 (total 411), 1,89 (2H, m), 2,33 (1H, m), of 2.56 (2H, m), 2,65 (3H, d), 2,70+ 1)

(Example 119)

Using 300 mg of (Z)-[4,4-debtor-1-[4-(2 - piperidinoethyl)amino]benzoyl-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 106 mg of 4 - dimethylaminopyridine, repeated the procedure similar to that described in example 11, and has obtained the hydrochloride, which was led from a mixture isopropanolamine ether to obtain 250 mg of the hydrochloride (Z)- [4'-[[4,4-debtor-5-[(4-dimethylaminopyridine)carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl] -3-methylpyrrole-2-carboxamide.

The melting temperature of 175-180oC

1H-NMR: ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,80 (total 8H), 2,12 (2H, m), 2,43 (2H, m), 2,65 (1H, m), 2,69 (6H, W), 2,85-to 3.33 (total 6H), of 3.45 (1H, m), 4,07 (1H, m), a 4.53 (1H, m), 4,88 (1H, m), PC 6.82 (1H, s), 6,85 (1H, m), 7,07-7,20 (total 3H), 7.24 to 7,41 (total 2H), 7,44 to 7.75 (total 5H), of 7.90 (1H, m), 11,10 (1H, m), 11,53 (1H, m)

MS (FAB): 656 (M++ 1)

(Example 120)

Using 240 mg of (Z)-[4,4-debtor-1-[4-[2-(2,6- dimethylpyrrole-1-yl]benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] acetic acid and 128 mg of Isopropylamine, repeated the procedure similar to that described in example 11, and received 184 mg of (Z) -4'-[[4,4-debtor-5-(N-isopropylcarbamate)carbonylmethyl-2, 3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2- (2,5-dimethylpyrrole-1-yl]benzanilide.

Data elements the 65,73 4,74 8,42 7,73

1H-NMR ( M. D. in CDCl3, internal standard TMS): 1,24 (6H, d ), of 1.95 (6H, s), 2,23-2,72 (total 2H), and 3.31 (1H, m), is 4.21 (1H, m), a 4.83 (1H, m), free 5.01 (1H, m), USD 5.76 (1H, m), between 6.08 (2H, s), 6,34 (1H, m), of 6.68 (1H, m), of 6.71 (1H, s),? 7.04 baby mortality-7,19 (total 5H), of 7.23 (1H, t), 7,37( 1H, d), a 7.62 (2H, m), a 8.34 (1H, DD)

MS (FAB): 596 (M++ 1)

(Example 121)

Using 539 mg of (Z)-[4,4-debtor-1-[4-(2-phenylbenzyl)-amino]benzoyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] -acetic acid and 0.3 ml of aqueous ammonia, repeating the reaction of example 11. Fell during the reaction, the crystals were washed with water and diethyl ether and received 493 mg of (Z)-4'- [(5-carbamoylmethyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin - 1-yl] carbonyl]-2-phenylbenzene.

Elemental analysis data (C32H25N3ABOUT3F2memorial plaques in CDCl3, internal standard TMS): is 2.37 (1H, W), of 2.64 (1H, Shir. ), 3,06 (1H, W), to 4.87 (1H, W), 6,46 (1H, s), of 6.75 (1H, d), 7,78 (1H, s), 10,30 (1H, s)

MC (FAB): 538 (M++ 1)

(Example 122)

Using 500 mg of (Z)-[4,4-debtor-1-[4-[2-(2- phenylbenzyl)amino]benzoyl] -2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 126 mg methylaminopropane, repeating the reaction of example 11. Fell during the reaction, the crystals were washed with water and dichloromethane and received 228 mg of (Z)- 4'-[[4,4-debtor-5-(N-methylcarbamoylmethyl)-2,3,4,5-tetrahydro - 1H-1-benzazepine-d6, internal standard TMS): is 2.37 (1H, m) to 2.66 (3H, d), of 2.72 (1H, m), 3,06 (1H, m), to 4.87 (1H, m), USD 5.76 (1H, s), 6,47 (1H, s), 6.75 in (1 H, m), 7,02 (2H, m), 7,14 (1H, t), 7.23 percent-7,60 (total 13H), by 8.22 (1H, m), 10,29 (1H, s)< / BR>
MS m/z( FAB): 552 (M++ 1)

(Example 123)

Using 500 mg of (Z) -[4,4-debtor-1-[4-(2-phenylbenzyl)-amino]benzoyl] -2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] -acetic acid and 151 mg of ethylenedichloride, repeating the reaction of example 11. The connection was led from ethanol and received 421 mg of (Z)-4'-[[5-(N-ethylcarbodiimide) -4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-phenylbenzene.

Melting point 264-266oC

Elemental analysis data (C34H29N3O3F2memorial plaques in DMSO-d6, internal standard TMS): of 1.06 (3H, t). of 2.35 (1H, m) to 2.67 (1H, m) and 3.15 (1H, m), 4,88 (1H, m), 6,47 (1H, s), 6,74 (1H, m), 7,02 (2H, m), 7,14 (1H, t), 7.24 to 7,58 (total 13H), of 8.27 (1H, m), 10,28 (1H, s)

MS m/z (FAB): 566 (M++ 1)

(Example 124)

Using 500 mg of (Z)-[4,4-debtor-1-[4-(2 - phenylbenzyl)-amino]benzoyl] -2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] -acetic acid and 110 mg Propylamine, repeating the reaction of example 11. The connection was led from a mixture of chloroform-hexane and received 400 mg of (Z)- 4'-[[4,4-debtor-5-(N-profilerenumeration)-2,3,4,5 - tetrahydro-1H-1-bend. in DMSO-d6, internal standard TMS): of 0.87 (3H, t), of 1.42 (2H, m), a 2.36 (1H, m) to 2.67 (1H, m) to 3.09 (3H, m), 4,88 (1H, m), 6.48 in (1H, s), 6,74 (1H, m), 7,02 (2H, m), 7,14 (1H, t), 7,25-to 7.59 (total 13H), 8,29 (1H, m), 10,29 (1H, s)< / BR>
MC m/z (FAB): 580 (M++ 1)

(Example 125)

Using 400 mg of (Z)-[4,4-debtor-1-[4-(2 - phenylbenzyl)-amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene]- uksusnoi acid and 66 mg of Isopropylamine, repeating the reaction of example 11. The connection was led from a mixture of chloroform-diethyl ether and received 374 mg of (Z)-4'-[[4,4-debtor-5-(N-isopropylaminomethyl) -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl] -2-phenylbenzene.

Melting point 236-238oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): a 1.11 (6H, d), a 2.36 (1H, m) of 2.64 (1H, m), of 3.94 (1H, m), 4,88 (1H, m), 6,46 (1H, s), 6,74 (1H, m), 7,02 (2H, m), 7,13 (1H, t), 7.24 to 7,40 (total 8H), 7,42-7,58 (total 4H), to 8.12 (1H, d), 10,28 (1H, s)< / BR>
MS m/z (FAB): 580 (M++ 1)

(Example 126)

Using 539 mg of (Z)-[4,4-debtor-1-[4-(2-phenylbenzyl)-amino]benzoyl-2,3, 4,5-tetrahydro-1H-1-benzazepin-5-ilidene] -acetic acid and 0.08 ml of cyclopropylamine, repeating the reaction of example 11. The crystals precipitated during the reaction in the precipitate, washed with water and dichloromethane and received 456 mg of (Z)-4'-[[5-(N - cyclopropylamino)methylene] -4,4-debtor-2,3,4,5-teenie elemental analysis (C35H29N3O3H2< / BR>
C% H% N% F%

calc.: 72,78 5,06 7,27 6,58

found: 72,51 5,33 7,33 6,39

1H-NMR ( M. D. in CDCl3, internal standard TMS): 0,46 (2H, m) of 0.65 (2H, m), 2,34 (1H, W), totaling 3.04 (1H, W), to 4.87 (1H, W), of 6.45 (1H, s), of 6.73 (1H, d), 7,10 (1H, d), 8,35 (1H, d), 10,29 ( 1H, s)

MS m/z (FAB): 578 (M++ 1)

(Example 127)

Using 539 mg of (Z)-[4,4-debtor-1-[4-(2 - phenylbenzyl)-amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] -acetic acid and 0.13 ml of benzylamine, repeating the reaction of example 11. The crystals precipitated during the reaction in the precipitate, washed with water and dichloromethane and received 506 mg of (Z)-4'- [[4,4-debtor-5-[(N-benzylcarbamoyl)methylene] -2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene.

Melting point 189-192oC

Elemental analysis data (C39H31N3O3H2memorial plaques in CDCl3,internal standard TMS) of 2.38 (1H, W), to 2.67 (1H, W), 3,05 (1H, W), 4,37 (2H, d), 4,88 (1H, W), to 6.57 (1H, W), of 6.73 (1H, d), 7,02 (2H, d), 7,14 (1H, t), 8,82 (1H, t), 10,28 (1H, s)

MC m/z (FAB): 628 (M-+ 1)

(Example 128)

Using 400 mg of (Z)-[4,4-debtor-1-[4-(2 - phenylbenzyl)-amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene]-acetic acid and 148 mg of cyclohexylamine, repeating the reaction of example 11. The connection K1 - benzazepin-1-yl] carbonyl]-2-phenylbenzene.

Melting point 262 to 264oC

Elemental analysis data (C38H35N3O3F2)

C% H% N% F%

calc.: to 73.65 5,69 6,78 6,13

found: 73,50 5,72 6,75 6,01

1H-NMR ( M. D. in CDCl3, internal standard TMS): 1,07-1,60 (total 6H), at 1.73 (2H, m), 2,94-3,60 (total 5H), is 4.85 (1H, m), 6,76 (1H, s), to 6.80 (1H, m), 7,01 (2H, m), 7,17 (1H, t), 7.24 to 7,58 (total 13H), 10,31 (1H, s)

MC (FAB): 619 (M++ 1)

(Example 129)

Using 500 mg of (Z)-[4,4-debtor-1-[4-(2-phenylbenzyl)- amino]benzoyl-2,3,4,5-etrahydro-1H-1-benzazepin-5-ilidene]- acetic acid and 151 mg of dimethylaminohydrolase, repeating the reaction of example 11. The connection was led from a mixture of ethanol-diethyl ether and received 411 mg of (Z)-4'-[[5- (N, N-dimethylcarbamoyl)-4,4-debtor-2,3,4,5-tetrahydro - 1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene.

Melting point 202-203oC

Elemental analysis data (C34H29N3O3F2< / BR>
C% H% N% F%

calc.: 72,20 5,17 7,43 6,72

found: 72,18 5,17 7,47 6,63

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2,25-and 2.79 (total 2H), 3,06 (3H, s) to 3.09 (3H, s), up 3.22 (1H, m), 4,96 (1H, m), of 6.31 (1H, s), 6,66 (1H, m), 6,83-6,95 (obsh. 3H), 7,02-7,11 (total 3H), of 7.23 (1H, t), 7,32-7,50 (total 8H), 7,56 (1H, t), to 7.84 (1H, d)

MC m/z( FAB): 566 (M++ 1)

(Example 130)

Islami and 136 mg of diethylamine, repeating the reaction of example 11. Obtained when this connection has led 113 diethyl ether and received 412 mg of (Z)-4'- 5-(N,N-diethylcarbamoyl)-4,4-debtor-2,3,4,5-tetrahydro - 1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene.

Melting point 175-176oC

1H-NMR ( M. D. in CDCl3, internal standard TMS): of 1.18 (3H, t), of 1.20 (3H, t), 2,27 - 2,80 (total 2H),3,23 (1H, m), of 3.46 (4H, m), to 4.98 (1H, m), 6,33 (1H, s), equal to 6.05 (1H, m), 6,93 (3H, m), 6,98-7,02 (total 3H), 7,22 (1H, t), 7,32-of 7.48 (total 8H), 7,55 (1H, t), 7,83 (1H, d)

MS m/z (FAB): 594 (M++ 1)

(Example 131)

Using 400 mg of (Z)-[4,4-debtor-1-[4-(2 - phenylbenzyl)-amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene]-acetic acid and 79 mg of pyrrolidine, repeating the reaction of example 11. The connection was led from a mixture of dichloromethane-diethyl ether-hexane and received 292 mg of (Z) -4'-[[4,4-debtor-5-[(1-pyrrolidinylcarbonyl)-methylene)- 2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] -2-phenylbenzene in the form of colorless amorphous solid.

Melting point 132-136oC

1H-NMR ( M. D. in CDCl3, internal standard TMS); 1,60-2,03 (total 4H), 2,25-2,80 (total 2H), 3,20 (1H, m), 3,43 - 3,60 (total 4H), 4,99 (1H, m), of 6.31 (1N, C) of 6.65 (1H, m), 6,93 (3H, m), 6,98-7,12 (total 3H), 7,22 (1H, t), 7,31-7,47 (total 8H), 7,52 (1H, t), to 7.84 (1H, e)

MC m/z (FAB): the DRO-1H-1 - benzazepin-5-ilidene]-acetic acid and 127 mg of piperidine, repeating the reaction of example 11. The connection was led from a mixture of chloroform-diethyl ether-hexane and the resulting received 288 mg of (Z)-4'-[[4,4-debtor-5 - piperidinecarbonitrile-2,3,4,5-tetrahydro-1H-1-benzazepin-1 - yl]carbonyl]-2-phenylbenzene in the form of colorless amorphous solid.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1,40-1,60 (total 6H), at 1.73 (2H, m), 2,94-3,60 (total 5H), is 4.85 (1H, m), 6,76 (1H, s), to 6.80 (1H, m), 7,01 (2H, m), 7,17 (1H, t), 7.24 to 7,60 (total 13H), 10,31 (1H, c)

MS m/z( FAB): 605 (M++ 1)

(Example 133)

Using 400 mg of (Z)-[4,4-debtor-1-[4-(2 - phenylbenzyl)-amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene]-acetic acid and 97 mg of the research, repeating the reaction of example 11. The connection was led from a mixture of isopropanol-diethyl ether, and received 324 mg of (Z)-4'-[(4,4 - debtor-5-morpholinosydnonimine-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl]-2-phenylbenzene.

The melting point of 161 to 165oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS); is 2.40 (2H, m), of 3.07 (1H, m), 3,42-3,60 (total 8H), 4,84 (1H, m), 6,76 (1H, s), to 6.80 (1H, m), 7,01 (2H, m), 7,18 (1H, t), 7,27-7,60 (total 13H), 10,32 (1H, s)

MC m/z (FAB): 608 (M++ 1)

(Example 134)

Using 500 mg of (Z)-[4,4-debtor-1-[4-(2 - phenylbenzyl)-aminer 11. The crystals precipitated during the reaction, precipitates were filtered and washed with water and dichloromethane to obtain 420 mg of (Z)-4'-[[5-(N-(2-hydroxyethyl)-carbamoylmethyl]-4,4 - debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2 - phenylbenzene.

Melting point 262-265oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): a 2.36 (1H, m), 2,68 (1H, m), 3.04 from (1H, m), up 3.22 (2H, m), of 3.45 (2H, m), 4,71 (1H, m), 4,88 (1H, m), 6,47 (1H, s), 6,74 (1H, m), 7,02 (2H, m), 7,16 (1H, t), 7,21-7,60 (total 13H), 8,35 (1H, t), 10,30 (1H, s)

MC m/z (FAB): 682 (M++ 1)

(Example 135)

Using 500 mg of (Z)-[4,4-debtor-1-[4-(2-phenylbenzyl)- amino]benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] - acetic acid and 140 mg of 2-methoxyethylamine, repeating the reaction of example 11. The connection was led from ethanol and obtained 420 mg of (Z)-4'-[[4,4-debtor-5-[N-(2 - methoxyethyl)carbamoylmethyl] -2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl]carbonyl]-2-phenylbenzene.

The melting point of 230-231oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): is 2.37 (1H, m), 2,69 (1H, m), of 5.03 (1H, m), 3,26 (3H, s), or 3.28 (2H, m) to 3.38 (2H, m), 4,89 (1H, m), 6.48 in (1H, s), 6,74 (1H, m), 7,02 (1H, m), 7,13 (1H, t), 7,26-to 7.59 (total 13H), 8,46 (1H, t), 10,28 (1H, s)

MC m/z (FAB): 595 (M++ 1)

(Example 136)

Using 506 mg (Z)-[1-[4-(2-ethoxybenzoyl)amine is the reaction of example 11. Received this product has led from a mixture of ethyl acetate-diethyl ether and received 100 mg of (Z)-4'-[(5 - carbamoylmethyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1 - yl] carbonyl] -2-ethoxybenzonitrile in the form of colorless amorphous solid.

Elemental analysis data (C28H25N3O4F20.5 H2O)

C% H% N% F%

calc.: 65,36 5,09 8,17 7,38

found: 65,24 5,13 8,12 7,22

1H-NMR ( M. D. in CDCl3, internal standard TMS): to 1.61 (3H, t), 2.4 to 2.8 (total 2H), 3,54 (1H, m) to 4.23 (2H, d), a 4.86 (1H, d), to 5.66 (1H, s), 6,14 (1H, s), 6.35mm (1H, s), 6,72 (1H, d), 6,94 (1H, d), 7,0-7,3 (total 5H), 7,38 (1H, d), 7,4-7,5 (total 3H), 8,24 (1H, d), 10,16 (1H, s)

MS m/z (FAB): 506 (M++ 1)

(Example 137)

Using 506 mg (Z)-[1-[4-(2-ethoxybenzoyl)amino]-benzoyl-4,4-debtor-2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene] acetic acid and 135 mg methylnoradrenaline, repeating the reaction of example 11. Received this product has led from a mixture of ethyl acetate-diethyl ether and received 360 mg of (Z)-4'-[[4,4-debtor-5-(N - methylcarbamoylmethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl]-2-ethoxy-benzanilide.

Melting point 213-215oC

Elemental analysis data (C29H27N3O4F2)

C% H% N% F%

calc.: 67,04 5,24 of 9.09 7,31

The 1H, m) to 3.34 (1H, m), 3,44 (2H, HF), to 4.17 (2H, q), 4,88 (1H, m), 6,36 (2H, m), of 6.68 (1H, d), to 6.67 (1H, d), of 7.0, and 7.1 (total 4H), of 7.23 (1H, t), 7,4 - 7,5 (total 4H), by 8.22 (1H, d), 10,14 (1H, s)

MS m/z (FAB): 534 (M++ 1)

(Example 139)

Using 506 mg (Z)-[1-[4-(2- ethoxybenzoyl)amino]-benzoyl-4,4-debtor-2,3,4,5-tetrahydro - 1H-1-benzazepin-5-ilidene] acetic acid and 0.10 ml of Propylamine, repeating the reaction of example 11. Received this product has led from a mixture of ethyl acetate-diethyl ether and was obtained 430 mg of (Z)-4'- [[4,4-debtor-5-(N-profilerenumeration)-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-ethoxybenzonitrile.

Melting point 214-216oC

Elemental analysis data (C31H31N3ABOUT4F2memorial plaques in CDCl3, internal standard TMS): and 0.98 (3H, t), 1.6 to 1.7 (total 5H), is 2.40 (1H, m) to 2.66 (1H, m), 3,3 - 3,4 (total 3H, m), 4,18 (2H, HF), 4,88 (1H, m), 6,36 (2H, W), of 6.68 (1H, d), 6.89 in (1H, d), of 7.0, and 7.1 (total 4H), of 7.23 (1H, t), 7,4-7,5 (total 4H), by 8.22 (1H, d), 10,15 (1H, s)

MC m/z (FAB): 548 (M++ 1)

(Example 140)

Using 506 mg (Z)-[1-[4-(2-ethoxybenzoyl) amino]-benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5 - ilidene] acetic acid and 0.10 ml of Isopropylamine, repeating the reaction of example 11. Received this product has led from a mixture of ethyl acetate-diethyl ether and received 450 mg of (Z)-4'- [[4,4-debtor-5-(N-isopropylcarbamate 230oC or higher

Elemental analysis data (C31H31N3ABOUT4F2memorial plaques in CDCl3, internal standard TMS): a 1.25 (6H, t) to 1.60 (3H, t), to 2.57 (1H, m) to 2.67 (1H, m) to 3.33 (1H, m), 4,18 (2H, HF), 4,25 (1H, m), 4,88 (1 H, d), 6,11 (1H, m), 6.35mm (1H, s), to 6.67 (1H, d), 6.89 in (1H, d), of 7.0, and 7.1 (total 4H), of 7.23 (1H, t), 7,4-7,5 (total 4H), by 8.22 (1H, d), 10,14 (1H, s)

MS m/z (FAB): 548 (M++ 1)

(Example 141)

Using 506 mg (Z)-[1-[4-(2-ethoxybenzoyl)amino]-benzoyl-4,4-debtor-2, 3,4,5-tetrahydro-1H-1-benzazepin - 5-ilidene] acetic acid and 0.08 ml of cyclopropylamine, repeating the reaction of example 11. Received this product has led from a mixture of ethyl acetate-diethyl ether and received 440 mg of (Z)-4'-[[5-(N-cyclopropanecarbonitrile) -4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl] -2-ethoxybenzonitrile.

Melting point 230oC or higher

Elemental analysis data (C31H29N3O4F2memorial plaques in CDCl3, internal standard TMS): 0,6-0,7 (total 2H), 0,8-0,9 (total 2H), 1,59 (3H, t), of 2.38 (1H, d), 2,68 (1H, d), 2,85 (1H, m), or 3.28 (1H, d), 4,14 (1H, HF), to 4.87 (1H, d), 6,33 (1H, s), and 6.6 and 6.7 (2H, m), 6,83 (1H, d), 7,07, (total 4H), 7,22 (1H, t), 7.3 to 7.4 (total 4H), to 8.20 (1H, d), 10,13 (1H, s)

MS m/z (FAB): 546 (M++ 1)

(Example 142)

Using 506 mg (Z)-[1-[4-(2-ethoxybenzoyl)amino-benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] who was stylizowane from a mixture of ethyl acetate-diethyl ether and received 450 mg of (Z)-4'-[[5- (N, N-dimethylcarbamoyl)-4,4-debtor-2,3,4, 5-tetrahydro - 1H-1-benzazepin-1-yl]-carbonyl]-2-ethoxybenzonitrile.

Melting point 195-198oC

Elemental analysis data (C30H29N3O4F2memorial plaques in CDCl3, internal standard TMS): to 1.61 (3H, t), 2,3-2,8 (total 2H), 3.04 from (3H, s) to 3.09 (3H, s), or 3.28 (1H, m), 4.26 deaths (2H, HF), 5,04 (1H, m), 6,34 (1H, s), 6,72 (1H, d), of 6.99 (1H, d), 7,1-7,5 (total 9H), to 8.25 (1H, d), 10,18 (1H, s)< / BR>
MC m/z (FAB): 534 (M++ 1)

(Example 143)

Using 506 kg (Z)-[1-[4-(2- ethoxybenzoyl)amino]-benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1 - benzazepin-5-ilidene] acetic acid and 0.13 ml of diethylamine, repeating the reaction of example 11. Received this product has led from a mixture of ethyl acetate-diethyl ether and received 410 mg of (Z)-4'-[[5-(N, N-diethylcarbamoyl)-4,4-debtor - 2,3,4,5-tetrahydro-1H-1-besaran-1-yl]carbonyl] -2 - ethoxybenzonitrile.

Melting point 164-165oC

Elemental analysis data (C32H33N3O4F2memorial plaques in CDCI3, internal standard TMS): to 1.21 (6H, t) to 1.60 (3H, t), 2.4 to 2.8 (total 2H), 3,30 (1H, m) to 3.67 (4H, HF), 4.26 deaths (2H, q), of 5.05 (1H, m), 6,38 (1H, c), of 6.71 (1H, d), 6,98 (1H, d),7,0-7,3 (total 5H), was 7.36 (1H, t), of 7.4-7.5 (a total 3H), 8,24 (1H, d), 10,17 (1H, s)

MC m/z (FAB): 562 (M++ 1)

(Example 144)

Using 506 mg (Z)-[1-[4-(2-ethoxybenzoyl)AMI is the Ktsia of example 11. Received this product has led from a mixture of ethyl acetate-diethyl ether and received 470 mg of (Z)-4'-[(4,4 - debtor-5-morpholinosydnonimine-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl]-2-ethoxybenzonitrile.

Melting point 144-147oC

1H-NMR ( M. D. in CDCI3, internal standard TMS): to 1.61 (3H, t), 2,4,2,8 (total 2H), 3,30 (1H, m) to 3.58 (2H, m), 3,74 (6H, m), 4.26 deaths (2H, q), of 5.05 (1H, m), 6,33 (1H, s), 6,74 (1H, d), of 6.99 (1H, d), and 7.1 and 7.6 (total 9H), to 8.25 (1H, d), 10,17 (1H, s)

MC m/z (FAB): 576 (M++ 1)

(Example 145)

Using 400 mg (Z)-[1-[4-(2-ethoxybenzoyl)amino] - benzoyl-4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ilidene] acetic acid and 163 mg thiomorpholine, repeating the reaction of example 11. The product was led from isopropanol and received 198 mg of (Z)-4'-[(4,4-debtor-5-dimorpholinyldiethyl - 2,3,4,5-tetrahydro-1H-1-benzazepin-1-1-yl)carbonyl]-2-ethoxybenzonitrile.

1H-NMR ( M. D. in CDCl3, internal standard TMS): to 1.61 (3H, t), 2,27-2,86 (total 6H), 3,26 (1H, m), 3,70-4,14 (total 4H), 4.26 deaths (2H, HF), 5,02 (1H, m), 6,33 (1H, s), 6,74 (1H, m), of 6.99 (1H, t), 7,07-7,29 (total 6H), was 7.36 (1H, m), 7,53 (3H, m), 8,24 (1H, m), 10,17 (1H, s)

MS m/z (FAB): 592 (M++ 1)

The following shows the structure of the compounds obtained in reference examples 6 to 10 and examples (cf. tables 2 and 3),

In addition to the compounds visualcalc these compounds can be synthesized by the processes and methods of synthesis, described above in the methods of preparation and examples, and modifications known to experts in the art, the particular experiments are not required.

Approximately 300 ml of distilled water for injection containing 0.75 g of the compound of the present invention and 0.1 g of lactic acid, was mixed with about 500 ml of distilled water for injection containing 100 g of lactose (or 26 g of glycerol), and the mixture was stirred. The contents of the resulting mixture was dissolved by heating the mixture at 60oC. After cooling the mixture to room temperature, the total solution volume was brought to 1000 ml of thus Obtained solution was filtered through a membrane filter, poured into capsules in portions of 2 ml and sapaw ampoules were sterilized, resulting in received injectable solution in each vial containing 1.5 mg of the compound of the present invention.

"The manufacture of tablets by weight of 5 mg

The compound of the present invention (25 mg) was mixed with 366 g of lactose and the mixture is crushed into powder using a mill, Sample Mill (production F. "Hosokawa Mirkon". After uniform mixing 391 g of crushed mixture of 91.5 g of corn starch in a car with a fluidized bed granulating and coating (production F. the modeling. After drying, obtained in the manner described granules were passed through a sieve of 24 mesh, was mixed with 2.5 g of magnesium stearate and then made them tablets (each weighing 1000 mg) on a rotary tabletting machine (manufactured by F. "Hata Takkosho") system Panametrics 6.5 mm diameter x 7.8 R. device for coating (production F. Freuhd Sangyo")) on the obtained tablets were sprayed 154 g of an aqueous solution for coating containing 12.5 g of hydroxypropylcellulose, 2.5 g of polyethylene glycol 6000, 3.5 g of talc and 1.5 g of titanium oxide, and as a result received film-coated tablets, each of which had a coating weight of 4 mg and contained 5.0 mg of the compound of the present invention.

1. Derived benzazepine represented by the General formula I, or its pharmaceutically acceptable salt

< / BR>
where one of R1and R2denotes the hydrogen atom and the other represents a group represented by the formula

< / BR>
where A1and A2may be the same or different from each other and each represents a single bond or lower alkylenes group;

m = 0 or 1,

B denotes a group represented by the formula

< / BR>
< / BR>
or

< / BR>
(the nitrogen atoms in these formulas can be oxidized is I B, may be the same or different optional),

R8denotes a hydrogen atom, a lower alkyl group; cycloalkyl group, hydroxyl group, lower alkoxygroup, carboxyl group, lower alkoxycarbonyl group, cyano, phenyl or naftalina group, nitrogen-containing aromatic five - or six-membered heterocyclic group which is selected from peredelnoj and pyrrolidino groups and which may be substituted by a lower alkyl group or amino group which may be substituted by a lower alkyl group; nitrogen-containing saturated five-semicolony heterocyclic group which is selected from pyrrolidinyl, piperidino, azabicyclo[2,2,1] octiles groups, which may be substituted by a lower alkyl group on the nitrogen atom in the ring, or a group represented by the formula

< / BR>
in which the nitrogen atom may be oxidized;

S and t may be the same or different from each other and each is an integer from 1 to 3 (provided that the sum of s and t is an integer from 3 to 5);

u is an integer from 2 to 7;

A3, A4, A5may be the same or different from each other and each represents a single bond, lower the PTA or an oxygen atom, then A3or A5represents the lower alkylenes group;

R9represents a hydrogen atom or a lower alkyl group;

q and r can be the same or different from each other and each is an integer from 1 to 3, provided that the sum of q and r is an integer from 3 to 5;

x represents a group-O - or-S(O)w-;

w = 0, 1, or 2;

R3and R4represent a hydrogen atom;

R5and R6represent a hydrogen atom, or R5and R6can be combined in the lower alkylenes group with the formation of a saturated carbon ring with adjacent carbon atoms;

n = 0 or 1;

R7represents a phenyl group which may have 1 to 5 substituents; naftalina group which may be substituted by a lower alkyl group, or an aromatic five - or six-membered heterocyclic group which is selected from thienyl, furillo, pyrrolidino, peredelnoj, imidazolidinone or triazolines groups and which may be substituted by a lower alkyl group, and each of the substituents of the phenyl group, R7chosen from:

a) a lower alkyl group which may be substituted by a halogen atom;

b) low alkoxygroup;

g) a phenyl group which may be substituted by a lower alkyl group, a halogen atom, a lower alkoxygroup;

h) imidazolidine, triazoline, pyrrolidino or peredelnoj groups which may be substituted by one or more lower alkyl groups.

2. Connection on p. 1 or its pharmaceutically acceptable salt, where the group represented by formula

< / BR>
selected from: 1) a single bond; 2) groups of the formula

< / BR>
3) lower alkalinous or 4) groups of the formula

< / BR>
where A1represents the lower alkylenes group, and R8represents a hydrogen atom; a cyano; a lower carboxyl group; lower alkoxycarbonyl group; a lower alkyl group; cycloalkyl group; a hydroxyl group; a lower alkoxygroup, phenyl or naftalina group, nitrogen-containing aromatic five - or six-membered heterocyclic group which is selected from peredelnoj, pyrrolidino group which may be substituted by a lower alkyl group, amino group which may be substituted by a lower alkyl group; nitrogen-containing saturated five-semicolony heterocyclic group which is selected from pyrrolidinyl, piperidylamine; or a group represented by the formula

< / BR>
in which the N atom may be oxidized, where q and r = 1, 2, or 3, and q + r = 3 to 5; X represents O or S(O)w;

w = 0, 1 or 2 and

R7represents a phenyl group which may have 1 to 5 substituents; naftalina group which may be substituted by a lower alkyl group; or an aromatic five - or six-membered heterocyclic group which is selected from thienyl, furillo, pyrrolidino, peredelnoj, imidazolidinone or triazolines groups which may be substituted by a lower alkyl group, and each of the substituents of the phenyl group, R7chosen from:

a) a lower alkyl group which may be substituted by a halogen atom;

b) low alkoxygroup;

c) halogen atom or nitro group;

(e) an amino group which may be substituted by a lower alkyl group;

g) a phenyl group which may be substituted by a lower alkyl group, a halogen atom or a lower alkoxygroup;

h) imidazolidine, triazoline or peredelnoj groups which may be substituted by a lower alkyl group.

3. Connection on p. 2 or its pharmaceutically acceptable salt, where the group represented by formula


< / BR>
in which the N atom may be oxidized, where q and r = 1, 2, or 3, and q + r = 3 to 5; X represents O or S(O)w;

w = 0, 1 or 2 and R7represents a phenyl group which may have 1 to 5 substituents; naftalina group or an aromatic five - or six-membered heterocyclic group which is selected from thienyl, furillo, pyrrolidino, peredelnoj, imidazolidinone or triazolines groups which may be substituted by an alkyl group, and each of the substituents for the phenyl group, R7chosen from:

automa halogen;

(e) an amino group which may be substituted by a lower alkyl group;

g) a phenyl group which may be substituted by a lower alkyl group, lower alkoxygroup;

h) imidazolidine, triazoline or pyrrolidino group.

4. Connection on p. 3 or its pharmaceutically acceptable salt, where, when the group represented by formula

< / BR>
represents: 1) a single bond, then p = 0 and R8represents a cyano, a carboxyl group or a lower alkoxycarbonyl group, or 2)

< / BR>
or 3) lower alkylenes group, then p = 0, 1 or 2 and R8represents a hydrogen atom; a lower alkyl group; a hydroxyl group; a lower alkoxygroup; phenyl group; nitrogen-containing aromatic five - or six-membered heterocyclic group which is selected from peredelnoj group which may be substituted by a lower alkyl group or amino group which may be substituted by a lower alkyl group; nitrogen-containing saturated five-semicolony heterocyclic group which is selected from pyrrolidinyl or piperidino groups which may be substituted by a lower alkyl group on the nitrogen atom in the ring, or a group represented by the formula
8
is

< / BR>
5. Connection on p. 4 or its pharmaceutically acceptable salt, where

1) when the group represented by formula

< / BR>
is a single bond, then

< / BR>
represents (I)-R8A(where R8Arepresents a cyano, a carboxyl group or a lower alkoxycarbonyl group);

2) when the group represented by formula

< / BR>
is

< / BR>
then

< / BR>
is

< / BR>
(where saand ta= 1, 2, or 3; sa+ ta= 3 - 5;

A3arepresents a single bond or lower alkylenes group and

R8brepresents a hydrogen atom, lower alkyl or phenyl group)

< / BR>
(where uaand ub= 4, 5 or 6;

A4aand A4beach represents a single bond, and R8crepresents a hydrogen atom);

< / BR>
(where ucis 4, 5 or 6;

A4cand A5aeach represents a single bond, and

R9aand R8dthe same or different from each other and each represents a lower alkyl group);

< / BR>
(where ud= 1, 4, 5 or 6;

A4drepresents a single bond, and

R8erepresents a hydrogen atom);
single bond or lower alkylenes group and

R8frepresents a hydrogen atom, cycloalkyl group, phenyl group, pyridyloxy group, hydroxyl group, lower alkoxygroup or a lower alkyl group);

< / BR>
(where A5crepresents the lower alkylenes group;

R5drepresents a single bond;

R9cand R9dthe same or different from each other and each represents a hydrogen atom or a lower alkyl group and

R8grepresents a hydrogen atom or a lower alkyl group) or

< / BR>
R8hrefers to a group represented by the formula

< / BR>
(where q and r = 1, 2, or 3, and q + r = 3 to 5;

X represents O or S(O)wand w = 0, 1 or 2),

or 3) when the group represented by formula

< / BR>
is the lowest Allenova group, then

< / BR>
represents a group

< / BR>
(where A1arepresents the lower alkylenes group;

sband tb= 1, 2, or 3; sb+ tb= 3 - 5;

A3arepresents a single bond, and

R8irepresents a hydrogen atom or a lower alkyl group),

< / BR>
(where A1brepresents the lower alkylenes group

ueis 4, 5 or 6;

A4erepresents a single bond, and

R8jpresented the P> and R9erepresent a hydrogen atom or a lower alkyl group and

R5edenotes a single bond).

6. Connection on p. 5 or its pharmaceutically acceptable salt, where R7represents a phenyl group which may be substituted by 1 to 3 substituents, each selected from a lower alkyl group which may be substituted by halogen atom, lower alkoxygroup, halogen atom, phenyl group which may be substituted by a lower alkyl group, imidazolidine, triazoline or pyrrolidino group which may be substituted by a lower alkyl group; naftalina group or thienyl, follow or pyrrolidino group which may be substituted by a lower alkyl group.

7. Connection on p. 6 or its pharmaceutically acceptable salt, where the group represented by formula

< / BR>
does

< / BR>
8. The compound according to any one of paragraphs.1 - 7 or its pharmaceutically acceptable salt, which is a Z-form.

9. Derived under item 1, selected from the group consisting of:

4'-[[4,4-debtor-5-(4-methylpiperazine)carbonylmethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene;

4'-[(4,4-debtor-5-piperazinylcarbonyl-2,3,4,5-teragren-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene;

4'-[[4,4-debtor-5-[(4-methyl-1,4-diazepin-1-yl)carbonylmethyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene;

4'-[[5-[(1,4-diazepin-1-yl)carbonylmethyl] -4,4-debtor-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene;

4'-[[4,4-debtor-5-[[N-methyl-N-(1-methyl-4-piperidyl)carbarnoyl] methylene]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]-carbonyl]-2-phenylbenzene;

4'-[[4,4-debtor-5-[[N-(3-hinokitiol)carbarnoyl] -methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene;

N-[4'-[[4,4-debtor-5-[[(4-dimethylaminopyridine)-carbonyl] methylene] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] phenyl-3-methylthiophene-2-carboxamide;

4'-[[4,4-debtor-5-(N-isopropylaminomethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene;

4'-[[4,4-debtor-5-[N-(2-methoxyethyl)carbamoylmethyl] -2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzene;

4'-[[4,4-debtor-5-(N-isopropylaminomethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-ethoxybenzene;

or their pharmaceutically acceptable salts or isomers.

10. The pharmaceutical composition exhibiting antagonistic activity against Organisatorische, characterized in that it contains the connection is tel.

11. Derived differentation General formula II or its salt

< / BR>
where R3matter specified in paragraph 1;

R10represents a hydrogen atom or a protective group for amino group.

12. Derived (substituted) aminomethyltransferase General formula III or its salt

< / BR>
where R3and R10have specified in the letter of 11 values.

 

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The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof

The invention relates to a new compound N,N-dimethyl-2-[5-(1,2,4-triazole-1-yl methyl)-1H-indol-3-yl] ethylamine sulphate salt (2:1) structural formula I and its pharmaceutically acceptable hydrate

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to a method for indole derivatives of General formula I, where F denotes a straight or branched C1-C4-alkylenes chain; R is a group of formula-CH2-CHR1-NR2R3where R1hydrogen; R2and R3the same and mean C1-C6-alkyl

The invention relates to a condensed heterocyclic compounds or their salts and inhibitors of squalene synthetase containing these compounds as an effective component

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds

The invention relates to 6-oxo-asiminoaei compounds, namely to new derivatives of 6-oxo-3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd] indole with, if necessary, in the 3rd or 4th position of the skeleton of the ring substituted aminoalkyl balance, and their acid salts of accession, and to pharmaceutical preparations containing these compounds, process for the preparation of these compounds and intermediates for their production

The invention relates to methods for new nitrogen-containing compounds of General formula I

Rwhere R1is hydroxy, lower alkanoyloxy, OCOT1Y2where: Y1, Y2is hydrogen, lower alkyl when X = CH2; R2group of the formula

ororor< / BR>
ororwhere n' is 0,1,2,3; n = 2,1,0, where: Y3Y4is hydrogen, lower alkyl, Y5- phenyl-lower alkoxy, hydrogen, lower alkoxy when X is - S R2group

CHY5ororwhere Y3, Y5have the specified values;

R3lowest alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R
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