Derivatives 4,1-benzoxazepine, pharmaceutical composition, method of inhibiting stvalentines in mammals, the method of inhibiting the growth of fungi in mammals

 

(57) Abstract:

Derived 4,1-benzoxazepin-2-it formula I, where R1is hydrogen or lower alkyl, alkene, alkyne, C3- C9-cycloalkyl, possibly substituted by 1 to 5 substituents, such as phenyl, naphthyl, C1-C6-cycloalkyl, furyl, indolin or halogen; R2and R3is hydrogen, lower alkyl, phenyl, possibly substituted by 1 to 3 substituents such as halogen, alkyl, halogen, C1- C4-alkoxy, hydroxy, and two adjacent substituents on the phenyl group may together form a ring or pyridyl; X is a bond or a group -(CH2)m-E-(CHR6)n-, m and n = 0, 1, 2 or 3, E is a bond or an atom of oxygen, sulfur, sulfoxide, sulfon, -NR5-, -NHCO-, -CONR7-, -NHCONH- (other designations, see p. 1 f-crystals of the invention). The compounds of formula I are useful for inhibition of stvalentines and fungus growth. 5 C. and 17 C.p. f-crystals, 90 PL.

The invention relates to a derivative of 4.1-benzoxazepin-2, or their salts, which are useful for inhibiting stvalentines and fungus growth, and to their use.

Hypercholesterolemia, high blood pressure and Smoking are the three main known factors causing ish is ractice or treatment, in addition to coronary disease and coronary sclerosis.

As pharmaceutical compositions for lowering blood cholesterol, attention was drawn to a composition for the control of the biosynthesis of cholesterol along with those that inhibit its absorption by binding bile acids, including, among others, cholesterol, colestipol (described, for example, in U.S. patent 4 027 009) and those that inhibit intestinal absorption of cholesterol by inhibiting acetophenone And cholesterol acyltransferase (AST), including melinamide (described in the French patent N 1 476 569). As pharmaceutical drugs to control cholesterol biosynthesis designed for medical use lovastatin (described in U.S. patent 4 231 938), simvastatin (described in U.S. patent 4 444 784), pravastatin (U.S. patent 4 346 227), and so on, which are able to inhibit especially 3-hydroxy-3-methylglutarylcoenzyme (HMG-CoA) reductase. However, the inhibition of HMG-CoA reductase is inhibited not only the biosynthesis of cholesterol, but also the biosynthesis of some other components, such as ubiquinone, dolichol and heme A, which are necessary for a living organism, so there is a risk of the result of unwanted side effects.

Stvalentines is formalitie reductive dimerization of two molecules of gamesinteractive in the form squalene.

On the other hand, compounds proposed as inhibitors of the biosynthesis of cholesterol in the inhibition stvalentines described in JPA H1 (1989) - 213 288, JPA H2 (1990) - 101 088, JPA H2 (1990) - 235 820, JPA H2 (1990) - 235 821, JPA H3 (1991) - 20 226, JPA H3 (1991) - 68 591, JPA H3 (1991) - 48 288, U.S. patent 5 390 019, Journal of Medicinal Chemistry 51(10), p. 1869 - 1871 (1988), U.S. patent 5 135 935 and WO 9 215 579.

Also, compounds proposed as inhibitors of the growth of fungi in the inhibition stvalentines described in JPA H4 (1992) - 279 589, EP 475 706 - A, EP 494 622 - a and EP 503 520 - A.

Among the derivatives of 4.1-benzoxazepine derivatives 4,1-benzoxazepin-2-it, in which the 2-position is substituted by geography, those in which one of the hydrogen atoms in the 3-position is substituted by another Deputy, described in JPA 557 (1982) - 345 765 and in Chem. Pharm. Bull., 34, 140 (1986).

It is known that ubiquinone, dolichol and hem And synthesized from farnesylpyrophosphate the path of the biosynthesis of cholesterol. Therefore, in order to avoid side effects due to the lack of these substances, it is desirable to inhibit the enzymes after farnesylpyrophosphate, especially stvalentines, by way of the biosynthesis of cholesterol.

After intensive research with the above viewpoint, the present inventors have found that derivatives of 4.1-benzoxazepin-2 of the present invention.

Therefore, the present invention provides:

(1) derivative 4,1-benzoxazepin-2-it General formula I

< / BR>
where R1is a hydrogen atom or optionally substituted hydrocarbon group; R2and R3independently are a hydrogen atom, optionally substituted lower alkyl, optionally substituted phenyl or optionally substituted heterocycle; X is a bond or a spacer having a chain length of 1 to 7 atoms; Y is an optionally esterified or dietaryguidelines carboxyl group, optionally substituted hydroxyl, optionally substituted amino, optionally substituted phenyl, optionally substituted by carbamoyl or N-containing heterocyclic residue having hydrogen atom capable of being deprotonirovannym, provided that when X is methylene and R1not an alkyl having more than 4 carbon atoms, Y is neither carboxyla or alkoxycarbonyl, and the ring may be optionally substituted, or their salts;

(2) derivative 4,1-benzoxazepin-2-it formula I'

< / BR>
where R1is a hydrogen atom or optionally substituted hydrocarbon group; R2and R3Neil, or optionally substituted heterocycle; X is a bond or a spacer with a chain length of 1 to 7 atoms; Y is an optionally esterified or dietaryguidelines carboxyla, optionally substituted hydroxyl, optionally substituted amino, optionally substituted phenyl, optionally substituted by carbamoyl or N-containing heterocyclic residue having hydrogen atom capable of deprotonization, provided that when X is methylene, Y is neither carboxyla or alkoxycarbonyl; and ring A optionally may be substituted, or its salts;

(3) the inhibitor stvalentines, comprising as an active ingredient derived from the 4.1-benzoxazepin-2-it General formula I"

< / BR>
where R1is a hydrogen atom or optionally substituted hydrocarbon group, R2and R3independently are a hydrogen atom, optionally substituted lower alkyl, optionally substituted phenyl or optionally substituted aromatic heterocycle; X is a bond or a spacer having a chain length of 1 to 7 atoms; Y is an optionally esterified or dietaryguidelines carboxyla, optionally substituted gidroksilaminom or N-containing heterocyclic residue, having a hydrogen atom capable of deprotonization; and the ring A can be optionally substituted, or their salts;

(4) the fungus growth inhibitor comprising as an active ingredient derived from the 4.1-benzoxazepin-2-it General formula I"

< / BR>
where R1is a hydrogen atom or optionally substituted hydrocarbon group; R2and R3independently are a hydrogen atom, optionally substituted lower alkyl, optionally substituted phenyl or optionally substituted aromatic heterocycle; X is a bond or a spacer with a chain length of 1 to 7 atoms; Y is an optionally esterified or dietaryguidelines carboxyla, optionally substituted hydroxyl, optionally substituted amino, optionally substituted phenyl, optionally substituted by carbamoyl or N-containing heterocyclic residue having hydrogen atom capable of deprotonization; and the ring A can be optionally substituted, or salts thereof.

Further, the present invention provides a method of obtaining new compounds represented by the General formula I or I', or their salts.

In the above formulae I, I' and I" as uglevodorodnaya groups with aliphatic chain, alicyclic hydrocarbon groups and aryl groups, preferred are hydrocarbon groups with aliphatic chain.

As hydrocarbon groups with aliphatic chain of the specified hydrocarbon groups mentioned hydrocarbon groups with straight or branched aliphatic chain, such as alkali, alkenyl and alkinyl, preferred are lower alkali, the lower alkenyl and lower alkinyl. As the lower alkyl groups are preferred C1-C7lowest alkali, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, neopentyl, tert.pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl and 1-ethylpropyl, preferred are C2-C5-alkali, more preferred are C4-C5-alkili. As the lower alkenyl groups are preferred C2-C6-lower alkenyl, examples of which include vinyl, allyl, 2-methylallyl, Isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-and particularly preferred are vinyl, allyl, Isopropenyl, 2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and 3-methyl-2-butenyl. As the lower etkinlik groups are preferred C2-C6lowest alkyline group, examples of which are ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. Among them, particularly preferred are ethinyl, 1-PROPYNYL and 2-PROPYNYL.

As the alicyclic hydrocarbon group specified hydrocarbon groups mentioned saturated and unsaturated alicyclic hydrocarbon group, examples of which are cycloalkyl group, cycloalkenyl group or cycloalkenyl group. As cycloalkyl groups are preferred C3-C9-cycloalkyl group, examples of which are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cycloneii. Among them, particularly preferred are C3-C9-cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples cycloalkenyl groups include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohex,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl and 2,5-cyclohexadiene-1-yl.

As the aryl group mentioned hydrocarbon groups mentioned monocyclic and condensed polycyclic aromatic hydrocarbon group, examples of which include phenyl, naphthyl, antril, tenantry and acenaphthylene. Among them, particularly preferred are phenyl, 1-naphthyl and 2-naphthyl.

As the substituent of the "optionally substituted hydrocarbon group" represented by R1mentioned optionally substituted aryl group, optionally substituted cycloalkyl group, or cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted amino, optionally substituted hydroxyl group, optionally substituted tirinya groups and halogen atoms (e.g. fluorine, chlorine, bromine and iodine). The amount of these optional substituents is in the range from 1 to 5 (preferably 1-3). As the aryl groups mentioned optionally substituted aryl groups mentioned phenyl, naphthyl, antril, tenantry and acenaphthylene. Among them, preferred are phenyl, 1-naphthyl and 2-naphthyl. As Deputy to the specified optional, sopoci), the halogen atoms (e.g. fluorine, chlorine, bromine and iodine) and (C1-C3is an alkyl group (e.g. methyl, ethyl and propyl). The amount of these optional substituents ranges from 1 to 2. As cycloalkyl groups mentioned optionally substituted cycloalkyl group can be mentioned C3-C7-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The type and number of substituents on the optionally substituted cycloalkyl group are the same as mentioned substituents for the above optionally substituted aryl groups. As cycloalkenyl group optionally substituted cycloalkenyl group can be mentioned C3-C6-cycloalkenyl groups, including cyclopropyl, cyclobutyl, cyclopentenyl and cyclohexenyl. The type and number of substituents on the optionally substituted cycloalkenyl group are the same as mentioned for the substituents of the above optionally substituted aryl groups. As a heterocyclic group optionally substituted heterocyclic group are mentioned aromatic heterocyclic group and a saturated or unsaturated non-aromatic is selected from among oxygen, sulfur and nitrogen, the preferred aromatic heterocyclic groups. As mentioned aromatic heterocyclic group are mentioned aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and aromatic condensed heterocyclic group (for example, benzofuranyl, ISO-benzofuranyl, benzo(b)thienyl, indolyl, isoindolyl, 1H-indazole, benzimidazole, benzoxazolyl, 1,2-benzisoxazole, benzothiazolyl, 1,2-benzothiazolyl, 1H-benzotriazolyl, hinely, ethanolic, cinnoline, hintline, honokalani, phthalazine, naphthylidine, purinol, pteridinyl, carbazolyl-carboline-carboline-carbolines, acridines, phenoxazines, phenothiazines, phenazines, femoxetine, thianthrene, phenanthridines, phenanthrolines, indolizinyl, pyrrolo(1,2-b)pyridazinyl, pyrazolo(1,5-a)pyridyl, imidazo-(1,2-a)pyridyl, imidazo(1,5-a)pyridyl, imidazo(1,2-b)pyridazinyl, imidazo(1,2-a)pyrimidine, eremitani, pyrazinyl, indolyl and isoindolyl. As these non-aromatic heterocyclic group can be mentioned, for example, oxiranyl, azetidine, oxetane, titanyl, pyrrolidinyl, tetrahydrofuryl, ciorani, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholine, piperazinil etc. as Deputy mentioned optionally substituted heterocyclic groups are referred to C1-C3-alkali (for example, methyl, ethyl, propyl). As the Deputy indicated optionally substituted amino group, optionally substituted hydroxyl, or optionally substituted Tilney group can be mentioned C1-C3-alkali (for example, methyl, ethyl, propyl). In the case when the hydrocarbon group in the optionally substituted hydrocarbon group represented by R1is the alicyclic hydrocarbon group or aryl, it may additionally be C1-C3is an alkyl group (e.g. methyl, ethyl, propyl).

In the above formulae I, I' and I" as optionally substituted lower alkyl groups represented by R2and R3you can mention C1-C6lower alkyl groups (e.g. methyl, ethyl, n-propyl, isopropyl, butyl, izobov>is an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl and tert.butyl. As Deputy mentioned optionally substituted lower alkyl groups include halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C1-C4-the lower alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.butoxy) along with others.

Substituents of "optionally substituted phenyl group" represented by R2and R3are independently represented by a halogen atom (e.g. fluorine, chlorine, bromine and iodine), optionally substituted C1-C4lower alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert.butyl), optionally substituted C1-C4-low alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.butoxy), optionally substituted hydroxyl, nitro-group and cyano, and optionally substituted phenyl group" may have 1 to 3 such Deputy. As the Deputy indicated optionally substituted lower C1-C4is an alkyl group or optionally substituted lower C1-C4-alkoxygroup can among others be mentioned halogen atoms (e.g. fluorine, chlorine, bromine yennai hydroxyl group among others may be mentioned the lower C1-C4is an alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert.butyl), C3-C6-cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), aryl groups (e.g. phenyl, 1-naphthyl and 2-naphthyl) and kalkilya group (e.g. benzyl, phenethyl). Further, two adjacent substituent in the phenyl group may be combined together to form a ring. Examples of such rings are the following formulas:

< / BR>
As the aromatic heterocyclic group "optionally substituted heterocyclic group" represented by R2and R3you can mention the same aromatic heterocyclic group, which was cited for R1. Among them, preferred are furin, thienyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl and isoindolyl. As Deputy mentioned aromatic heterocyclic group can result in a lower C1-C3is an alkyl group (e.g. methyl, ethyl and propyl), along with the others.

As the spacer having a chain length of 1 to 7 atoms represented by X may be described bivalent chain of which the number of atoms constituting the straight chain is 1 to 7, it can be BDE m and n denote independently 0, 1, 2, or 3; E is a bond or an oxygen atom, a sulfur atom, a sulfoxide, sulfonal, -NHCO-, or-NHCONH-, where R6and R7independently mean a hydrogen atom, optionally substituted lower alkyl, optionally substituted aralkyl or optionally substituted phenyl, R5is a hydrogen atom, a lower alkyl, aralkyl or acyl.

As the alkyl group in the "optionally substituted lower akilah" represented by R6and R7can be C1-C6is an alkyl group with straight or branched chain (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. butyl, n-pentyl, isopentyl, neopentyl and so on). As Vice-optionally substituted alkyl group can be mentioned aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, imidazolyl and isoindolyl), optionally substituted amino, optionally substituted hydroxyl group, optionally substituted tirinya group, optionally esterified carboxyl group and halogen atoms (e.g. fluorine, chlorine, bromine and iodine). As Deputy optionally substituted amino, optionally substituted, hydroc kilenyi group (for example, methyl, ethyl and propyl). As the optionally esterified carboxyl group can be mentioned methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, 1-mattoxicator, 2-mattoxicator, are preferred methoxycarbonyl, etoxycarbonyl, propoxycarbonyl.

As aranceles group "optionally substituted Uralkalij group" represented by R6and R7, may be mentioned benzyl, naphthylmethyl, phenylethyl, phenylpropyl, phenylbutyl, etc., as Deputy mentioned "optionally substituted aranceles group" can be mentioned halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C1-C3-alkoxygroup (for example, methoxy, ethoxy, propoxy, etc.,), hydroxyl, amino, carboxyl, sulfhydryl etc.

As Deputy optionally substituted phenyl groups represented by R6and R7, there can be mentioned halogen atoms (e.g. fluorine, chlorine, bromine and iodine), C1-C3-alkoxygroup (for example, methoxy, ethoxy, propoxy, etc.,), and C1-C3is an alkyl group (e.g. methyl, ethyl, propyl, etc.,).

R6may be different depending on the respective methylene chain.

lower alkyl (e.g., methyl, ethyl, propyl, butyl, tert. butyl, etc.,), C7-C15-aralkyl (for example, benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl and so on).

As the acyl group represented by R5you can mention lower alcoholnye group (formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl), lower alkenols group (acryloyl, methacryloyl, crotonoyl and isocrotonic), cycloalkylcarbonyl (cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl and cyclohexanecarbonyl), lower alkanesulfonyl group (mesyl, econsultancy and propanesulfonyl), aroline group (benzoyl, p-toluoyl, 1-naphtol, 2-naphtol), aryl lower alcoholnye group (phenylacetyl, phenylpropionyl, hydrotropes and phenylbutyric), aryl lower alkenols group (cynnamoyl and Atropos) and arenesulfonyl group (benzazolyl and p-toluensulfonyl) along with others.

Examples of the optionally esterified carboxyl groups represented by Y include lower alkoxycarbonyl group (methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. butoxycarbonyl, Deut. butoxycarbonyl, pentyloxybenzoyl, isopentyl the Nile, 1-mattoxicator and benzyloxycarbonyl).

These lower alkoxycarbonyl group may have 1 or more substituents at any possible positions. Examples of such substituents include optionally substituted hydroxyl, optionally esterified carboxyl group, optionally substituted carbamoyl group optionally substituted phenyl group, optionally substituted C3-C6-cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), lower C1-C3-alkeline group (for example, vinyl, allyl, etc.,) and the 5-membered heterocyclic residue containing 1 to 3 oxygen atom. As the Deputy indicated optionally substituted hydroxyl group may be mentioned lower alcoholnye group (e.g., pivaloyl, etc.,), and optionally esterified carboxyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and cyclohexyloxycarbonyl). As a Deputy in the specified optionally esterified carboxyl group may be mentioned lower C1-C4-alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl in the specified optionally substituted carbamoyl group can be mentioned lower C1-C3is an alkyl group (e.g. methyl, ethyl and propyl), C3-C6-cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), phenyl, benzyl, and optionally esterified carboxyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl). As the substituent in the above optionally substituted phenyl group or optionally substituted C3-C6-cycloalkyl group can result in a lower C1-C3is an alkyl group (e.g. methyl, ethyl, propyl) and lower C1-C3-alkoxygroup (for example, methoxy, ethoxy and propoxy). The specified 5-membered heterocyclic residue may have 1 or more substituents at any possible position. Examples of such substituents include lower C1-C3is an alkyl group (e.g. methyl, ethyl and propyl) and oxo. Next specified heterocyclic group may be combined with the benzene ring with the formation of condensed cycle.

Specified aryloxyalkyl group may have one or more substituents at any possible position. Examples of such substituents include lower C1-C3is an alkyl group (e.g. methyl, ethyl and provenue carboxyl group (for example, methoxycarbonyl, etoxycarbonyl and propoxycarbonyl).

Also optionally esterified carboxyl group represented by Y may be dietaryguidelines.

Examples of the substituents in the optionally substituted hydroxyl group represented by Y include C1-C4lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert.butyl), C3-C6-cycloalkyl group (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), aryl groups (e.g. phenyl, 1-naphthyl and 2-naphthyl) and kalkilya groups (e.g. benzyl and phenethyl).

Examples of the substituents in the optionally substituted amino group represented by Y include lower C1-C4is an alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert. butyl), C3-C6-cycloalkyl group (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), aryl groups (e.g. phenyl, 1-naphthyl and 2-naphthyl), and kalkilya groups (e.g. benzyl and phenethyl). Also two Deputy at the nitrogen atom can be combined with the formation of cyclic amino group. Examples of such cyclic amino groups include 1-azetidine, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinil and 1-piperazin is (for example, benzyl, phenethyl, etc.,), aryl group (e.g. phenyl, etc.,) or similar in the 4-position.

Examples of the substituents in the optionally substituted phenyl group represented by Y include optionally substituted lower C1-C4-alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert.butyl), lower C1-C4-alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert. butoxy), optionally esterified carboxyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl and Deut.butoxycarbonyl), optionally substituted phenyl, optionally substituted amino, and N-containing heterocyclic residue having hydrogen atom capable of deprotonization.

As the substituent in the optionally substituted lower C1-C4is an alkyl group or optionally substituted phenyl group can be mentioned optionally esterified carboxyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl and Deut.butoxycarbonyl). As a Deputy in kazmer, methyl, propyl and ethyl). Specified N-containing heterocyclic residue includes tetrazol-5-yl, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl.

Examples of the substituents in the optionally substituted carbamoyl group represented by Y include lower C1-C4is an alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl and tert.butyl), C3-C6-cycloalkyl group (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), aryl groups (e.g. phenyl, 1-naphthyl and 2-naphthyl) and kalkilya groups (e.g. benzyl and phenethyl). Also two Deputy at the nitrogen atom can be combined with the formation of cyclic amino group. Examples of such cyclic amino groups include 1-azetidine, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinil and 1-piperazinil with lower C1-C3is an alkyl group (e.g. methyl, ethyl, propyl, etc.,), aracelio group (for example, benzyl, phenethyl, etc.,), aryl group (e.g. phenyl, etc.,), optionally substituted by halogen (e.g. fluorine, chlorine, bromine or iodine), or similar in the 4-position. Below piperidino can be combined with the benzene ring with the formation of a condensed cycle.

the run Y include tetrazol-5-yl, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl.

As the substituent of ring A, we can cite the halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-C4optionally substituted alkyl groups (e.g. methyl, ethyl, propyl, butyl and tert.butyl), C1-C4optionally substituted alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.butoxy), nitro and ceanography. Ring A may have 1 to 3, preferably one or two substituent. And these substituents may form a loop with each of the neighboring substituents. As the substituent in the optionally substituted lower alkyl group or optionally substituted lower alkoxygroup can be mentioned a halogen atom (e.g. fluorine, chlorine, bromine, iodine), and 1 - 3 of such halogen atom may be substituted at arbitrary positions.

And when X is a formula

< / BR>
where the symbols have the above values, E is preferably a bond or-CONH-. When E is-CONH-, preferably m = 1, n = 1 or m = 2, n = 1, especially m = 1, n = 1. In this case, R6preferably is hydrogen, benzyl, and 3-indolylmethane, especially a hydrogen atom is scrap, especially carboxyla.

Further preferred substituents of ring A include the absence of the Deputy, the lower alkoxygroup or a halogen atom, particularly preferred are methoxy or chlorine atom.

As salts of the compounds I, I' or I" can be mentioned pharmaceutically acceptable salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluensulfonate, methanesulfonate, etc., metal salts such as sodium salt, potassium salt, calcium salt, aluminum salt, etc., and basic salts such as triethylamine salt, guanidine salt, ammonium salt, hydrazine powered salt, quinine salt, Tikhonova salt, etc.

Further, the present invention provides a method of obtaining a compound represented by formula I or formula I'

< / BR>
where each symbol has the meaning as defined above, or their pharmaceutically acceptable salts, which consists in the reaction of cyclization of the compound represented by formula

< / BR>
where W means

< / BR>
where R1- halogen (e.g. fluorine, chlorine, bromine and iodine) or a group-OSO3CH3and the deposits are described below.

Among the compounds of formulas I and I' of the compounds of formula Ia

< / BR>
where R4is C1-C8the alkyl or aralkyl, and other symbols have the above meanings, can be obtained by methods A, B, C (see the end of the description).

2-Aminobenzophenone as starting material can be synthesized according to or in accordance with the method described by D. A. Walsh, Synthesis, 677 (1980) or by the method specified in the above link.

The reaction between compounds of formula II and formula IV, and formula VIII with the compound of the formula IX in A way or the reaction of compounds of formula X with the compound of the formula XI and a compound of formula XIV with a compound of formula XII in method B can be carried out using generally known reaction of acylation. For example, the reaction of acylation of the present invention can be carried out in a solvent which is a solvent of the type of simple ether, such as diethyl ether, tetrahydrofuran, dioxane, etc., and halogenated solvent type, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., the solvent of the hydrocarbon type, such as benzene, toluene, hexane, heptane, etc., dimethylformamide, dimethyl sulfoxide, etc. and saverilluminated, the triethylamine, triethylenediamine, tetramethylethylenediamine and etc., inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., sodium hydride, potassium hydride) among others. Relative to one mole of the compound represented by formula II, VIII, X and XIV, the acid chloride of the acid and methanesulfonamide formula III and an ester of 4-chloroformmethanol acid is usually used in an amount of from 1 to 10 mol, preferably 1 to 3 mol. The reaction time usually ranges from about 1 to 48 hours, preferably from about 5 to 10 hours, the reaction Temperature is in the range from -50 to 100oC, preferably from about 0 to 50oC.

And the reaction of the compound of formula IV with the compound of the formula VI in method A, and the reaction of the compounds of formula II with the compound of the formula X and the compounds of formula XIII with a compound of formula XIV in the method can be performed in a solvent of the type of simple ether, such as diethyl ether, tetrahydrofuran, dioxane, etc., solvent type of hydrocarbon, such as benzene, toluene, hexane, heptane, etc., solvent, type of alcohol, such as methanol, ethanol, propanol, butanol, etc., acetone or dimethylformamide, and in the head of the sodium, potassium carbonate, sodium hydride, potassium hydride or similar ). In relation to one mol of the compound represented by formula II, formula IV or formula XIII, a compound of formula V is usually used in an amount of from 1 to 10 mol, preferably about 1 to 2 mol. The reaction temperature is in the range from 0 to 100oC, preferably from about 20 to 50oC. the reaction Time ranges from 1 to 24 h, preferably it is about 3 - 10 PM

And the reduction of the carbonyl group in the compound of formula IX to the compound of formula Ia' in method A, the compound of formula II to the compound of formula XIII and the compound of formula XI to the compound of formula XII in the method may be performed in proton solvent (e.g. methanol, ethanol, propanol, butanol, etc.,) or in an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.,) in the presence of a complex metal hydride (for example, sociallyengaged, natroalunite, nutritionallybalanced, sodium borohydride, etc.,). Relative to 1 mol of each of the compounds represented by formula IX, formula II and formula XI, such a complex metal hydride, as described above, is used in quantity, usually the temperature value of the reaction is in the range from -20 to 100oC, preferably from 20 to 50oC.

The reaction of cyclization of compounds of formula XII to a compound of formula Ia' in method B can be performed in a solvent, for example, the type of simple ether, such as diethyl ether, tetrahydrofuran, dioxane, etc., solvent type of hydrocarbon, such as benzene, toluene, hexane, heptane, etc., solvent, type of alcohol, such as methanol, ethanol, propanol, butanol, etc., acetone, dimethylformamide or etc., in the presence of the appropriate base (e.g. sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, of sodium hydride, potassium hydride, etc.,). With respect to 1 mol of the compound represented by formula XII, the base, as described above, is used usually in an amount of from 1 to 5 mol, preferably from about 1 to 2 mol. The reaction temperature is usually in the range from -20 to 200oC, preferably from 20 to 100oC. the reaction Time is usually from 1 to 20 h, preferably 2 to 5 o'clock

The reaction of the compound of formula VI to the compound VIII in method A can be carried out in alcohol represented by formula VII, and depending on necessity, in the presence of an inorganic acid such as nitric acid, hydrochloric acid is or methansulfonate acid, at a temperature of from -20 to 100oC, preferably from 20 to 50oC. the reaction Time is from 10 to 100 h, preferably 10-48 hours

The compound of formula Ia can be obtained in accordance with the traditional way.

Among the compounds represented by formulas I and I', the compound of formula Ib

< / BR>
where the symbols have the above meanings, can be obtained by hydrolysis of compounds of formula Ia, for example during processing of compounds of formula Ia with an acid or a base. More specifically, the compound of formula Ia is treated with an aqueous solution of mineral acid (e.g. nitric acid, hydrochloric acid, Hydrobromic acid, acid ion, sulfuric acid or similar ) or hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide) at a temperature lying in the range from 0 to 150oC, preferably from 20 to 50oC. the Strength of the acid or base is usually in the range from 1 to 10 H, preferably 4 to 10 H. The reaction time varies depending on the reaction temperature, but usually it is in the range from 1 to 24 h, preferably 2 to 10 hours

The compound of General formula Ib'

< / BR>
where the symbols have the meanings specified the data previously. Solvent used may be any that does not harm the reaction, examples of which are acetone, dioxane, tetrahydrofuran, dichloromethane, dichloroethane or chloroform. As the oxidizing agent can be used permanganate, chromic acid or Nickel peroxide. In this case, the oxidizing agent is used in amounts in the range from 0.5 to 20 molar equivalents, preferably from 1 to 3 molar equivalents per mole of the compounds of formula Ic', the reaction temperature is in the range from 0 to 100oC, preferably from 15 to 50oC when the reaction time from 0.5 to 5 h, preferably from 1 to 2 o'clock

Among the compounds used as intermediates for the synthesis of compounds of formula I or I', the compound of formula XIX

< / BR>
where the symbols have the above meanings, can be obtained by the reaction of compounds of formula Ib with diphenylphosphorylacetate in the environment of a solvent in the presence of base followed by treatment of the resulting product acid in the solvent. The solvent used in the reaction between the compound of formula Ib and diphenylphosphorylacetate, can be any, because it does not interfere with the reaction, for example, dimethylformamide simple ester, such as ether, tetrahydrofuran or dioxane. Typical examples of bases include triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine. On 1 mol of the compounds of formula Ib using 1 to 10 molar equivalents, preferably 1.5 to 3 molar equivalent diphenylphosphinite. The reaction temperature is in the range from -20 to 50oC, preferably from 0 to 20oC, and the reaction time is from 0.5 to 5 h, preferably 1 to 2 hours In case of processing of the product obtained by the above reaction solvent used may be water, dioxane, dimethylformamide, etc. and used as the acid may be a mineral acid such as sulfuric acid, hydrochloric acid, nitric acid or Hydrobromic acid. The reaction temperature is in the range from 20 to 200oC, preferably from about 50 to 100oC, and the reaction time is from 0.5 to 5 h, preferably 1 - 2 hours

Among the compounds of formulas I and I', the compound of formula Ic

< / BR>
where the symbols have the above meanings, can be obtained by reduction of compound of formula Ia. More specifically, the compound of formula Ic can be obtained by treating compounds M sodium) in proton solvent (for example, methanol, ethanol, propanol, butanol, etc.,) or in an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.,). On 1 mol of the compounds of formula Ia is a complex metal hydride compound is used in an amount of usually from 0.3 to 5 molar equivalents, preferably from 0.5 to 2 molar equivalents. The reaction temperature is in the range from -20 to 100oC, preferably from 0 to 20oC. the reaction Time is from 0.5 to 10 h, preferably 1 to 3 hours And the compounds of formula Ic can be obtained also when turning the amine part of the compounds of formula XIX in a hydroxyl group. For example, the compound of formula Ic can be obtained by adding sodium nitrite to the compound of formula XIX in a solvent in the presence of acid, followed by treatment of the resulting azide in a solvent in the presence of a base. In the way sideropenia, for example, using 0.5 - 3, preferably 1 to 1.5 molar equivalent of sodium nitrite per 1 mol of compound XIX. The acid can be used any, if it does not harm the reaction, usually used acetic acid or sulfuric acid. The reaction temperature ranges from -20 to 20oC, preferably 0 to 5oC and vratam azide compound in a hydroxyl group is for example, to use as a base, for example sodium bicarbonate, potassium bicarbonate, sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide, or, etc., in water or in an aqueous organic solvent (e.g., solvent type of alcohol, such as methanol, ethanol, propanol, butanol, or etc., the solvent of the ether type, such as tetrahydrofuran, dioxane or etc.) dimethylformamide, etc., the reaction Temperature is in the range from 20 to 200oC, preferably 50 - 100oC, the reaction time is from 5 minutes to 2 hours, preferably from 15 to 30 minutes

The compound of General formula XX

< / BR>
where the symbols have the above meanings and Z' is a halogen (chlorine, bromine and iodine), which is an intermediate product for the synthesis of compounds of formula I, can be obtained similarly to the method used in the case of receiving the Ic connection from the connection of the nineteenth, by diazotization of the compounds of formula XIX with sodium nitrite in hydrochloric acid, Hydrobromic acid or idiscovered acid, followed by heating diazotized compounds. The reaction temperature is in the range from 20 to 200oC, preferably 50 - 100oC, and the reaction time sostavljae Id

< / BR>
where Y' is, in addition to the definitions given above for Y, esterified carboxyl group, and other symbols have the above meanings, can be obtained by condensing the compounds of formula Ib with a compound of formula XXI

< / BR>
where the symbols have the above values, more specifically, the Ib connection and the connection of the XXI condense the solvent using a condensing agent, and if necessary, in the presence of a base. Used solvents are the hydrocarbon solvents such as benzene, toluene, hexane, heptane, etc., type halogenated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., type ethers such as ethyl ether, tetrahydrofuran, dioxane, etc., acetonitrile, dimethylformamide, etc. as the basis, among other uses triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine. As the condensing agent can lead those that are used for peptide synthesis, and among them cyclohexylcarbodiimide, diethylthiophosphate and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. On 1 mol of the compounds of formula Ib is used as a compound of formula XXI in the amount of from 0.5 to 2 Michelle from 0.5 to 5 molar equivalents, preferably 1-2 mol of equivalentof. The reaction temperature is in the range from 0 to 100oC, preferably from 20 to 50oC, and the reaction time is from 0.5 to 24 h, preferably from 1 to 5 o'clock

Among the compounds of formula I and I', the compound of formula Ie

< / BR>
where the symbols have the above meanings, can be obtained by the reaction of compounds Ib with diphenylphosphorylacetate in a solvent in the presence of base, followed by the interaction of the resulting compound with the compound XXI. As the solvent used for the reaction between compound Ib and diphenylphosphorylacetate may be used any solvent which has no adverse effect on the reaction, examples can be dimethylformamide, or a halogenated solvent type, such as dichloromethane, chloroform, dichloroethane, etc., and the solvent of the type of simple ester, such as a simple ether, tetrahydrofuran, dioxane, etc., Examples of usable bases are triethylamine, 4-dimethylaminopyridine, triethylenediamine or tetramethylethylenediamine. On 1 mol of the compounds of formula Ib are used 1-10, preferably 1.5 to 3 molar equivalent diphenylphosphinite. The reaction temperature nahoditesj 1-2 hours

Examples of solvents used for the reaction between the compound thus obtained above, and the compound of the formula XXI are the halogenated solvent type, such as dichloromethane, dichloroethane, chloroform, etc., solvent type simple ether such as ether, tetrahydrofuran, dioxane, etc., acetonitrile, dimethylformamide, among others. Depending on the need to apply Foundation. As a basis you can lead an organic basis, including triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine. 1 mol of compound I using 0.5-3, preferably 1-1.5 molar equivalents of compound XXI. The reaction temperature is in the range from 0 to 150oC, preferably from 30 to 100oC, and the reaction time ranges from 0.5 to 24 hours, preferably 1-3 hours

Among the compounds of formulas I and I', the compound of formula If

< / BR>
where the symbols have the above meanings, can be obtained by condensation of compound XIX with a compound of formula XXII

< / BR>
where the symbols have the meanings given above. This reaction can be carried out exactly the same as the connection Id.

Among the compounds of formulas I and I' are the connection forms of the symbols have the meanings mentioned previously, can be obtained by the reaction of compounds of formula IC or the compounds of formula XIX with a compound of formula XXIII

< / BR>
where the symbols have the above meanings. More specifically, the IC connection or the connection of the nineteenth enter into reaction with the compound XIII in an alcohol solvent such as methanol, ethanol, propanol, butanol, etc., solvent type simple ether, such as diethyl ether, tetrahydrofuran, dioxane, etc. or dimethylformamide, along with others, in the presence of bases, including inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc., organic base, such as triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine etc., or sodium hydride. On 1 mol of compound IC or XIX using 0.5-1.5 molar equivalent of compound XXIII, and on 1 mol of compound IC or XIX use 1-5, preferably 1-2 molar equivalent of the base; the reaction temperature is in the range from 0 to 200oC, preferably from 20 to 100oC, and the reaction time is 0.5 to 24 hours, preferably 1-3 hours

Among the compounds of formulas I and I', the compound of formula Ih

< / BR>
where the symbols have the above C the symbols have the above meanings. Apply aprotic solvent, examples of which are ethyl ether, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide or the like. If necessary, may be used an inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, an organic base such as triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine, sodium hydride, cesium fluoride or so on 1 mol of compound XX apply 0.5-5, preferably 1-2 molar equivalents of compound XXV. The reaction temperature is in the range from 0 to 200oC, preferably 20-100oC, and the reaction time is from 10 min to 5 h, preferably from 30 minutes to 2 hours

Among the compounds represented by formulas I and I', the compound of formula Ii

< / BR>
where the symbols have the above meanings, can be obtained by hydrolysis of compounds of formula Ij

< / BR>
where Y" is, among other previously mentioned values for Y, esterified carboxyl group, and other symbols have the above meanings. More specifically, the hydrolysis is carried out in such solvents as water, methanol, ethanol, propanol or butanol, in the presence of hydroxide Shelocta sodium, of potassium bicarbonate, sodium carbonate or potassium carbonate, or in the presence of a mineral acid (e.g. nitric acid, hydrochloric acid, Hydrobromic acid, iodic acid or sulfuric acid) or triperoxonane acid, at a temperature of from 10 to 150oC, preferably from 10 to 50oC. Although the reaction time varies depending on the reaction temperature, it is usually from 1 to 24 h, preferably about 2-10 hours

Although the compound represented by formula I, the present invention has the ability to inhibit stvalentines and antifungal activity among the compounds used in the present invention, there are compounds that can inhibit other enzymes in the pathway of biosynthesis of cholesterol. Essentially we can say that the compound of formula I of the present invention inhibits the biosynthesis of cholesterol, it is useful for the prophylaxis or treatment of hypercholesterolemia or coronary sclerosis in mammals (e.g. mice, rats, rabbits, dogs, cats, cows, pigs and people) and, in addition, for the prevention or treatment of fungal infections.

The specified compound I can be administered to the person orally or nearline. Wadeite sugar pills and tablets covered with foil), syrups, emulsions, suspensions or so on, These compositions can be prepared there are generally ways and contain carriers or excipient commonly used for pharmaceutical preparations, such carriers or excipient as lactose, starch, sucrose or magnesium stearate, in the manufacture of tablets.

Examples not oral compositions for injection are injections and suppositories, and injections include hypodermic injection, intradermal injection, intramuscular injection. These injectables can be prepared generally known methods, more specifically, by suspension or emulsion of the compound of the present invention in sterile water or oil, usually used for preparation of compositions for injection. The aqueous liquid used to prepare drugs for injection include physiological saline and an isotonic solution and, if necessary, suitable suspendisse agent, such as sodium carboxymethyl cellulose, non-ionic surfactant or etc., can also be used. As oil can lead sesame oil, soybean oil, etc. and benzylbenzoate who you are for injection is usually poured into appropriate capsules.

The compound of formula I or its salt can be safely used with low toxicity. Although the daily dose varies depending on the condition and weight of the patient, type of connection, route of administration and other factors, for example in the case of the introduction of the compounds of the present invention for the treatment of hypercholesterolemia daily oral dose for an adult is about 1 to 500 mg, preferably about 10 to 200 mg. In this interval was not observed toxicity.

The compounds of formula I as inhibitors stvalentines effectively applied to a mammal, such as man, in therapeutically effective amount, which is usually provided oral daily dose for an adult human of from about 1 to about 500 mg, preferably about 10 to 200 mg. if not oral use (for example, in the form of injections or suppositories) a therapeutically effective amount is a daily dose is from about 0.1 to about 100 mg, preferably about 1 to 20 mg.

Compounds of the present invention also show a wide range of antifungal activity, as determined by the methods of dilution in broth or on agar.

The compounds of formula I" with antifungal treatment effectively applied to a mammal, such as man, in therapeutically effective amount, which is usually provided oral daily dose for an adult human of from about 0.1 to about 100 mg, preferably about 1 to 50 mg. When not oral use, such as injection or candle, a therapeutically effective daily dose is about 0.1 - 100 mg, preferably about 1 to 50 mg.

Abbreviations for amino acids and other, used in the present description, based on abbreviations specified by the Commission for the nomenclature of IUPAC-YB, or abbreviations commonly used in related fields. Some examples are given below. When the amino acid may be an optical isomer, it has the L-configuration, unless otherwise indicated.

Trp or Y - Tryptophan

Ser or S - serine

Asp or D - Aspartic acid

Clu or E - Glutamic acid

Me - Methyl

Et - Ethyl

Ph - Phenyl

The following examples, reference examples, examples, formulation examples and tests are intended to illustrate the present invention in more detail and should not be construed as defining granov depending on the form of compounds, receive due to the presence of asymmetric carbon atom at the 3 - and 5-m positions. Isomers in which the substituents in the 3-m and 5-m positions are oriented in the same direction with respect to the plane of the 7-membered ring, called CIS-isomers, whereas those in which the substituents in the 3-m and 5-m positions are oriented in opposite directions, are called TRANS-isomers.

Reference example 1

TRANS-7-chloro-5-(2-chlorophenyl)-1,2,3,5-tetrahydro-1-methyl-2-oxo-4,1-benzoxazepin-3-acetic acid, ethyl ester

(1) Ethyl-3-(N-(2-chlorobenzoyl)-4-chlorophenyl)carbarnoyl)acrylate

To a suspension of 5.0 g of 2-amino-5-chloro-2'-chlorobenzophenone and 2.5 g of sodium bicarbonate in 100 ml of methylene chloride are added dropwise 3.3 grams of monoethylene ester polychlorinated fumaric acid for 30 minutes the Mixture is stirred for 2 h at room temperature, then there is added water, then shake. Separate the organic layer, dried over sodium sulfate, then the solvent is distilled off under reduced pressure, to obtain 4.8 g of ethyl ester of 3-(N-(2-(2-chlorobenzoyl)-4-chlorophenyl)carbarnoyl)-acrylic acid in the form of crystals with so pl. 113 - 114oC.

Elemental analysis for C19H15Cl2NO
To a suspension of 0.15 g of sodium hydride in 20 ml of N,N-dimethylformamide was added with stirring and ice cooling 3.0 g of previously obtained crystals. The mixture is stirred 10 min at 0oC, then add back 2.0 g under the conditions, then the mixture is stirred for 2 h at room temperature. The reaction mixture was poured into ice-water, then exteriour with ethyl acetate. Atrocity layer washed with water and dried, the solvent is distilled off under reduced pressure to obtain 2.8 g of ethyl ester of 3-(N-(2-(2-chlorobenzoyl)-4-chlorophenyl)-N-methylcarbamoyl)acrylic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1725 (C=O), 1670 (C=O), 1490, 1370, 1300, 1180, 1115, 920, 740.

NMR spectrum (200 MHz, CDCl3) : of 1.27 (3H, t, CH2) 3,18 (3H, s, -N), 4,18 (2H, CH3), is 6.78 (2H, d, -CH=CH-), and 7.1 to 7.7 (7H, m).

(3) Ethyl ester of 3-(N-(4-chloro-2--hydroxy-2-Chlorobenzyl)phenyl)-N-methylcarbamoyl)acrylic acid

In 50 ml of methanol was dissolved 2.8 g of oily product obtained previously, are added back to 0.2 g of sodium borohydride, stirred the mixture for 30 min at room temperature. The reaction mixture was concentrated under reduced pressure, then extracted with ethyl acetate. The organic layer was washed with water, dried, and distilled under reduced pressure. When to acid, so pl. 128 - 130oC.

Elemental analysis for C20H19Cl2NO4-oxy-(2-chlorophenyl)methyl)aniline

Dissolve in 50 ml of glacial acetic acid 5.0 g of 4-chloro-2-(-hydroxy-(2-chlorophenyl)methyl)aniline. To the solution was added 2.5 g of cyclohexanecarboxaldehyde. To the mixture was added with stirring and ice cooling 1.06 g sodium borohydride within 40 minutes the Reaction mixture was poured into ice-water, then extracted with ethyl acetate. The organic layer is washed with diluted sodium hydroxide solution, then water, then dried. The solvent is distilled off under reduced pressure to obtain 6.2 g of N-cyclohexylmethyl-4-chloro-2-(-hydroxy-(2-chlorophenyl)methyl)aniline in the form of crystals with so pl. 91 - 92oC.

Elemental analysis for C20H23Cl2NO:

Calculated, %: C 65,94; H 6,36; N 3,84

Found, %: C 65,79; H 6,32; N 3,71

(2) Ethyl ester of 3-(N-(4-chloro-2-(-hydroxy-2-chloroformate)-phenyl)-N-cyclohexyloxycarbonyl)acrylic acid

Dissolved in 80 ml of methylene chloride 6.0 g obtained above crystals. Added to the solution with stirring and ice cooling dropwise a solution of 2.8 g of monoethylene ester acid chloride of fumaric acid in 20 ml of methylene chloride for 30 minutes the Reaction mixture was paramesh is spending purify by chromatography on silica gel (eluent: hexanitrate = 3: 1), obtain 6.5 g of ethyl ester of 3-(N-(4-(chloro-2-(-hydroxy-2-chloroformate)-N-cyclohexyloxycarbonyl)acrylic acid in the form of an oily product.

The IR spectrum of theNeamaxtcm-1: 3400 (OH), 2940, 1730 (C=O), 1660 (C=O), 1630, 1300, 1180, 1040.

1H-NMR spectrum (200 MHz, CDCl3) : 0,8 - 2,0 (14H, multiplet, CH2CH3-cyclohexane), 2,6 - 3,5 (2H, multiplet, -N cyclohexane), 4.0 to 4.5 (2H, multiplet, CH3), 6,05 to 7.7 (10H, multiplet).

(3) Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-cyclohexylmethyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid

Dissolve in 100 ml of standard 6.5 g of oily product obtained above was added thereto 5 g of potassium carbonate and stirred the mixture for 15 h at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate is extracted with ethyl acetate. The organic layer is washed with water and dried, the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel (eluent:hexyl-ethyl acetate = 8:1), gain of 5.2 g of ethyl ester of 3,5-TRANS-7-chloro-5-(2-chlorophenyl)-1-cyclohexylmethyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid in powder form.

The IR spectrum of theNeamaxtcm-1: 2940, network, %: C 63,68; H 5,96; N 2,86

Found, %: C 63,48; H 5,98; N 2,71

Reference example 3

Working according to the method of reference example 2, to obtain compounds shown in tables 1 to 4.

Example 1

Work by the method of reference example 2, to obtain compounds shown in tables 5 and 6.

In tables 1 - 12 shows the physico-chemical characteristics of the intermediate products obtained in reference example 3 and example 1.

Reference example 4

TRANS-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid

In a mixture of 10 ml of methanol and 4 ml of water suspended in 0.5 ethyl ester of 3,5-TRANS-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid. To the suspension was added 0.8 g of potassium carbonate and stirred the mixture for 3 h at 60oC. the Reaction mixture was concentrated under reduced pressure, then added water and then extracted with ether. The aqueous layer was acidified with diluted hydrochloric acid, then extracted with ethyl acetate. The organic layer is washed with water and dried, then concentrated under reduced pressure. The concentrate is purified by chromatography on silica gel, to obtain 0.21 g of 3,5-TRANS-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro the C for C18H15Cl2NO4:

Calculated, %: C 56,86; H 3,98; N 3,68

Found, %: C 56,86; H 4,24; N 3,53

Reference example 5

Work by the method of reference example 4, to obtain compounds shown in tables 13 to 15.

Example 2

Work by the method of reference example 4, to obtain compounds shown in table 16.

Reference example 6

TRANS-1-benzyl-7-chloro-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid

Conduct hydrolysis 0.3 g of ethyl ester of TRANS-1-benzyl-7-chloro-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid, described in JPA S57(1982)-35576, according to the method described in reference example 4, to obtain 0.12 g of TRANS-1-benzyl-7-chloro-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid as a white powder.

Example 3

Ethyl ester of TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

(1) 2-Isobutylamino--(o-tolyl)benzyl alcohol

Using 2.5 g of 2-amino--(o-tolyl)benzyl alcohol and 1.17 ml of isobutyl aldehyde, carry out reaction according to the method of reference example 2(1) obtain 3.1 g of 2-isobutylamino--(o-tolyl)benzyl alcohol in the form of butter.

The IR spectrum of theNeamaxt- 2,0 (1H, m) to 2.29 (3H, s), 2.0 to 2.3 and 2.9 - 3,1 (1H, each m), 3.9 to 4.5 (3H, m), 5,9 - 6,4 (2H, m), 6,6 - 6,9 (1H, m), 6,95 - 7,9 (8H, m).

(2) Ethyl ester of 3-(N-(2-(-hydroxy-2-methylbenzyl)phenyl-N-isobutyl)carbarnoyl)acrylic acid

Work by the method of reference example 2(2), 1.3 g of 2-isobutylamino--(o-tolyl)benzyl alcohol is introduced into reaction with monoecious ester acid chloride of fumaric acid, obtain 3.1 g of ethyl ester of 3-(N-(2-(-hydroxy-2-methylbenzyl)phenyl-N-isobutyl)-carbarnoyl)acrylic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 3400 (OH), 1720, 1655, 1630 (C = C, C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 0,7 - 1,1 (6H, m) to 1.21 (3H, t, J = 7.0 Hz), 1.5 to 2.0 (1H, m) to 2.29 (3H, s), 2.0 to 2.3 and 2.9 - 3,1 (1H, each m), 3.9 to 4.5 (3H, m), 5,9 - 6,4 (2H, m), 6,6 - 6,9 (1H, m), 6,95 - 7,9 (8H, m).

(3) Ethyl ester of TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Work by the method of reference example 2(3), is introduced into the reaction 1.8 g of ethyl ester of 3-(N-(2-( - hydroxy-2-methylbenzyl)phenyl-N-isobutyl)carbarnoyl)acrylic acid. The reaction product is crystallized from water-ethanol, get to 2.41 g of ethyl ester of TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of prisms with so pl. 88 - 90oC.

The IR spectrum of theNBR> Calculated, %: C 72,89; H 7,39; N 3,54

Found, %: C 73,18; H 7,25; N 3,54

Example 4

Work according to the method of example 3, to obtain compounds shown in tables 17 and 18.

In tables 19 - 22 shows the physico-chemical properties of intermediate products.

Example 5

TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Work by the method of reference example 4, carry out the hydrolysis of 2.0 g of ethyl ester of TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid, gain of 1.23 g of TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of prisms with so pl. 192 - 195oC.

The IR spectrum of theNeamaxtcm-1: 1735, 1650 (C = O).

Elemental analysis for C22H25NO4:

Calculated, %: C 71,91; H 6,66; N 3,81

Found, %: C 71,86; H is 6.78; N 3,80

Example 6

Work by the method of reference example 4 using the compound obtained in example 4, to obtain compounds shown in table 23.

Example 7

TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid, pivaloyloxymethyl ether

Dissolved in 10 ml of N,N-dimethylformamide, 0.5 g Mere 2. To the solution was added 0,43 ml pivaloyloxymethyl, of 0.52 ml of N,N-diisobutylamine and 0.2 g of KI. Mix all night stirred at room temperature, the reaction mixture was added 100 ml of water and 100 ml of ethyl acetate, then extracted. An ethyl acetate layer was washed with an aqueous solution of potassium bisulfate, aqueous sodium bicarbonate solution and water, successively, then dried over anhydrous magnesium sulfate. Then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel (hexane-ethyl acetate = 10:1 to 5:1) obtain 0.55 g pivaloyloxymethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzoxazepin-3-acetic acid.

The IR spectrum of theNeamaxtcm-1: 1750, 1675 (C = O)

Elemental analysis for C27H31Cl2NO6:

Calculated, %: C 60,45; H of 5.82; N, 2,61

Found, %: C 60,38; H to 5.93; N, 2,48

Reference example 7

Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

(1) 5-Chloro--(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzoyl alcohol

To a solution of 5.0 g of 2-amino-5-chloro--(2-chlorophenyl)benzyl alcohol and and 3.72 g of 2,4-dimethoxybenzaldehyde in 50 ml of acetic acid is then poured into 200 ml of water and extracted with 2 x 200 ml ethyl acetate. An ethyl acetate layer is washed 1H sodium hydroxide, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel (hexane-ethyl acetate = 5:1) obtain 7.5 g of 5-chloro--(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzamide alcohol in the form of butter.

1H-NMR spectrum (CDCl3) : of 3.78 (3H, s), with 3.79 (3H, s), 3,65 - of 3.95 (1H, m), 4,27 (2H, s), x 6.15 (1H, s), 6,35 - of 7.55 (10H, m).

(2) Ethyl ester of 3-(N-(4-chloro-2-oxybenzyl)phenyl)-N-(2,4-dimethoxybenzyl)carbarnoyl)acrylic acid

A solution of 2.24 g of monoethylene ester of fumaric acid and 3.4 ml of thionyl chloride in 10 ml of toluene is stirred for 30 min at 90oC. Then the solvent is distilled off under reduced pressure, to obtain the acid chloride of monoethylene ester of fumaric acid. This product and 5.0 g of 5-chloro--(2-chlorophenyl)-2-(2,4-dimethoxybenzyl)aminobenzamide alcohol obtained in (1), dissolved in 100 ml of methylene chloride. To the solution was added a 2.01 g of sodium bicarbonate and stirred the mixture for 30 min at room temperature. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel (hexane-ethyl acetate = 2: 1) obtain 5.5 g of the ECL.

The IR spectrum of theNeamaxtcm-1: 3390 (OH), 1720, 1610 (C = O), 1655 (C = C).

1H-NMR spectrum (200 MHz, CDCl3) : 1,2 - 1,4 (3H, m), 3,4 - 3,9 (6H, m), 3.95 to a 4.4 (3H, m), 4,45 - of 4.75 (1H, m), 5.25-inch and 5.6 (1H, m), 6,0 - 8,05 (13H, m).

(3) Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

In 50 ml of ethanol was dissolved 5.5 g of ethyl ester of 3-(N-(4-chloro-2-(2-chloro-oxybenzyl)phenyl)-N-(2,4-dimethoxybenzyl)carbarnoyl)acrylic acid obtained in (2). To the solution was added 1.4 g of potassium carbonate and stirred mixture of 2 hours To the reaction mixture was added 200 ml of water and 300 ml of ethyl acetate. The mixture is extracted. An ethyl acetate layer washed with water and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel, get ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo - 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1675 (C = O).

Elemental analysis for C28H27Cl2NO6:

Calculated, %: C 61,77; H 5,00; N TO 2.57

Found, %: C 62,06; H 5,26; N 2,61

Reference example 8

TRANS-7-Chlo 1.0 g of ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid, obtained in reference example 7 in 20 ml of methanol is added 10 ml of aqueous solution of 0.51 g of potassium carbonate, and then stirred for 1 h at 60oC. the Reaction mixture is acidified with 50 ml of 1H hydrochloric acid and extracted with 100 ml of ethyl acetate. An ethyl acetate layer washed with water and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate =1: 1 ~ hexane-methylene chloride-ethanol = 5:5:1) obtain 0.43 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of a powdery product.

The IR spectrum of theKBrmaxcm-1: 1715, 1670 (C = O).

Elemental analysis for C26H23Cl2NO6:

Calculated, %: C 60,48; H 4,49; N 2,71

Found, %: C 60,21; H to 4.73; N 2,72

Example 8

Ethyl ester of 1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

(1) 2-(5-oxitetraciclina-2-carbonyl)aminobenzophenone

A mixture of 4.9 g of 5-oxitetraciclina-2-carboxylic acid and 5.5 ml of thionyl chloride is refluxed for 2 hours and Then distilled thionyl chloride under reduced pressure to obtain 5 - oxitetraciclina the solution of sodium bicarbonate, all stirred 1 h at room temperature. An ethyl acetate layer washed with water and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2: 1) obtain 6.5 g of 2-(5-oxitetraciclina-2-carbonyl)aminobenzophenone in the form of needles with so pl. 100-102oC.

The IR spectrum of theKBrmaxcm-13300 (HH), 1790, 1690, 1640 (C = O)

Elemental analysis for C18H15NO4:

Calculated, %: C 69,89; H 4,88; N 4,53

Found, %: C 69,98; H 5,01; N TO 4.41

(2) 2-(N-benzyl-N-(5-oxitetraciclina-2-carbonyl) aminobenzophenone

Dissolved in 20 ml of N,N-dimethylformamide 3.0 g of 2-(5-oxitetraciclina-2-carbonyl)aminobenzophenone obtained in (1). To the solution was added 1.73 ml benzylbromide, 2.67 g of potassium carbonate and 0.1 g of tetrabutylammonium. Mix all night stirred at room temperature. The reaction mixture is extracted with a mixture of 200 ml of ethyl acetate and 100 ml of water. An ethyl acetate layer was washed with a 0.1 H hydrochloric acid and aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (aloe the-benzyl-N-(5-oxitetraciclina-2-carbonyl) aminobenzophenone in the form of needles with so pl. 142 - 143oC.

The IR spectrum of theKBrmaxcm-1: 1780, 1660, 1650 (C = O).

Elemental analysis for C25H21NO4:

Calculated, %: C 75,17; H and 5.30; N 3,51

Found, %: C 75,05; H 5,59; N 3,49

(3) 3-(N-benzyl-N-(4-etoxycarbonyl-2-hydroxy)butyryl)aminobenzophenone

In 100 ml of ethanol is dissolved 5.0 g of 2-(N-benzyl-N-(5-oxitetraciclina-2-carbonyl) aminobenzophenone obtained in (2). To the solution was added 0.2 ml of concentrated sulfuric acid and leave the mixture for 7 days. Distilled ethanol under reduced pressure. The residue is extracted with a mixture of 100 ml of water and 200 ml of ethyl acetate. An ethyl acetate layer was washed with aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate. Then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column (eluent: hexane-ethyl acetate = 2:1) obtain 2.8 g of 2-(N-benzyl-N-(4-etoxycarbonyl-2-hydroxy)butyryl)aminobenzophenone in the form of butter.

The IR spectrum of theNeamaxtcm-1: 3400, 1735, 1670 (C = O).

Mass spectrum (m/e): 445 (M+).

1H-NMR spectrum (200 MHz, CDCl3) : of 1.20 (3H,t,J=7.2 Hz ), of 1.65 to 3.0 (2H, m), 2,2 - 2,6 (2H,m), the 3.65 to 3.7 (1H, W), of 4.05 (2H, K, J= 7,2 Hz), 4,0 is 4.35 (1H, m), 4,69 (1H, d, J=14.4 Hz), to 4.87 (1H, d, J=14.4 Hz) and 6.9 to 7.9 (14H, m).

(4) etoxycarbonyl-2-oxy)-butyryl)aminobenzophenone, obtained in (3), dissolved in 30 ml of ethyl acetate. To the solution was added with ice cooling 0.73 ml methanesulfonanilide and 1.31 ml of triethylamine. The mixture is stirred for 2 h at room temperature. Then the reaction mixture is washed 1H hydrochloric acid and aqueous sodium bicarbonate solution successively, dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent:hexane-ethyl acetate =2:1) obtain 3.2 g of 2-(N-benzyl-N-(4-etoxycarbonyl-2-methansulfonate)butyryl)aminobenzophenone in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1670 (C = O).

Mass spectrum (m/e): 523 (M+).

1H-NMR spectrum (200 MHz, CDCl3) : 1.1 to about 1.35 (3H, m), of 2.0 to 2.6 (4H, m), 3,14 + to 3.36 (3H, each s), 3,9 - 4,7 (3H, m), is 4.93 (d, J = 14,2 Hz) + of 5.53 (d, J = 14,8 Hz) (1H), of 5.05-5,15 (m) 5,15 - 5,3 (m)(1H), 7.0 and a 7.85 (14H, m).

(5) Ethyl-CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionate and ethyl-TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionate

In 30 ml of ethanol was dissolved 3.2 g of 2-(N-benzyl-N-(4-ethoxy-carbonyl-2-methansulfonate)butyryl)aminobenzophenone obtained in (4). To the solution was added while cooling limes to room temperature. The reaction mixture is acidified by adding 100 ml of 1H hydrochloric acid, then extracted with 200 ml of ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 10:1 to 5:1), obtained as the first fraction of 0.73 g of ethyl ester of CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of needles with so pl. 107 - 108oC.

The IR spectrum of theKBrmaxcm-1: 1735, 1670 (C=O).

Elemental analysis for C27H27NO4:

Calculated, %: C 75,50; H 6,34; N 3,26

Found, %: C 75,21; H 6,44; N 3,27

1H-NMR spectrum (200 MHz, CDCl3) : to 1.21 (3H, t, J=7.2 Hz), 2,2 - 2,4 (2H, m) to 2.55 (2H, t, J=7.0 Hz), and 3.72 (1H, d, J=16.0 Hz), 4,10 (2H, K, J=7,2 Hz), to 4.23 (1H, t, J= 6.5 Hz), 4,70 (1H, d, J = 16.0 Hz), 5,95 (1H, s), 7,0 - 7,5 (14H, m).

B as a second faction obtain 0.3 g of ethyl ester of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1670 (C = O).

Mass spectrum (m/e): 429 (M+).

1H-NMR (200 MHz, CDCl3) : of 1.17 (3H, t, J=7,1 Hz), 2,05 - 2,4 (2H, m), 2.49 USD (2H, t, 2">

Example 9

Ethyl ester of CIS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

(1) 2',5-Dichloro-2-(5-oxitetraciclina-2-carbonyl)aminobenzophenone

Work according to the method of example 8(1), is introduced into the reaction of 15 g of 2-amino-2',5-dichlorobenzophenone with 5-oxitetraciclina-2-carbonylchloride, obtain 18.1 g of 2', 5-dichloro-2-(5-oxitetraciclina-2-carbonyl)aminobenzophenone, so pl. 170 - 173oC.

The IR spectrum of theKBrmaxcm-1: 3250 (NH), 1775, 1695, 1640 (C = O).

Elemental analysis for C18H13Cl2NO4:

Calculated, %: C 57,16; H of 3.46; N 3,70

Found, %: C 57,29; H 3,55; N 3,57

(2) 2-[N-benzyl-N-(5-oxitetraciclina-2-carbonyl)]amino-2',5-dichlorobenzophenone

Work according to the method of example 8(2), is introduced into the reaction of 20 g of 2',5-dichloro-2-(5-oxitetraciclina-2-carbonyl) aminobenzophenone obtained in (1), benzylbromide, obtain 24.5 g of 2-[N-benzyl-N-(5-oxitetraciclina-2-carbonyl)]amino-2',5-dichlorobenzophenone in the form of butter.

The IR spectrum of theNeatmax/cm-1: 1780, 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 2.1 - 2.55 (2H, m), 2.65 - 3.0 (2H, m), 4.01 (doctor J = 14.4 Hz) + 4.29 (d, J = 14.4 Hz) (1H), 4.75 - 4.9 (1H, m), 5.29 (d, J=14.4 Hz) + 5.47 (d, J = 14.4 Hz)(1H), 6.6 - 7.6 (13H, m).

(3) is walking out of 23 g of 2-(N-benzyl-N-(5-oxitetraciclina-2-carbonyl) amino-2', 5-dichlorobenzophenone obtained in (2) obtain 17 g of (2-(N-benzyl-N-(4-etoxycarbonyl-2-oxy)-butyryl)-amino-2',5-dichloropentane.

The IR spectrum of theNeamaxtcm-1: 1730, 1660 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.1 - 1.35 (3H, m), 1.6 - 2.0 (2H, m), 2.3 - 2.8 (2H, m), 3,9 - 4,8 (4H, m), 5.34 (d, J=14.4 Hz) + 5.69 (d, J =14.4 Hz) (1H), 6.8 - 7.6 (12H, m).

(4) 2-(N-benzyl-N-(4-etoxycarbonyl-2 - methansulfonate)-butyryl)amino-2',5-dichlorobenzophenone

Work according to the method of example 8(4), on the basis of 17 g of 2-(N-benzyl-N-(4-etoxycarbonyl-2-hydroxy)butyryl)amino-2', 5-dichlorobenzophenone, obtain 19 g of 2-(N-benzyl-N-(4-etoxycarbonyl-2-methansulfonate)butyryl)amino-2',5-dichlorobenzophenone in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1675 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.1-1.35 (3H, m), 1.9 - 2.6 (4H, m), 3.17 + 3.32 (3H, each s), 4.85 - 5.0 (m) + 5.05 - 5.15 (m) (1H), 5.45 (d, J = 14.4 Hz) + 5.72 (d, J = 14.4 Hz) (1H), 6.9 - 7.6 (12H, m).

(5) Ethyl ester of CIS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,3-benzoxazepin-3-propionic acid and ethyl ester of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

Work according to the method of example 8(5), on the basis of 19 g of 2-(N-benzyl-N-(4-etoxycarbonyl-2-mechanim. As a first fraction get 3.1 g of ethyl ester of CIS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1670 (C = O).

As a second faction obtain 3.3 g of ethyl ester of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro - 4,1-benzoxazepin-3-propionic acid in the form of prisms with so pl. 122-123oC.

The IR spectrum of theNeamaxtcm-1: 1740, 1670 (C = O).

Elemental analysis for C27H25Cl2NO4:

Calculated, %: C, 65.07; H, 5.06; N, 2.81

Found, %: C, 65.30; H, 5.09; N, 2.81

Example 10

Ethyl ester of 7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

(1) 2', 5-Dichloro-2-(N-methyl-N-(5-oxitetraciclina-2 - carbonyl aminobenzophenone

Dissolve in 100 ml of acetone and 15 g of 2',5-dichloro-2-(5-oxitetraciclina-2-carbonyl)aminobenzophenone obtained in example 9(1). Added to a solution of 4.96 ml under the conditions and 11 g of potassium carbonate, the mixture is stirred for 3 days at room temperature. The reaction mixture is dispersed under reduced pressure. The residue is extracted, was added 200 ml of water and 300 ml of ethyl acetate. An ethyl acetate layer is I. Purify the residue by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2:1 to 1:1) obtain 13.5 g of 2', 5-dichloro-2-(N-methyl-(5-oxitetraciclina-2-carbonyl) aminobenzophenone in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1780, 1675 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 2.1 - 3.0 (4H, m), 3.08 + 3.14 (3H, each s), 4.75 - 4.9 (1H, m), 7.1 - 7.7 (7H, m).

(2) 2',5-Dichloro-2-(N-(4-etoxycarbonyl-2-hydroxy)butyryl-N-methyl)aminobenzophenone

Work according to the method of example 8(3), on the basis of 13.5 g of 2',5-dichloro-2-(N-methyl-N-(5-oxitetraciclina-2-carbonyl) aminobenzophenone, obtain 9.5 g of 2', 5-dichloro-2-(N-(4-etoxycarbonyl-2-hydroxy)butyryl)-N-methyl)aminobenzophenone in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1670, 1660 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.1 - 1.4 (3H, m), 1.5.-1.9 (2H, m), 2.0 - 2.75 (2H, m), 3.0-3.5 (3H, m), 3.95-4.05 (4H, m), 7.2 - 7.7 (7H, m).

(3) 2',5-Dichloro-2-(N-(4-etoxycarbonyl-3 - methanesulfonate)-butyryl-N-methyl)aminobenzophenone

Work according to the method of example 8(4), 9.5 g of 2',5-dichloro-2-(N-(4-etoxycarbonyl-2-hydroxy)butyryl-N-methyl)aminobenzophenone obtained in (2), enter into reaction with methanesulfonamido, obtain 11.0 g of 2',5-dichloro-3-(N-(4-etoxycarbonyl-2-methansulfonate)butyryl-N is SS="ptx2">

1H-NMR spectrum (200 MHz, CDCl3) : 1.1 - 1.35 (3H, m), 1.9 - 2.7 (4H, m), 3.0 - 3.7 (6H, m), 3.9 - 4.25 (2H, m), 4.9 - 5.7 (1H, m), 7.3 - 7.75 (7H, m).

(4) Ethyl ester of 7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid.

Work according to the method of example 8(5), on the basis of 11.0 g of 2',5-dichloro-2-(N-(4-etoxycarbonyl-2-methansulfonate)butyryl-N-methyl)aminobenzophenone obtained in (3), the reaction product is purified by chromatography on a column of silica gel, receive 4.17 g of a mixture of CIS - and TRANS-isomers of ethyl ester of 7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-propionic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1735, 1675 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.19 (3H, t, J = 7.2 Hz), 1.21 (3H, t, J = 7.2 Hz), 2.0 - 2.4 (4H, m), 2.4 - 2.6 (4H, m), 3.15 (3H, s), 3.51 (3H, s), 3.95 - 4.2 (5H, m), 4.36 (1H, t, J = 6.6 Hz), 5.99 (1H, s), 6.16 (1H, s), 6.50 (1H, d, J = 2.4 Hz), 7.05-7.8 (13H, m).

Example 11

Ethyl ester of 1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

(1) 4'-Methoxy-2-(5-oxitetraciclina-2-carbonyl) aminobenzophenone

Work according to the method of example 8(1), on the basis of 8 g of 2-amino-4'-methoxybenzophenone, which enter into reaction with 5-oxitetraciclina-2-CT">

The IR spectrum of theNeamaxtcm-1: 1780, 1685, 1625 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 2.3 - 2.8 (4H, m), 3.89 (3H, s), 4.9 - 5.05 (1H, m), 6.9 - 7.85 (7H, m), 8.5 - 8.6 (1H, m), 11.2 (1H, Shir).

(2) 2-(N-benzyl-N-(5-oxitetraciclina-2-carbonyl) amino-4'-methoxybenzophenone

Work according to the method of example 8(2), 12 g of 4'-methoxy-2-(5-oxitetraciclina-2-carbonyl)aminobenzophenone obtained in (1), enter into reaction with benzolamide, obtain 13.2 g of 2-(N - benzyl-N-(5-oxitetraciclina-2-carbonyl)amino-4'- methoxybenzophenone in the form of prisms c so pl. 137 - 138oC.

The IR spectrum of the Neamaxtcm-1: 1775, 1660, 1645 (C = O).

Elemental analysis for C26H23NO5:

Calculated, %: C 72.71; H, 5.40; N, 3.26

Found, %: C 72.98; H, 5.46; N, 3.22

(3) 2-(N-benzyl-N-(4-etoxycarbonyl-2-hydroxy)butyryl) amino-4'-aminobenzophenone

Work on methodology 8(3), on the basis of 13.0 g of 2-(N-benzyl-N-5-oxitetraciclina-2-carbonyl) amino-4'-methoxybenzophenone obtained in (2) obtain 10.5 g of 2-(N-benzyl-N-(4-etoxycarbonyl-2-hydroxy)butyryl)amino-4'-methoxybenzophenone in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1650 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.1 - 1.35 (3H, m), 1.7 - 2.1 (2H, m), 2.2 - 2.55 (2H, m), 3.88 is sulfonyloxy)-butyryl)amino-4-methoxybenzophenone

Work according to the method of example 8(4), is introduced into reaction with methanesulfonamido 10.5 g of 2-(N-benzyl-N-(4-etoxycarbonyl-2-hydroxy)butyryl)amino-4'-methoxybenzophenone, obtain 8.5 g of 2-(N-benzyl-N-(4-etoxycarbonyl-2-methansulfonate)butyryl)amino-4' -methoxybenzophenone in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1670, 1660 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.1 - 1.3 (3H, m), 2.0 - 2.6 (4H, m), 3.14 + 3.38 (3H, s), 3.89 + 3.91 (3H, s), 3.9 - 4.6 (3H, m), 4.9 - 5.65 (2H, m), 6.8 - 7.9 (13H, m).

(5) Ethyl ester of CIS-1-benzyl-5-(4-methoxyphenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid and ethyl ester of TRANS-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

Work according to the method of example 8(5), on the basis of 8.5 g 2-(N-benzyl-N-(4-etoxycarbonyl-2-methansulfonate)butyryl) amino-4'-methoxybenzophenone obtained in (4), get mixed product, which is purified by chromatography on a column of silica gel, receiving as a first fraction 2.0 g of ethyl ester of CIS-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-propionic acid in the form of needles with so pl. 95 - 96oC.

The IR spectrum of theKBrmaxcm-1: 1730, 1670 (C = O).

Elemental aneste second faction obtain 0.88 g of ethyl ester of TRANS-1 - benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.17 (3H, t, J=7.1 Hz), 2.1 - 2.4 (2H, m), 2.47 (2H, t, J = 7.1 Hz), 3.82 (1H, s), 3.95 - 4.2 (3H, m), 4.87 (1H, d, J= 14.6 Hz), 5.42 (1H, s), 6.58 (1H, d, J = 7.2 Hz), 6.8-7.5 (12H, m).

Example 12

Methyl ester of 1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

(1) 2-(N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl)aminobenzophenone

A mixture of 7.6 g of 2-chloro-4-methoxycarbonylamino acid, 9.2 ml of thionyl chloride and 30 ml of toluene is stirred for 30 minutes at 80oC, then the solvent is distilled off under reduced pressure to obtain 2-chloro-4 - methoxycarbonylmethylene. A mixture of this compound, 5.0 g of 2-benzylaminopurine, 100 ml of ethyl acetate and 100 ml of saturated aqueous sodium bicarbonate solution stirred for 30 min at room temperature. An ethyl acetate layer washed with water and dried with anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 5.1), obtain 1.2 g of 2-(N-benzyl - N -(2-chloro-4-methoxycarbonyl)butyryl)aminobenzophenone in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1735, 1655 (C = O).

The M4.53 (1H, d, J 14.4 Hz), 4.92 (IH, d, J = 14.4 Hz), 6.9 - 7.75 (14H, m).

(2) 2-(N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl) aminodiphenylamine

(Method A)

In 30 ml of methanol was dissolved 1.2 g of 2-(N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl)aminobenzophenone. To the solution was added with ice cooling 0.135 g of sodium borohydride. The mixture is stirred for 30 min at room temperature, then the solvent is distilled off under reduced pressure. To the residue add 100 ml of 1H hydrochloric acid for acidification of the solution which is then extracted with 100 ml of ethyl acetate. An ethyl acetate layer was washed with aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2:1) obtain 1.1 g of 2- (N-benzyl-N-(2-chloro-methoxycarbonyl)butyryl) aminodiphenylamine.

The IR spectrum of theNeamaxtcm-1: 3430 (OH), 1735, 1660 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.95 - 2.65 (4H, m), 3.2 - 4.4 (6H, m), 5.1 - 5.5 (1H, m), 5.75 - 6.15 (1H, m), 6.5 - 7.85 (14H, m).

(The way IN)

A mixture of 6.2 g of 2-chloro-4-methoxycarbonylamino acid and 12.6 ml of thionyl chloride is refluxed for 30 minutes, then evaporated RA is 2-benzylaminoacetonitrile, 100 ml of ethyl acetate and 100 ml of saturated aqueous sodium bicarbonate solution stirred for 1 h at room temperature. An ethyl acetate layer washed with water and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2:1) obtain 5.3 g of 2-(N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl)aminodiphenylamine in the form of butter.

(3) Methyl ester of CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid and methyl ester of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

In 20 ml of tetrahydrofuran was dissolved 1.1 g of 2-(N-benzyl-N-(2-chloro-4-methoxycarbonyl)butyryl)aminodiphenylamine. To the solution was added 107 mg of sodium hydride (60% in oil), the mixture is stirred for 1 h at room temperature. To the reaction mixture was added 50 ml of 1H hydrochloric acid for acidification of the solution which is then extracted with 100 ml of ethyl acetate. An ethyl acetate layer was washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-Zipin-3-propionic acid in the form of plates with so pl. 134 - 135oC.

The IR spectrum of theKBrmaxcm-1: 1740, 1670 (C = O).

Elemental analysis for C25H25NO4:

Calculated, %: C, 75.16; H the 6.06; N, 3.37

Found, %: C, 74.74; H, 5.97; N, 3.38

From the second fraction allocate 0.18 g of methyl ester of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of needles with so pl. 116 - 118oC.

The IR spectrum of theKBrmaxcm-1: 1740, 1670 (C = O).

Elemental analysis of C26H25NO4:

Calculated, %: C, 75.16; H, 6.06; N, 3.73

Found, %: C, 75.22; H, 5.94; N, 3.58

Example 13

CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin - 3-propionic acid

In 20 ml of methanol was dissolved 0.5 g of ethyl ester of CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 8. To the solution was added 7 ml of 1H of sodium hydroxide and stirred the mixture for 30 min at room temperature. The reaction mixture was acidified with 100 ml of 1H hydrochloric acid, then extracted with 150 ml of ethyl acetate. An ethyl acetate layer washed with water and dried over anhydrous magnesium sulfate. Then the solvent is distilled off under reduced pressure to obtain 0.46 g of CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3 - 1670 (C = O).

Elemental analysis for C25H23NO4:

Calculated, %: C, 74.80; H, 5.77; N, 3.49

Found, %: C, 74.52; H, 5.85; N, 4.42

Example 14

TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

Work according to the method of example 13, 1.0 g of ethyl ester of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 8, is subjected to hydrolysis, to obtain 0.81 g of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of plates with so pl. 148 -150oC.

The IR spectrum of theKBrmaxcm-1: 1735, 1650 (C = O).

Elemental analysis for C25H23NO4:

Calculated, %: C 74.80; H, 5.77; N, 3.49

Found, %: C 74.66; H, 5.78; N, 3.55

Working on the above methodology, 0.9 g of methyl ester of TRANS-1-benzyl-2-oxo-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 12, is subjected to hydrolysis, to obtain 0.86 g of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid.

Example 15

CIS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

Work according to the method of example 13, 3.1 g of ethyl ester of CIS-1-benzyl-7-hlaut hydrolysis, obtain 2.9 g of CIS-1-benzyl-7-chloro-5-(2 - chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of prisms with so pl. 135 - 137oC.

The IR spectrum of theKBrmaxcm-1: 1725, 1640 (C = O).

Elemental analysis for C25H21Cl2NO4:

Calculated, %: C, 63.84; H, 4.50; N, 2.98

Found, %: C, 64.02; H, 4.76; N, 2.88

Example 16

TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

Work according to the method of example 13, 2.7 g of ethyl ester of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 9, is subjected to hydrolysis, to obtain 2.5 g of TRANS-1-benzyl - 7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-propionic acid in the form of prisms with so pl. 192 - 194oC.

The IR spectrum of theKBrmaxcm-1: 1730, 1640 (C = O).

Elemental analysis for C25H21Cl2NO4:

Calculated, %: C 63.84; H, 4.50; N, 2.98

Found, %: C, 63.99; H, 4.57; N, 2.92

Example 17

7-Chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-propionic acid

Work according to the method of example 13, 4.1 g of ethyl ester of 7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzox what - methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of oil from a mixture of CIS - and TRANS-compounds (1:1).

The IR spectrum of theNeamaxtcm-1: 1705, 1670 (C = O)

1H-NMR spectrum (200 MHz, CDCl3) : 2.0-2.4 (4H, m), 2.45 - 2.7 (4H, m), 3.14 (3H, s), 3.50 (3H, s),4.00 (1H, DD, J= 7.2 x 5.4 Hz), 4.35 (1H, t, J= 6.7 Hz), 5.99 (1H, s), 6.16 (1H, s), 6.50 (1H, d, J = 2.2 Hz), 7.0 - 7.81 (13H, m).

Example 18

CIS-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-propionic acid

Work by the method of 13, 1.7 g of ethyl ester of CIS-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 11, is subjected to hydrolysis, to obtain 1.5 g of CIS-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid in the form of prisms with so pl. 107 - 109oC.

The IR spectrum of theKBrmaxcm-1: 1715, 1670 (C = O).

Elemental analysis for C26H25NO5:

Dedicated, %: 72.35; H, 5.84; N, 3.25

Found, %: C, 72.26; H, 5.90; N, 3.10

Example 19

TRANS-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid

Work according to the method of example 13, 0.85 g of ethyl ester of TRANS-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-C-propionic acid is subjected to hydrolysis, to obtain 0.78 g of TRANS-1-benzyl-5-(4-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-b is 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 2.05 - 2.35 (2H, m), 2.52 (2H, t, J = 7.1 Hz), 3.81 (1H, s), 4.00 (1H, DD, J = 7.3 x 5.7 Hz), 4.39 (1H, d, J = 14.4 Hz), 5.40 (1H, s), 5.49 (1H, d, J = 14.4 Hz), 6.57 (1H, d, J=7.2 Hz), 6.8 - 7.5 (12H, m).

Example 20

TRANS-1-benzyl-3-(3-oksipropil)-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-he

A mixture of 0.4 g of methyl ester of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-oxazepan-3-propionic acid obtained in example 12, 0.16 g of sodium borohydride and 0.16 g of lithium chloride in 15 ml of tetrahydrofuran is stirred for 10 min at room temperature. To the mixture was added 30 ml of ethanol, stirred for 2 h at 60oC. To the reaction mixture was added 100 ml of 1H hydrochloric acid and 150 ml of ethyl acetate. An ethyl acetate layer was washed with aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2: 1) obtain 0.19 g of TRANS-1-benzyl-3-(3-oksipropil)-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-it is in the form of needles with so pl. 59 - 62oC.

The IR spectrum of theKBrmaxcm-1: 1645 (C = O).

Elemental analysis for C25H25NO3:

Calculated, %: C, 77.49; H, 6.50; N, 3.61

Found, % Work according to the method of example 20, 0.23 g of methyl ester of CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 12, is subjected to recovery, getting 0.09 g of CIS-1-benzyl-3-(3-oksipropil)-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-it is in the form of needles with so pl. 94 - 95oC.

The IR spectrum of theKBrmaxcm-1: 1675, 1660 (C = O).

Elemental analysis for C25H25NO3:

Calculated, %: C 77.49; H, 6.50; N, 3.61

Found, %: C 77.44; H, 6.49; N, 3.76

Example 22

N-(CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)aminoethanol

In 5 ml of N,N-dimethylformamide is dissolved 0.3 g of CIS - 1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 13, and 0.054 ml ethanolamine. To the solution was added with ice cooling 0.17 g of diethylphosphonoacetate and 0.14 ml of triethylamine. The mixture is stirred for 30 min at room temperature, then add 100 ml of water. The mixture is extracted with 2 x 100 ml of ethyl acetate. An ethyl acetate layer is washed 1H hydrochloric acid and aqueous sodium bicarbonate solution successively, dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (Alwin-3-propionyl)-aminoethanol in the form of needles with so pl. 117 - 119oC.

The IR spectrum of theKBrmaxcm-1: 1670, 1640 (C = O).

Elemental analysis for C27H28N2O40.5 H2O:

Calculated, %: C, 71.50; H, 6.44; N, 6.18

Found, %: C, 71.29; H, 6.47; N, 5.98

Example 23

N-(TRANS-1-benzyl-1-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)aminoethanol

Work according to the method of example 22, 0.25 g of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 14, condense with ethanolamine, obtain 0.20 g of N-(TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-propionyl)aminoethanol in the form of plates with so pl. 125 -127oC.

The IR spectrum of theKBrmaxcm-1: 1675, 1645 (C = O).

Elemental analysis for C27H28N2O4:

Calculated, %: C, 72.95; H, 6.35; N, 6.30

Found, %: C, 72.70; H, 6.36; N, 6.19

Example 24

Methyl ester of N - (CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan

In 10 ml of N,N-dimethylformamide is dissolved 0.35 g of CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid obtained in example 13, and 0.23 g of hydrochloric acid methyl ester of L-tryptophan. To the solution was added with ice cooling 0.15 g ditillo adding 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer is washed 1H hydrochloric acid and aqueous sodium bicarbonate solution successively, dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 1: 1) obtain 0.50 g of methyl ester of N-(CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-C-propionyl)-L-tryptophan in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1740, 1665 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 2.15 - 2.5 (4H, m), 3.27 (2H, t, J=4.7 Hz), 3.62 + 3.63 (3H each, s), 3.71 (1H, d, J=16.0 Hz), 4.15 - 4.3 (1H, m), 4.68 (1H, d, J = 16.0 Hz), 4.8 - 5.0 (1H, m), 5.85 (1H, s), 6.15 - 6.35 (1H, m), 6.9 - 7.6 (19H, m), 8.13 (1H, Shir).

Example 25

N -(CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan

Dissolved in 10 ml of methanol, 0.5 g of methyl ester of N-(CIS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan obtained in example 24. To the solution add 5 ml of 1H sodium hydroxide and stir the mixture for 1 h at room temperature. The reaction mixture is acidified by adding 100 ml of 1H hydrochloric acid, then extracted with 100 ml of ethyl acetate. An ethyl acetate layer washed with water and dried over anhydrous sulfate communicated to the DRO-4,1-benzoxazepin-3-propionyl)-L-tryptophan in the form of a powdery product.

The IR spectrum of theKBrmax/cm-1: 1730, 1660 (C = O).

Elemental analysis for C36H33N3O5:

Calculated, %: C, 73.58; H 5.66; N, 7.15

Found, %: C, 73.56; H, 6.07; N, 6.79

Example 26

Methyl ester of N-(TRANS-1-benzene-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan

Work according to the method of example 24, 0.2 g of TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionic acid condense with hydrochloric acid methyl ester of L-tryptophan, obtain 0.28 g of methyl ester of N-(TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3 - propionyl)-L-tryptophan in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1740, 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 2.1 - 2.4 (4H, m), 3.15 - 3.3 (2H, m), 3.6 - 3.7 (3H, m), 3.95 - 4.15 (1H, m), 4.8 - 5.0 (2H, m), 5.45 (1H, s), 5.49 (1H, d, J = 14.2 Hz), 6.05 - 6.2 (1H, m), 6.45 - 6.6 (1H, m), 6.9 - 7.6 (18H, M), 8.03 (1H, Shir).

Example 27

N-(TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan

Work according to the method of example 25, is subjected to hydrolysis 0.28 g of methyl ester of N-(TRANS-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan obtained in example 26, obtain 0.24 g of N-(TRANS-1-Benn CLASS="ptx2">

The IR spectrum of theKBrmaxcm-1: 1730, 1660 (C = O).

Elemental analysis of C36H33N3O5:

Calculated, %: C 72.69; H, 5.73; N, 7.06

Found, %: C, 72.82; H, 5.84; N, 6.79

Example 28

Methyl ester of N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan

Work according to the method of example 24, condense 0.3 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-2-propionic acid obtained in example 16, with hydrochloric acid, the methyl ester of L-tryptophan, obtain 0.41 g of methyl ester of N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo - 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1735, 1660 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 2.1 - 2.45 (4H, m), 3.2 - 3.35 (2H, m), 3.64 + 3.66 (3H, each s), 3.95 - 4.15 (1H, m), 4.65 - 4.8 (1H, m), 4.8 - 5.0 (1H, m), 5.5 - 5.65 (1H, m), 5.76 (1H, s), 6.0 - 6.2 (1H, m), 6.35 - 6.45 (1H, m), 6.9 -7.7 (16H, m), 8.16 (1H, Shir).

Example 29

N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-L-tryptophan

Work according to the method of example 25, is subjected to hydrolysis 0.41 g of methyl ester of N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-Bel)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-propionyl)-L-tryptophan in the form of a powdery product.

The IR spectrum of theKBrmaxcm-1: 1730, 1660 (C = O).

Elemental analysis for C36H31Cl2N3O5:

Calculated, %: C, 65.86; H, 4.76; N, 6.40

Found, %: 66.13; H, 5.02; N, 6.24

Example 30

Ethyl ester of N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-D-tryptophan

Work according to the method of example 24, conduct condensation 0.3 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-propionic acid with hydrochloric acid ester of D-tryptophan, obtain 0.43 g of ethyl ester of N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-D-tryptophan in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1665 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.1 - 1.3 (3H, m), 2.1 - 2.45 (4H, m), 3.2 - 3.35 (2H, m), 3.95 - 4.2 (3H, m), 4.65 - 4.8 (1H, m), 4.8 - 5.0 (1H, m), 5.5 - 5.65 (1H, m), 5.76 (1H, s), 6.0 - 6.2 (1H, m), 6.35 - 6.45 (1H, m), 6.9 - 7.7 (16H, m), 8.13 (1H, Shir).

Example 31

N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-D-tryptophan

Work according to the method of example 25, conduct hydrolysis 0.43 g of ethyl ester of N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-propionyl)-D-Tr is benzoxazepin-3-propionyl)-D-tryptophan in the form of a powdery product.

The IR spectrum of theKBrmaxcm-1: 1725, 1660 (C = O).

Elemental analysis for C36H31Cl2N3O5:

Calculated, %: C, 65.86; H, 4.76; N, 6.40

Found, %: C, 65.30; H, 5.15; N, 6.03

Example 32

Methyl ester of N-(TRANS-7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylacetic)-L-tryptophan

To a mixture of 0.6 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in reference example 4 was added 0.42 g of hydrochloric acid methyl ester of tryptophan and 10 ml of dimethylformamide with stirring under ice cooling, and 0.73 g of diethylphosphoramidite. To the resulting mixture were then added 0.55 ml of triethylamine. The reaction mixture was stirred 40 min at room temperature, then poured into ice-water, then extracted with ethyl acetate. The organic layer is washed with diluted aqueous solution of potassium bisulfate, aqueous solution of sodium bicarbonate and water successively, dried and concentrated under reduced pressure. The concentrate is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 1:1 to 1:3). From the first fractions of the eluate obtain 0.33 g of methyl ester of N-(TRANS-7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-1,2,3,5 the analyses for C30H27Cl2N3O5:

Calculated, %: C 62.08; H, 4.69; N, 7.24

Found, %: C, 61.82; H, 4.71; N, 6.95

From the subsequent fractions of the eluate obtain 0.28 g steric isomer of the above compound, so pl. 159 - 160oC.

Elemental analysis for C30H27Cl2N3O5:

Calculated, %: C 62.08; H, 4.69; N, 7.24

Found, %: C 61.94; H, 4.50; N, 6.69

Example 33

Work according to the method of example 32, receive connections, are shown in tables 24 to 28, using the compounds of reference examples 5 and 2.

Example 34

N-(TRANS-7-chloro-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylacetic)-L-tryptophan

Dissolved in a mixture of 8 ml of methanol and 4 ml of tetrahydrofuran, 0.2 g of methyl ester of N-(TRANS-7-chloro-5-(2-chlorophenyl)-1-methyl-1, 2,3,5-tetrahydro-4,1-benzoxazepin-3-ylacetic)-L-tryptophan, obtained from the first fraction of the sample 32. To the solution was added 200 mg of potassium carbonate and 5 ml of water, the mixture is stirred for 3 h at 60oC. the Reaction mixture was concentrated under reduced pressure. Set the pH of the concentrate is equal to 3 using 1H hydrochloric acid, then extracted with ethyl acetate. The organic layer is washed with water and dried, the solvent is distilled off under reduced pressure. The residue is purified x is R-5-(2-chlorophenyl)-1-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetic)-L-tryptophan in the form of colorless powdery product.

The IR spectrum of theKBrmaxcm-1: 3700-2200 (COOH), 1660 (CO), 1485, 1250, 1110, 740.

1H-NMR spectrum (200 MHz, CDCl3) : 2.2-3.2 (4H, m), 3.24 (3H, s, ), 4.2 (1H, m, C3(H) 4,63 (1H, m), 5.73 (1H, s, C5-H), 6.34 (1H, d, C6-H), 6.6-7.7 (10H, m).

Elemental analysis for C29H25Cl2N3O51/2 C4H8O21/2 H2O:

Calculated, %: C 60.10; H, 4.88; N, 6.78

Found, %: C 60.11; H, 4.89; N, 6.69

Hydrolized by the method described above 0.2 g of compound, lirovannomu subsequently by chromatography on a column of silica gel, to obtain 0.11 g of crystals steric isomer, so pl. 165 - 167oC.

Elemental analysis for C29H25Cl2N3O51/2 C4H8O21/2 H2O:

Calculated, %: C 60.53; H, 4.84; N, 6.83

Found, %: C 60.44; H, 4.88; N, 6.83

Example 35

Work according to the method of example 34, receive connections, are shown in tables 29 to 33.

Example 36

(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methylamine

In 5 ml of dimethylformamide was dissolved 1.0 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-oxazepine-3-acetic acid obtained in reference example 5. To the solution was added 0.3 ml of triethylamine, ZAT is room temperature, then poured into ice-water. The mixture is extracted with ether. The organic layer is washed with water and dried, then concentrated under reduced pressure. The concentrate is dissolved in 100 ml of benzene, and then refluxed for 30 minutes, the Reaction mixture was concentrated under reduced pressure. To the concentrate was added 6 ml of concentrated hydrochloric acid, a mixture of 1 h refluxed. The reaction mixture was concentrated under reduced pressure. The concentrate is alkalinized by addition of 5% aqueous potassium carbonate solution, then extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. To the residue was added ethanol solution 4H hydrochloric acid, to obtain the hydrochloride, obtain 0.85 g of the hydrochloride (TRANS-1-benzyl-7-chloro-5-(2 - chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methylamine in the form of crystals with so pl. 245 - 250oC.

Elemental analysis for C23H20Cl2N2O23/2H2O:

Calculated, %: C, 56.34; H, 4.82; N, 5.71

Found, %: C 56.65; H, 4.44; N, 6.09

Example 37

Work according to the method of example 36, get connections given in table 34.

Example 38

Atroven.

In 4 ml of dimethylformamide was dissolved 0.3 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-oxazepine-3-acetic acid obtained in reference example 5. To the solution was added 0.15 ml of triethylamine. To the mixture was added with stirring and ice cooling 0.18 g diphenylphosphinite. The reaction mixture was stirred 1 h at room temperature, then added ice-water and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. To the concentrate was added 10 ml of benzene, the mixture is refluxed for 1 h under stirring. To the reaction mixture was added 0.14 g of hydrochloric acid ethyl ester of glycine and 0.15 ml of triethylamine. The mixture is then boiled for 3 h under reflux. The reaction mixture was concentrated under reduced pressure. The concentrate is extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. Recrystallized crystals obtained from the residue from a mixture of ethyl acetate and hexane, to obtain 0.33 g of the target compound as white crystals with so pl. 200 - 201oC.

Elemental analysis for C28H27Cl2N3O5:

Calculated, %: C 60.44; the NS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methylaminomethyl) glycine. To the solution was added 0.2 g of potassium carbonate and 2 ml of water, the mixture is stirred for 3 h at 60oC. the Reaction mixture was concentrated under reduced pressure, water is added and extracted with ether. The aqueous layer was acidified to pH 3 with diluted hydrochloric acid, then extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure to obtain a crystalline residue. Recrystallization from ethyl acetate gives 0.18 g of N-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl-methylaminomethyl)-glycine in the form of colorless crystals with so pl. 153 - 155oC.

Elemental analysis for C26H23Cl2N3O5KBrmaxcm-1: 3700 - 2200 (COOH), 1740 (CO), 1670 (CO), 1420, 1250, 1170, 1080, 750.

1H-NMR spectrum (200 MHz, CDCl3) : 3.8 - 5.1 (6H, m), 5.75 (1H, s5-H), 6.40 (1H, s6-H), 7.0 - 7.8 (16H, m).

Elemental analysis for C32H26Cl2N2O52/3H2O:

Calculated, %: C 62.34; H, 4.74; N, 4.54

Found, %: C at 62.40; H, 4.44; N, 4.32

Example 45

TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-3-(3-methoxycarbonyl-methylcarbamoyl)methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

To a mixture of 0.25 g of (TRANS-1-benzyl-7-HLG potassium salt of Palmyra radon acid and 4 ml of dimethylformamide, under stirring and cooling on ice, 0.13 g of diethylphosphonoacetate and 0.23 ml of triethylamine. The reaction mixture was stirred 40 min at room temperature, then added ice-water, then extracted with ethyl acetate. The organic layer was washed with aqueous solution of sodium bisulfate, aqueous solution of sodium bicarbonate and water successively, and then dried. The solvent is distilled off, the residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate-ethanol = 10: 10: 1) obtain 0.22 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-3-(3 - methoxycarbonyl-methylcarbamoyl)methyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepine in the form of a white powder.

The IR spectrum of theKBrmaxcm-1IS : 3370 (NH), 2950, 1745 (CO), 1670 (CO), 1480, 1420, 1250.

1H-NMR spectrum (200 MHz, CDCl3) : 3.31 (2H, c, CO2), 3.74 (3H, s, OCH3), 3.7 - 4.2 (3H, m), 4.8 (1H, d), 5.6 (1H, d), 5.8 (1H, c, C5-H), 6.42 (1H, d, C6-H), 7.2 -7.8 (1H, m).

Elemental analysis for C27H24Cl2N2O5KBrmaxcm-1: 3700 - 2200 (COOH), 1730 (CO), 1670 (CO), 1480, 1240.

1H-NMR spectrum (200 MHz, CDCl3) : 3.31 (2H, s, -SOSOON), 3.7 - 4.2 (3H, m), 4.75 (1H, d), 5.62 (1H, d), 5.77 (1H, s, C5-H), 6.44 (1H, d, C6-H), 7.04 (1H, t, NH), 7.2 -7.7 (11H,m).

Elemental analysis for C26H22
TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methanol and 3,5-TRANS-7-chloro-3-chloromethyl-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

In a mixture of 12 ml of glacial acetic acid and 10 ml of water is suspended 2.0 g of (TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)methylamine hydrochloride, obtained in example 36. To the suspension are added dropwise while cooling with ice and stirring, 1 ml of an aqueous solution of 1.0 g of sodium nitrite in 10 minutes the Reaction mixture was stirred 1 h at room temperature, then poured on ice-water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and water successively, and then dried, the solvent is distilled off under reduced pressure. The residue is dissolved in 50 ml of methanol, then add 5 ml of 10% aqueous potassium carbonate solution. The mixture is stirred for 15 min at 60oC. the Reaction mixture was concentrated under reduced pressure. The concentrate is extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 4:1 to 1: 1). From the first then tcvetnyh crystals with so pl. 177 - 179oC.

Mass spectrum (m/e): 445 (M+).

Elemental analysis for C23H18Cl3NO2:

Calculated, %: C 61.83; H, 4.06; N, 3.14

Found, %: C, 62.11; H, 4.01; N, 3.38

From the later part of the eluate allocate 1.05 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methanol as colorless needles with so pl. 158 - 159oC.

Mass spectrum (m/e): 427, 429 (M+).

Elemental analysis for C23H19Cl2NO3:

Calculated, %: C, 64.49; H, 4.47; N, 3.27

Found, %: C, 64.36; H, 4.39; N, 3.34

Example 47

Work according to the method of example 46, get connections given in table 35.

Example 48

TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-carboxylic acid.

Dissolved in 20 ml of acetone, 0.5 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methanol obtained in example 46. To the solution are added dropwise with stirring at room temperature, 0.5 ml of Jones reagent. The reaction mixture was stirred for 1 h at room temperature, then concentrated under reduced pressure. The concentrate is extracted with ethyl acetate. The organic layer is washed with water and dried, ZAT-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-carboxylic acid as white crystals with so pl. 177 - 178oC.

Elemental analysis for C23H17Cl2NO4:

Calculated, %: C, 62.46; H, 3.87; N, 3.17

Found, %: C, 62.24; H, 3.93; N, 3.30

Example 49

Work according to the method of example 48, get connections given in table 36.

Example 50

Ethyl ester of 3-(TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl)thioglycolate acid

Dissolved in 6 ml of acetonitrile, 0.2 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-3-chloromethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine. To the solution was added 0.08 g of ethyldiglycol and 0.1 g of cesium fluoride. The mixture is refluxed for 40 minutes under stirring. The reaction mixture was concentrated under reduced pressure. The concentrate is extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 4:1) obtain 0.16 g of ethyl-3-[TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]-thioglycolate in the form of colorless needles with so pl. 153 - 154oC.

Elemental analysis for C27H25Cl2NO4S:

Calculated, %: C, 61.13; H, 4.75; N is 2-4,1 oxazepan-3-ylmethyl]glycolic acid

In a mixture of 4 ml of methanol and 2 ml of tetrahydrofuran is dissolved 0.11 g of the ester of 3-[TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl] thioglycolic. To the solution was added 0.2 g of potassium carbonate and 2 ml of water, then the mixture is stirred for 1 h at 60oC. the Reaction mixture was concentrated under reduced pressure. The concentrate is acidified with diluted hydrochloric acid, then extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. Of the remainder receive 90 mg of 3-(TRANS-7-chloro-1-benzyl-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl)thioglycolic in the form of white crystals with so pl. 148 - 149oC.

Elemental analysis for C25H21Cl2NO4S:

Calculated, %: C 59.77; H, 4.21; N, 2.79

Found, %: 59.89; H, 4.31; N, 2.77

Example 52

3-[TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]glycolic acid

To a suspension of 50 mg of sodium hydride in 4 ml of dimethylformamide was added 0.2 g of TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methanol with stirring and ice cooling. The mixture is stirred for 10 min at the same temperature, seaut into ice-water and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of potassium bisulfate, aqueous solution of sodium bicarbonate and water successively and dried, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 5:1) get the crystals. The crystals are dissolved in 5 ml of methanol. To the solution was added 0.2 g of potassium carbonate and 2 ml of water. The mixture is stirred for 5 h at 60oC. the Reaction mixture was concentrated under reduced pressure. Acidified concentrate diluted hydrochloric acid, then extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. Of the remainder receive 50 mg of 3-[TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]glycolic acid in the form of white crystals with so pl. 92 - 94oC.

Elemental analysis for C25H21Cl2NO51/2 C4H10O 1/2H2O:

Calculated, %: C 60.91; H, 5.11; N, 2.63

Found, %: C, 60.95; H, 4.99; N, 2.77

Example 53

Methyl ester of N-[TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylcarbonyl]tryptophan

Work according to the method of example 32, in response enter 0.4 g of 3,5-tree 48, get the crude product which is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate-methylene chloride = 9:3:1). From the first portion of the eluate obtain 0.25 g of the product as a white powder.

The IR spectrum of theKBrmaxcm-1: 3400 (NH), 1740 (CO), 1690 (CO), 1655 (CO).

1H-NMR spectrum (200 MHz, CDCl3) : 3.44 (2H, d), 3.64 (3H, s, OCH3), 4.55 (1H, C3-H), 4.70 (1H, m, PhCH2), 5.03 (1H, m), 5.69 (1H, m, PhCH2), 5.79 (1H, s5-H), 6.37 (1H, d6-H), 6.9 - 8.2 (15H, m)

From subsequent portions of the eluate obtain 0.22 g of the target compound in the form of an amorphous product.

The IR spectrum of the KBrmaxcm-1: 3400 (NH), 1740 (CO), 1695 (CO), 1660 (CO), 1520, 1480, 1240.

1H-NMR spectrum (200 MHz, CDCl3) : 3.2 - 3.55 (2H, m), 3.70 (3H, s, OCH3), 4.53 (1H, s, C3-H), 4.62 (1H, d), 5.06 (1H, m), 5.63 (1H, d), 5.76 (1H, s5-H), 6.33 (1H, d6-H), 6.8 - 8.4 (15H, m).

Example 54

N-[TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylcarbonyl]tryptophan

Work according to the method of example 34, based on the ethyl ester of N-[TRANS-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-ylcarbonyl]tryptophan obtained in example 53. From 0.25 g of the compound obtained in the first eluate, receive 70 mg of b is H27Cl2N3O5H2O:

Calculated, %: C, 63.16; H, 4.52; N, 6.50

Found, %: C, 63.34; H, 4.63; N, 6.42

Of 0.22 g of compound, lirovannomu subsequently, obtain 0.11 g of a colorless amorphous solid product.

The IR spectrum of the KBrmaxcm-1: 3700 - 2200 (NH, COOH), 1740 (CO), 1680 (CO), 1660 (CO), 1525, 1240.

1H-NMR spectrum (200 MHz, CDCl3) : 3.40 (2H, m), 4.54 (1H, s), 4.63 (1H, d), 5.05 (1H, m), 5.63 (1H, d), 5.70 (1H, s, C5-H), 6.31 (1H, d, C6-H), 6.8 - 8.4 (15H, m).

Elemental analysis for C34H27Cl2N3O5:

Calculated, %: C, 64.97; H, 4.33; N, 6.67

Found, %: C 64.70; H, 4.58; N, 6.49

Example 55

N-(Tris-7-chloro-1-isopropyl-5-phenyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylacetic]glycine ethyl ester

Dissolve in 5 ml of methanol, 0.3 g of ethyl ester of 3,5-CIS-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid, described in JPA S57(1982)-35576. To the solution was added 0.3 g of potassium carbonate and 2 ml of water. The mixture is stirred for 8 h at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, then extracted with ether. The aqueous layer was separated, add diluted hydrochloric acid to pH 3. The organic layer is washed with water and su is. Product and 0.07 g of hydrochloric acid ethyl ester of glycine dissolved in 4 ml of dimethylformamide. To the solution was added with stirring and ice cooling 0.1 g of diethylphosphonoacetate, and then 0.2 ml of triethylamine. The reaction mixture was stirred 1 h at room temperature, then poured into ice-water, extracted with ethyl acetate. The organic layer was washed with an aqueous solution of potassium bisulfate, aqueous solution of sodium bicarbonate and water successively, and then dried. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2:1 to 3:2), obtain 0.11 g of N-(CIS-7-chloro-1-isopropyl-5-phenyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-ylacetic)-glycine ethyl ester in the form of a crystalline product with so pl. 188-190oC.

Elemental analysis for C24H27ClN2O5:

Calculated, %: C, 62.81; H, 5.93; N, 6.10

Found, %: C 62.52; H, 6.10; N, 6.04

Example 56

N-[CIS-7-chloro-1-isopropyl-5-phenyl)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetic]glycine

In a mixture of 2 ml of methanol and 1 ml of water is suspended 48 mg of ethyl ester of N -(TRANS-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ylacetic)glycine obtained in example 55. To actionnow mixture is equal to 4 with dilute hydrochloric acid, then extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The crystals obtained from the residue is recrystallized from ether and hexane, to obtain 29 mg of N-(CIS-7-chloro-1-isopropyl-5-phenyl-1,2,3,5-tetrahydro-2-oxo-4,1-oxazepan-3-ylacetic)glycine in the form of white needles.

The IR spectrum of theKBrmaxcm-1: 3700 - 2200 (COOH), 1710 (CO), 1680 (CO), 1480, 1250, 700.

1H-NMR spectrum (200 MHz, CDCl3) : 2.7 - 3.4 (2H, m), 4.4 (1H, DD, C3-H), 4.75 (1H, d), 5.34 (1H, s, C5-H), 5.5 (1H, d), 6.48 (1H, s, C6-H), 6.9 - 7.6 (12H, m).

Elemental analysis for C24H20ClNO43/4H2O:

Calculated, %: C, 66.20; H, 4.98; N, 3.22

Found, %: C 66.12; H, 5.19; N, 2.97

Example 57

Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2 - oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-butyric acid

(1) a Solution of 0.72 ml oxalicacid in 10 ml of methylene chloride is cooled to -65oC, add there dropwise a solution of 0.63 ml of dimethyl sulfoxide in 2 ml of methylene chloride for 5 min, then stirred for 5 min. To the mixture are added dropwise over 15 min a solution of 2.5 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethanol obtained in example 47, 15 ml Meiling who have a cooling bath. The mixture is stirred for 10 min at room temperature, then add 50 ml of 1N. hydrochloric acid, then stirred. Methylenchloride layer is dried over anhydrous magnesium sulfate and then the solvent is distilled off under reduced pressure to obtain 2.3 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetaldehyde in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1720, 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 1.29 (3H, t, J=7.1 Hz), 1.29 (3H, d, J = 7.0 Hz), 1.56 (3H, d, J =6.8 Hz), 2.7 - 2.85 (2H, m), 3.91 (1H, t, J= 6.5 Hz), 4.19 (2H, K, J=7.1 Hz), 4.75 - 5.0 (1H, m), 5.90 (1H, dt, J=15.6, 1.5 Hz), 6.01 (1H, s), 6.51 (1H, d, J = 2.4 Hz), 6.97 (1H, dt, J = 15.6, 7.2 Hz), 7.2 - 7.8 (6H, m), 9.83 (1H, s).

(2) was Dissolved in 20 ml of toluene, 1.5 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetaldehyde. To the solution was added 2.0 g (etoxycarbonyl-methylene)triphenylphosphorane and stirred the mixture for 3 h at 90oC. Distilled off the solvent and purify the residue by chromatography on a column of silica gel (hexane-ethyl acetate = 10:1) obtain 1.28 g of ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-crotonic acid in the form of prisms with so pl. 126 - 127oC.

The IR spectrum of theKBrmaxwith the but % 62.34; H, 5.45; N, 3.03

Found, %: C 62.47; H, 5.28; N, 3.08

(3) was Dissolved in 20 ml of ethyl acetate 0.45 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-crotonic acid. To the solution was added 1 g of 10% palladium on coal and subjecting the mixture to catalytic recovery at room temperature and atmospheric pressure. Allow to absorb theoretical amount of hydrogen, then remove the catalyst and ethyl acetate is distilled off under reduced pressure. The residue is crystallized from a small volume of hexane, to obtain 0.37 g of ethyl ester of 7-TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-butyric acid in the form of prisms with so pl. 100 - 101oC.

The IR spectrum of theKBrmaxcm-1: 1730, 1670 (C = O).

Elemental analysis for C24H27Cl2NO4:

Calculated, %: C, 62.07; H, 5.86; N, 3.02

Found, %: C, 62.35; H, 5.93; N, 2.95

Example 58

TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-butyric acid

Dissolve in 5 ml of ethanol 0.25 g of ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-butyric acid. To the solution was added 4 ml of 1H of sodium hydroxide, the mixture is then peremeshayet 100 ml of ethyl acetate. An ethyl acetate layer washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 0.20 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-butyric acid in the form of prisms with so pl. 158 - 160oC.

The IR spectrum of theKBrmaxcm-1: 1710, 1670 (C = O).

Elemental analysis for C22H23Cl2NO4:

Calculated, %: C 60,56; H 5,31; N 3,21

Found, %: C 60,62; H 5,18; N 3,23

Example 59

Ethyl ester of N-[TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

Work according to the method of example 24, from 0.4 g of TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid and hydrochloric acid ethyl ester of glycine, get to 0.47 g of ethyl ester of N-[TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid in the form of needles with so pl. 137 - 138oC.

The IR spectrum of theKBrmaxcm-1: 3360 (NH), 1745, 1655 (C = O).

Elemental analysis for C26H32N2O5:

Calculated, %: C 69,01; H 7,13; N IS 6.19

Found, %: C 69,01; H 7,18; N 6,26

Example 60

N-[TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-Ben is N-[TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid, obtained in example 59, conduct hydrolysis, obtain 0.26 g of N-[TRANS-1-isobutyl-2-oxo-5-(o-tolyl)-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetyl]aminouksusnoy acid in the form of prisms with so pl. 220 - 223oC.

The IR spectrum of theKBrmaxcm-1: 1755, 1670, 1630 (C = O).

Elemental analysis for C24H26N2O5:

Calculated, %: C 67,91; H of 6.65; N 6,60

Found, %: C 67,96; H 6,86; N 6,69

Example 61

Ethyl ester of N-[TRANS-5-(2-forfinal)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

Enter into reaction with hydrochloric acid ethyl ester, glycine and 0.4 g of TRANS-5-(2-forfinal)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained by the method of example 6, are working according to the method of example 24, obtain 0.45 g of ethyl ester of N-[TRANS-5-(2-forfinal)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid in the form of needles with so pl. 166 - 168oC.

The IR spectrum of theKBrmaxcm-1IS : 3370 (NH), 1750, 1660 (C = O).

Elemental analysis for C25H29FN2O5:

Calculated, %: C 65,78; H 6,40; N 6,14

Found, %: C 65,89; H 6,34; N 6,15

Example 62

N-[TRANS-5-(2-forfinal)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-tetrahydro - 4,1-benzoxazepin-3-acetyl]aminouksusnoy acid, obtained in example 61, according to the method of example 25, obtain 0.27 g of N-[TRANS-5-(2-forfinal)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid in the form of prisms with so pl. 201 - 203oC.

The IR spectrum of theKBrmaxcm-1: 1755, 1670, 1630 (C = O).

Elemental analysis for C23H25FN2O5:

Calculated, %: C 64,48; H 5,88; N 6,54

Found, %: C 64,54; H 5,95; N 6,51

Example 63

Ethyl ester of N-[TRANS-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

Dissolved in 10 ml of N,N-dimethylformamide and 0.4 g of TRANS-1-isobutyl-5-(2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 6, and 0.18 g of hydrochloric acid ethyl ester of glycine. To the solution was added with ice cooling to 0.22 g of diethylphosphonoacetate and 0.35 ml of triethylamine. The mixture is stirred for 30 min at room temperature, then add 100 ml of water and 100 ml of ethyl acetate, then extracted. An ethyl acetate layer is washed 1H hydrochloric acid and aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate - 1:1), the aminouksusnoy acid in the form of needles with so pl. 135 - 137oC.

The IR spectrum of theKBrmaxcm-1: 1750, 1670 (C = O).

Elemental analysis for C26H32N2O6:

Calculated, %: C 66,65; H 6,88; N 5,98

Found, %: C 66,72; H 6,91; N 5,98

Example 64

N-[TRANS-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

Dissolve in 5 ml of ethanol, 0.3 g of ethyl ester of N-[TRANS-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]aminouksusnoy acid obtained in example 63. To the solution was added 1H sodium hydroxide and stir the mixture for 15 minutes, then it is acidified by adding 50 ml of 1H hydrochloric acid, then extracted with 100 ml of ethyl acetate. An ethyl acetate layer washed with water, then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 0.27 g of N-[TRANS-1-isobutyl-5-(2-methoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid in the form of prisms with so pl. 210 - 211oC.

The IR spectrum of theKBrmaxcm-1: 1760, 1670, 1630 (C = O).

Elemental analysis for C24H28N2O6:

Calculated, %: C 65,44; H 6,41; N 6,36

Found, %: C 65,32; H 6,38; N 6,33

Example 65

TRANS-7-chloro-5-(2-chlorphen the na-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid, obtained in reference example 5, and 0.15 ml of N-methylmorpholine. To the solution was added with 0.13 ml of atilglukuronida at -10oC and stirred mixture of 10 minutes To the mixture was added 0.15 g of sodium borohydride, and then added dropwise within 5 min methanol and stirred for 30 min at 0oC. the Reaction mixture was poured in 50 ml of 1H hydrochloric acid, then extracted with 100 ml of ethyl acetate. An ethyl acetate layer was washed with aqueous sodium bicarbonate solution, then dried over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel, get 0,41 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzoxazepin-3-ethanol in the form of prisms with so pl. 188 - 189oC.

The IR spectrum of theKBrmaxcm-1: 3430 (OH), 1650 (C = O).

Elemental analysis for C20H21Cl2NO3:

Calculated, %: C 60,92; H lower than the 5.37; N 3,55

Found, %: C 61,12; H 5,39; N 3,72

Example 66

Ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

Dissolved in 10 ml of N,N-dimethylformamide 0.3 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid and 0.12 g solankis of triethylamine. The mixture is stirred for 30 min at room temperature, then add 100 ml of water and 100 ml of ethyl acetate, then extracted. An ethyl acetate layer is washed 1H hydrochloric acid and aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column (hexane-ethyl acetate = 1:1) obtain 0.31 g of ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid in the form of needles with so pl. 197 - 199oC.

The IR spectrum of theKBrmaxcm-1: 1755, 1670, 1655 (C = O).

Elemental analysis for C24H26Cl2N2O5:

Calculated, %: C 58,43; H 5,31; N 5,68

Found, %: C 58,73; H 5,33; N 5,80

Example 67

N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

Dissolved in 10 ml of ethanol, 0.2 g of ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminouksusnoy acid obtained in example 66. To the solution was added 2 ml of 1H sodium hydroxide and stir the mixture for 15 minutes To the reaction mixture was added 100 ml of 1H aqueous solution of the salt to the th, then dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure to obtain 0.18 g of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminouksusnoy acid in the form of crystals with so pl. 134 - 135oC.

The IR spectrum of theKBrmaxcm-1: 1725, 1650 (C = O).

Elemental analysis for C22H22Cl2N2O51/2Et2O:

Calculated, %: C 57,38; H 5,42; N 5,58

Found, %: C 57,48; H 5,59; N 5,58

Example 68

Work according to the method of example 66, get connections, are shown in tables 37 and 38 in the form of crystalline or oily products.

Example 69

Work according to the method of example 67, receive connections, are shown in tables 39 and 40.

Example 70

Work by the method of Reference example 2, get the connection given in table 41.

Table 42 summarizes the physico-chemical properties of intermediate products.

Example 71

Ethyl ester of TRANS-7-chloro-5-(2,4,6-trimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

(1) 2-acetylamino-5-chloro-2',4',6'-trimethoxybenzene

The solution to 2.41 g of 1,3,5-trimethoxybenzene in 10 ml dry then it is carbonated the minutes This solution is added dropwise to a solution of 2.0 g of 6-chloro-4-methyl-4H-3,1-benzoxazin-4-she's in 20 ml of dry tetrahydrofuran. Then the mixture was stirred at 0oC for 1 h, the solvent is distilled off, the residue is acidified with diluted hydrochloric acid and extracted with ethyl acetate. Then wash the extract with diluted hydrochloric acid and aqueous sodium bicarbonate solution, the solvent is distilled off and the residue chromatographic on a column of silica gel, to obtain 1.28 g of crystals. The melting point 159 - 160oC.

Elemental analysis for C18H18ClNO5:

Calculated, %: C 59,44; H 4,99; N 3,85

Found, %: C 59,39; H 4,94; N 3,86

(2) 2-amino-5-chloro-2',4',6'-trimethoxybenzene

A mixture of 4.7 g of 2-acetylamino-5-chloro-2',4',6'-trimethoxybenzene, 50 ml 6H hydrochloric acid and 50 ml of ethanol is refluxed for 1 h Then the solvent is distilled off under reduced pressure, the residue is alkalinized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. Then the extract is washed with water and dried to remove solvent and the residue chromatographic on a column of silica gel, to obtain 3.75 g of crystals.

(3) 2-amino-5-chloro--2,4,6-trimethoxyphenyl)benzyl alcohol

To a solution of 3.0 g of 2-amino-5-hlaut within 1 hour Then add water and extracted with a solution of the ethyl acetate, dried over anhydrous magnesium sulfate, and then remove the solvent under reduced pressure and chromatographic the residue on a column of silica gel, to obtain 2.9 g of crystals.

(4) 5-chloro--(2,4,6-trimethoxyphenyl)-2-(neopentylene)-benzyl alcohol

After stirring solution of 2.5 g of 2-amino-5-chloro--(2,4,6-trimethoxyphenyl)benzyl alcohol, 1,01 ml trimethylacetaldehyde and 0.56 g of acetic acid in 30 ml of ethanol for 1.5 h add 0,81 g cyanoborohydride sodium and stirred overnight. After concentration and subsequent dilution with water, the solution extracted with ethyl acetate. After removal of solvent the residue chromatographic on a column of silica gel, to obtain 2.2 g of crystals.

(5) Ethyl ester of 3-[N-(4-chloro-2-(-hydroxy-2,4,6-trimethoxybenzyl)phenyl] -N-neopentylene acrylic acid

In 30 ml of dichloromethane contribute 2.0 g 5-chloro--(2,4,6-trimethoxyphenyl)-2-(neopentylene)benzyl alcohol, 0,99 of monoethylene ether chlortoluron acid and 0.85 grams of sodium bicarbonate, the mixture is stirred for 30 minutes To the reaction mixture was added water and the organic layer is dried, and then remove the solvent and the residue chromatographic on a column with MDA-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

In 30 ml of ethanol contribute 2.5 g of ethyl ester of 3-[N-4-chloro-2-(-hydroxy-2,4,6-trimethoxybenzyl)phenyl] -N-neopentylene-acrylic acid and of 1.33 g of potassium carbonate, the mixture is stirred overnight at room temperature. After addition of ethyl acetate the mixture is washed with water and dried, then remove the solvent and the residue chromatographic on a column of silica gel, to obtain 2.0 g of crystals. So pl. 154 - 155oC.

Elemental analysis for C22H34ClNO2:

Calculated, %: C 62,36; H 6,59; N 2,69

Found, %: C 62,51; H 6,32; N 2,67

Example 72

Work according to the method of example 71, receive connections, are shown in tables 43 and 44.

Example 73

Work according to the method of example 71, except that the use of isobutyl aldehyde instead of trimethylacetaldehyde, get connections, are shown in tables 45 to 47.

Example 74

The compounds obtained in examples 71 and 72, hydrolized by the method of reference example 5 and example 2, get connections, are shown in tables 48 and 49.

Example 75

Hydrolyzing the compound obtained in example 73, according to the method of reference example 5 and example 2, get connections, are shown in tables 50 and 51.

Example 76

n-Butyl EF the R 0.4 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid, obtained in example 2 of 0.21 ml of n-butylated and 0.21 ml of triethylamine in 5 ml of dimethylformamide is stirred overnight at room temperature. After adding ethyl acetate, the mixture was washed with diluted hydrochloric acid, aqueous sodium bicarbonate solution and water. Then the solution is dried, the solvent is distilled off and the residue chromatographic on a column of silica gel, to obtain 0.25 g of crystals. So pl. 106 - 109oC.

Elemental analysis for C26H31Cl2NO4:

Calculated, %: C 63,42; H 6,35; N 2,84

Found, %: C 63,42; H to 6.39; N 2,71

Example 77

Work according to the method of example 76, receive connections, are shown in tables 52 to 54.

Example 78

Phenyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Dissolve 0.3 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2, and 0,072 g of phenol in 12 ml of dichloromethane and add 10 ml of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and then stirred for 1.5 h at room temperature. The reaction mixture was concentrated, added ethyl acetate and the mixture washed with water, then the organic layer is dried and evaporated solution is x2">

Elemental analysis for C28H27Cl2NO4:

Calculated, %: C 65,63; H 5,31; N 2,73

Found, %: C 65,55; H the 5.45; N 2,46

Example 79

The compound obtained in example 2, is treated by the method of example 78, get the connection given in table 55.

Example 80

Cyclohexylmethyl TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Work according to the method of example 78, on the basis of 0.3 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2, and 0.09 g of cyclohexylaniline get to 0.19 g of crystalline compounds. So pl. 157 - 158oC.

Elemental analysis for C28H33Cl2NO3S:

Calculated, %: C 62,91; H 6,22; N 2,62

Found, %: C 62,94; H between 6.08; N, 2,40

Example 81

t-Butyl ether TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

To a solution of 1.2 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2 in 40 ml of dichloromethane, was added 10 ml of isobutene and 0.1 ml of concentrated sulfuric acid, the mixture was kept at room temperature, the content of inorganic fillers layer washed with water and dried, then remove the solvent and the residue chromatographic on a column of silica gel, to obtain 1.07 g of crystals with so pl. 141 - 142oC.

Elemental analysis of C26H31ClNO4:

Calculated, %: C 63,42; H 6,35; N 2,84

Found, %: C 63,52; H 6,37; N 2,80

Example 82

Carboxymethylate ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3.5-tetrahydro-4,1 - benzoxazepin-3-acetic acid

Dissolve 0.3 g of tert.butoxycarbonylmethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 77, 3 ml triperoxonane acid, and the solution incubated at room temperature for 30 minutes After concentrating the solution was added ethyl acetate, then washed with water and then dried, after which remove the solvent and the residue is recrystallized from petroleum ether, to obtain 0.24 g of crystals with so pl. 186 - 190oC.

Elemental analysis for C24H25Cl2NO61/2H2O:

Calculated, %: C 57,27; H to 5.21; N 2,78

Found, %: C 57,38; H of 5.05; N 2,78

Example 83

Methyl ester 2-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminobenzoic acid

Dissolve 0.35 g alocrom example 5 in 10 ml of toluene, was added 0.63 ml of thionyl chloride, and then stirred for 30 min at 90oC. Solution concentrate and dissolve the residue in 10 ml of dichloromethane, added with 0.13 ml of methyl ester of 2-aminobenzoic acid and 0.14 ml of triethylamine and then stirred for 30 min at room temperature. After concentrating the solution was added ethyl acetate and washed with a mixture of diluted hydrochloric acid, aqueous sodium bicarbonate solution and water. Remove solvent and the residue chromatographic on a column of silica gel, to obtain 0.25 g of crystals. So pl. 188 - 190oC.

Elemental analysis for C28H26Cl2N2O5:

Calculated, %: C 62,11; H 4,91; N 5,24

Found, %: C 61,94; H 4,91; N 5,24

Example 84

Work according to the method of example 83, receive connections, are shown in tables 56 and 57.

Example 85

2-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminobenzoic acid

Conduct hydrolysis 0.15 g of methyl ester of 2-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminobenzoic acid, obtained in example 83, according to the method of example 34, obtain 0.11 g of crystals with so pl. 208 - 211oC.

Cell battery (included) 61,22; H TO 4.68; N 5,35

Example 86

Carry out the hydrolysis of the compound obtained in example 84, according to the method of example 34, receive connections, are shown in table 58.

Example 87

Ethyl ester of 4-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminobenzoic acid

Work according to the method of example 83, on the basis of 0.6 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2, and 0.27 g of ethyl ester of 4-aminobenzoic acid, gain of 0.43 g of crystals with so pl. 218 - 220oC.

Elemental analysis for C31H32Cl2N2O5:

Calculated, %: C expenses 63.81; H of 5.53; N 4,80

Found, %: C 63,79; H 5,38; N 4,70

Example 88

Work according to the method of example 82, receive connections, are shown in tables 59 and 60.

Example 89

The compounds obtained in examples 87 and 88, is treated by the procedure of examples 24 and 82 receive connections are shown in tables 61 and 62.

Example 90

TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ndimethylacetamide

Dissolve 1.0 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid and 0.5 g of chloride and 0.7 ml of triethylamine, then stirred for 30 min at room temperature. After adding water, the solution extracted with ethyl acetate, then washed with water, after which the solvent is distilled off and the residue is recrystallized receive 0.75 g of crystals with so pl. 271 - 272oC.

Elemental analysis for C21H22Cl2N2O3:

Calculated, %: C 59,87; H 5,26; N 6,65

Found, %: C 59,91; H 5,33; N 6,91

Example 91

Work according to the method of example 90, from the compound obtained in example 2 and reference example 5, and various amines, get connections, are shown in tables 63 - 67.

Example 92

Ethyl ester of 7-chloro-5-(2-chlorophenyl)-1-isobutyl-5-methyl-1,2,3,5-tetrahydro-4-benzoxazepin-3-acetic acid

(1) 4-chloro-2-[-hydroxy--methyl-(2-chlorophenyl)methyl]aniline

Added dropwise tertrahydrofuran ring solution of the Grignard reagent, prepared from 0.45 g of magnesium and 1.2 g under the conditions, to a solution of 2.0 g of 2-amino-5-chloro-2'-chlorobenzophenone in 20 ml of tetrahydrofuran. After boiling under reflux for 10 minutes the mixture is cooled and water is added a saturated aqueous solution of ammonium chloride, the mixture is extracted with ethyl acetate. The solvent is distilled off and the residue chromatographic on a column with silica gel-isobutyl-4-chloro-2-[-oxo--methyl-(2-chlorophenyl)methyl] aniline

To a solution of 1.2 g of 4-chloro-2-[-oxo--methyl-(2-chlorophenyl)-methyl]aniline and 0.32 g of Isobutyraldehyde in 8 ml acetic acid, was added 0.25 g sodium borohydride, then 40 min stirred at room temperature. After adding water, the reaction mixture was extracted with ethyl acetate, and then the solvent is distilled off and the residue chromatographic on a column of silica gel, to obtain 1.4 g of oil.

1H-NMR spectrum (CDCl3) : 0,75, to 0.80 (6H, each d, CH3), to 1.67 (1H, m) to 1.99 (3H, s, CH3), is 2.74 (2H, d), 7,05 one - 7.8 (7H, m).

(3) Ethyl ester of 3-[N-chloro-2-[-oximeter-(2-chlorophenyl) methyl]phenyl] -N-isobutylamino]acrylic acid

Dissolve 1.4 g of N-isobutyl-4-chloro-2-[-oxo--methyl-(2-chlorophenyl)methyl] aniline in 15 ml of dichloromethane and added 0.7 g of sodium bicarbonate, and then added dropwise a solution of 0.68 g nanometrology ether chlortoluron acid in 4 ml dichloromethane for 20 minutes After washing the mixture with water and drying, the solvent is distilled off and the residue chromatographic on a column of silica gel, to obtain 0.65 g of crystals with so pl. 153 - 154oC.

Elemental analysis for C24H27Cl2NO4:

Calculated, %: C 62,07; H 5,86; N 3,02

Found, %: C 62,19; H 5,86; N 2,90

(4) Ethyl ester of 7-chloro-3-(2-chlorophenyl)-1-isobutylphenyl)phenyl]-N-isobutylamino] acrylic acid are dissolved in 10 ml ethanol and added 0.35 g of potassium carbonate, then stirred for 12 h. After adding water, the reaction mixture was extracted with ethyl acetate and dried, the solvent is distilled off and the residue chromatographic on a column of silica gel, to obtain 0.8 g of crystals, so pl. 119 - 120oC.

Elemental analysis for C24H27Cl2NO4:

Calculated, %: C 62,07; H 5,86; N 3,02

Found, %: C 62,08; H to 5.93; N 2,98

Example 93

7-Chloro-5-(2-chlorophenyl)-1-isobutyl-5-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid

Dissolve 0.3 g of ethyl ester of 7-chloro-5-(2-chlorophenyl)-1-isobutyl-5-methyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid in 10 ml of methanol and add 2 ml of 10% aqueous potassium carbonate solution, and then stirred at 40 min 70oC. After acidification with diluted hydrochloric acid, the reaction mixture was extracted with ethyl acetate. After drying the extract to remove the solvent and the residue is recrystallized from ethyl acetate-hexane, to obtain 0.16 g of crystals with so pl. 153 - 154oC.

Elemental analysis for C22H23Cl2NO4:

Calculated, %: C 60,56; H 5,31; N 3,21

Found, %: C 60,59; H 5,32; N 2,92

Reference example 9

Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-(2,2,2-triptorelin)-1,2,3,5-tetrahydro-2-oxo-4,1-btore 1.0 g of 2-amino-5-chloro--(2-chlorophenyl)benzyl alcohol in 12 ml of dichloromethane is added a solution of 0.8 g of anhydrous triperoxonane acid in 2 ml of dichloromethane. After the reaction was added an aqueous solution of sodium bicarbonate and the organic layer is dried, and then remove the solvent and the residue is recrystallized from hexane, to obtain 1.3 g of crystals.

(2) 5-chloro--(2-chlorophenyl)-2-(2,2,2-triptoreline) benzyl alcohol

To a suspension of 0.25 g of sociallyengaged in 20 ml of absolute ethyl ether is added dropwise a solution of 1.2 g of 5-chloro--(2-chlorophenyl)-2-(triptorelin)benzyl alcohol in 5 ml of tetrahydrofuran. After stirring the mixture at room temperature for 1 h, the organic layer is dried, then the solvent is distilled off and the residue chromatographic on a column of silica gel, to obtain 1.0 g of oil.

(3) Ethyl ester of 3-[N-[4-chloro-2--hydroxy-2-chloroformate)-phenyl] -N-(2,2,2-triptorelin)carbarnoyl]acrylic acid

Work by the method of reference example 1, starting from 5-chloro--(2-chlorophenyl)-2-(2,2,2-triptoreline)benzyl alcohol and nanometrology ether chlortoluron acid, receive oil.

(4) Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-(2,2,2-triptorelin)-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid.

Ethyl ester of 3-[N-[4-chloro-2--hydroxy-2-chloroformate)-phenyl]-N-(2,2,2-triptorelin)carboxyl] acrylic acid formation is Liz for C21H18Cl2NO4F3:

Calculated, %: C 52,96; H 3,81; N 2,94

Found, %: C 52,93; H 3,88; N 2,91

Reference example 10

Work according to the methods of reference examples 2 and 9, get connections given in table 68.

Example 94

Work according to the methods of reference examples 2 and 9, get connections given in table 69.

Reference example 11

Treated with compounds obtained in reference examples 9 and 10, according to the method of reference example 4, to obtain compounds shown in table 70.

Example 95

The compound obtained in example 94, treated by the method of reference example 4, to obtain compounds shown in table 71.

Physico-chemical properties of the intermediate products obtained in reference examples 9 and 10 and example 94, are presented in tables 72 and 73.

Example 96

Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-propionic acid

(1) TRANS-7-chloro-5-(2-chlorophenyl)-3-(2-cyanoethyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin

Suspended 0.3 g of 7-chloro-3-(2-chloroethyl)-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin and 0.1 g of sodium cyanide are suspended in 6 tatom, then the solvent is distilled off and the residue chromatographic in the column on silica gel, to obtain 0.25 g of crystals, so pl. 194-195oC.

Elemental analysis for C23H24Cl2N2O2:

Calculated, %: C 64,04; H 5,61; N OF 6.49

Found, %: C 63,96; H of 5.55; N 6,66

(2) Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-propionic acid

To 0.2 g of TRANS-7-chloro-5-(2-chlorophenyl)-3-(2-cyanoethyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine add 6 ml of ethanol solution 6H hydrogen chloride, followed by 6 h refluxed. After removal of solvent was added water and ethyl acetate, the organic layer is dried, remove the solvent and the residue chromatographic on a column of silica gel, to obtain 0.18 g of crystals with so pl. 130 - 131oC.

Elemental analysis for C25H29Cl2NO4:

Calculated, %: C 62,76; H 6,11; N 2,93

Found, %: C 62,78; H 6,12; N 2,68

Example 97

TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-propionic acid

90 mg of ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-propionic acid obtained in example 96, the initial analysis for C23H25Cl2NO4:

Calculated, %: C 61,34; H ceiling of 5.60; N 3,11

Found, %: C 61,34; H 5,65; N 2,89

Example 98

TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ethanol

Work according to the method of example 65, on the basis of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetic acid obtained in example 2, to obtain 1.5 g of crystals.

Example 99

Ethyl ester of 3-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ileti]thioglycolic

(1) TRANS-7-chloro-3-(2-chloroethyl)-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin

Dissolve 1.0 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-ethanol obtained in example 98, 25 ml of toluene and added 0.1 ml of pyridine and 0.4 ml of thionyl chloride, and then stirred for 30 min at 100oC. After removal of the solvent under reduced pressure the residue is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution and dried, after removal of the solvent the residue chromatographic on a column of silica gel, to obtain 0.8 g of crystals with so pl. 138-140oC.

Elemental analysis for C21H22Cl3NO2
Add 0.15 g of TRANS-7-chloro-3-(2-chloroethyl)-5-(2-chlorophenyl)-1-isobutyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine, 0.08 g of ethyl ester of thioglycolic and 0.1 g of cesium fluoride to 5 ml of acetonitrile, and then refluxed for 40 minutes After adding ice water and extraction with ethyl acetate the organic layer is dried, remove the solvent and the residue chromatographic on a column of silica gel, to obtain 0.17 g of oil.

1H-NMR spectrum (CDCl3) : 0,93 1,03 (6H, each d), of 1.26 (3H, t), 1,8-2,4 (3H, m), 2,8 (2H, m), 3,19 (2H, s), 3,42 (1H, DD), of 4.0-4.4 (4H, m), 6,12 (1H, s), 6,51 (1H, d), 7,2-7,8 (6H, m).

Example 100

3-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]thioglycolate acid

Work according to the method of example 51, from 0.17 g of ethyl ester of 3-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ileti] thioglycolic obtained in example 99, obtain 0.18 g of crystals with so pl. 194-195oC.

Elemental analysis for C23H25Cl2NO4S:

Calculated, %: C 57,26; H 5,22; N 2,90

Found, %: C 57,27; H 5,20; N 2,96

Example 101

3-[TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ileti]sulfonyloxy knocksedan-3-ileti] thioglycolic in 8 ml of dichloromethane, obtained in example 99, and add 0.25 g of m-chloroperbenzoic acid, then stirred for 1 h To the reaction mixture was added aqueous sodium bicarbonate solution, then washed and dried the organic layer, removing the solvent, after which the remainder chromatographic on a column of silica gel, to obtain 0.18 g of oil, which is then subjected to the procedure of hydrolysis of the ethyl ester by the procedure of example 51, the gain of 0.13 g of crystals with so pl. 171-172oC.

Elemental analysis for C23H25Cl2NO6S:

Calculated, %: C 5,70; H 4,90; N 2,72

Found, %: C 53,62; H of 4.95; N 2,68

Example 102

TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-[3-(tetrazol-5-yl)-phenylenecarbonyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

(1) TRANS-7-chloro-5-(2-chlorophenyl)-3-(3-cyanobenzeneboronic)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

To a solution of 0.5 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2, and 0.15 g m-cyanoaniline in 10 ml of dichloromethane was added 0.35 g of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 20 mg of dimethylaminopyridine, then stirred at room temperature for 4 h the Solution concentrate and dissolve the residue with silica gel, get to 0.48 g of crystals with so pl. 213 - 214oC.

Elemental analysis for C29H27Cl2N3O3:

Calculated, %: C 64,93; H 5,07; N 7,83

Found, %: C 64,68; H 4,96; N OF 7.90

(2) TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-[3-tetrazol-5-yl) phenylenecarbonyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

A solution of 0.2 g of TRANS-7-chloro-5-(2-chlorophenyl)-3-(3 - cyanobenzeneboronic)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine and 80 mg of sodium azide in 5 ml of dimethylformamide is stirred for 60 h at 90oC. After adding water, the mixture is washed with water, and then remove the solvent and the residue chromatographic on a column of silica gel, to obtain 0.11 g of crystals with so pl. 218-220oC.

Elemental analysis for C29H28Cl2N6O3:

Calculated, %: C 59,64; H to 4.92; N 14,39

Found, %: C 59,44; H to 4.87; N 14,30

Example 103

TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-[4-(tetrazol-5-yl) phenylenecarbonyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin. The target compound is synthesized according to the method of example 102.

(1) TRANS-7-chloro-5-(2-chlorophenyl)-3-(4-cyanobenzeneboronic)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin. So pl. 257-259oC.

Elemental analysis,33; H 5,13; N OF 7.64

(2) TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-3-[4-(tetrazol-5-yl) phenylenecarbonyl] -oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin. So pl. 206 - 210oC.

Elemental analysis for C29H28Cl2N6O31/4 H2O:

Calculated, %: C 59,64; H to 4.92; N 14,39

Found, %: C 59,71; H 4,96; N 14,34

Example 104

TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-3-[(tetrazol-5-yl) methylaminomethyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

(1) TRANS-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylphosphonate)-1-isopropyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

Dissolve 0.3 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in reference example 5 and 0.1 g of sulphate of aminoacetonitrile in 5 ml of dimethylformaldehyde, add 0,18 of diethylphosphonoacetate and 0.17 ml of triethylamine, then stirred for 1 h at room temperature. After adding water, the mixture extracted with ethyl acetate, washed with water and then dried. After removal of solvent the residue chromatographic on a column of silica gel, to obtain 0.31 g of crystals with so pl. 216 - 217oC.

Elemental analysis for C22H21Cl2N3O3:

Calculated, aminocarbonylmethyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

TRANS-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylphosphonate)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin and sodium azide treated by the method of example 102, receive crystals with so pl. 253 - 254oC.

Elemental analysis for C22H22Cl2N6O3:

Calculated, %: C 54,00; H a 4.53; N 17,17

Found, %: C 53,85; H to 4.68; N 17,02

Example 105

TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-[(tetrazol-5-yl) methylaminomethyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-wasnow acid obtained in example 2, is treated by the method of example 102 and 104 receive a crystalline compound

(1) TRANS-7-chloro-5-(2-chlorophenyl)-3-(cyanomethylphosphonate)-1 - isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin. So pl. 168-169oC

Elemental analysis for C23H23Cl2N3O3:

Calculated, %: C 60,01; H 5,04; N 9,13

Found, %: C 60,11; H 5,28; N 9,15

(2) TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-[(tetrazol-5-yl)methylaminomethyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin. So pl. 234 - 235oC.

Elemental analysis for C23H24Cl2N6O3:

Calculated, %: C 54,88; H 4,81; Tyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

(1) TRANS-7-chloro-5-(2-chlorophenyl)-3-cyanomethyl-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

Dissolve 0.5 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ndimethylacetamide, obtained in example 91, 0,38 g carbonyldiimidazole and 1.14 g of allylbromide in 10 ml of acetonitrile, then 4 h refluxed. The solution is concentrated and added ethyl acetate, then washed with water, after which the solvent is distilled off and the residue chromatographic on a column of silica gel, gain of 0.44 g of crystals with so pl. 158 - 159oC.

Elemental analysis for C21H20Cl2N2O2:

Calculated, %: C 62,54; H 5,00; N 6,95

Found, %: C 62,68; H 5,13; N 7,22

(2) TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-[(tetrazol-5-yl)methyl] -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

Work according to the method of example 102, on the basis of 0.2 g of TRANS-7-chloro-5-(2-chlorophenyl)-3-cyanomethyl-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine receive 90 mg of crystals with so pl. 202 - 203oC.

Elemental analysis for C21H21Cl2N5O2:

Calculated, %: C 56,51; H 4,74; N 15,69

Found, %: C 56,29; H 4,70; N 15,67

Example 107

TRANS-7-chloro-5-(2-chloromethyl)-1-isobutyl-3-[2-(tetrazol-5-yl)ethyl]-2-oxo-1,2,3,5-t is rehydro-4,1-benzoxazepin

Add 0.5 g of TRANS-7-chloro-3-(2-chloroethyl)-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine obtained in example 99, and 0.4 g of sodium cyanide in 8 ml of dimethylsulfoxide, and then stirred for 40 min at 100oC. After adding water, the reaction mixture was extracted with ethyl acetate, the organic layer washed with water and dried, and then remove the solvent and the residue chromatographic in column (silica gel, obtain 0.45 g of oil.

1H-NMR spectrum (CDCl3) : 0,93, of 1.03 (6H, each d), 1,85 - 2,4 (3H, m) at 2.59 (2H, t), of 3.43 (1H, DD), of 4.05 (1H, DD), to 4.33 (1H, DD), 6,14 (1H, s), 6,53 (1H, d), 7.3 to 7.8 for (6H, m).

(2) TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-3-[2-(tetrazol-5-yl)ethyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

Work according to the method of example 102, on the basis of TRANS-7-chloro-5-(2-chlorophenyl)-3-(2-cyanoethyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine get 0,22 g of crystals with so pl. 125 - 127oC.

Elemental analysis for C22H23Cl2N5O2:

Calculated, %: C 57,40; H 5,04; N 15,21

Found, %: C 57,15; H 5,26; N 14,97

Example 108

TRANS-7-chloro-5-(2-chlorophenyl)-3-[2-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)ethyl]-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin

In 5 ml of ethanol was added 0.25 g of TRANS-7-chloro-5-(2-x is cislago hydroxylamine and 0.23 g of sodium carbonate, then 18 h refluxed. After removal of solvent added ethyl acetate, the mixture is washed with water and dried, after removal of the solvent the residue is recrystallized from ethyl acetate. So pl. 212 - 214oC.

Elemental analysis for C22H25Cl2N3O3:

Calculated, %: C 58,67; H ceiling of 5.60; N WAS 9.33

Found, %: C 58,84; H of 5.68; N 9,24

To 5 ml of ethyl acetate was added 0.1 g of this amidoxime, 0.1 g of carbonyldiimidazole and 0.5 ml of triethylamine, then refluxed for 24 hours the Solution is concentrated and the residue is dissolved in ethyl acetate, washed with water and dried, and then remove the solvent and the residue is recrystallized from ethyl acetate, to obtain 85 mg of crystals with so pl. 241 - 242oC.

Elemental analysis for C22H23Cl2N3O4:

Calculated, %: C 57,99; H to 4.87; N 8,82

Found, %: C 57,79; H 5,07; N 9,00

Example 109

Tert.butyl ester of N-[(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -L-alanine and tert.butyl ester of N-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-L-alanine

In 20 ml of N,N-dimethylformamide was dissolved 0.5 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,ester of alanine, under ice cooling to this solution was added 0.26 g of diethylphosphonoacetate and 0.41 ml of triethylamine. After 30 min stirring at room temperature, the extraction is carried out by adding 100 ml of water and 150 ml ethyl acetate. An ethyl acetate layer was washed with 5% aqueous solution of potassium bisulfate and sodium bicarbonate, and after drying over anhydrous magnesium sulfate it dispersed under reduced pressure. The residue is then purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2:1) to receive the first fraction of 0.17 g of tert.butyl ether N-[(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -L-alanine in the form of lamellar crystals with so pl. 146 - 147oC.

Elemental analysis for C28H34Cl2N2O5:

Calculated, %: C 61,20; H 6,24; N 5,10

Found, %: C 61,20; H 6,33; N 5,15

As well as the second faction get 0,22 g tert-butyl ether N-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-L-alanine in the form of butter.

The IR spectrum of theNeamaxtcm-1: 3330 (NH), 1730, 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : of 0.93 (3H, DD, J = 6,8 Hz) of 1.03 (3H, d, J = 6,8 Hz) of 1.34 (3H, t, J = 7,0 Hz) of 1.46 (9H, s, so VI), 1.85 to 2= 2.2 Hz), 7,2 - a 7.85 (6H, m).

Example 110

N-[(3S, 5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-L-alanine

In 10 ml 4H hydrochloric acid in dioxane dissolving 0.16 g of tert-butyl ether N-[(3S, 5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -L-alanine obtained in example 109, and the solution of the whole night was stirred at room temperature. After the pickup under reduced pressure conducting crystallization from hexane-diethyl ether, to obtain 0.12 g of N-[(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetyl] -L-alanine in the form of a powdery product.

Elemental analysis for C24H26Cl2N2O5:

Calculated, %: C 58,43; H 5,31; N 5,68

Found, %: C 58,43; H the 5.65; N, 5,54

1H-NMR spectrum (200 MHz, d6-DMSO) : to 0.89 (3H, d, J = 6.8 Hz), were 0.94 (3H, d, J = 6.6 Hz), 1,25 (3H, d, J = 7.2 Hz), 1.7 to 1.9 (1H, m), 2,4 - by 2.55 (2H, m) to 3.58 (1H, DD, J = 14,0, 5.0 Hz), 4,1 - 4,4 (3H, m), of 5.99 (1H, s), 6,30 (1H, d, J = 2.4 Hz), 7,45 one - 7.8 (4H, m), with 8.33 (1H, d, J = 7,6 Hz), of 12.53 (1H, Shir, HH).

Example 111

N-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-L-alanine

In 10 ml 4H hydrochloric acid solution in dioxane was dissolved 0.2 g of tert. butyl ether N-[(3R, 5S is e 109, and stirred the mixture for 4 h at room temperature. After the pickup under reduced pressure conducting crystallization from hexane-diethyl ether, to obtain 0.17 g of N-[(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzoxazepin-3-acetyl]-L-alanine in the form of lamellar crystals with so pl. 120 - 124oC.

Elemental analysis for C24H26Cl2N2O5Neamaxtcm-1: 1740, 1675 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : of 0.93 (3H, d, J = 6.8 Hz), of 1.02 (3H, d, J = 6.6 Hz), for 1.49 (3H, d, J = 7.2 Hz), 1.85 to 2.1 a (1H, m), 2.91 in (1H, DD, J = 17,0, a 5.4 Hz), and 3.72 (3H, s), or 4.31 (1H, DD, J = 13,8, and 8.4 Hz), 3,19 (1H, DD, J = 17,0, 8.0 Hz), 3,44 (1H, DD, J = 13,8, a 5.4 Hz), of 4.44 (1H, DD, J = 8.0 a, 5,4 Hz), 5,07 (1H,, J = 7,2 Hz), 6,14 (1H, s), of 6.52 (1H, d, J = 2.2 Hz), 7,2 - 7,8 (6H, m).

A second faction get to 0.63 g of methyl ester of (R)-O-[(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-lactic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1740, 1675 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : of 0.93 (3H, d, J = 6,8 Hz) of 1.03 (3H, d, J = 6.6 Hz), to 1.48 (3H, d, J = 7.0 Hz), 1.85 to 2.1 a (1H, m), with 2.93 (1H, DD, J = 16,8, 7,2 Hz), 3,10 (1H, DD, J = 16,8, 6.2 Hz), 3,43 (1H, DD, J = 13,8, a 5.4 Hz), or 3.28 (3H, s), 4,34 (1H, DD, J = 13,8, a 5.4 Hz), of 4.45 (1H, t, J = 6.6 Hz), 5,12 (1H,, J = 7,0 Hz), 6,16 (1H, s), of 6.52 (1H, d, J = 2.2 G EPIN-3-acetic acid

In 20 ml of methanol is dissolved 0.45 g of methyl ester of (R)-O-[(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-lactic acid, obtained in example 112, add back 10 ml of an aqueous solution containing of 0.37 g of potassium carbonate, the mixture is stirred for 40 min at 60oC. This mixture is concentrated under reduced pressure and the concentrate is extracted by adding 50 ml of 1H hydrochloric acid and 100 ml of ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate and distill under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3:1; eluent: hexane-etrangere-ethanol = 5: 5: 1) obtain 53 mg of (3S,5R)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of prismatic crystals with so pl. 183 - 186oC.

[]2D0+223,7o(c = 0,47, methanol)

Elemental analysis for C21H21Cl2NO4:

Calculated, %: C 59,73; H 5,01; N 3,32

Found, %: C 59,36; H 5,09; N 3,19

Example 114

(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

In 20 ml of methanol was dissolved 0.6 g of methyl ester of (R)-O-[(3R,5S)-7-chloro-5-(2-CHL, ribault there 10 ml of an aqueous solution containing of 0.49 g of potassium carbonate, the mixture is stirred for 40 min at 60oC. the Mixture is concentrated under reduced pressure and the concentrate is extracted by adding 50 ml of 1H hydrochloric acid and 100 ml of ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3:1; eluent: hexane-methylene chloride-ethanol = 5: 5:1) obtain 54 mg of (3R,5S)-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of prismatic crystals with so pl. 182 - 185oC.

[]2D0-215o(c = 0,43, methanol)

Elemental analysis for C21H21Cl2NO4]2D0= +222,6o(c = 1.0, methanol)

Elemental analysis for C26H29Cl2NO6:

Calculated, %: C 59,78; H ceiling of 5.60; N 2,68

Found, %: C 59,87; H of 5.75; N, 2,41

As a second faction obtain 0.6 g of methyl ester of (R)-O-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetyl]-lactic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1745, 1675 (C = O).

Example 116

Methyl ester of (S)-O-[(3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -lactic acid and methyl ester of (S)-O-[(3S, 5R)-7-chloro-5-(2-chlorophenyl)-1 - neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]lactic acid

In 150 ml of methylene chloride was dissolved 10 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2, and 4.77 g of methyl ester of (S)-lactic acid. To the solution was added with ice cooling at 5.27 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.3 g of 4-dimethylaminopyridine. The mixture is stirred for 2 h at room temperature, then washed 1H solutions of hydrochloric acid and sodium bicarbonate, dried over magnesium sulfate. Then the solvent is distilled off under reduced pressure. The residue was separated and purified using chromatography on a column of silica gel (eluent: hexane-diethyl ether = 3:1), obtained as the first fraction 2.7 g of methyl ester of (S)-O-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -lactic acid in the form of crystallity analysis for C26H29Cl2NO6:

Calculated, %: C 59,78; H ceiling of 5.60; N 2,68

Found, %: C to 59.82; H 5,69; N OF 2.51

A second faction get 2.8 g of methyl ester of (S)-O-[(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -lactic acid in the form of crystalline prisms with so pl. 119 - 120oC.

[]2D0+160,1o(c = 0,7, methanol)

Elemental analysis for C26H29Cl2NO6:

Calculated, %: C 59,78; H ceiling of 5.60; N 2,68

Found, %: C 59,69; H 5,63; N 2,67

Example 117

(3S, 5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

In 20 ml of methanol was dissolved 0.4 g of methyl ester of (R)-O-[(3S,5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -lactic acid, obtained in example 115. To the solution was added 10 ml of an aqueous solution containing 0.32 g of potassium carbonate; the reaction mixture is then stirred for 2 h at 60oC and concentrated under reduced pressure, then extracted by adding 50 ml of 1H hydrochloric acid and 50 ml of ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate, and then dispersed under reduced pressure. The residue is purified by chromatography on a column)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of needles with so pl. 241 - 245oC.

[]2D0+244,8o(c = 0,52, methanol)

Elemental analysis for C22H23Cl2NO4]2D0-252,0o(c = 0.5, methanol)

Elemental analysis for C22H23Cl2NO4:

Calculated, %: C 59,94; H lower than the 5.37; N 3,28

Found, %: C 59,84; H 5,28; N 3,31

The filtrate is dispersed under reduced pressure, the residue is then dissolved in 30 ml of ethanol, add back 0.3 ml of concentrated sulfuric acid, then the mixture is stirred for 2 days. Distill under reduced pressure, then the extraction is carried out by adding 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer was washed with aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate and distill under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 5:1) get to 0.63 g of ethyl ester of (3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of crystal prisms, so pl. 120-121oC.

[]2D0235,5o(or = 0.51, methanol)

Elemental analysis for C24H27Cl2NO4:

Calculated, %: C 62,07; H 5,86; N 3,02

Found, %: C 62,10; H 5,95; N 2,93

Also, the slave is ntil-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -lactic acid, get 0,37 g (3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid.

Example 119

Ethyl ester of N-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

Dissolve in 5 ml of N,N-dimethylformamide 0.15 g (3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 118 and 58 mg of hydrochloric acid ethyl ester of glycine. To the solution was added with ice cooling 71 mg of diethylphosphonoacetate and 0.12 ml of triethylamine. After 30 min stirring the reaction mixture at room temperature, it is extracted by adding 50 ml of water and 50 ml of ethyl acetate. An ethyl acetate layer is washed 1H hydrochloric acid and aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and distill under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 1:1) obtain 0.16 g of ethyl ester of N-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminouksusnoy acid in the form of lamellar crystals with so pl. 138-139oC.

[]2D0-220,8o(C = 0.45, and methanol)

the but %: C 59,86; H 5,94; N 5,12

Example 120

N-[(3R, 5S)-7-chloro-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

In 5 ml of ethanol is dissolved 0.12 g of ethyl ester of N-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzoxazepin-3-acetyl] aminouksusnoy acid obtained in example 119, add there 2 ml 1H sodium hydroxide. The reaction mixture was stirred 15 min at room temperature, then spend extracted by adding 50 ml of 1H hydrochloric acid and 50 ml of ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate and distill under reduced pressure to obtain 0.10 g of N-[(3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminouksusnoy acid in the form of a powdery product.

[]2D0-229,8o(c = 0,46, methanol)

Elemental analysis for C24H26Cl2N2O5:

Calculated, %: C 58,43; H 5,31; N 5,68

Found, %: C 58,56; H 5,63; N 5,57

Example 121

(3S, 5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid and (3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

In ethanologenic in example 2, and quinine equal polyarnosti. Then the mixture is concentrated and added 150 ml of ethyl acetate and conduct crystallization under cooling with ice. Thus obtained crystals are dissolved in a mixture of ethanol and ethyl ether and allow to pass recrystallization. Remove the mother liquor from the resulting crystals concentrate and get the rest. This residue is recrystallized from hexane and the resulting crystals are dissolved in ethyl acetate. Quinine from this solution is removed with diluted hydrochloric acid. The residue after removal of the solvent from recrystallization using hexane is the result of (3S, 5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of crystals. Then remove the solvent from the mother liquor remaining from the first crystallization. The residue is dissolved in ethyl acetate, and remove quinine hydrochloric acid. Remove the solvent receive the residue, which is recrystallized using a mixture of ethanol and ethyl ether. After removal of the formed in this way crystals concentrate the mother liquor and the residue is recrystallized using hexane, the result is (3R P CLASS="ptx2">

Example 122

Ethyl ester of (3S, 5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid and ethyl ester of (3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

To ethyliodide in dimethylformamide as the solvent and in the presence of potassium carbonate is added as a separate reactions (3S, 5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid and (3R, 5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 121, the result of the above compounds. Ethyl ester of (3S, 5R)-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid has so pl. 117-118oC.

[]2D0+224,6o(C = 0,5, MeOH)

Elemental analysis for C24H27Cl2NO4:

Calculated, %: C 62,07; H 5,86; N 3,02

Found, %: C 62,01; H 5,88; N 2,97

Example 123

Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

(1) 2-amino-5-chloro-2'-oxybisethane

A mixture of 2.15 g of 2-amino-5-chloro-2'-methoxybenzophenone and 20 ml of 47% HBR boiled for 1 h with oony the solution is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 10:1), gain of 1.9 g of 2-amino-5-chloro-2'-oxybenzene in the form of needles with so pl. 51 - 52oC.

Elemental analysis for C13H10ClNO2:

Calculated, %: C 63,04; H 4,07; N 5,66

Found, %: C 62,90; H of 4.04; N 5,61

A mixture of 10 g of 2-acetylamino-5-chloro-2'-methoxybenzophenone and 100 ml of 47% HBR 2 h refluxed. The solution is neutralized with sodium hydroxide and extracted with 200 ml of ethyl acetate. The extraction solution was washed with water and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 5:1) obtain 8.0 g of 2-amino-5-chloro-2'-oxybenzene in the form of needles.

(2) 2-amino-5-chloro-2'-ethoxybenzene

In 10 ml of N,N-dimethylformamide was dissolved 1.5 g of 2-amino-5-chloro-2'-oxybenzene obtained in (1), add there 1.26 g of potassium carbonate and 0.63 ml of ethyliodide. The reaction mixture was stirred for 3 h at room temperature, then extracted with 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous sulfate is exan-ethyl acetate = 5:1), obtain 1.6 g of 2-amino-5-chloro-2'-ethoxybenzene in the form of butter.

The IR spectrum of the Neamaxtcm-1: 3460, 3340 (NH), 1610 (C=O).

1H-NMR spectrum (200 MHz, CDCl3) : to 1.21 (3H, t, J = 7.0 Hz), Android 4.04 (2H, K, J = 7,0 Hz), 6,1 - 6,5 (2H, Shir, NH2), of 6.65 (1H, d, J = 8,8 Hz), 6,9 - 7,1 (2H, m), 7,15 - to 7.35 (3H, m), 7,35 is 7.5 (1H, m).

(3) 2-amino-5-chloro--(2-ethoxyphenyl)benzyl alcohol

Dissolved in 30 ml of ethanol, 1.5 g of 2-amino-5-chloro-2'-ethoxy benzophenone obtained in (2), then added 0.34 g of sodium borohydride. The reaction mixture was stirred overnight at room temperature. The ethanol is then distilled off under reduced pressure, and after dissociation adding an aqueous solution of hydrochloric acid the extraction is carried out with 100 ml of ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3:1) obtain 1.35 g of 2-amino-5-chloro--(2-ethoxyphenyl)benzyl alcohol in the form of crystalline prisms with so pl. 80 - 81oC.

Elemental analysis for C15H16ClNO2:

Calculated, %: C 64,87; H of 5.81; N 5,04

Found, %: C 64,77; H of 5.81; N 4,85

(4) 5-chloro--(2-ethoxy-phenyl)-2-isobutylbenzene in (3), and add to 0.47 g Isobutyraldehyde, to which are added while cooling with ice 0.24 g sodium borohydride. The reaction mixture was stirred 30 min at room temperature, after which the extraction is carried out by adding 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer is washed 1H sodium hydroxide, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 20:1 to 5: 1) obtain 1.5 g of 5-chloro--(2-ethoxyphenyl)-2-sibutraminepassage alcohol in the form of butter.

The IR spectrum of theNeamaxtcm-1: 3520, 3410 (NH, OH).

1H-spectrum (200 MHz, CDCl3) : of 0.90 (3H, d, J = 6,8 Hz) of 0.91 (3H, d, J = 6.6 Hz), of 1.41 (3H, t, J = 7.0 Hz), 1,7 - 2,0 (1H, m), 2,89 (2H, d, J = 6.8 Hz), 3,2 - 3,6 (1H, Shir), of 4.13 (2H, K, J = 7,0 Hz), 4,7 - 5,1 (1H, Shir), 5,97 (1H, s), 6,55 (1H, d, J = 8.6 Hz), 6,85 to 7.4 (6H, m).

(5) Ethyl ester of 3-[N-[4-chloro-2-(2-ethoxy--oxybenzyl)-phenyl]-N-isobutylamino]acrylic acid

The solution containing 0.84 g of monoethylene ester of fumaric acid and 1.28 ml of thionyl chloride in 10 ml of toluene, stirred for 30 min at 90oC. the solvent is Distilled off under reduced pressure, get monotropy ester acid chloride of fumaric acid. This product and 1.5 lorida, add back 0.75 g of sodium bicarbonate and stirred the mixture for 30 min at room temperature. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 4:1), gain of 1.95 g of ethyl ester of 3-[N-[4-chloro-2-(2-ethoxy--oxybenzyl)phenyl] -N-isobutylamino] acrylic acid in the form of butter.

The IR spectrum of the Neamaxtcm-1: 3400 (OH), 1720, 1660, 1630 (C = C, C = O).

1H-NMR spectrum (200 MHz, CDCl3) : 0,65 - 1,0 (6H, m), 1,15 - 1,5 (6H, m), 1,6 - 2,0 (1H, m), 2,3 - 3,0 (2H, m), 3,9 - 4,4 (5H, m), 5,8 - 6,3 (3H, m), 6,6 - 8,05 (7H, m).

(6) Ethyl ester of TRANS-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid.

Dissolved in 30 ml of ethanol 1,95 g of ethyl ester of 3-[N-[4-chloro-2-(2-ethoxy--oxybenzyl)phenyl]-N-isobutylamino] acrylic acid obtained in (5), add back of 1.17 g of potassium carbonate and stirred the mixture overnight. The reaction mixture was extracted by adding 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate and distill under reduced pressure. The residue is purified by chromatography on co-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of crystalline prisms with so pl. 129 - 130oC.

Elemental analysis for C25H30ClNO5:

Calculated, %: C 65,28; H 6,67; N 3,05

Found, %: C, compared with 65.38; H 6,44; N 2,91

Example 124

TRANS-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Dissolved in 30 ml of methanol to 1.25 g of ethyl ester of TRANS-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 123, add back 10 ml of an aqueous solution containing 0.75 g of potassium carbonate, the mixture is then stirred for 3 h at 60oC. After concentrating the reaction mixture under reduced pressure it is acidified by adding 50 ml of 1H hydrochloric acid, and extracted with 100 ml of ethyl acetate. The extraction solution was washed with water and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2: 1; eluent, hexane-dichloromethane-ethanol = 5:5:1) obtain 0.66 g of TRANS-7-chloro-5-(2-ethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid in the form of crystalline prisms with so pl. 190 - 192oC.

Elemental analysis for C23H25ClNO5:

Calculated, %: C 63,96; H is util-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid.

(1) 2-amino-2'-benzyloxy-5-chlorobenzophenone

Dissolved in 30 ml of N,N-dimethylformamide 5.0 g of 2-amino-5-chloro-2'-oxybenzene obtained in example 123 (1), added back to 4.2 g of potassium carbonate and 2.9 ml of benzylbromide; then the mixture is stirred for 2 h at room temperature. The mixture is extracted with 150 ml of water and 200 ml ethyl acetate, an ethyl acetate layer washed with water and dried over anhydrous magnesium sulfate, and then dispersed under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 10:1 to 5:1) obtain 6.4 g of 2-amino-2-benzyloxy-5-chlorobenzophenone in the form of prisms with so pl. 110 - 111oC.

Elemental analysis for C20H16ClNO2:

Calculated, %: C 71,11; H of 4.77; N 4,15

Found, %: C 71,34; H 4,80; N 4,23

(2) 2-amino(2-benzyloxyphenyl)-5-chlorbenzoyl alcohol

Dissolved in 50 ml of methanol, 6.0 g of 2-amino-2'-benzyloxy-5-chlorobenzophenone obtained in (1), there was added 1.12 g of sodium borohydride and stirred mixture of 4 h at room temperature. After distillation of the ethanol under reduced pressure is conducted dissociation adding an aqueous solution of hydrochloric acid, neutralizing the reaction mixture by adding 50 ml of 1H sodium hydroxide and extracted with 200 ml of ethyl acetate. Utilize which are square-5.9 g of 2-amino--(2-benzyloxyphenyl)-5-chlorobenzylamino alcohol in the form of lamellar crystals, so pl. 120 - 121oC.

Elemental analysis for C20H18ClNO2:

Calculated, %: C 70,69; H of 5.34; N 4,12

Found, %: C 70,85; H 5,16; N 4,24

(3) -(2-benzyloxyphenyl)-5-chloro-2-sibutramine.basically alcohol

Dissolve in 50 ml of acetic acid, 5.0 g of 2-amino--(2-benzyloxyphenyl)-5-chlorobenzylamino alcohol obtained in (2), and 1.47 ml of Isobutyraldehyde. Added to the solution under ice cooling 0.74 g sodium borohydride. The reaction mixture was stirred 30 min at room temperature, then add 150 ml of water and the extraction is carried out with 200 ml of ethyl acetate. The extraction solution was washed with 1H sodium hydroxide and dried over anhydrous magnesium sulfate, then the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 20: 1 to 5:1) obtain 5.6 g -(2-benzyloxyphenyl)-5-chloro-2-sibutraminepassage alcohol in the form of crystalline prisms with so pl. 79 - 80oC.

Elemental analysis for C24H26ClNO2:

Calculated, %: C 72,81; H 6,62; N 3,54

Found, %: C 72,95; H 6,62; N 3,62

(4) Ethyl ester of 3-[N-[4-chloro-2-(2-benzyloxy-oxybenzyl)phenyl]-N-isobutylamino]acrylic acid

A solution consisting of 2.65 g of monoethylene ether reduced pressure, get monotropy ester acid chloride of fumaric acid. This product and 5.6 g -(2-benzyloxyphenyl)-5-chloro-2-sibutraminepassage alcohol obtained in (3), dissolved in 100 ml of methylene chloride, then add of 2.38 g of sodium bicarbonate and stirred the mixture for 30 min at room temperature. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate; then the solvent is distilled off under reduced pressure to obtain 6.4 g of ethyl ester of 3-[N-[4-chloro-2-(2-benzyloxy-oxybenzyl)phenyl] -N-isobutylamino] acrylic acid in the form of crystalline prisms with so pl. 169 - 171oC.

Elemental analysis for C30H32ClNO5:

Calculated, %: C 69,02; H 6,18; N 2,68

Found, %: C 69,24; H 6,04; N 2,71

(5) Ethyl ester of TRANS-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid

Dissolved in 150 ml of ethanol 6.0 g of ethyl ester of 3-[N-[4-chloro-2-(2-benzyloxy-oxybenzyl)phenyl] -N-isobutylamino] acrylic acid obtained in (4), add there 3,18 g of potassium carbonate, the mixture is then stirred overnight. The solvent is distilled off under reduced pressure and the residue is extracted with adding 150 ml of water and 200 ml of ethyl acetate. An ethyl acetate layer is washed with water and sushi is as a column of silica gel (eluent: hexane-ethyl acetate = 5: 1), obtain 5.8 g of ethyl ester of TRANS-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of crystalline prisms with so pl. 146 - 147oC.

Elemental analysis for C30H32ClNO5:

Calculated, %: C 69,02; H 6,18; N 2,68

Found, %: C 69,20; H 6,21; N 2,95

Example 126

TRANS-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Dissolved in a mixture of 20 ml methanol and 10 ml of tetrahydrofuran, 0.5 g of ethyl ester of TRANS-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 125. To this solution was added 10 ml of an aqueous solution containing 0.66 g of potassium carbonate, and stirred the mixture for 6 h at 60oC. the Reaction mixture was concentrated under reduced pressure, acidified with it by adding 50 ml of 1H hydrochloric acid and extracted with 100 ml of ethyl acetate. The extraction solution was washed with water and dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The remainder chromatographic on a column of silica gel (eluent: hexane-ethyl acetate = 3:1, eluent: hexane-dichloromethane-ethanol = 5:5:1) obtain 0.21 g of TRANS-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1>/P>Elemental analysis for C28H28ClNO5:

Calculated, %: C 68,08; H 5,71; N 2,84

Found, %: C 68,07; H of 5.75; N 2,85

Example 127

Ethyl ester of TRANS-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Dissolved in 50 ml of ethyl acetate, 3.5 g of ethyl ester of TRANS-5-(2-benzyloxyphenyl)-7-chloro-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid obtained in example 125. To this solution was added 1.0 g of 10% palladium on coal and carry out the hydrogenolysis under normal temperature and pressure. After absorption of the calculated amount of hydrogen to remove the catalyst and ethyl acetate is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3: 1) obtain 2.8 g of ethyl ester of TRANS-7-chloro-5-(2 oksifenil)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid in the form of butter.

The IR spectrum of theNeamaxtcm-1: 3380 (OH), 1730, 1670, 1650 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : of 0.90 (3H, d, J = 6.6 Hz), 0,99 (3H, d, J = 6.6 Hz), 1,24 (3H, t, J = 7.2 Hz), 1,9 - 2,2 (1H, m), 2,85 (1H, DD, J = 17,8 Hz, 5.0 Hz), 2,97 (1H, d, J = 17,8, 8,2 Hz), to 3.41 (1H, DD, J = 13,8, 6.4 Hz), 4,16 (2H, K, J = 7,2 Hz), 4,30 (1H, DD, J = 13,8, and 7.8 Hz), 4,49 (1H, DD, J = 8,2, 4.8 Hz), 5,97 (1H, s),-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Dissolved in 10 ml of methanol, 0.4 g of ethyl ester of TRANS-7-chloro-5-(1 oksifenil)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 127, add back and 5 ml of an aqueous solution containing 0.51 g of potassium carbonate, the mixture is then stirred for 1 h at 60oC. the Reaction mixture is condensed under reduced pressure, acidified by adding 50 ml of 1H hydrochloric acid and extracted with 100 ml of ethyl acetate. The extraction solution was washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2:1; eluent: hexane-dichloromethane-ethanol = 5:5:2), obtain 0.11 g of TRANS-7-chloro-5-(2 oksifenil)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid in the form of crystalline prisms with so pl. 238 - 242oC (Razlog.).

Elemental analysis for C21H22ClNO5:

Calculated, %: C 62,45; H 5,49; N 3,47

Found, %: C 62,55; H of 5.68; N 3,41

Example 129

Ethyl ester of TRANS-7-chloro-1-isobutyl-5-(2-isoprinosine)-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-acetic acid.

Dissolved in 10 ml of N,N-dimethylformamide and 0.7 g of ethyl ester of TRANS-7-chloro-5-(2 oksifenil)- 0.34 g of potassium carbonate and 0.24 ml of isopropylidene, then the mixture is stirred overnight at room temperature. The mixture is extracted with 100 ml of water and 150 ml ethyl acetate. An ethyl acetate layer is washed 1H hydrochloric acid and sodium bicarbonate, dried over anhydrous magnesium sulfate and distill under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3:1) obtain 0.55 g of ethyl ester of TRANS-7-chloro-1-isobutyl-5-(2-isopropoxyphenyl)-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of needles with so pl. 135 - 137oC.

Elemental analysis for C26H32ClNO5:

Calculated, %: C 65,88; H to 6.80; N 2,96

Found, %: C 66,09; H 6,83; N 3,24

Example 130

TRANS-7-chloro-1-isobutyl-5-(2-isopropoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Dissolved in 20 ml of methanol, 0.4 g of ethyl ester of TRANS-7-chloro-5-(2-isopropoxyphenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 129. To this solution was added 10 ml of an aqueous solution containing a 0.23 g of potassium carbonate, the mixture is then stirred for 3 h at 80oC. the Reaction mixture was concentrated under reduced pressure, acidified by adding 50 ml of 1H hydrochloric acid and extracted with 100 ml utilize the tel under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3: 1, eluent: hexane-dichloromethane-ethanol = 5:5:1) obtain 0.24 g of TRANS-7-chloro-1-isobutyl-5-(2-isopropoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of crystalline prisms with so pl. 146 - 149oC.

Elemental analysis for C24H28ClNO50,2 H2O:

Calculated, %: C 64,12; H 6,37; N 3,11

Found, %: C 64,18; H 6,37; N 3,28

Example 131

Ethyl ester of TRANS-7-bromo-1-neopentyl-2-oxo-5-(2-pyridyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

(1) 2-Amino-5-bromo--(2-pyridyl)benzyl alcohol

Dissolve in 100 ml of methanol, 10 g of 2-amino-5-bromophenyl-2-pyridylketone. To the solution was added 1.7 g of sodium borohydride and stirred for 30 minutes, the Methanol is distilled off under reduced pressure. The residue is treated with an aqueous solution of hydrochloric acid. The decomposed residue is then neutralized with 200 ml of an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2:1) obtain 9.0 g of 2-amino-5-bromo--(2-pyridyl)benzo is A:

Calculated, % 5: C to 51.64; H of 3.97; N 10,04

Found, %: C 51,61; H 3,93; N 10,04

(2) 5-Bromo-2-neopentylene--(2-pyridyl)benzyl alcohol

Dissolved in 20 ml of acetic acid, 2.0 g of 2-amino-5-bromo--(2-pyridyl)benzyl alcohol obtained in (1), together with 0,86 ml trimethylacetaldehyde. To the solution was added 0.36 g of sodium borohydride under ice cooling. The reaction mixture was stirred for 30 min at room temperature and extracted with a mixture of 100 ml of water and 150 ml ethyl acetate. An ethyl acetate layer is washed 1H sodium hydroxide, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 5:1) obtain 2.4 g of 5-bromo-2-neopentylene--(2-pyridyl)benzyl alcohol in the form of butter.

The IR spectrum of theNeamaxtcm-1: 3390, 3280 (NH, OH).

1H-NMR spectrum (200 MHz, CDCl2) : to 0.80 (9H, s, But), 2,68 (2H, s) 5,69 (1H, s), 6.48 in (1H, d, J = 8,4 Hz), 7,1 - to 7.35 (4H, m), 7,55 to 7.7 (1H, m), an 8.5 and 8.6 (1H, m).

(3) Ethyl-3-[N-[4-bromo-2--(2-pyridyl)oxymethyl] phenyl]- N-neopentylene]acrylate

Dissolve in 50 ml of dichloromethane 2.4 g of 5-bromo-2-neopentylene--(2-pyridyl)benzyl alcohol obtained in (2). To the solution was added to 1.15 g of sodium borohydride and of 1.23 g of the Ute water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2: 1) obtain ethyl-3-[N-[4-bromo-2-[-(2-pyridyl)oxymethyl] phenyl]-N-neopentylene]acrylate in the form of prisms with so pl. 165 - 166oC.

Elemental analysis for C23H27BrN2O4:

Calculated, %: C 58,11; H 5,72; N OF 5.89

Found, %: C 58,21; H 5,65; N 6,14

(4) Ethyl-TRANS-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo - 1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetate

Dissolved in 30 ml of ethanol 2.0 g ethyl-3-[N-[4-bromo-2-[-(2-pyridyl)oxymethyl]phenyl]-N-neopentylene]acrylate obtained in (3). To the solution was added to 1.16 g of potassium carbonate and the mixture overnight stirred at room temperature. The solvent is distilled off under reduced pressure. The residue is extracted with 100 ml of water and 100 ml of ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified on a column of silica gel (eluent: hexane-ethyl acetate = 3:1), gain of 1.9 g of ethyl TRANS-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetate in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1730, 1675 (C = O).

1H-NMR spectrum (CDCl<, ,44 (1H, DD, J = 7,8, 5.8 Hz), 4,49 (1H, d, J = 13,8 Hz), 6,07 (1H, s), 6,59 (1H, d, J = 2.2 Hz), a 7.2 to 7.9 (5H, m), 8.6 out of 8.7 (1H, m).

Example 132

TRANS-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid

Dissolved in 20 ml of methanol and 1.9 ethyl-TRANS-7-chloro-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetate obtained in example 131. To the solution was added 10 ml of an aqueous solution containing 1.1 g of potassium carbonate. The mixture 30 min refluxed and concentrate under reduced pressure. The concentrate is crystallized by adding 30 ml of an aqueous solution of hydrochloric acid. The product is filtered and recrystallized from hexane and ethanol, earn 1.25 g of TRANS-7-bromo-1-neopentyl-5-(2-pyridyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid in the form of prisms, so pl. 263oC (Razlog.).

Elemental analysis for C21H23BrN2O4:

Calculated, %: C 56,39; H 5,18; N 6,26

Found, %: C 56,39; H 5,18; N 6,10

Example 133

Ethyl-N-benzyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminoacetic

Dissolved in 10 ml of dimethylformamide 0.3 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-UKS is phosphoroamidite together from 0.19 ml of triethylamine under ice cooling. The mixture is stirred for 30 min at room temperature, then extracted with 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer is washed 1H hydrochloric acid and aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3: 1) obtain 0.56 g of ethyl-N-benzyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminoacetate in the form of prisms, so pl. 195 - 197oC.

Elemental analysis for C33H36Cl2N2O5:

Calculated, %: C 64,81; H to 5.93; N 4,58

Found, %: C 64,84; H 5,97; N 4,45

Example 134

N-Benzyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminouksusnoy acid

In 15 ml of methanol is dissolved 0.3 g ethyl-N-benzyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminoacetate obtained in example 133. To the solution was added 4 ml of sodium hydroxide solution and the mixture is stirred for 20 minutes the Reaction mixture after acidification with 50 ml 1H HCl extracted with 100 ml of ethyl acetate. An ethyl acetate layer washed with water and dried over anhydrous sulfate, Magnox-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminouksusnoy acid

the form of prisms with so pl. 190 - 192oC.

Elemental analysis for C31H32Cl2N2O5:

Calculated, %: C expenses 63.81; H of 5.53; N 4,80

Found, %: C 64,02; H of 5.85; N 4,81

Example 135

Methyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-N-phenylenediacetic

A mixture of 0.6 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2, 10 ml of thionyl chloride and 10 ml of toluene is stirred for 30 min at 90oC, then concentrated under reduced pressure. Concentrate TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl - 1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepin-3-acetylchloride dissolved in 10 ml of methylene chloride. To the solution was added 0.27 g of methyl ester of N-phenylglycine and 0.23 ml of triethylamine. The mixture is stirred for 1 h at room temperature and extracted with 100 ml of ethyl acetate. The organic layer was washed with 1H HCl and aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrate under reduced pressure.

The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3: 1) obtain 0.35 g of methyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-UB>2
N2O5:

Calculated, %: C expenses 63.81; H of 5.53; N 4,80

Found, %: C 63,78; H 5,59; N 4,60

Example 136

N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-N - Veniaminovna acid

Dissolved in 3 ml of methanol, 0.25 g of methyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] -N - phenylenediacetic obtained in example 135. To the solution was added 1 ml of 1H of sodium hydroxide. The mixture is stirred for 1.5 h at 60oC, then acidified with 50 ml of 1H HCl for extraction with ethyl acetate. An ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, get to 0.23 g of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]-N - phenylaminopropyl acid in the form of prisms with so pl. 238 - 240oC.

Elemental analysis for C30H30Cl2N2O5:

Calculated, %: C 63,27; H 5,31; N 4,92

Found, %: C 63,46; H 5,54; N 4,70

Example 137

Ethyl N-[TRANS-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl]aminoacetic

Dissolved in 10 ml of dimethylformamide 0.3 g of TRANS-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-wks of diethylphosphonoacetate and 0.24 ml of triethylamine under ice cooling. The mixture is stirred for 30 min at room temperature and then extracted with 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer was washed with 1H HCl and aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The ethyl acetate is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 1:1) obtain 0.33 g of ethyl-N-[TRANS-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminoacetic in the form of needles with so pl. 233 - 236oC.

Elemental analysis for C27H33ClN2O6:

Calculated, %: C 62,72; H to 6.43; N 5,42

Found, %: C 62,54; H 6,47; N 5,28

Example 138

N-[TRANS-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3 - acetyl]aminouksusnoy acid

Dissolve in 5 ml of ethanol and 0.25 g of ethyl-N-[TRANS-7-chloro-5-(2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl] aminoacetate obtained in example 137. To the solution was added 2 ml of 1H of sodium hydroxide. After 15 min stirring, the reaction mixture was acidified with 100 ml of 1H HCl and extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. The ethyl acetate is distilled off under reduced pressure to obtain N-[travice prisms with so pl. 239 - 242oC.

Elemental analysis for C25H29ClN2O5:

Calculated, %: C 61,41; H 5,98; N 5,73

Found, %: C 61,38; H 5,91; N OF 5.83

Example 139

TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methylamine hydrochloride

Work according to the method of example 36, treated with 1.0 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2. The product is a 0.9 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methylamine hydrochloride in the form of lamellar crystals, so pl. 173 - 175oC.

Elemental analysis for C21H24Cl2N2O2HCl H2O:

Calculated, %: C 54,62; H of 5.89; N 6,06

Found, %: C 54,77; H 5,95; N OF 5.83

Example 140

Methyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]carbamoylated

Dissolved in 10 ml of N,N-dimethylformamide 0.3 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methylamine hydrochloride obtained in example 139, and 0.12 g monomethylamine potassium salt. To the solution was added to 0.13 g diethylphosphoramidite together 0.11 ml of triethylamine in odes and 100 ml of ethyl acetate. An ethyl acetate layer was washed with 1H HCl and aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate. Then distilled off ethyl acetate under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 1:1) obtain 0.28 g of methyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]carbamoylated in the form of butter.

The IR spectrum of theNeamaxtcm-1: 3330 (NH), 1740, 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : of 0.94 (9H, s, T.-VI), or 3.28 (2H, s) to 3.38 (1H, d, J=a 13.9 Hz), 3,74 (3H, s), 3,7 - of 3.85 (2H, m) to 3.99 (1H, t, J= 6,1 Hz), of 4.54 (1H, d, J=a 13.9 Hz), and 6.25 (1H, s), of 6.52 (1H, d, J=1.9 Hz), a 7.2 to 7.9 (7H, m, NH).

Example 141

N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]carbamoylation acid

Dissolve in 5 ml of ethanol 0.28 g of methyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] carbamoylated obtained in example 140. To the solution was added 2 ml of 1H sodium hydroxide and the mixture is stirred for 10 min at room temperature. The reaction mixture is acidified with 50 ml of 1H hydrochloric acid and then extracted with 50 ml ethyl acetate. An ethyl acetate layer was washed with water, dried over magnesium sulfate is hydro-4,1-benzoxazepin-3-methyl] carbamoyloximes acid in the form of lamellar crystals with so pl. 135 - 138oC.

Elemental analysis for C24H26Cl2N2O5:

Calculated, %: C 58,43; H 5,31; N 5,68

Found, %: C 58,48; H 5,42; N 5,52

Example 142

Tert. butyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]aminoacetate

A mixture of 2.5 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methylamine hydrochloride obtained in example 139, with 0.93 ml ethylchloride, of 1.87 g of potassium carbonate and 50 ml of acetonitrile is refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the concentrate is extracted with 100 ml of water and 150 ml ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The ethyl acetate is evaporated under reduced pressure, get 1,95 g of tert. butyl-N-[TRANS-7-chloro-5-(2-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]-aminoacetate in the form of butter.

The IR spectrum of theNeamaxtcm-1: 3330 (NH), 1735, 1675 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : of 0.94 (9H, s, two), the 1.44 (9H, s, so By) to 3.00 (1H, DD, J=12,2, 6.4 Hz), 3,11 (1H, DD, J=12,2, 6.2 Hz), to 3.33 (2H, s) to 3.36 (1H, d, J=14,0 Hz), Android 4.04 (1H, t, J=6.3 Hz), to 4.52 (1H, d, J=14,0 Hz), of 6.26 (1H, s), of 6.52 (1H, d, J=1,8 Hz), 7,2 - a 7.85 (6H, m).

Elemental analysis for C23H26Cl2N2O4: to 0.89 (9H, two), a 3.2 - 3,55 (2H, m), 3,68 (1H, d, J=14,0 Hz), 3,88 (2H, s), 4,32 (1H, d, J=14,0 Hz), 4,3 - 4,5 (1H, m), to 6.19 (1H, s), to 6.39 (1H, d, J=2,42 Hz), 7,5 - 8,1 (6H, m).

Example 144

Tert. butyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]-N-methanesulfonylaminoethyl

Dissolve 5 ml of N, N-dimethylformamide of 0.44 g of tert.butyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] aminoacetate obtained in example 142. To the solution was added 0,072 ml methanesulfonanilide and 0.14 ml of triethylamine under ice cooling. After 30 min stirring at room temperature the reaction mixture is extracted with 100 ml vobonute sodium and dried over anhydrous magnesium sulfate. The ethyl acetate is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate = 3:1) receive and 0.37 g of tert.butyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]-N - methanesulfonylaminoethyl in the form of prisms with so pl. 178 - 180oC.

Elemental analysis for C28H36Cl2N2O6S:

Calculated, %: C 56,09; H equal to 6.05; N 4,67

Found, %: C 55,92; H the 6.06; N 4,47

Example 145

N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]-N-methanesulfonylaminoethyl acid

Dissolved in 20 ml 4H HCl-dioxane solution of 0.25 g of tert.butyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] -N-methanesulfonylaminoethyl obtained in example 144. After 8 h of stirring at room temperature the reaction mixture was concentrated under reduced pressure. The residue is treated with hexane and ethyl acetate, to obtain 0.21 g of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] -N-methanesulfonylaminoethyl acid in the form of prisms with so pl. 236 - 238oC.

Elemental analysis for C24H28Cl2N2O6S:<2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]-N-(p-toluensulfonyl)aminoacetate

Dissolved in 10 ml of N, N-dimethylformamide, 0.5 g of tert.butyl-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] aminoacetate obtained in example 142. To the solution was added to 0.22 g of p-toluensulfonate together with 0.16 ml of triethylamine under ice cooling.

The mixture is stirred for 1 h at room temperature, then extracted with 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer was washed with a 5% solution of potassium bisulfate and aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 5: 1), tert get.butyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]-N-(p-toluensulfonyl) aminoacetate in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1740, 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : to 0.92 (9H, s, so-Bu) 2,39 (3H, s) to 3.36 (1H, d, J=14,0 Hz), 3,66 (1H, DD, J=15,6 to 6.4 Hz), a-3.84 (1H, DD, J=15,6, 5,9 Hz), 3,98 (1H, d, J=18,4 Hz), 4,2 - 4,3 (1H, m), the 4.29 (1H, d, J=18,4 Hz), of 4.45 (1H, d, J=14,0 Hz), of 6.20 (1H, s), 6,46 (1H, s, J=2.1 Hz), 7,15 - in 7.7 (10H, m).

Example 147

N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-be what about the solution of 0.5 g of tert.butyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] -N-(p-toluensulfonyl) aminoacetate, obtained in example 146. After 4 h stirring at room temperature the reaction solution is concentrated under reduced pressure. The residue is treated with hexane and diethyl ether, gain of 0.41 g of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] -N-(p-toluensulfonyl) aminouksusnoy acid in the form of needles with so pl. 132 - 134oC.

Elemental analysis for C30H32Cl2N2O6S:

Calculated, %: C 58,16; H to 5.21; N TO 4.52

Found, %: C 58,01; H 5,32; N 4,55

Example 148

Tert. butyl-N-acetyl - N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]-aminoacetic

Dissolved in 10 ml of N,N-dimethylformamide, 0.5 g of tert.butyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] aminoacetate obtained in example 142. To the solution was added 0,082 ml acetylchloride and 0.16 ml of triethylamine under ice cooling.

The mixture is stirred for 30 min at room temperature and then extracted with 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer was washed with a 5% solution of potassium bisulfate and aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, the et.butyl-N-acetyl-N - [TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]aminoacetate in the form of butter.

The IR spectrum of theNeamaxtcm-1: 1740, 1670 (C = O).

1H-NMR spectrum (200 MHz, CDCl3) : to 0.92 and 0.94 (9H, each s, so-Bu) of 1.95 and 2.15 (3H, each s, so-Bu) at 3.35 and 3.38 (1H, each d, J = 14,0 Hz), 3,7 - 4,3 (5H, m), 4,45, and 4,48 (1H, each d, J = 14,0 Hz), 6,23 and 6,28 (1H, each s), 6,45 - 6,55 (1H, m), 7.3 to 7.8 for (6H, m).

Example 149

N-Acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]aminouksusnoy acid

Dissolved in 20 ml 4H HCl-dioxane solution of 0.5 g of tert.butyl-N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] aminoacetate obtained in example 148. After stirring over night at room temperature the mixture is concentrated under reduced pressure. The concentrate is treated with hexane and diethyl ether, receive and 0.37 g of powdered N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl - 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] aminouksusnoy acid.

Elemental analysis for C25H28Cl2N2O5:

Calculated, %: C 59,18; H 5,56; N 5,52

Found, %: C 59,36; H 5,70; N 5,50

1H-NMR spectrum (200 MHz, CDCl3) : to 0.92 and 0.94 (9H, each with. so-Bu), 2.00 and of 2.20 (3H, each s), 3,3 - 3,5 (1H, m), 3,7 - 4,5 (6H, m), 6,22 and 6,28 (1H, each s), 6,45 - 6,55 (1H, m), 7 the Idro-4,1-benzoxazepin-3-methyl]aminometilbensana acid

(A) are Mixed in 30 ml of acetonitrile, 1.0 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methylamine hydrochloride, obtained in example 139, 0.6 g of methyl-4-bromoethylamine and 0.75 g of potassium carbonate. The mixture is boiled for 2 hours under reflux. After adding 0.2 g methyl-4-bromoethylamine continue boiling under reflux for another 5 h, then concentrated under reduced pressure. The concentrate is extracted with 100 ml of water and 150 ml ethyl acetate. An ethyl acetate layer washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and purify the residue by chromatography on a column of silica gel (eluent: hexane-ethyl acetate= 10:1 - 1:2), obtain 0.15 g of methyl ester of 4-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzoxazepin-3-methyl] aminometilbensana acid in the form of prisms with so pl. 171 - 173oC.

Elemental analysis for C30H32Cl2N2O4:

Calculated, %: C 64,87; H of 5.81; N 5,04

Found, %: C 64,88; H 5,97; N 4,76

(B) was Dissolved in 20 ml of ethanol, 0.45 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methylamine hydrochloride obtained in example 139. To the solution was added to 0.19 g m is matney temperature to the mixture was added 82 mg cyanoborohydride sodium. After additional stirring for 2 h at room temperature the mixture is concentrated under reduced pressure and extracted concentrate 100 ml of water and 100 ml of ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The organic solvent is distilled off under reduced pressure and purify the residue by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 1:1) obtain 0.31 g of methyl ester of 4-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl]aminometilbensana acid.

Example 151

Methyl ester of 4-[N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] -N - methanesulfonyl] aminometilbensana acid

Dissolve in 5 ml of N, N-dimethylformamide 0.3 g of methyl ester of 4-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] aminobenzoic acid, obtained in example 150. To the solution was added 0.05 ml of methanesulfonanilide and 0.09 ml of triethylamine. After 1 h stirring at room temperature the reaction mixture is extracted with 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer is washed 1H hydrochloric acid and an aqueous solution of bicarbonate into three what s on a column of silica gel (eluent: hexane-ethyl acetate = 2:1), obtain 0.27 g of methyl ester of 4-[N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-2-methyl]-N-methanesulfonyl]aminometilbensana acid in the form of needles with so pl. 173 - 174oC.

Elemental analysis for C31H34Cl2N2O6S:

Calculated, %: C 58,77; H 5,41; N 4,42

Found, %: C 58,59; H of 5.68; N 4,19

Example 152

4-[N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] -N-methanesulfonyl] aminomethylbenzoic acid

Dissolved in 10 ml of methanol, 0.17 g of methyl ester of 4-[N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] -N-methanesulfonyl] aminometilbensana acid obtained in example 151. After adding 4 ml of 1H sodium hydroxide solution is stirred for 1 h at 60oC. the Reaction mixture was then acidified with 50 ml of 1H hydrochloric acid and extracted with 50 ml ethyl acetate. An ethyl acetate layer washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.16 g of 4-[N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-methyl] -N - methanesulfonyl] aminometilbensana acid in the form of prisms with so pl. 235 - 237oC.

Element EN is N 4,29

Example 153

TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethanol

Dissolve in 200 ml of tetrahydrofuran was 14.7 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetic acid obtained in example 2, and 4.51 ml of N-methylmorpholine. To the solution was added to 3.92 ml atilglukuronida at -10oC, then the mixture is stirred for 15 minutes After adding 3,86 g of sodium borohydride and 200 ml of methanol are added dropwise to the solution. The mixture is stirred for 1 h at room temperature, and then concentrated. After adding 200 ml of 1H hydrochloric acid concentrate is extracted with 200 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by chromatography with silica gel (eluent: hexane-ethyl acetate = 1:1) obtain 14.2 g of TRANS-7-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1 - benzoxazepin-3-ethanol in the form of colorless crystals with so pl. 157 - 159oC.

Elemental analysis for C22H25Cl2NO3:

Calculated, %: C 62,56; H 5,97; N 3,32

Found, %: C 62,30; H of 6.02; N 3,17

Example 154

Ethyl ester of N-[TRANS-7-chloro-5-(2-X5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetaldehyde

To 25 ml of dichloromethane solution containing 0,70 ml oxalicacid, add 5 ml of dichloromethane solution containing of 0.71 ml of dimethyl sulfoxide, at -78oC, then stirred for 5 min. To the solution is slowly added 10 ml of dichloromethane solution containing 1,69 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethanol obtained in example 160, then stirred for 15 min at -78oC. To the reaction mixture added to 2.79 ml of triethylamine and stirred for further 1 h at 0oC and 1.5 h at room temperature. After adding 100 ml of water, the extraction is carried out with 100 ml of dichloromethane. The dichloromethane layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 1:1) obtain 1.08 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetaldehyde in the form of light yellow crystals with so pl. 173 - 176oC.

Elemental analysis for C22H23Cl2NO30.5 H2O:

Calculated, %: C 61,55; H 5,63; N 3,26

Found, %: C 61,27; H 5,49; N 3,17

(2) Ethyl ester of N-[TRANS-7-(chloro-5-(2-chlorophenyl)-1-neopentane-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetaldehyde, obtained in example 161(1), and 0.56 g of hydrochloric acid ethyl ester of glycine was added 10 ml of ethanol containing 0,13 g cyanoborohydride sodium dropwise within 1.5 hours After 3 h of additional stirring, the reaction mixture is extracted with 200 ml of water and 200 ml of ethyl acetate. An ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and purify the residue by chromatography on a column of silica gel (eluent: ethyl acetate), to obtain 0.75 g of an amorphous solid of ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]aminouksusnoy acid.

Elemental analysis for C26H32Cl2N2O4:

Calculated, %: C 61,54; H 6,36; N OF 5.53

Found, %: C 61,16; H 6,29; N 5,56

1H-NMR spectrum (CDCl3) : of 0.93 (9H, s, so-Bu) of 1.26 (3H, t, J = 7.2 Hz), 1,90 - of 2.15 (3H, m), was 2.76 (2H, DD, J = 7,2, 6,6 Hz) to 3.38 (1H, d, J = a 13.9 Hz), to 3.38 (2H, s), a 4.03 (1H, DD, J = 6,6, 6.2 Hz), 4,17 (2H, K, J = 7,2 Hz), 4,51 (1H, d, J = a 13.9 Hz), 6,24 (1H, s), 6,51 (1H, d, J = 1.6 Hz), 7,30 is 7.50 (5H, m), 7,70 - 7,80 (1H, m).

Example 155

Ethyl ester of N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]-aminouksusnoy acid

In 5 ml of N, N-dimethylformamide is dissolved 0 is acetate, obtained in example 154. To the solution was added 0,031 ml acetylchloride and 0,050 ml of triethylamine under ice cooling. After 30 min stirring under ice cooling, the reaction mixture is extracted with 40 ml water and 40 ml of ethyl acetate. An ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 1:3) obtain 0.15 g of an amorphous solid of ethyl ester of N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]aminouksusnoy acid.

Elemental analysis for C28H34Cl2N2O50,4 H2O:

Calculated, %: C 60,41; H 6,30; N 5,03

Found, %: C 60,44; H to 6.43; N 4,96

1H-NMR spectrum (CDCl3) : of 0.93 and 0.94 (9H, each s, so-Bu), 1,20 - of 1.32 (3H, m), 1,95 - of 2.20 (2H, m), 1,95 and 2.13 (all 3H, each s), 3,32 - 3,68 (3H, m), 3,90 - 4,27 (5H, m), 4,48 and 4.50 (total 1H, each d, J = 13,8 Hz), 6,22 and 6,24 (total 1H, each s), 6.50 and 6,53 (total 1H, each d, J = 2.0 Hz), 7.29 trend is 7.50 (5H, m), 7,65 - 7,80 (1H, m).

Example 156

N-Acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]aminouksusnoy acid

To 5 ml of methanol containing 0.11 g etiloogies 155, add 1 ml of 0.5 M aqueous solution of potassium carbonate. After 30 min stirring at 60oC, the reaction mixture was acidified with 0.5 ml of 1H hydrochloric acid and the extraction is carried out with 20 ml water and 20 ml of ethyl acetate. An ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is treated with ether, obtain 0.07 g of white powdery N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-ethyl]aminouksusnoy acid, so pl. 210-212oC.

Elemental analysis for C26H30Cl2N2O5:

Calculated, %: C 59,89; H 5,80; N lower than the 5.37

Found, %: C 59,78; H of 5.85; N 5,13

Example 157

Ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -N-methanesulfonylaminoethyl acid

B 5 ml of N, N-dimethylformamide was dissolved 0.15 g of ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -aminouksusnoy acid obtained in example 154. To the solution was added 0,028 ml methanesulfonanilide and 0,050 ml of triethylamine under ice cooling. After 30 min stirring under ice cooling the extraction is carried out with 40 ml Woe. The solvent is distilled off under reduced pressure, and the residue purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 2:1) obtain 0.12 g of ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro - 4,1-benzoxazepin-2-ethyl]-N-methanesulfonylaminoethyl acid in the form of a white powder with so pl. 134 - 135oC.

Elemental analysis for C27H34Cl2N2O6S:

Calculated, %: C 55,38; H of 5.85; N 4,78

Found, %: C 55,66; H 5,98; N BR4.61

Example 158

N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]-N-methanesulfonylaminoethyl acid

Work according to the method of example 156, hydrolyzing 0.12 g of ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -N-methanesulfonylaminoethyl acid obtained in example 157, obtain 0.10 g of a white powder of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -N-methanesulfonate acid so pl. 135 - 137oC.

Elemental analysis for C25H30Cl2N2O6S 0,5 H2O:

Calculated, %: C 53,00; H 5,52; N 4,94

Found, %: C 53,25; H 5,78; N 4,71

Example 159

Ethyl ester of N-[tranoi acid

In 5 ml of N, N-dimethylformamide was dissolved 0.15 g of ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]aminouksusnoy acid obtained in example 154. To the solution was added 0,069 g p-toluensulfonate together with 0,050 ml of triethylamine under ice cooling. After 30 min stirring under ice cooling, the reaction mixture is extracted with 40 ml water and 40 ml of ethyl acetate. An ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. An ethyl acetate layer dispersed under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate = 3: 1) obtain 0.17 g of amorphous ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -N-p-toluensulfonate acid.

Elemental analysis for C33H38Cl2N2O6S:

Calculated, %: C 59,91; H 5,79; N 4,23

Found, %: C 60,25; H 6,01; N 4,04

1H-NMR spectrum (CDCl3) : of 0.94 (9H, s, so-Bu) and 1.15 (3H, t, J = 7.2 Hz), 1,90 - of 2.30 (2H, m), is 2.41 (3H, s), 3,20 - of 3.60 (2H, m) to 3.41 (1H, d, J = 140 Hz), 3,97 - 4,18 (5H, m), 4,50 (1H, d, J = 14,0 Hz), 6,23 (1H, s), of 6.52 (1H, s), 7,21 is 7.50 (7H, m), 7,62 - 7,80 (3H, m).

Example 160

N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-OK the e of example 156, conduct hydrolysis 0.15 g of ethyl ester of N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -N-p - toluensulfonate acid in the form of a white powder with so pl. 274-277oC.

Elemental analysis for C31H34Cl2N2O6S:

Calculated, %: C 58,77; H 5,41; N 4,42

Found, %: C 58,70; H 5,59; N 4,13

Example 161

Methyl ester of 4-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]aminometilbensana acid

A mixture of 0.42 g of TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetaldehyde obtained in example 154(1), of 0.30 g of hydrochloric acid salt of methyl ester of 4-aminometilbensana acid and 30 ml of ethanol is stirred for 2 h at room temperature. Then to the mixture is slowly added dropwise 5 ml of ethanol containing 0.06 laborgerate sodium. After 2 h stirring, the reaction mixture was extracted with 100 ml of water and 100 ml of ethyl acetate. An ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic solvent is distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: ethyl acetate), receive the amorphous methylamino acid.

Elemental analysis for C31H34Cl2N2O4:

Calculated, %: C, compared with 65.38; H of 6.02; N 4,92

Found, %: C 64,99; H 6,11; N 5,19

1H-NMR spectrum (CDCl3) : of 0.94 (9H, s, so-Bu), 1,98 - of 2.26 (3H, m), 2,65 - 2,90 (2H, m) to 3.38 (1H, d, J = 14,0 Hz), 3,83 (2H, s), 3,91 (3H, s) 4,06 (1H, t, J = 6.2 Hz), 4,49 (1H, d, J = 14,0 Hz), 6,21 (1H, s), the 5.51 (1H, d, J = 2.0 Hz), 7,26 to 7.62 (8H, m), 7,92 - 8,02 (2H, m).

Example 162

Methyl ester of 4-[N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]]-aminometilbensana acid

Work according to the method of example 155, of 0.13 g of methyl ester of 4-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -aminometilbensana acid obtained in example 161, treated with 0.13 g of amorphous methyl ester 4-[N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]]-aminometilbensana acid.

Elemental analysis for C33H36Cl2N2O5:

Calculated, %: C 64,81; H to 5.93; N 4,58

Found, %: C 65,14; H 6,12; N 4,11

1H-NMR spectrum (CDCl3) : of 0.93 (9H, s, so-Bu) 2,00 - of 2.20 (2H, m), 2,02 and 2.18 (total 3H, each s), 3,20 - of 3.60 (3H, m), 3,78 - 4,00 (1H, m), 3,91 and 3,93 (total 3H, each s), 4,42 was 4.76 (3H, m), 6,21 (1H, s), of 6.50 (1H, d, J = 1,86 Hz), 7,17 - of 7.70 (8H, m), of 7.95 (1H, d, J = 8.0 Hz), 8,02 (1H4,1-benzoxazepin-3-ethyl]]-aminomethylbenzoic acid

Work according to the method of example 156, hydrolyzing 0.10 g of methyl ester of 4-[N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]]-aminometilbensana acid obtained in example 162, obtain 0.08 g of white powder of 4-[N-acetyl-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]]-aminometilbensana acid so pl. 242 - 244oC.

Elemental analysis for C32H34Cl2N2O5:

Calculated, %: C 64,32; H 5,74; N 4,69

Found, %: C 64,34; H by 5.87; N 4,66

Example 164

Methyl ester of 4-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl]-N-methanesulfonyl]aminobenzoic acid

Work according to the method of example 157, treated with 0.13 g of methyl ester of 4-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] aminobenzoic acid, obtained in example 161, obtain 0.12 g of methyl ester of 4-N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -N-methanesulfonyl] aminometilbensana acid in the form of colorless crystals with so pl. 172 and 174oC.

Elemental analysis for C32H36Cl2N2O6S:


Work according to the method of example 156, hydrolyzing 0.09 g of methyl ester of 4-[N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ethyl] -N-methanesulfonyl] aminometilbensana acid obtained in example 164, obtain 0.06 g of 4-[N-[TRANS-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5 - tetrahydro-4,1-benzoxazepin-3-ethyl] -N-methanesulfonyl]aminometilbensana acid in the form of colorless crystals with so pl. 185 - 187oC.

Elemental analysis for C31H34Cl2N2O6S109cells), obtained by incubation in a modified environment Daleko-Needle (37oC in the presence of 5% CO2) suspended in 10 ml chilled on ice in buffer solution (100 mm califofnia buffer (pH of 7.4), 30 mm nicotinamide and 2.5 mm MgCl2). Cells break by means of ultrasonic sound (30, twice). Obtained in this dubbing the microsome fraction is obtained by the same procedure as in experimental example 1, and then it is suspended in chilled on ice 100 mm califorina buffer (pH 7,4) (approximately the protein concentration of 4 mg/ml). This suspension is used as enzyme solution. The results are shown in table 89.

Experimental example 4

Dei is and filter paper (produced by "Toyo Seisakusho", 8 mm in diameter) moistened with 100 μg/ml solution of compound I in methanol, placed on the agar plate, which is incubated at 28oC for 2 days, and measuring the zone of growth inhibition around the disk of filter paper. Use the following culture medium:

A: agar medium based on nitrogen yeast (pH 7.0);

B: agar medium peptone-yeast extract-glucose (pH 7.0).

Protivogribkoe spectrum of the compound I are shown in table 90.

Mentioned below are the test fungi deposited at Institute for fermentation. Osaka, Japan (IFO). Their rooms storage are shown in table 90.

Experimental example 5

In vivo cholesterolgenesis in the liver.

A six-week male rats Sprague-Dole gave 5% cholestyramine as a feed additive for 4 days. They enter the compound at a dose of 30 mg/kg as a suspension in 0.5% methylcellulose solution and intravenous give 2 µci (14C)acetate over 1 h after injection. An hour later, the rats kill and remove the liver. Extracted hepatitis sterols petroleum ether after saponification and measure the radioactivity of the fraction deposited by digitonin. The compound of example 1-(4) inhibits hepatitis cholesterolosis 38. the R> Agents that inhibit stvalentines that contains as its effective component derived 4,1-benzoxazepin-2-it is shown by the formula I of the present invention, or its salt, in the case when it is used as a therapeutic agent, hypercholesterinemia, can be formulated in accordance with the following regulations.

1. Capsules mg:

(1) Compound obtained in example 29 - 19 - 10

(2) Lactose - 90

(3) Microcrystalline cellulose 70

(4) magnesium Stearate - 10

One capsule - 180

Mixed (1), (2) and (3) and half of (4), the mixture granularit, then add the balance of (4). The mixture is filled gelatin capsule.

2. Tablets mg

(1) Compound obtained in example 28 - 19 - 10

(2) Lactose - 35

(3) Corn starch - 150

(4) Microcrystalline cellulose 30

(5) magnesium Stearate - 5

One tablet - 230

Mixed (1), (2) and (3) and two-thirds (4) and half of (5), the mixture granularit, then add the balance of (4) and (5). The mixture is molded by pressing, get a tablet.

3. Injection, mg:

(1) Sodium salt of the compound obtained in example 28 - 19 - 10

(2) Inositol - 100

(3) Benzyl alcohol 20

One amp is p is transferred into a vial and the vial sealed. All processes carried out in sterile conditions.

4. Capsules mg:

(1) Compound obtained in example 1 - 4 - 10

(2) Lactose - 90

(3) Microcrystalline cellulose 70

(4) magnesium Stearate - 10

One capsule - 180

Mixed (1), (2) and (3) and half of (4), the mixture granularit, then add the balance of (4). The mixture is filled gelatin capsules.

5. Tablets mg

(1) Compound obtained in example 1 - 4 - 10

(2) Lactose - 35

(3) Corn starch - 150

(4) Microcrystalline cellulose 30

(5) magnesium Stearate - 5

One tablet - 230

Mix(1), (2), (3) and two-thirds (4) and half of (5), the mixture granularit, then add the balance of (4) and (5). The mixture is molded by pressing, get a tablet.

6. Injection, mg:

(1) Sodium salt of the compound obtained in example 1 - 4 - 10

(2) Inositol - 100

(3) Benzyl alcohol 20

One ampoule 130

Dissolve (1), (2) and (3) in distilled water for injection to obtain a total volume of 2 ml, the solution is transferred into a vial, the vial sealed. All processes are under sterile conditions.

1. Derived 4,1-benzoxazepin-2-she formulas (I)

< / BR>
where R1(i) hydrogen atom or (ii) the hydrocarbon hrly, lower alkenes and lower alkynes, and alicyclics hydrocarbon group, such as C3-C9-cycloalkyl group, and the hydrocarbon group is unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of: 1) phenyl and naphthyl, 2) C1-C6-cycloalkyl, 3) a heterocyclic group selected from the group consisting of furyl and indolyl, and 4) of the halogen atom in which group 1 is unsubstituted or substituted 1 - 2 C1-C3-alkoxygroup;

R2and R3independently of one another (i) hydrogen, (ii) lower alkyl, (iii) phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali, 3) lower C1-C4-alkoxygroup, 4) a hydroxy-group, where group 2) unsubstituted or substituted by 1 to 3 halogen atoms, group 4) unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl; and two adjacent substituents on the phenyl group may together form a ring, or (iv) pyridyl;

X is a bond or a connecting group with a chain length of 1 to 7 atoms selected from the group consisting of - (CH2)m-E-(CHR6)n-, where m and n denote the independent the SUB>7
- or-NHCONH-, where R5is hydrogen, lower alkyl, methylsulphonyl, 4-methylbenzenesulfonyl or acyl, R6and R7independently of one another (i) hydrogen, (ii) lower alkyl which is unsubstituted or substituted by substituents selected from the group containing a heterocyclic group selected from the group consisting of: 1) indolyl, 2) a hydroxy-group, 3) possibly esterified carboxypropyl and 4) phenyl; (iii) benzyl; (iv) phenyl;

Y represents (I) may esterified or theatrevision carboxypropyl, (II) a hydroxy-group, (III) an amino group which is unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali, in which two substituent at the nitrogen atom together form a cyclic group, (IV) phenyl, which is unsubstituted or substituted by substituents selected from the group consisting of: 1) lower C1-C4-alkali, 2) lower C1-C4-alkoxygroup, 3) possibly esterified carboxypropyl, 4) phenyl, 5) an amino group which is unsubstituted or substituted by lower C1-C3-alkilani, and 6) N-containing heterocyclic residue having hydrogen atom capable of deprotonates, such as tetrazol-5-yl, where each of groups 1 and 4) unsubstituted iitaly, selected from the group consisting of lower C1-C4-alkali and benzyl, in which two Deputy at the nitrogen atom may together form a cyclic amino group, which is optionally combined with phenyl, unsubstituted or substituted by halogen atoms; (VI) N-containing heterocyclic residue having hydrogen atom capable of deprotonates, which are selected from the group consisting of tetrazol-5-yl and 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl;

provided that when X is methylene and R1is other than alkyl, with the number of carbon atoms is greater than 4, then Y is different from carboxypropyl and alkoxycarbonyl; and

ring, And unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali and 3) lower C1-C4-alkoxygroup in which group 2) unsubstituted or substituted by 1 to 3 halogen atoms, and these substituent may form a ring with each of the neighboring substituents or its salt.

2. Derived 4,1-benzoxazepin-2 on p. 1, where R1is an aliphatic chain hydrocarbon group.

3. Derived 4,1-benzoxazepin-2 on p. 2, where R1is a lower alkyl group.

4. Derived 4,1-benzoxazepin-2 on p. 4, where R1- C4-C5is an alkyl group.

6. Derived 4,1-benzoxazepin-2 on p. 1, in which R2and R3is phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali, 3) lower C1-C4-alkoxygroup, 4) a hydroxy-group, in which group 2) unsubstituted or substituted by 1 to 3 halogen atoms, group 4) unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl; and two adjacent substituents on the phenyl group may together form a ring.

7. Derived 4,1-benzoxazepin-2 on p. 1, where Y (I) perhaps the esterified carboxypropyl or (II) N-containing heterocyclic residue having hydrogen atom capable of deprotonates, which are selected from the group consisting of tetrazol-5-yl and 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl.

8. Derived 4,1-benzoxazepin-2 on p. 1 of formula (I')

< / BR>
where R1(i) hydrogen atom or (ii) a hydrocarbon group selected from the group consisting of aliphatic chain hydrocarbon group, such as lower alkali, lower alkenes and lower alkynes, and alicyclic ugley or substituted 1 - 5 substituents selected from the group consisting of: 1) phenyl and naphthyl, 2) C3-C6-cycloalkyl, 3) a heterocyclic group selected from the group consisting of furyl and indolyl, and 4) a halogen atom, in which group 1 is unsubstituted or substituted 1 - 2 C1-C3-alkoxygroup;

R2and R3independently of one another (i) hydrogen, (ii) lower alkyl, (iii) phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali, 3) lower C1-C4-alkoxygroup, 4) a hydroxy-group, in which group 2) unsubstituted or substituted by 1 to 3 halogen atoms, group 4) unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl; and two adjacent substituents on the phenyl group may together form a ring, or (iv) pyridyl;

X is a bond or a connecting group with a chain length of 1 to 7 atoms selected from the group consisting of - (CH2)m-E-(CHR6)n-, where m and n represent independently from each other 0, 1, 2 or 3, E is a bond or an oxygen atom, a sulfur atom, sulfoxide, sulfon, -NR5-, NHCO-, CONR7- or-NHCONH-, where R5is hydrogen, lower alkyl, methylsulphonyl, 4-metalbeast or substituted by substituents, selected from the group consisting of: 1) indolyl, 2) a hydroxy-group, 3) possibly esterified carboxypropyl and 4) phenyl, (iii) benzyl; (iv) phenyl;

Y represents: (I) the possible esterified or theatrevision carboxypropyl, (II) a hydroxy-group, (III) an amino group which is unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali, in which two Deputy together form a cyclic group, (IV) phenyl, which is unsubstituted or substituted by substituents selected from the group consisting of: 1) lower C1-C4-alkali, 2) lower C1-C4-alkoxygroup, 3) possibly esterified carboxypropyl, 4) phenyl, 5) an amino group which is unsubstituted or substituted by lower C1-C4-alkilani, and 6) N-containing heterocyclic residue having hydrogen atom capable of deprotonates, such as tetrazol-5-yl, where each of groups 1 and 4) unsubstituted or substituted possibly esterified with carboxypropyl, (V) carbarnoyl, which is unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl, in which two Deputy at the nitrogen atom may together form a cyclic amino group, kuorikoski residue, having a hydrogen atom capable of deprotonates, which are selected from the group consisting of tetrazol-5-yl and 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl;

provided that when X is methylene, Y is different from carboxypropyl and alkoxycarbonyl; and

ring, And unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali and 3) lower C1-C4-alkoxygroup in which group 2) unsubstituted or substituted by 1 to 3 halogen atoms, and these substituent may form a ring with each of the neighboring substituents;

or its salt.

9. Derived 4,1-benzoxazepin-2 on p. 8, where R1is a chain aliphatic hydrocarbon group.

10. Derived 4,1-benzoxazepin-2 on p. 9, where R1is lower alkyl.

11. Derived 4,1-benzoxazepin-2 on p. 10, where R1the lowest C1-C7-alkyl.

12. Derived 4,1-benzoxazepin-2 on p. 8, in which R2and R3is phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali, 3) lower C1-C4-alkoxygroup and 4) a hydroxy-group, in which group 2) is not uppy, contains the lowest C1-C4-alkali and benzyl; and two adjacent substituents on the phenyl group may together form a ring.

13. Derived 4,1-benzoxazepin-2 on p. 8, in which Y (I) perhaps the esterified carboxypropyl or (II) N-containing heterocyclic residue having hydrogen atom capable of deprotonates, which are selected from the group consisting of tetrazol-5-yl and 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl.

14. Pharmaceutical composition for inhibiting stvalentines in mammals, characterized in that it contains a therapeutically effective amount of a derivative of 4.1-benzoxazepin-2-it according to p. 1 or 8 or its salt and a pharmaceutically acceptable carrier.

15. A method of inhibiting stvalentines in mammals, wherein introducing a therapeutically effective amount of a derivative of 4.1-benzoxazepine formula (I")

< / BR>
where R1(i) hydrogen atom or (ii) a hydrocarbon group selected from the group consisting of aliphatic chain hydrocarbon group, such as lower alkali, lower alkenes and lower alkynes, and alicyclic hydrocarbon group, such as C3-C9-cycloalkyl group, and the soup: 1) phenyl and naphthyl, 2) C3-C6-cycloalkyl, 3) a heterocyclic group selected from the group consisting of furyl and indolyl, and 4) a halogen atom, in which group 1 is unsubstituted or substituted 1 - 2 C1-C3-alkoxygroup;

R2and R3independently of one another (i) hydrogen, (ii) lower alkyl, (iii) phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of 1) halogen atoms, 2) the lower C1-C4-alkali, 3) lower C1-C4-alkoxygroup, 4) a hydroxy-group, in which group 2) unsubstituted or substituted by 1 to 3 halogen atoms, group 4) unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl; and two adjacent substituents on the phenyl group may together form a ring, or (iv) pyridyl;

X is a bond or a connecting group with a chain length of 1 to 7 atoms selected from the group consisting of - (CH2)m-E-(CHR6)n-, where m and n represent independently from each other 0, 1, 2 or 3, E is a bond or an oxygen atom, a sulfur atom, sulfoxide, sulfon, -NR5-, -NHCO-, -CONR7- or-NHCONH-, where R5is hydrogen, lower alkyl, methylsulphonyl, 4-methylbenzenesulfonyl or acyl, R6and R7independently from each other indolyl, 2) a hydroxy-group, 3) possibly esterified carboxypropyl, 4) phenyl, (iii) benzyl; or (iv) phenyl;

Y represents: (I) the possible esterified or theatrevision carboxypropyl, (II) a hydroxy-group, (III) an amino group which is unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali, in which two substituent at the nitrogen atom together form a cyclic group, (IV) phenyl, which is unsubstituted or substituted by substituents selected from the group consisting of: 1) lower C1-C4-alkali, 2) lower C1-C4-alkoxygroup, 3) possibly esterified carboxypropyl, 4) phenyl, 5) an amino group which is unsubstituted or substituted by lower C1-C4-alkilani, and 6) N-containing heterocyclic residue having hydrogen atom capable of deprotonates, such as tetrazol-5-yl, where each of groups 1 and 4) unsubstituted or substituted possibly esterified with carboxypropyl, (V) carbarnoyl, which is unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl, in which two Deputy at the nitrogen atom may together form a cyclic amino group, which does not necessarily obyedinenie a hydrogen atom, can deprotonates, which are selected from the group consisting of tetrazol-5-yl and 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl;

ring, And unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali and 3) lower C1-C4-alkoxygroup in which group 2) unsubstituted or substituted by 1 to 3 halogen atoms, and these substituent may form a ring with each of the neighboring substituents;

or its salt.

16. The method according to p. 15, where R1is a chain aliphatic hydrocarbon group.

17. The method according to p. 16, where R1- lower alkyl group.

18. The method according to p. 17, where R1the lowest C1-C7-alkyl.

19. The method according to p. 15, in which R2and R3is phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali, 3) lower C1-C4-alkoxygroup, 4) a hydroxy-group, in which group 2) unsubstituted or substituted by 1 to 3 halogen atoms, group 4) unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl; and two adjacent substituents on the phenyl group is roxyrama or (II) N-containing heterocyclic residue, having a hydrogen atom capable of deprotonates, which are selected from the group consisting of tetrazol-5-yl and 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl.

21. The pharmaceutical composition inhibiting fungal growth in a mammal, characterized in that it contains a therapeutically effective amount of a derivative of 4.1-benzoxazepin-2-it according to p. 1 or 8 or its salt and a pharmaceutically acceptable carrier.

22. Method of inhibiting fungus growth in a mammal, characterized in that administered a therapeutically effective amount of a derivative of 4.1-benzoxazepine formula (I")

< / BR>
where R1(i) hydrogen atom or (ii) a hydrocarbon group selected from the group consisting of aliphatic chain hydrocarbon group, such as lower alkali, lower alkenes, lower alkynes, and alicyclic hydrocarbon group, such as C3-C9-cycloalkyl group, and the hydrocarbon group is unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of: 1) phenyl and naphthyl, 2) C3-C6-cycloalkyl, 3) a heterocyclic group selected from the group consisting of furyl and indolyl, and 4) halogen atoms, in which group 1 is unsubstituted or replacement is lower alkyl, (iii) phenyl, which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: (1) halogen atoms, 2) the lower C1-C4-alkali, 3) lower C1-C4-alkoxygroup, 4) a hydroxy-group, where group 2) unsubstituted or substituted by 1 to 3 halogen atoms, group 4) unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl; and two adjacent substituents on the phenyl group may together form a ring, or (iv) pyridyl;

X is a bond or a connecting group with a chain length of 1 to 7 atoms selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n represent independently from each other 0, 1, 2 or 3, E is a bond or an oxygen atom, a sulfur atom, sulfoxide, sulfon, -NR5-, -NHCO-, -CONR7- or-NHCONH-, where R5is hydrogen, lower alkyl, methylsulphonyl, 4-methylbenzenesulfonyl or acyl, R6and R7independently of one another (i) hydrogen, (ii) lower alkyl which is unsubstituted or substituted by substituents selected from the group consisting of 1) indolyl, 2) a hydroxy-group, 3) possibly esterified carboxypropyl, 4) phenyl, (iii) benzyl or (iv) phenyl;

Y - (I) may esterified or theatrevision carboxypropyl, (II) hydrox is high and C1-C4-alkali, in which two substituent at the nitrogen atom together form a cyclic group, (IV) phenyl, which is unsubstituted or substituted by substituents selected from the group consisting of: 1) lower C1-C4-alkali, 2) lower C1-C4-alkoxygroup, 3) possibly esterified carboxypropyl, 4) phenyl, 5) an amino group which is unsubstituted or substituted by lower C1-C4-alkilani, and 6) N-containing heterocyclic residue having hydrogen atom capable of deprotonates, such as tetrazol-5-yl, where group 1) and 4) unsubstituted or substituted possibly esterified with carboxypropyl, (V) carbarnoyl, which is unsubstituted or substituted by substituents selected from the group consisting of lower C1-C4-alkali and benzyl, in which two Deputy at the nitrogen atom may together form a cyclic amino group, which is optionally combined with phenyl, unsubstituted or substituted by halogen atoms; or (VI) N-containing heterocyclic residue having hydrogen atom capable of deprotonates, which are selected from the group consisting of tetrazol-5-yl and 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl;

ring, And unsubstituted or substituted by 1 to 3 substituents selected from the group that contains the th group 2) unsubstituted or substituted 1 - 3 halogen atoms, and these substituents may form a ring with each of the neighboring substituents:

or its salt.

Priority points:

20.04.92 on PP.1 - 20;

21.12.92 on PP.1 - 20 varieties radicals;

19.04.93 on PP.21 and 22.

 

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FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

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

17 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

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