Derivatives benzazepin, benzoxazepin or benzodiazepin-n - acetic acid, method of their production and the drug containing

 

(57) Abstract:

Describes the new derivatives of benzazepin, benzoxazepin, benzodiazepin - N-acetic acids of the General formula I, where R1represents (lower) alkoxy (lower) alkyl group, a lower CNS residue, which is substituted by lower CNS group, phenyl(lower)alkyl group or phenyloxy(lower)alkyl group, which, if necessary, in the phenyl ring may be substituted by lower alkyl, lower alkoxyl or halogen, or naphthyl(lower)alkyl group, A stands for CH2, O or S; R2denotes hydrogen or halogen, R3denotes hydrogen or halogen, R4denotes hydrogen or forming biolabeling ester group, and R5denotes hydrogen or forming biolabeling ester group, and physiologically tolerated salts of the acids of formula I. They are valuable, effective against effects on heart, pharmacological properties and are clearly expressed the overwhelming influence of the neutral endopeptidase with a favorable profile of action on the basis of which they reduce coming in heart failure high cardiac pressure napolnitelyami formula I and medicine, containing them. 3 s and 5 C.p. f-crystals, 5 PL.

The present invention relates to new derivatives of benzazepin, benzoxazepin and benzothiazepin-N-acetic acid, which in-position to the nitrogen atom contain an oxo group in position 3 substituted 1-(carboxyethyl)-cyclopentanecarbonyl - amino residue, and to their salts and biolabeling (biostability) esters, as well as containing these compounds, pharmaceutical compositions and a method for producing these compounds.

The present invention is the task of finding new benzazepine, benzoxazepine and benzodiazepinovyh compounds with valuable pharmacological properties. Further, the basis of the invention is to find new, used to treat heart failure, pharmaceutical biologically active substances.

Currently, it is found that proposed according to the invention are new, containing in position 3, if necessary, esterified to complex ester 1-(carboxyethyl) cyclopentanecarbonyl-balance derivatives benzazepin, benzoxazepin and benzothiazepin-N-acetic acids have valuable, effective against effects on heart, formatdate with a favorable profile actions on the basis of which they reduce coming in heart failure high cardiac filling pressure and thus relieve the heart and can cause increased lioresa.

The invention relates therefore to new compounds of General formula (I)

(see the formula (I) in Annex)

where R1denotes lower alkoxy - lower alkyl group, lower CNS residue which is substituted by lower CNS group;

phenyl (lower) alkyl group or phenyloxy (lower) alkyl group, which, if necessary, in the phenyl ring may be substituted by lower alkyl, lower alkoxyl or halogen; or naphthyl (lower) alkyl group;

A stands for CH2, O or S;

R2denotes hydrogen or halogen;

R3denotes hydrogen or halogen;

R4denotes hydrogen or forming biolabeling ester group, and

R5denotes hydrogen or forming biolabeling ester group, and to the physiologically tolerated salts of the acids of formula (I).

If in the compounds of formula (I), the substituents represent or contain lower alkyl or CNS group, they can be linear or razvitii or a methoxy group. If the substituents denote halogen or contain halogen substituents, taking into account in particular fluorine, chlorine or bromine, preferably fluorine or chlorine.

In the compounds of formula (I), A may denote a methylene group, oxygen or sulfur, and preferably represents methylene.

The compounds of formula (I) in the phenyl ring may contain substituents R2and R3. Preferably both of the substituent R2and R3or at least, however, one of these substituents represent hydrogen.

R1represents preferably contains an aromatic ring residue, for example, if necessary substituted phenyl-(lower) alkyl or phenyloxy (lower) alkyl residue, in which the lower Allenova chain may contain 1-4, preferably 1-2, carbon atoms. In particular, R1is an if necessary substituted fenetylline group, which if necessary can be substituted one or more times by halogen, lower alkoxyl or lower alkyl, or naphthylethylene group. If R1denotes a substituted lower alkoxyl (lower) alkoxy (lower) alkyl group, it predpochtitelno 1-2, carbon atoms and substituted lower alkoxyl, in particular a methoxy group.

The compounds of formula (I), if necessary, are esterified to ester derivatives of dicarboxylic acids. Depending on the form of application is biolabels complex monetary, in particular compounds, where R4means forming biolabeling ester group, and R5denotes hydrogen, or dicarboxylic acid, the latter is suitable in particular for intravenous administration.

As forming biolabels ester groups, R4and R5suitable lower alkyl groups, if necessary substituted in the phenyl ring by lower alkyl or associated with two adjacent carbon atoms of the lower alkalinous chain phenyl or phenyl (lower) alkyl group; if necessary substituted in the dioxolane ring by lower alkyl dioxyalkylene group or, if necessary, replaced in oxymethylene the group of lower alkyl (C2-C6)-alkanolamine group. If the forming biolabeling ester group, R4or R5denotes lower alkyl, it can be predpochytaly ester group is if necessary, substituted phenyl (lower) alkyl group, it Allenova chain may contain 1 to 3, preferably 1, carbon atoms. If the phenyl ring is substituted by lower alkalinous chain, it can contain 3-4, in particular 3, carbon atoms. As forsteriana substituents R4and/or R5suitable in particular phenyl, benzyl or indanyl. If R4and/or R5represent, if necessary, replaced alkanoyloxy group, its alkanoyloxy group can contain 2-6, preferably 3-5, carbon atoms and preferably branched and may, for example, be pivaloyloxymethyl balance (= tert.- butylcarbamoyl balance).

According to the invention, the new compounds of formula (I) and their salts get that in itself known by way of the acid of General formula (II):

(see the formula (II) in Annex)

where R1have the above significance and R4ameans for protective acidic function group, or their reactive derivatives enter into interaction with amines of General formula (III);

(see formula (III) in Annex)

where R2, R3and A have the above meaning, a RAU (IV) in Annex)

where R1, R2, R3, R4a, R5aand A have the above meaning, and compounds of the formula (IV) simultaneously or in any sequence after one another otscheplaut protective for acid function group R4aand R5aif they are not desirable, forming biolabeling ester group; and in the desirable case, depending on the circumstances, the released acid group atrificial to complex ester with an alcohol of General formula (V) or its reactive derivative of General formula (Va):

(see formulas (V) and (Va) in the Annex)

where R6means forming biolabeling ester group, and X denotes tsepliaeva reactive group;

in the desirable case, the resulting acid of the formula (I) transferred to their physiologically tolerated salt or salts of the acids of formula (I) is transferred into the free acid.

As physiologically-tolerated salts of dicarboxylic acids or complex monoamino formula (I) take into account the alkali metal salts, alkaline earth metal or ammonium, for example, salts of sodium or calcium, or salts with physiologically acceptable pharmacologically it is s (I) contain two chiral carbon atom, namely bearing amide side chain carbon atom in position 3 of cyclic skeleton and bearing residue R1the carbon atom in the amide side chain. Thus the connection can be in several optically active stereoisomeric forms or in the form of a racemate. The present invention includes both the racemic mixtures and pure isomeric compounds of formula (I).

The interaction of the acids of formula (II) with amines of the formula (III) obtaining the amides of the formula (IV) can be performed by itself normal to obtain amide groups by amino-acylation methods. As alleluya means you can use the acid of formula (II) or its reactive derivative. As reactive derivatives taking into account particularly the mixed anhydrides or galodamadruga acids. For example, you can use the anhydrides or bromohydrin acids of the formula (II) or mixed esters of acids of the formula (II) with organic sulfonic acids, for example, (lower) alkanesulfonyl, as for example, methanesulfonate, or aromatic sulphonic acids, such as, for example, benzosulfimide, or substituted lower alkyl or halogen benzolate in an inert under reaction conditions an organic solvent, preferably at temperatures between -20oC to room temperature. As solvents particularly suitable halogenated hydrocarbons like dichloromethane, or aromatic hydrocarbons as benzene or toluene, or cyclic ethers like tetrahydrofuran or dioxane, or mixtures of these solvents.

Acylation, in particular when as Alliluyeva funds are used mixed acid anhydride of the formula (II) with the acid, it is advisable to carry out in the presence of cyclotosaurus reagent. As ciclofosfamida means of suitable soluble in the reaction mixture grounds, in particular organic bases, such as tertiary (lower)alkylamines followed and pyridine, as, for example, triethylamine, Tripropylamine, pyridine, 4-dimethylaminopyridine, 4-diethylaminophenyl or 4-pyrrolidinedione. Used in excess organic bases may simultaneously serve as solvents.

Mixed anhydrides of the acid of formula (II) with organic sulfonic acids preferably be obtained in situ by reacting the acid of formula (II) with halogenerator, especially the acid chloride, organic sulfonic acids and forth without vydeleny as alleluya funds exploit the acid of formula (II), the interaction of the amino compounds of the formula (III) with acids of the formula (II) is also advisable to carry out in the presence of known from the chemistry of peptides suitable for the formation of amide, reagent binding. As an example of binding reagents that promote amide formation with the free acids due to the fact that they react with the acid in situ in the formation of a reactive derivative of the acid should especially be called alkylhalogenide, for example, cycloalkylcarbonyl as dicyclo - hexylcaine or 1-ethyl-3-/3-(dimethylamino)propyl/carbodiimide, carbonyldiimidazole and N-(lower) alkyl-2-halogenopyrimidines salts, in particular halides and tozilaty, preferably N-methyl-2-chloropyridine-iodide (see, for example, Mukaijama in Angewandte Chemie, 91, S. 789-812). Interaction in the presence of the reagent of suitable binding can be performed at temperatures from -30oC to +50oC, when using solvents, such as halogenated hydrocarbons and/or aromatic solvents, if appropriate in the presence of cyclotosaurus amine.

From obtained by reacting compounds of the formula (II) with compounds of the formula (III) compounds of the formula (IV) in itself is x desirable in the compounds of formula (I), forming biolabeling ester groups.

As the protective groups R4aand R5ayou can choose by themselves the usual protection of the acid function of the protective groups, which are then again otscheplaut according to themselves known methods. Suitable protective for acid function groups are known, for example, McOmie "Protective Groups in Organic Chemistry", Plenum Press and Greene, "Protective groups in Organic Synthesis", Wiley, Intersience Publication.

If you want to obtain the compounds of formula (I) in which R4and R5identical, it is better in the original compounds of formulas (II) and (III) to choose the identical protective group, R4aand R5a.

If you want to obtain the compounds of formula (I), where R4and R5have a different value, it is better in the original compounds of formulas (II) and (III) to choose different protective groups that can be selectively split themselves known under various conditions. As examples, three, useplease under different conditions protective groups should be called:

1. difficult methyl or ethyl esters, which are easily broken down in basic terms, however, much more stable towards acidic conditions or hydrogenolysis;

2. tert.-butyl is the solution to the basic conditions or hydrogenolysis; and

3. complex benzyl esters, which can easily be split hydrogenations or basic conditions, however, are considerably more stable towards acidic conditions.

If, for example, need to get a dicarboxylic acid of the formula (I), where R4and R5both represent hydrogen, as the protective groups R4aand R5apreferably use otsepleniya in the acidic conditions of the protective group, for example tert.-bucilina group, obtained by reacting compounds of the formula (II) with compounds of the formula (III) complex tert.-butyl esters of the formula (IV) is then cleaved by treatment with acid. Splitting can be done, for example, by treatment with triperoxonane acid as such or in solution triperoxonane acid in a halogenated hydrocarbon, e.g. dichloromethane, or by treating with gaseous HCl in an inert under the reaction conditions an organic solvent, such as ethyl acetate. The reaction can be conducted at temperatures from -25oC to room temperature.

If, for example, need to get a monocarboxylic acid of the formula (I), where R4means forming biolabeling ester group, and R5 is x R4ais desirable, forming biolabeling ester group, for example, ethyl group, and as a protective group, R5ain the compounds of the formula (III) use of protective groups, which hatshepsuts in conditions that do not split R4-OCO-group. If R4-OCO-group is a relatively acid group complex ethyl ester, as a protective group, R5asuitable, for example, tsepliaeva using acid tert.-bucilina group or hydrogenations tsepliaeva group as benzyl.

If R4ain the compounds of formula (II) is sensitive to acid, forming biolabeling ester group as a protective group, R5ain the compounds of the formula (III), it is advisable to choose hydrogenations tsepliaeva group as benzyl, and split it from obtained by reacting compounds of the formula (II) with compounds of the formula (III) source of the compounds of the formula (IV) hydrogenations. The hydrogenolysis can be performed by catalytic hydrogenation in the presence of a catalyst, preferably Pd/C - catalyst, in an organic inert under reaction conditions R is different to carry out catalytic hydrogenation under hydrogen pressure of 4-5 bar at room temperature.

To obtain the compounds of formula (I), where R4means forming biolabeling ester group, and R5denotes hydrogen, it is also possible, however, to choose the starting compound of the formula (II) and (III) with different protective groups R4aand R5awith different reactivity and obtained by reacting compounds of the formula (II) with compounds of the formula (III) compounds of the formula (IV) to split first protective group, R4awhile maintaining the protective group R5athen in the reaction product of General formula (IV'):

(see the formula (IV') in the Appendix)

where R1, R2, R3, R5aand A have the above value, enter the desired forming biolabeling ester group, R4by reacting the free acid groups of compounds of formula (IV') with the compound of the formula (V) or formula (VI) and then from the resulting compounds of the formula (IV) to split the protective group R5a.

So, for example, from compounds of the formula (IV), where R4ameans tsepliaeva using an acid protective group, especially tert-boutelou group, and R5ameans kislotostabilen protective group, for example, benzyl, you can first split using Cilmi for the formation of esters ways you can atrificial with alcohol of formula (V) or the corresponding compounds of formula (Va). As tseplyaesh reactive groups X in the compounds of the formula (Va) is suitable halogen, in particular chlorine or bromine, or organic sulfoxylates residue, for example, the residue (lower) alkanesulfonyl, as, for example, methanesulfonate, or a residue of aromatic sulfonic acids, as benzosulfimide, or substituted lower alkyl or halogen of benzosulfimide as toluenesulfonic acid. For the esterification to complex ether alcohols of the formula (V) can be administered during the interaction, for example, with an acid of the formula (IV') or a reactive derivative of this acid is in itself known for the acylation of alcohols. The interaction can be realized, for example, under the conditions specified for the interaction of the compounds of the formula (II) with compounds of the formula (III).

Similarly, by appropriate choice of different protective groups can also be obtained the compounds of formula (I), where R5means forming biolabeling ester group, and R4denotes hydrogen or different from R5forming biolabeling ester group.

In the case of the above interactions of chiral centres in the source compounds of formulas (II) and (III) do not change, so Thurs is tomarow. To obtain pure isomers and thus optically uniform compounds of formula (I) better pure enantiomeric compounds of the formula (II) to enter into interaction with pure enantiomeric compounds of the formula (III). If pure enantiomeric compound of formula (II) enter into interaction with the racemic compound of formula (III) or racemic compound of formula (II) enter into interaction with pure enantiomeric compound of formula (III), then, depending on the circumstances, receive a mixture of two diastereomers, which is desirable in case you can divide itself in a known manner. The interaction of racemic compounds of formula (II) with the racemic compounds of the formula (III) leads to the corresponding mixture of 4 isomers, which are desirable in the case itself in a known manner can be divided.

The initial compounds of the formula (II) can be obtained in itself known methods.

For example, compounds of General formula (IIa):

(see formula (IIa) in the Annex)

where R4ahave the above significance, and R1ais specified for R1value except (lower) alkoxy (lower) alkoxymethyl balance, the floor is
and R1ahave the above significance, enter into interaction with cyclopentanecarbonyl acid of the formula (VII)

see formula (VII) in the application

The reaction can be conducted in itself known in the conditions of accession by Michael in an inert under reaction conditions an organic solvent by reacting cyclopentanecarbonyl acid with a strong, capable of forming dianion cyclopentanecarbonyl acid base and subsequent interaction with the derived complex acrylic ester of the formula (VI). As solvents suitable ethers, in particular cyclic ethers, such as tetrahydrofuran. As strong bases suitable non nucleophilic organic amides of alkali metals, such as, for example, diisopropylamide lithium. It is advisable cyclopentanecarbonyl acid in tetrahydrofuran to enter into interaction with two equivalents of diisopropylamide lithium and then the reaction mixture is injected into the interaction with the compound of the formula (VI). The reaction temperature may range from -70oC and 0oC.

Compounds of General formula (IIb):

see formula (IIb) in the application

where R4ahave the above significance and R1bBorovoy acid of General formula (VIII):

see formula (VIII) in the application

where R4ahave the above significance and V denotes halogen, enter into interaction with cyclopentanecarbonyl acid of the formula (VII) and the resulting reaction product of General formula (IX):

see formula (IX) in the application

where R4ahave the above significance, enter into an interaction with compounds of General formula (Xb):

see formula (Xb) in the application

where R1band X have the above meaning. The interaction of ester halogencarbonic acid of the formula (VIII) with cyclopentanecarbonyl acid of the formula (VII) can be done by itself in a known manner in an inert under the reaction conditions, the solvent in the presence of a strong, capable of forming dianion cyclopentanecarbonyl acid base. For example, the interaction can be performed in the conditions described for interaction cyclopentanecarbonyl acid with compounds of the formula (VI). The subsequent interaction of the acids of formula (IX) with compounds of formula (Xb) can be done by itself in a known manner suitable for the alkylation of esters of carboxylic acids conditions in an inert under the reaction conditions an organic solvent in the presence of a strong base is Italy suitable ethers, in particular cyclic ethers like tetrahydrofuran or dioxane. As strong bases can be applied hydrides or amides of alkali metals, for example, diisopropylamide lithium.

The compounds of formula (II) on the raw residue R1the carbon atom have a center of chirality and fusion are obtained in the form of their racemates. Optically active compounds can be obtained from racemic mixtures by itself in a known manner, for example by chromatographic separation on chiral separating means or by introducing into engagement with suitable optically active bases, for example, with --methylbenzylamino or pseudoephedrine, and subsequent separation into their optical antipodes by fractional crystallization of the salts obtained.

Derivatives of esters of acrylic acid of formula (VI) can be obtained in itself known due to the fact that derivatives of esters (di/lower/alkylphosphine)-acetic acid of General formula (XI):

(see formula (XI) in the Annex)

where R4aand R1ahave the above significance and R7and R8each signify lower alkyl, preferably methyl or ethyl, enter into interaction with formaldehy formula (XI) can enter into interaction with paraformaldehyde in a simple ester, preferably in cyclic simple ether like tetrahydrofuran, in the presence of a base, preferably not nucleophilic alcoholate of alkali metal tert.-butyl potassium, at a temperature from -20oC to +30oC.

The compounds of formula (XI) can be obtained in itself known due to the fact that derivatives phosphonooxy acid of General formula (XII):

(see formula (XII) in the Annex)

where R4a, R7and R8have the above significance, enter into an interaction with compounds of the formula (Xa):

(see formula (Xa) in the Annex)

where Raand X have the above meaning. The interaction can be performed in the conventional alkylation conditions in an inert under the reaction conditions of the polar aprotic organic solvent in the presence of a base at temperatures in the range of 0 - 80oC. is Preferably introduced the compounds of formula (Xa), where X denotes halogen, in particular bromine or iodine, or toilet. As suitable solvents, for example amides as dimethylformamide, or ethers. As grounds not suitable nucleophilic alkali metal alcoholate, such as, for example, tert.-butyl potassium.

The compounds of formula (VI) also the>/BR>where R4aand R1ahave the above significance, in itself known manner is treated with formaldehyde in basic conditions. Thus, derivatives of malonic acid of the formula (XIII), for example, you can enter into interaction with an aqueous solution of formaldehyde in the presence of a secondary organic amine, in particular piperidine, at temperatures of 0-30oC, preferably at temperatures below room temperature. Derivatives of malonic acid of the formula (XIII) can also be entered into interaction with paraformaldehyde in pyridine at temperatures of 40-60oC.

Complex monoether of malonic acid of the formula (XIII) can be obtained by the fact that complex diesters of malonic acid of General formula (XIV):

(see formula (XIV) in the Annex)

where R4ahave the above significance and R9denotes lower alkyl, especially methyl, or benzyl, enter into an interaction with compounds of the formula (Xa) and the resulting complex derivatives diesters of malonic acid of General formula (XV):

(see formula (XV) in the Annex)

where R1a, R4aand R9have the above meaning, by partial hydrolysis transferred to complex derivatives monoamino of malonic acid of the formula (XIII).

Stnum way through the interaction of a complex ester of the formula (XIV) with the compound of the formula (Xa) in a polar aprotic organic solvent, preferably in dimethylformamide, in the presence of a base, for example, nucleophilic alcoholate of alkali metal tert.-butyl potassium, at temperatures in the range 0-80oC. Interaction can be realized, for example, under the conditions specified for the interaction of the compounds of formula (XI) with compounds of formula (Xa).

The obtained substituted complex diesters of malonic acid of the formula (XV) by removal of residue R9in itself known manner can be translated into the corresponding complex monoether of malonic acid of the formula (XIII). If the protective group R4aand the remainder R9represent different residues with different reactivity, removal of residue R9it is better to choose such conditions, in which the residue R4ais not affected. If R9denotes benzyl, the removal can be accomplished by itself in a known manner hydrogenations. The lower complex alkalemia esters R9split itself known hydrolytically, depending on the kind of the alkyl residue in an acidic or alkaline conditions. Preferably R9represents ethyl, which can be split by alkaline hydrolysis. For atout using a hydroxide of an alkali metal, for example, potassium hydroxide. If the R4aand R9identical, the quantity of alkali metal hydroxide is taken so small that there was only partial hydrolysis.

The compounds of formula (III) can be obtained in itself known due to the fact that compounds of General formula (XVI):

(see formula (XVI) in the Annex)

where R2, R3and A have the above meaning and R10R11N-group is a protected using protection for the amino function group, amino group, enter into an interaction with compounds of General formula (XVII):

(see formula (XVII) in the Annex)

where R5aand X have the abovementioned meaning, and in the resulting reaction product of General formula (XVIII):

(see formula (XVIII) in the Annex)

where R2, R3, R5aA and R10R11N - group has the above value of R10R11N-group release free amino group. The interaction of compounds of formula (XVI) with compounds of the formula (XVII) can be done in different ways, in and of itself is usual for the alkylation of amides. It is preferable to use the compounds of formula (XVII), in which X denotes halogen, preferably bromine or iodine. Usaemail in cyclic simple ether, as tetrahydrofuran, in the presence of a base. As grounds suitable non nucleophilic base, such as tert.-butyl potassium. In the desirable case, the interaction can also be carried out in the presence of alkali metal hydroxide, e.g. potassium hydroxide, in a two-phase system in the presence of a catalyst transfer phases, for example, Tetra(lower) alkylhalogenide as tetrabutylammonium.

Then in the resulting compounds of the formula (XVIII) by removal of the protective group in itself known, you can release the amino group. To protect the amino group can be used by itself known to protect amino groups, again easily otsepleniya protective group, for example, known from the chemistry of peptides, protective groups. Suitable protective group, for example, known from E. McOmie "Protective groups in Organic chemistry" Plenum Press, 1971. For example, as a protective group suitable talimena group or tert. -butoxycarbonyl group or benzyloxycarbonyl group. Depending on the values of R5adepending on the circumstances, you need to choose protective groups, which are then hatshepsuts under conditions in which the unaffected group, R5a. As useplease in the CI ethanolamine or hydrazine at elevated temperatures, for example, at temperatures of 70-90oC. Talimena group is suitable, for example, as a protective group for compounds where A represents sulfur. As tsepliaeva by acid protective groups are suitable, for example, tert.-butoxycarbonyl group which can be split by treatment with acid, for example, by processing triperoxonane acid or gaseous hydrogen chloride in ethyl acetate. Tert.-Butoxycarbonyl group is suitable, for example, as a protective group for compounds where A stands for oxygen. As hydrogenations tsepliaeva protective groups are suitable, for example, benzyloxycarbonyl group which can be split by hydrogenation using hydrogen in the presence of a catalyst of palladium-on-charcoal grill.

The compounds of formula (III) contain a center of chirality at the carbon atom bearing the amino group. If coming from optically pure starting compounds of the formula (XVI), are optically pure compounds of formula (III). It relates in particular to such compounds, where A denotes an oxygen or sulphur. If you come from racemic compounds of the formula (XVI), you also get the racemic compounds of the formula (III). It takes place generally in a known way can be divided into their optical isomers, for example, by chromatographic separation on chiral separating materials or by entering into cooperation with suitable optically active acids, for example tartaric acid, and the subsequent separation of the optical antipodes by fractional crystallization of the salts obtained. To enhance the yield of the desired optical isomer when interacting with suitable optically active acids simultaneously with or after the subsequent deposition of salt one isomer using an optically active acid in the reaction mixture can be accomplished secondary racemization remaining in the solution of isomer by adding preferably an aromatic aldehyde, such as benzaldehyde. This racemization center of chirality is caused by imine formation with the aldehyde.

The compounds of formula (XVI) can be obtained in itself known. For example, compounds of General formula (XVIa):

(see formula (XVIa) in Annex)

where R2, R3and R10R11N-group has the above value, you can get that in the compounds of General formula (XIX):

(see formula (XIX) in the Annex)

where R2, R3and Y have the above meaning, which you can enter into interaction with the salt of an alkali metal amide R10R11NH, preferably with phthalimide potassium. The interaction can be performed in an inert under the reaction conditions aprotic organic solvent, preferably dimethylformamide, at temperatures of 40-80oC.

The compounds of formula (XIX) can be obtained in itself known, by Beckmann rearrangement oxomnik compounds of General formula (XX):

(see formula (XX), Annex)

where R2, R3and Y have the above significance, the fact that the compounds of formula (XX) in a Beckmann rearrangement treated with acid. The compounds of formula (XX) it is better to re-group in the compounds of formula (XIX) by treatment with polyphosphoric acid at temperatures of 60-90oC.

The oximes of the formula (XX) can be obtained from cyclic ketones of General formula (XXI):

(see formula (XXI), Annex)

where R2and R3have the above significance, the fact that ketones of the formula (XXI) for the introduction of the residue Y is first treated with a halogen and the resulting halogenated ketones then injected into interaction with hydroxylamine. The most useful to halogenoalkane ketone and the subsequent formation of the oxime can be single-stage pic is first treated with a halogen and then to the reaction mixture are added hydroxylamine. Hydroxylamine is more expedient to use in the form of a salt of hydroxylamine, for example, hydrochloride, and to the reaction mixture, add a little water. The method can be carried out at temperatures of 0-40oC, preferably at room temperature.

Compounds of General formula (XVIb):

(see formula (XVIb) in Annex)

where R2, R3and R10R11N-group has the above value, and Aadenotes oxygen or sulfur, can be obtained in itself known, by cyclization of aromatic amino acids of General formula (XXII):

(see formula (XXII), Annex)

where R2, R3, Aaand R10R11N-group have the above significance. Cyclization of compounds of formula (XXII) proceeds with the removal of water and it can make itself known to get lactam ways. Thus, the cyclization can be accomplished, for example, in the presence of an acid activating group, known from the chemistry of peptides to obtain amides, binding reagent, for example, carbodiimide, in an inert under the reaction conditions of the polar organic solvent, for example dimethylformamide. The interaction can be realized, for example, under the conditions specified the PU agent can also be used diethylphosphinic and interaction is carried out in the presence of an organic base, for example, three (lower) alkylamine as triethylamine.

Compounds of General formula (XXII) can be obtained in itself known, by the recovery of the corresponding nitro compounds of General formula (XXIII):

(see formula (XXIII) in the Annex)

where R2, R3, Aaand R10R11N-group have vysheukazannoe value. The restoration of the nitro-group can be in itself known to restore nitro-benzene compounds to aniline compounds of ways, for example by catalytic hydrogenation in the presence of palladium-on-coal as a catalyst. Recovery is also possible when using other reducing agents that produce hydrogen in situ, such as a mixture of metallic iron/hydrochloric acid or metallic zinc/hydrochloric acid.

The compounds of formula (XXIII) can be obtained in itself known by reacting o-fluoro-nitrobenzene compounds of General formula (XXIV):

(see formula (XXIV) in the Annex)

where R2and R3have the above significance, with acids of General formula (XXV):

(see formula (XXV), Annex)

where Aaand R10R11N-group are Vysocina-group of which is protected. The interaction is carried out in an inert under the reaction conditions an organic solvent in the presence of a base. The interaction of ftorirovannogo with strongly nucleophilic derivative of cysteine can be done in a lower alcohol or mixture of alcohol and water in the presence of a weak base like sodium bicarbonate. To interact with relatively weaker nucleophilic derivative of serine would be best to use a strong base, such as alkali metal hydride, in a polar organic solvent as dimethylformamide.

In the desirable case, after the formation of the compounds of formula (XXIII) originally present in the compounds of formula (XXV) the security for the amino function, a group by itself in a known manner can be exchanged for another protective for amino function group, which in its better reactivity differs from that of the remainder R5aand thus better suited for further processing of the compounds of formula (XXIII).

The compounds of formula (I) and their pharmacologically acceptable salts differ in interesting pharmacological properties. In particular substances have an inhibitory effect on neutral endopeptidase (= NEP). NEP predstavitelskogo peptide (= ANP). Due to its inhibitory effect on the activity of NEP substances can improve the biological activity and the duration of life of the most vulnerable on account NEP natriuretic peptides, in particular ANP, and therefore suitable for the treatment of painful conditions, which will favorably influence the impact of such hormones, particularly heart failure.

In the case of heart failure due to disease caused by reduced cardiac bandwidth activities come to a reflex increased peripheral resistance and thus to stagnation of blood in the circulation of the lungs and the heart. Further pressure is high due to the filling of the heart, which causes a stretching of the wall of the ventricle into the atrium and ventricles of the heart. Under these circumstances, the heart functions as an endocrine organ, i.e. it is able to allocate to the bloodstream ANP, which has pronounced vasodilator and diuretichesky/natriuretic activities. ANP acts buck on high blood pressure due to filling of the heart. This is due to the diuresis/natriuresis (decrease in total circulating mass of blood and due to miniseason heart action ANP is treated as endogenous cardiotoxicity mechanism. The action of ANP, however, only briefly, as the hormone is rapidly cleaved under the action of NEP.

On the basis of their suppressive NEP properties proposed according to the invention compounds can improve cardiotoxicity the mechanism of action of ANP and have a particularly high efficiency in relation to strengthening diuretichesky/natriuretic activities.

Proposed according to the invention compounds differ favorable profile actions with good tolerability and have significant selectivity for inhibiting NEP actions and also may have a slight inhibitory effect on endothelin converting enzyme (= ECE). At extremely high stages of heart failure reflex come to high blood levels of angiotensin-II, endothelin and catecholamines and together with this to further increase peripheral resistance and pressure due to filling of the heart, resulting in hypertrophies and expands the myocardium (heart muscle). Inhibiting ECE additional properties may exacerbate the downward impact of the proposed according to the invention substances on the peripheral fight is different pharmacological test methods in vitro and in vivo.

Description pharmacological methods:

1. Determination of the minimum toxic dose

The male mice weighing 20-25 g orally administered a maximum dose of 300 mg/kg of the test substance. Within 3 hours the animals carefully monitored in relation to symptoms of toxicity. Within a time span of 72 hours after the introduction of the additional register all the symptoms and deaths. Associated symptoms are also observed and recorded. See if the death or severe toxic symptoms, the following mice injected into increasingly smaller doses until no more will appear toxic symptoms. The lowest dose that causes death or severe toxic symptoms, indicated in the table below as A minimum toxic dose. Specified in table A number examples refer to the following examples of the preparation.

2. An in vitro study of the vast NEP effects of substances and the determination of the affinity of the molecules to the enzyme molecule

To detect the vast actions proposed according to the invention substances on neutral endopeptidase ( =NEP) in a standard test in vitro study the inhibitory effects of substances occurring with fermentee inhibitory efficiency of substances determine their Kivalue (= inhibition constant). KiValue current ingibiruet on the enzyme test substance represents the dissociation constant of the complex enzyme - test substance,

accordingly, complex (enzyme - substrate) - the test substance and has the dimension of concentration.

The implementation of the test

To implement the test, depending on the circumstances, prepare 100 ál samples of different incubation solutions containing 10 ng of purified NEP (E. C. 3.4.24.11) and, depending on the circumstances, different amounts of the test substance and the substrate (Met-enkephalin) and 50 mmol of Tris-buffer (= Tris (hydroxymethyl)aminomethane/HCl, pH 7,4).

On one test substance, depending on the circumstances, prepare 24 incubation solution with 3 different concentrations of the test substance (test substance), depending on the circumstances, in combination with the content of Met-enkefalina 2, 5, 7, 10, 12, 15, 40 and 100 µmol.

In each test, depending on the circumstances, together also handle two different control incubation solutions, firstly to control enzyme, which does not contain any of the test substances, and secondly to control substrate, which is not soterias in a water bath with shaking. The reaction of the enzyme after 15 minutes initiated by adding substrate (Met-enkephalin) and after the time of incubation is stopped by heating for 5 minutes at 95oC. Then the incubation solution, which terminated the reaction, centrifuged for 3 minutes at 12000 g and the supernatant is determined concentration neprevzoidennogo substrate and formed by means of the enzymatic reaction products of hydrolysis. For this purpose, depending on the circumstances, samples of the supernatant liquids separated by HPLC (= high performance liquid chromatography) on gidrofobizirovannym silica gel, and the products of the enzymatic reaction and nepovsemestnoy substrate determined photometrically at a wavelength of 205 nm. For HPLC separation using a separation column (4.6 x 250 mm), which is filled as the separation material inverted phases with Encapharm100 RR 18.5 microns. The flow of solvent is 1.4 ml/min, column heated to 40oC. Eluting the tool A is 5 mm H3PO4pH of 2.5, and eluting the tool is In an acetonitrile +1% 5 mm H3PO4pH of 2.5.

From the measured in different schityvat itself known Ki- is. In the following table are found for the test substances Ki-values. Listed in the table of the examples refer to the following examples of the preparation.

3. In vitro studies of the vast ECE steps substances

To detect the vast actions proposed according to the invention substances on converting the endothelium of the enzyme ( =ECE) standard test in vitro investigate the inhibitory activity of substances derived from the enzymatic activity of ECE hydrolytic destruction of Big-endothelin-1 (Big ET-1). At the same time as measures of inhibitory efficiency of substances determine their IC50-is. IC50- Is active against the enzyme of the test (test) of a substance is the concentration of test substance at which inhibited 50% of the enzymatic activity ECE.

The receipt contains ECE membrane fraction of endothelial cells

Egg cells of the Chinese hamster (= Chiense hamster ovarian cells, hereinafter simply referred to as CHO cells), in which recombinante exprimarea human ECE (see Schmidt and others Federation of European Biochemical Soieties Letters, 356 (1994), 238-243), are lysed and the cell membrane is separated by zentrifugenbau is repeated centrifugation. Containing ECE cell membrane fraction is again suspended in 100 mm Tris/HCl - buffer (=Tris (hydroxymethyl)aminomethane/HCl, pH 7.0, containing 250 mm NaCl) and up to enzyme test should be stored frozen at -70oC.

The implementation of the test

To implement the test are prepared, depending on the circumstances, the sample 100 ál of each different incubation solutions containing 5 μg protein containing ECE preparation of endothelial cell membranes and, depending on the circumstances, different amounts of the test substance and 24 µmol of substrate (synthetic peptide: H2N-Asp-Ile-Ala-Trp-Phe-Asn-Thr-Pro-Glu-His-Val-Val-Pro-Tyr - Gly-Leu-Gly-COOH) and 100 mmol Tris-buffer (= Tris(hydroxymethyl)aminomethane/HCl, pH 7.0, containing 250 mmol of sodium chloride). Moreover, in each of the incubation solution contained 100 μmol of Tirana and 10 µmol captopril and 1 mmol of phenolsulfonephthalein, 100 µmol of pepstatin A (= protease inhibitor) and 100 µmol of amantadine (= protease inhibitor).

On one test substance is prepared, depending on the circumstances, 6 different incubation solutions with 3 different concentrations of the test substance, depending on the circumstances, for double definitions.

In the case of each test depends on colazione solutions pre-incubated for 15 minutes at 37oC, before adding substrate. The enzymatic reaction initiated by adding substrate; it lasts for 60 minutes at 37oC and stopped by heating the incubation solution for 5 minutes at 95oC. Generated by the enzymatic reaction of the substrate, the products of hydrolysis of H2N-Asp-Ile-Ala-Trp - COOH and H2N-Phe-Asn-Thr-Pro-Glu-His-Val-Val-Pro-Tyr - Gly-Leu-Gly-COOH determined using high performance liquid chromatography (HPLC). The implementation of the determination by HPLC carried out as in the case of the above in vitro studies of the vast NEP action.

From the measured in different samples of the concentrations of the products of hydrolysis for each test substance count itself known IC50. In the following table C are found for the tested substances IC50values.

4. In vivo determination of the effect of substances on diuresis/nutrient in the case of rats with associated with increase in load

Investigate in vivo activity in the case of rats with associated with increase in load. In this experiment, by infusion of isotonic sodium chloride cause high cardiac filling pressure, which Ty carried out using male Wistar rats with body weight 200-400, If neuroleptanalgesia (fentanyl; Hypnormmanufacturer: company Janssen) in the right femoral vein insert a catheter for peripheral infusion (Hintegrundinfusion) and bulk load using isotonic sodium chloride. After opening the abdominal cavity into the bladder enter the second catheter and bandage the urethra so as to measure the amount of urine, nutrient and calibres.

The abdominal cavity is again closed and the animals get a long-term infusion of sodium chloride solution (0.5 ml /100 g body weight) during the entire period of experience 2 hours. After a period of equilibration for 30 minutes in the preliminary phase prior to the introduction of the test substance, depending on the circumstances, three times in a time interval of 10 minutes to collect urine samples. These preliminary values (= "Predrug"-values) determined to additionally check that the experimental animals there is a continuous urination.

Then containing the subjects of the substance solution injected intravenously (injection of drugs into the femoral vein) or orally (stomach tube) groups, depending on the circumstances, from 10 rats. In the case of both forms of introduction, depending on the circumstances, the control group Paul the Les intravenous respectively, after 120 minutes after oral administration of substances rats increased load volume of sodium chloride solution intravenously (2 ml /100 g body weight within 2 minutes) and after a period of time of 60 minutes to collect the urine. Define released during this period of time the amount of urine and measure the contained amounts of sodium and potassium. Of the released amounts of urine to determine what is happening when the bulk load increase allocation compared to the prior values.

In the following table D indicate the coming bulk load after administration of the test substance improve urination in% (based on what is happening in the volumetric load after administration of placebo increase in the urinary tract. Further, it also contains released during volume loading after administration of the test substance in the number of sodium and potassium in% (based on the amount of sodium and potassium released during volume loading after administration of a placebo.

The above test results show that the compounds of formula (I) have a greater affinity for NEP and due to this suppression, destroying ANP enzyme increase of ANP level in the blood and thanks SS="ptx2">

On the basis of the above-described actions of the compounds of formula (I) suitable as pharmaceuticals for the larger mammals, particularly humans, to treat heart failure and to facilitate diuresis/natriuresis, especially if suffering from heart failure patients. This dicarboxylic acid of the formula (I) and their salts should be used in parenteral, especially intravenous, administered dosage forms, and complex mono - or diesters of formula (I) suitable use in orally injected dosage forms. The applied dose individually may be different, and, of course, vary depending on the type of curable condition, used substances and the form of administration. For example, parenteral formulations in General contain less biologically active substances than oral medications. In General, however, the introduction of larger mammals, in particular humans, suitable dosage form with the content of biologically active substances 1-200 mg per single dose.

As pharmaceuticals, the compounds of formula (I) may be contained together with conventional pharmaceutical auxiliary substances and can prepare itself known methods in the conventional solid or liquid carriers, as, for example, lactose, starch or talcum powder, or liquid paraffins, and/or when using conventional pharmaceutical excipients, such as fillers tablets (Sprengmittel, agents, dissolution or preservatives.

The following examples have more to explain the invention, but in no way limiting its scope.

The structures of new compounds is guaranteed by spectroscopic studies, in particular by analysis of NMR, mass, IR and/or UV spectra and, if necessary, by determining the values of optical rotation.

Example 1: tert.-Butyl ether 3-{1-/2'-(etoxycarbonyl)-4'- phenyl-butyl/cyclopentane-1-carbylamine} -2,3, 4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A). To a solution of 160,1 g diethyl ester of malonic acid in 1 l of dimethylformamide at a temperature of 15oC portions add 123,4 g of tert.-the butyl potassium. The reaction mixture is stirred for 30 minutes, then at room temperature was added dropwise a solution of 207,7 g geneticbased in 200 ml of dimethylformamide. Then the reaction mixture is heated for one hour at 60oC and leave again to cool off. The dimethylformamide is evaporated under reduced talentcast, washed with water, dried over sodium sulfate and evaporated. Remaining in the form of oily residue the crude product is purified by distillation under reduced pressure. Get 202,5 g of ethyl ester of 2-etoxycarbonyl-4-phenyl-butane acid. So Kip. = 148 - 153oC (1.5 mm RT. Art.).

B.). To a solution of 23.6 g videolooking complex diapir in 285 ml of ethanol is added a solution of 6.17 g of potassium hydroxide in 76 ml of water while cooling with ice. The reaction mixture is stirred several hours at room temperature. The ethanol is then evaporated under reduced pressure and the residue is treated with a mixture of simple tert.-butyl ether with water. The organic phase is separated and discarded, and the aqueous phase while cooling with ice acidified with dilute aqueous hydrochloric acid and then repeatedly extracted with methyl-tert. - butyl simple ether. Combined phase in methyl-tert.- butyl ether washed with water, dried over sodium sulfate and evaporated under reduced pressure. Get to 20.1 g of crude oily ethyl ester of 2-carboxy-4-phenyl-butane acid, which without further purification enter into interaction next.

In). For 20.2 g videolooking of the product under ice cooling follower for several hours at room temperature, then diluted with methyl tert.-butyl simple ether, washed with an aqueous solution of potassium hydrosulfate and water, dried over sodium sulfate and evaporated. The residue is dried under reduced pressure. Obtain 14.8 g of ethyl ester - (2-phenylethyl)acrylic acid.

G). In nitrogen atmosphere of 25.2 ml Diisopropylamine dissolved in 150 ml of absolute tetrahydrofuran and cooled to -35oC. To the solution was added dropwise 100 ml of a 1.6 n solution of utility in n-hexane. After that the reaction mixture is stirred for 30 minutes at 0oC and then added dropwise a solution of 8.1 ml cyclopentanecarbonyl acid in 20 ml of absolute tetrahydrofuran. The reaction mixture is stirred 2 hours at 0oC. then was added dropwise a solution of 16.8 g obtained in paragraph (C) complex acrylic ester in 20 ml of absolute tetrahydrofuran, the reaction mixture is left to stand for 2 hours at 0oC and then for several hours at -15oC. processing the reaction mixture is acidified with 10% aqueous hydrochloric acid solution and extracted with n-hexane. The organic phase is washed 7 times with Polynesians aqueous sodium bicarbonate solution and once with water, dried over sodium sulfate and evaporated under is when using a mixture of n-hexane with ethyl acetate (8:2). Get a 19.6 g of pure 1-/2'-(etoxycarbonyl)-4'-phenyl-butyl/cyclopentane-1 - carboxylic acid with so pl. 68-69oC.

D). To a solution of 100 g - tetralone in 820 ml of methanol under ice cooling slowly added dropwise to 108.3 g of bromine. Then the reaction mixture is stirred for 30 minutes at room temperature and then at room temperature add first 122,4 g of hydroxylamine-hydrochloride and then 110 ml of water. The mixture is stirred for 3 days at room temperature. After that add the following 493 ml of water, and 1 hour later falls white precipitate. The reaction mixture was stirred over the next 3 days and then cooled to 5oC. the Precipitate is sucked off, washed with water and dried at 40oC under reduced pressure. Get 136,7 g of 2-bromo-3,4-dihydronaphthalene - 1(2H)-he-oxime with so pl. 130-132oC.

E). of 79.5 g Videolooking of oxime are added in several portions to 452 g heated to 80oC polyphosphoric acid and the reaction mixture stirred for 18 hours at 80oC. Then carefully diluted with 710 ml of water and the mixture is stirred for 2 hours at room temperature. The formed precipitate is sucked off, washed with water, aqueous sodium bicarbonate solution, e is the 60oC. Receive 66.6 g of 3-bromo-4,5-dihydro-1H-1 - benzazepin-2-(3H)-she's so square 168-170oC.

W). 80 g Videolooking product is suspended in 140 ml of dimethylformamide. The suspension is mixed with a solution of 72.6 g phthalimide potassium in 205 ml of dimethylformamide and then stirred for 16 hours at 60oC. For processing, cooled to room temperature and slowly added dropwise to 800 ml of water and the mixture is stirred for 2 hours under ice cooling. The resulting slurry of crystals are sucked off and washed first with a mixture of water with dimethylformamide and then with methyl - tert.-butyl simple ether and then dried for 2 days at 60oC and reduced pressure. Get 73,3 g of 4,5 - dihydro-3-phthalimido-1H-1-benzazepin-2(3H)-it is with melting 185-195oC.

C). To a suspension of 27 g videolooking product in 90 ml of dimethylformamide under cooling with ice add a solution of 12.3 g of tert.-betulina potassium in 40 ml of dimethylformamide. After stirring for 30 minutes under ice cooling for one hour at 0-5oC was added dropwise 20.7 g of tert.-butyl ether bromoxynil acid. Stirred for 1 hour at 0oC. then the reaction mixture is heated to 40oC for 3 hours was added dropwise the resulting precipitate and the remaining solid residue is crystallized from methyl tert.-butyl ether. The formed crystals are sucked off, washed with water and methyl tert.butyl ether and dried under reduced pressure at 60oC. Gain of 26.3 g of tert. -butyl ether 2,3,4,5-tetrahydro-2 - oxo-3-phthalimido-1H-1-benzazepin-1-acetic acid, with so pl. 194 - 197oC.

And). 7 g videolooking of ester for 5 minutes add to a 13.8 ml heated to 80oC ethanolamine. After 5 minutes formed a clear solution which is cooled to room temperature and diluted with 105 ml of toluene. The solution is shaken out with 140 ml of 5% aqueous solution of sodium chloride, the organic phase is separated, dried over sodium sulfate and evaporated. The remaining residue is crystallized from methyl tert.- butyl ether. Obtain 4.0 g of tert.-butyl ester 3-amino - 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid, with so pl. 117-118oC.

K). 2.9 g videolooking amine and 3.2 g viseporodicnog in paragraph (G) of the acid dissolved in 100 ml of dichloromethane. To the reaction mixture while cooling with ice add 2.2 ml of N - methylmorpholine, 1.27 g hydroxy-benzotriazole and 3,81 g N-ethyl-N- (3-dimethylaminopropyl)carbodiimides. After that the reaction mixture is stirred for 1 hour at room temperature. For treatment the of Ulfat potassium, with water, aqueous sodium bicarbonate solution and again with water. The organic phase is then dried over sodium sulfate and the solvent is evaporated under reduced pressure. The thus obtained crude product is purified by column chromatography on silica gel under slightly elevated pressure ( = flash chromatography) when using a mixture of n-hexane with ethyl acetate, and an ethyl acetate fraction eluting funds during elution is increased from the original 1:9 to 3:7. Gain of 5.4 g of pure target compound as an oily product.

IR spectrum (film): 3400 cm-1, 1725 cm-1, 1660 cm-1.

Example 2: 3-{1-/2'-(etoxycarbonyl-4'-phenyl-butyl/cyclopentane - 1-carbylamine}-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid

5 g of tert. -Butyl ester 3-{ 1-/2'-(etoxycarbonyl)-4'- phenylbutyl/cyclopentane-1-carbylamine} -2,3,4,5-tetrahydro-2 - oxo-1H-1-benzazepin-1-acetic acid (receipt, see example 1) are dissolved in 16 ml triperoxonane acid. The solution is stirred for 3 hours at room temperature. For processing, triperoxonane acid is evaporated under reduced pressure. The remaining residue is dissolved in dichloromethane and the solution washed with water until neitralnoe the residue is repeatedly stirred with n-hexane and depending on the circumstances, again evaporated to dryness. Obtain 3.4 g of the target compound in the form of a solid foam with a melting 81-104oC.

Example 3: Tert.-Butyl ester of (3S,2'R)-3- {1-/2'-(etoxycarbonyl)-4'-phenyl-butyl/cyclopentane-1-carbylamine - 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A). 30.5 g of 1-/2'-(etoxycarbonyl)-4'-phenyl-butyl/cyclopentane - 1-carboxylic acid (receipt see example 1 G) and 11.6 g of L-(-)- -methylbenzylamine when heated, dissolved in ethanol. The reaction mixture for 12 hours, cooled in the refrigerator, then the resulting slurry of crystals are sucked off, dried and repeatedly (up to a constant magnitude of rotation) is recrystallized from ethanol and then dried under reduced pressure. Get 17,7 g-methylbenzylamine salts of the above acids with so pl. 118-121oC, optical rotation []2D0= +5,6o(C = 0,5, in methanol).

For the release of this acid salt is treated with a mixture of water with dichloromethane and the mixture is acidified aqueous solution of potassium hydrosulfate. The organic phase is separated, and the aqueous phase is extracted three more times with dichloromethane. The combined organic extracts washed with water, g of pure (2'R)-1-/2'- (etoxycarbonyl)-4'-phenyl-butyl/cyclopentane-1-carboxylic acid; the optical rotation []2D0= +7,4o(C = 0,651 in methanol).

B). It heated up to 65oC to a solution of 24.5 g of racemic tert.-butyl ester 3-amino-2,3,4,5-tetrahydro-2 - oxo-1H-1-benzazepin-1-acetic acid (receipt see example 1) add a solution 12,65 g L-(+)-tartaric acid in 54 ml heated to 65oC ethanol. The reaction mixture is stirred for one hour at room temperature. Then was added dropwise a solution 1,72 ml of benzaldehyde in 1.3 ml of ethanol. The resulting suspension is refluxed for 14 hours at 80oC and then cooled down to room temperature. The resulting crystalline precipitate is sucked off, treated with 80 ml of ethanol and again within 8 hours refluxed. Then cooled to room temperature and the crystals are sucked off and dried at 50oC and under reduced pressure. Get to 23.6 g of the tartrate salt so pl. 195-196oC and the value of the optical rotation []2D0= -152o(C = 0.5 in methanol).

To release the base of 23.6 g of the tartrate salt in a mixture of 250 ml of water and 108 ml of dichloromethane with stirring, cooled to 0oC and by adding an aqueous solution of MMA is Ana and the combined organic phases, dried over sodium sulfate and concentrate under reduced pressure. The remaining residue is crystallized from methyl tert.-butyl ether and dried under reduced pressure. Obtain 12.2 g of tert.-butyl ether (3S)-3-amino-2,3,4,5 - tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid, with so pl. 113-115oC and the value of the optical rotation []2D0= -276,2o(C = 0.5 in methanol).

In). to 5.4 g Obtained above in paragraph (A) acid are dissolved in 60 ml of anhydrous dichloromethane. The solution is mixed with 2,33 ml of triethylamine and cooled to -20oC. and Then slowly added dropwise a solution of 1.31 ml of the acid chloride of methansulfonate in 5 ml of anhydrous dichloromethane. After stirring for 15 minutes, was added dropwise a solution of 4.8 g obtained above in paragraph (B). Amin and of 2.33 ml of triethylamine in 60 ml of dichloromethane. Then the reaction mixture is stirred for 1 hour at room temperature. For processing, the reaction mixture is added to water, the organic phase is separated and washed with an aqueous solution of potassium hydrosulfate and then with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The remaining crude product is purified by flash chromatography on 500 g of silica gel with primenenie connection in the form of oil; the optical rotation []2D0=-115,2o(C = 0,463 in methanol).

Example 4: (3S, 2'R)-3-{ 1-/2'-(Etoxycarbonyl)-4'- phenyl-butyl-cyclopentane-1-carbylamine} -2,3,4,5-tetrahydro-2 - oxo-1H-1-benzazepin-1-acetic acid

9.4 g of tert. -Butyl ether (3S,2'R)-3-{1-/2'-(etoxycarbonyl)- 4'-phenyl-butyl-cyclopentane-1-carbylamine} -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt see example 3) under ice cooling is dissolved in 15 ml of dichloromethane. The solution is mixed with 31 ml triperoxonane acid and the reaction mixture was incubated for approximately 12 hours at 4oC in the refrigerator. For processing dichloromethane and triperoxonane acid is evaporated under reduced pressure. The resulting crude product is treated with ethyl acetate, the resulting solution was washed with water, diluted aqueous sodium bicarbonate solution and again with water. The organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure. The remaining residue purified by flash chromatography on silica gel, and as an eluting funds are used first dichloromethane and then a mixture of dichloromethane with methanol (95: 5). The resulting product is dried for 2 days at 80oC and when PON the optical rotation []2D0= -131,0o(C=0.5; in methanol).

Example 5: tert.-Butyl ester 3-{1-/2'-{tert.- butoxycarbonyl)-4'-phenyl-butyl/cyclopentane-1-carbylamine} -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

A). 118 g of tert.-Butyl ether dimethyltitanocene acid in the atmosphere of nitrogen dissolved in 875 ml of anhydrous dimethylformamide. To the solution under ice cooling type of 58.9 g of tert.-the butyl potassium. Then the reaction mixture is briefly heated at 60oC and then allowed to cool to room temperature. To the reaction mixture was added dropwise a solution of 104,9 g geneticbased in 110 ml of dimethylformamide. After that, the reaction mixture is heated for 2 hours at 60oC. For processing, dimethylformamide then evaporated under reduced pressure and the remaining residue is dissolved in methyl-tert. -butyl ether. The solution is acidified with an aqueous solution of potassium hydrosulfate. Then the organic phase is separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product was then purified by flash chromatography on 3 kg of silica gel when using a mixture of dichloromethane with methyl-tert.-butyl ether (4:1) as elwira oily product.

In). 105,1 g Videolooking product in an atmosphere of nitrogen dissolved in 705 ml of anhydrous tetrahydrofuran. To the solution was added 28.4 g of paraformaldehyde. Then slowly added dropwise a solution of 32.5 g of tert.-the butyl potassium in 100 ml of tetrahydrofuran. After that the reaction mixture is stirred for 1 hour. For processing, the reaction mixture is acidified with cold aqueous solution of potassium hydrosulfate and diluted with methyl tert.-butyl ether. Then the organic phase is separated, washed with water, dried over sodium sulfate and concentrate under reduced pressure. The resulting crude product was then purified by flash chromatography on 700 g of silica gel when using a mixture of n-hexane with ethyl acetate (9: 1). Receive and 47.0 g of tert.-butyl ester - (phenethyl)acrylic acid in the form of a colorless oil.

In). To a cooled to -50oC to a solution of 50.2 ml Diisopropylamine in 450 ml of absolute tetrahydrofuran was added dropwise 200 ml of a 1.6 M solution of utility in n-hexane and the reaction mixture was incubated another 30 minutes at 0oC. Then, at this temperature was added dropwise a solution of 16.2 ml cyclopentanecarbonyl acid in 40 ml of absolute tetrahydrofuran. The reaction mixture is stirred for the next 2 hours at 0oC. Poreporena. The reaction mixture is stirred for the next 2 hours at 0oC and then for several hours and allowed to stand at -15oC. processing the reaction mixture while cooling with ice, acidified with saturated aqueous solution of potassium hydrosulfate and thrice extracted with n-hexane. The combined organic phases are washed 7 times polysystem aqueous solution of sodium bicarbonate and then with water, then dried over sodium sulfate and evaporated under reduced pressure. The obtained oily crude product is crystallized from ice n-hexane. Get a 41.9 g of pure crystalline 1-/2'-(tert. -butoxycarbonyl)- 4'-phenyl-butyl/cyclopentane-1-carboxylic acid with so pl. 75 - 77oC.

G). 3.3 grams Videolooking product, 2.7 g of tert.-butyl ester 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt see example 1)), 1,53 ml of N-methylmorpholine and 1.18 g of hydroxybenzotriazole in an atmosphere of nitrogen dissolved in 93 ml of absolute dichloromethane. To this solution while cooling with ice add to 3.52 g of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimides. Then the reaction mixture is stirred for 2 hours under ice cooling. For processing, the reaction mixture is washed and again with water. The organic phase is dried over sodium sulfate and concentrate under reduced pressure. The remaining crude product is purified by flash chromatography on 200 g of silica gel when using a mixture of n-hexane with ethyl acetate (7:3) as eluting tools and crystallized from methyl tert.-butyl ether. Get to 4.2 g of pure target compound with so pl. 110-114oC.

Example 6: 3-/1-(2'-Carboxy-4'-phenyl-butyl)cyclopentane - 1-carbylamine/-2,3,4,5-tetrahydro-2-oxo-1H-1 - benzazepin-1-acetic acid

4.1 g of tert. -Butyl ester 3-{1- /2'-(tert.-butoxycarbonyl)-4'-phenyl-butyl/cyclopentane-1 - carbylamine} -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1 - acetic acid (receipt see example 5), at a temperature of 4oC and with the exclusion of moisture dissolved in 13 ml triperoxonane acid. The resulting solution was stirred for a further 3 hours at this temperature. For processing the reaction mixture was concentrated under reduced pressure. To completely remove triperoxonane acid residue is repeatedly mixed with dichloromethane and again evaporated. The resulting residue is then dissolved in dichloromethane, the solution is washed with water, dried over sodium sulfate and concentrate under reduced pressure. Remaining as a residue when S="ptx2">

Example 7: tert. -Butyl ester (3S,2'R)-2-{1- /2'-(tert.-butoxycarbonyl)-4'-phenyl-butyl/cyclopentane-1 - carbylamine} -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1 - acetic acid.

A). 68 g of 1-/2'-(tert.-Butoxycarbonyl)-4'-phenyl-butyl/ cyclopentane-1-carboxylic acid (receipt see example 5)) and 23.5 ml of 1 - ( -) - methylbenzylamine when heated, dissolved in 200 ml of ethanol. The reaction mixture is treated as described in example 3 (A). Get 32,2 g - methylbenzylamine salts of the above acids with so pl. 118-119oC; optical rotation is:

[]2D0+9,2o(C = 0,5, in methanol). For the release of this acid salt is treated further as described in example 3 (A) method. Obtain 23 g of (2'R)-1-/2'-(tert.-butoxycarbonyl)-4'- phenyl-butyl/cyclopentane-1-carboxylic acid with so pl. 68-70oC; optical rotation []2D0= + 15,4o(C = 0.5 in methanol).

B). 60.1 g Viseporodicnog acid is injected into the interaction from 50.3 g of tert. - butyl ether (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1 - benzazepin-1-acetic acid (receipt see example 3 (B)), as described in example 3), and the resulting reaction mixture is treated as described in example 3 is UP>o
(C = 0.5 in methanol).

Example 8: (3S,2'R)-3-/1-(2'-Carboxy-4'-phenyl-butylcyclohexane - 1 carbylamine/-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

93 g of tert. -Butyl ether (3S,2'R)-3-{1-/2'-(tert.- butoxycarbonyl)-4'-phenyl-butyl/cyclopentane-1-carbylamine} - 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt see example 7) as described in example 6 method of hydrolyzing using triperoxonane acid and the reaction mixture is treated as described in example 6. Get 63,5 g of target compound in the form of a solid foam with a melting 97-122oC; optical rotation []2D0=-136,20o(C = 0.5 in methanol).

Example 9: Benzyl ester of (3S,2'S)-3- {1-/2'-(tert-butoxycarbonyl)-3'-(2-methoxyethoxy) propyl/cyclopentane-1-carbylamine}-3,4-dihydro-4-oxo-1,5 - benzoxazepin-5(2H)-acetic acid.

A). To a solution of 100 g of 3-bromopropionic acid in 200 ml of diethyl ether, add 7 ml of sulfuric acid and the reaction mixture is cooled to -20oC. Then add 123 ml of liquefied isobutane. The reaction mixture is stirred for several hours at room temperature in the pressure vessel. Then the reaction mixture with Aleut and the aqueous phase is again extracted with ether. The combined organic phases are washed with aqueous solution of sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product is distilled under reduced pressure. Get 100 g of tert.-butyl ester 3-bromo-propionic acid. So Kip. 75-77oC (20 mm RT.cent.).

B). of 50.4 ml Diisopropylamine in the atmosphere of nitrogen dissolved in 300 ml of absolute tetrahydrofuran and the solution is cooled to -70oC. To the solution at this temperature slowly added dropwise to 200 ml of a 1.6 M solution of utility in n-hexane. The reaction mixture is left to warm to 0oC, stirred for 30 minutes at this temperature and again cooled to -20oC. At this temperature was added dropwise a solution of 16.2 ml cyclopentanecarbonyl acid in 30 ml of absolute tetrahydrofuran. Then the reaction mixture is stirred for 2 hours at room temperature. After that, the mixture is cooled to -10oC and slowly added dropwise to a cooled to -10oC to a solution of 35 g of tert.-butyl ester 3-bromo-propionic acid in 100 ml of tetrahydrofuran. The reaction mixture is stirred for several hours at room temperature. For the purpose of processing, the mixture is acidified with dilute aqueous dissolve stragiht three times in 100 ml of diethyl ether. The combined organic extracts washed with aqueous solution of sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. The remaining residue is dissolved in 300 ml of diethyl ether. The solution is shaken out 6 times with aqueous sodium bicarbonate solution and then 4 times with 10% aqueous solution of sodium carbonate. The combined solution of sodium carbonate is acidified under cooling with ice and extracted with three times 150 ml of ether. These ethereal extracts are combined with the ether solution and the resulting solution was washed with aqueous solution of sodium chloride, dried over sodium sulfate and concentrate under reduced pressure. The resulting crude product is crystallized from ice n-hexane. Get to 7.7 g of pure 1-/2'-(tert.- butoxycarbonyl)ethyl/-1-cyclopentanecarbonyl acid so pl. 78 - 81oC.

In). 30 ml of Diisopropylamine in the atmosphere of nitrogen dissolved in 100 ml of absolute tetrahydrofuran and the solution is cooled to -70oC. To the solution was added dropwise 132 ml of a 1.6 M solution of utility in n-hexane and the reaction mixture is stirred for a further 30 minutes at 0oC and then cooled to -70oC. thereafter, to the reaction mixture successively added dropwise a solution of 24.2 g obtained above in paragraph (absolute tetrahydrofuran. The reaction mixture is stirred for 16 hours at room temperature. For processing the reaction mixture contribute in a mixture of ice and water, acidified with an aqueous solution of potassium hydrosulfate and extracted with three times 300 ml of ethyl acetate. The combined organic phases are washed with an aqueous solution of sodium chloride, dried over sodium sulfate and concentrate under reduced pressure. The remaining crude product is purified by flash chromatography on 500 g of silica gel when using a mixture of dichloromethane and ether (8:2) as eluting funds. Gain of 26.5 g of pure 1-/2'-(tert.-butoxycarbonyl)-3'-(2-methoxyethoxy)-propyl/-cyclopentane-1-carboxylic acid in the form of butter.

G). 36,7 g Viseporodicnog racemic acid is dissolved in 184 ml of n-hexane and the solution is mixed with an 18.4 g of (+)-pseudoephedrine. The precipitation by briefly boiling under reflux is again dissolved. Then the solution is cooled and allowed to stand for several hours in the refrigerator. The resulting crystalline precipitate is sucked off, washed with ice n-hexane and 4 times recrystallized from n-hexane. Obtain 16.2 g of salt of pseudoephedrine above acids with so pl. 89 - 91oC. the optical salt is suspended in n-hexane, and the reaction mixture is acidified with ice water solution of potassium hydrosulfate. The organic phase is separated, and the aqueous phase is 2 more times extracted with n-hexane. The combined organic phases are washed with aqueous sodium chloride, dried over sodium sulfate and evaporated under reduced pressure. The residue is dried under reduced pressure at 50oC. Gain of 9.9 g of (2'S)-1-/2'- (tert.-butoxycarbonyl)-3'-(2-methoxyethoxy)-propyl/cyclopentane - 1-carboxylic acid in the form of oil; the value of the optical rotation []2D0=+2,9o(C = 1 in methanol).

D). and 17.2 g of sodium Hydride (80%), in nitrogen atmosphere and with exclusion of moisture, dissolved in 400 ml of anhydrous dimethylformamide. To this solution at 0oC slowly added dropwise a solution of 50 g of L-BOC-serine ( =N-(tert.-butoxycarbonyl)-serine) in 50 ml of anhydrous dimethylformamide. The reaction mixture is left to rise slowly to 15oC, and then added dropwise to the solution with 37.4 g of o-NITROPHENOL in 50 ml of dimethylformamide, and the reaction mixture is stirred several hours at room temperature. For the purpose of processing, the reaction mixture is poured into ice water solution of potassium hydrosulfate. Then mnogokratni. The aqueous phase is separated, washed with ether and then acidified with a solution of potassium hydrosulfate and extracted with ethyl acetate. An ethyl acetate extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. Get a 54.2 g of crude (2S)-3-(2-nitrophenoxy)-2-(tert.- butoxycarbonylamino)-propionic acid, which without further purification enter into interaction next.

E). 54,2 g Viseporodicnog acid are dissolved in 600 ml of methanol. The solution is mixed with 1.8 g of palladium catalyst (5% palladium-on-coal). Then for 1 hour hydronaut when the hydrogen pressure of 5 bar. Then the catalyst is filtered off and the filtered solution is concentrated under reduced pressure. The resulting crude product is crystallized from a mixture of methyl-tert.- butyl ether n-hexane under ice cooling. Get to 30.1 g of (2S)-3-(2-aminophenoxy)-2-(tert. -butoxycarbonylamino)- propionic acid with so pl. 87-91oC, optical rotation []2D0= +55,9o(C = 1 in methanol).

W). 13.3 g Viseporodicnog acid, with the exclusion of moisture, dissolved in 71 ml of anhydrous dimethylformamide. To the solution while cooling with ice, add 7,8 ml diethylethanolamine in 6 ml dimethylformamide temperature. Then the reaction mixture for the purpose of processing, poured into ice water and repeatedly extracted with methyl-tert.-butyl ether. The combined organic phases are dried and evaporated under reduced pressure. Remaining as residue crude product is crystallized from ethanol. Obtain 1.3 g of (3S)-3-(tert. -butoxycarbonylamino)- 2,3-dihydro-1,5-benzoxazepin-4(5H)-she; optical rotation []2D0= -194 (C = 1 in methanol).

C). 16 g Videolooking product, with the exclusion of moisture, dissolved in 313 ml of tetrahydrofuran. To the solution successively added dropwise a solution of 7.1 g of tert.-the butyl potassium in 30 ml of tetrahydrofuran and a solution of 10.9 ml benzyl ether bromoxynil acid in 10 ml of tetrahydrofuran. The reaction mixture is stirred for 1 hour at room temperature. Then, for processing, diluted with methyl tert.-butyl ether, washed with water, the organic phase is dried over sodium sulfate and concentrate under reduced pressure. The resulting crude product was then purified by flash chromatography on 500 g of silica gel when using a mixture of n-hexane with ethyl acetate (3:2) as eluting funds. Get to 20.5 g of pure benzyl ester of (3S)-3-(tert.-butoxycarbonylamino)-4-oxo-3,4-dihydro-1,5-P>o(C =0,68 in methanol).

And). 20 g Videolooking product is dissolved in 137 ml of dichloromethane. The solution is mixed with 77 ml triperoxonane acid and stirred for 1 hour. Then concentrate under reduced pressure, the residue is dissolved in dichloromethane and mixed with an aqueous sodium bicarbonate solution until an alkaline reaction. The organic phase is separated, washed with water, dried over sodium sulfate and concentrate under reduced pressure. Obtain 15.7 g of pure benzyl ester of (3S)-3-amino-4-oxo-3,4-dihydro-1,5 - benzoxazepin-5(2H)-acetic acid; optical rotation []2D0= -187,5o(C = 0,536 in methanol).

K). 15.7 g Videolooking product is dissolved in 48 ml of anhydrous dichloromethane and the solution at room temperature sequentially mixed with 1.6 g obtained above in paragraph (G) of the acid, of 0.79 ml of N-methylmorpholine and 1.83 g of N-ethyl-N'-(3-dimethylaminopropyl)- carbodiimide-hydrochloride. The reaction mixture was stirred for further 1 hour at room temperature. Then, order processing, sequentially washed with water, aqueous solution of potassium hydrosulfate, with water, aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated under reduced yeah who gives a mixture of n-hexane with ethyl acetate (7:3) as eluting funds. Obtain 1.8 g of the target compound in the form of oil; the value of the optical rotation []2D0= -96,3o(C = 0,326 in methanol).

Example 10: Benzyl ester of (3S,2'S)-3-{1-/2'- carboxy-3'-(2-methoxyethoxy)propyl/cyclopentane-1-carbylamine} - 4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-acetic acid.

1.6 g of Benzyl ester of (3S,2'S)-3-{1-/2'-(tert.- butoxycarbonyl)-3'-(2-methoxyethoxy)propyl/cyclopentane-1 - carbylamine} -4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)- acetic acid (receipt see example 9) under ice cooling is dissolved in 5 ml triperoxonane acid. The solution is left to stand for several hours at a temperature of 4oC. Then, for processing evaporated under reduced pressure and the remaining as residue crude product is purified by flash chromatography on silica gel when using a mixture of dichloromethane with methyl-tert.-butyl ether and methanol (85:15:5). After drying obtain 1.0 g of the target compound in the form of oil; the value of the optical rotation []2D0= -117,2o(C = 0,42 in methanol).

Example 11: (3S, 2'S)-3-(1-/2'-Carboxy-3'-(2 - methoxyethoxy)-propyl/cyclopentane-1-carbylamine)-4 - oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-acetic acid.

DRO-1,5-benzoxazepin-5(2H)-acetic acid (see getting example 10) was dissolved in 50 ml of ethanol. To the solution was added 0.2 g of palladium catalyst (5% palladium-on - coal). After that hydronaut for 2 hours under hydrogen pressure of 5 bar. For processing, is filtered from the catalyst, the filtered solution is evaporated under reduced pressure and the remaining residue is dried. Obtain 0.7 g of the target compound in the form of a foamy product: optical rotation []2D0= -142,6o(C = 0.5 in methanol).

Example 12: tert.-Butyl ester (3R)-3-(1-/2'- (tert.-butoxycarbonyl)-4'-(4-pertenece)-butyl/cyclopentane - 1-carbylamine)-4-oxo-3,4-dihydro-1,5-benzothiazepin-5 (2H)-acetic acid.

A). 20.5 g of tert.-Butyl ether dimethyltitanocene acid is injected into the interaction of with 25 g of 4-fortunecity.com as described in example 5 (A) method. The reaction mixture was treated as in example 5 (A). Get to 20.4 g of tert.-butyl ether complex of 4-(4-pertenece)-2-(dimethylphosphino)-n-butyric acid.

B). 20,4 g Videolooking product enter into interaction with 4.8 g of paraformaldehyde as described in example 5 (B) method. The reaction mixture is treated as described in example 5 (B). As the crude product is linesa chromatographic purification used in the nearest stage.

In). 15.2 g Videolooking product enter into interaction with 5.1 ml cyclopentanecarbonyl acid as described in example 5 In) method. The reaction mixture is treated as described in example 5). Obtain 6.0 g of 1-/2'-(tert. -butoxycarbonyl)-4'-(4 - pertenece)-butyl/cyclopentane-1-carboxylic acid with so pl. 58 - 63oC and a further 7.6 g of oily, still slightly contaminated product.

G). To a solution of 100 ml of 1-fluoro-2-nitro-benzene in 1800 ml of ethanol is added a solution of 122,4 g N-acetyl-L-cysteine and 181,9 g of sodium bicarbonate in 550 ml of water. The reaction mixture is refluxed for 3 hours, then cooled to room temperature and filtered from the precipitate. The filtrate is concentrated to approximately volume of 700 ml and the remaining residue is treated with 1.8 l of water. The aqueous phase is extracted with diethyl ether and then set to pH 1 by adding concentrated aqueous solution of hydrochloric acid. Roll a yellow solid, which sucked. Get 253,6 g of crude R-(2-nitrophenyl)-N-acetyl-L-cysteine, which without further purification enter into interaction next.

D). 253,6 g Videolooking product is mixed with 825 ml of 18 M sulfuric acid and 3.3 l of water. Reaction with concentrated ammonia solution. Precipitated during this solid is sucked off and recrystallized from water. Obtain 143 g of R-(2-nitrophenyl)-L-cysteine.

E). 100 g Videolooking product and 62.2 g of potassium carbonate dissolved in 7 l of water. Then for 3 hours portions add 120 g of carbamaxepine and the reaction mixture is stirred for 5 hours and again within a few hours left to stand. Then precipitated precipitated solid is sucked off and the filtrate is brought to pH 2-3 with concentrated aqueous hydrochloric acid. Drop down when this precipitate is sucked off, washed repeatedly with water and then Usacheva approximately 1 l of ethanol under mild heating (about 40oC). After cooling, the solid is sucked off and dried in air. Get 100 g of (2R)-3-(2-nitrophenylthio)-2-phthalimido - propionic acid, which without further purification enter into interaction next.

W). 100 g Videolooking product are suspended in 1.5 l of methanol. To the resulting suspension add 0.8 g of 5% palladium-on-coal and the reaction mixture hydronaut for 5 hours. Then the catalyst is separated and the solvent is evaporated under reduced pressure. Get 71,6 g of crude (2R)-3- (2-aminophenylthio)-2-deistvie next.

C). 71,6 g Videolooking product is dissolved in dimethylformamide. To the solution was added 38.0 g 1-/3- (dimethylamino)propyl/-3-ethyl-carbodiimide-hydrochloride and the reaction mixture is stirred for 3 hours at room temperature. Then the reaction mixture is diluted with 1.5 l of ethyl acetate and extracted repeatedly 1.5 l 1 N. aqueous solution of sodium bicarbonate. The organic phase is then washed with twice 200 ml of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is purified by flash chromatography on a column when using a mixture of ethyl acetate with cyclohexane (1:1) as the eluting means. Receive and 46.3 g of (3R)-2,3-dihydro-3-phthalimido-1,5-benzothiazepin-4(5H)-it.

And). To a solution of 46.3 g videolooking product in 300 ml of tetrahydrofuran added 10.6 g of powdered potassium hydroxide and 4.8 g of tetrabutylammonium. The reaction mixture was cooled to 0oC and then slowly added dropwise to 23.2 ml of tert.-butyl ether bromoxynil acid. The reaction mixture is stirred for further 3 hours at room temperature. Then filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is treated with diethyl ether and the ether phase is low pressure. The remaining oily product is mixed with ethyl acetate and diethyl ether. The residue is sucked off. Obtain 34 g of (3R)-5-(tert.-butoxycarbonylmethyl)-2,3-dihydro-3 - phthalimido-1,5-benzothiazepin-4(5H)-it is in the form of a solid substance. After concentration of the mother liquor under reduced pressure to obtain 25 g of slightly contaminated oily product. The optical rotation []2D0= -146o(C = 0.8 in dichloromethane).

K). 2 g Videolooking product is mixed with 7.5 ml of ethanolamine and the mixture is stirred for 10 minutes at 80oC. Then the heat source is removed and stirred for further next 30 minutes. After the reaction mixture, for the purpose of processing, mixed with 70 ml of 5% aqueous solution of sodium chloride and the resulting mixture is extracted with toluene. The organic phase is separated, dried over sodium sulfate and evaporated to dryness under reduced pressure. Gain of 1.46 g of crude, still containing toluene tert.-butyl ether (3R)-3-amino-4-oxo-3,4-dihydro - 1,5-benzothiazepin-5(2H)-acetic acid in the form containing toluene solids.

L). To 100 ml of dry dichloromethane added 1.45 g videolooking product of 1.75 g obtained in paragraph (C) derived cyclopent is to give 0oC and add to 1.76 g of 1-ethyl-3-(3 - dimethylaminopropyl)-carbodiimide-hydrochloride and the reaction mixture was stirred at room temperature for 5 hours. For processing, the reaction mixture was mixed with 1 M solution of potassium hydrosulfate, the organic phase is separated and washed with 1 M solution of potassium bicarbonate and a saturated solution of sodium chloride, dried over sodium sulfate and evaporated to dryness under reduced pressure. The resulting crude product was then purified by column flash chromatography with use of a mixture of n-hexane with ethyl acetate (4:1) as the eluting means. Get 1,9 g of target compound in the form of butter.

IR spectrum (film): 3366 cm, 3059 cm, 2969 cm, 2874 cm, 1727 cm, 1657 cm, 1505 cm-1.

Example 13: (3R)-3-(1-/2'-Carboxy-4'-(4-pertenece) butyl/cyclopentane-1-carbylamine)-4-oxo-3,4 - dihydro-1,5-benzothiazepin-5(2H)-acetic acid.

to 1.9 g of tert. -Butyl ether (3R)-3-(1-/2'-(tert.-butoxycarbonyl)- 4'-(4-pertenece)butyl/cyclopentane-1-carbylamine)-4-oxo-3,4-dihydro - 1,5-benzothiazepin-5(2H)-acetic acid (receipt see example 12) described in example 6 method of hydrolyzing using triperoxonane acid. The reaction mixture is treated as described in example 6. P is em.-Butyl ester (3R)-3-(1-/2'- (tert.-butoxycarbonyl)-5'-(3,4-acid)of pencil/cyclopentane - 1-carbylamine)-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-acetic acid.

A). 6.7 g of Triphenylphosphine are dissolved in 200 ml of acetonitrile. After cooling the solution to 0oC was added dropwise 1.3 ml of bromine. Then the cooling bath is removed and added dropwise a solution of 5 g of 3-(3,4 - acid)-1-propanol in 80 ml of acetonitrile. The reaction mixture was then refluxed, with the help of separator repeatedly for 6 hours, depending on the circumstances, take 10 ml of the distillate and the selected number replace with fresh acetonitrile. For processing, the solvent is evaporated under reduced pressure and the remaining residue is treated with diethyl ether and filtered. The filtrate is concentrated under reduced pressure and the residue purified by column flash chromatography when using mixtures of cyclohexane with methyl-tert. -butyl ether (7:2). Obtain 5.5 g of 3-(3,4-acid)-1-bromo-propane in the form of a colorless oil.

B). 5.5 g Videolooking product described in example 5 (A) enter into interaction with 3.8 ml of tert.-butyl ether dimethyltitanocene acid. The reaction mixture is treated as described in example 5 (A). Gain of 6.1 g of tert.-butyl ester of 4- (3,4-acid)-2-(dimethyl-phosphono)-valerianic acid as a colourless oil.

In). The reaction mixture is treated as described in example 5B). The resulting crude product was then purified by column flash chromatography with use of a mixture of methyl-tert.- butyl ether and cyclohexane (1:3) as eluting funds. Get 3,4 oily tert.-butyl ester 1-/3- (3,4-acid)propyl/acrylic acid.

G). 3.4 g Videolooking product enter into interaction with 1.3 ml cyclopentanecarbonyl acid as described in example 5 In) method. The reaction mixture is treated as described in example 5). The crude product is purified by column flash chromatography when using mixtures of ethyl acetate with cyclohexane (1:3) as eluting funds. Obtain 2.5 g of oily 1-/2-(tert.- butoxycarbonyl)-5-(3,4-acid)of pencil/cyclopentanecarbonyl acid.

D). 2.5 g Videolooking product is dissolved in 50 ml of acetonitrile. At a temperature of 0oC, with the exclusion of moisture, to the solution was added sequentially to 4.2 ml diisopropylethylamine, 1.7 g of 2-chloro-1-methylpyridinium and 2.5 g of tert.-butyl ether complex (3R)-3-amino-4-oxo-3,4-dihydro-1,5-benzodiazepine - 5(2H)-acetic acid (receipt see example 12)). The reaction mixture is stirred for further 30 minutes at 0oC and 2 hours at room temperature. For processing, reachesthe shaken first with a dilute aqueous solution of hydrochloric acid and then with water. The organic phase is separated, the introductory phase is extracted 2 more times with dichloromethane. Then the combined organic phases are dried over sodium sulfate and concentrate under reduced pressure. As residue obtained 3 g of target compound in the form of oil. Thin layer chromatography on silica gel: Rf- value = 0,4 (eluting agent cyclohexane/ethyl acetate = 1:1).

Example 15: (3R)-3-{ 1-/2'-Carboxy-5'-(3,4-acid) of pencil/-cyclopentane-1-carbylamine} -4-oxo-3,4-dihydro-1,5 - benzothiazepin-5(2H)-acetic acid.

3 g of tert.-Butyl ether complex (3R)-3-(1-/2'-(tert.- -butoxycarbonyl)-5-(3,4-acid)of pencil/cyclopentane-1 - carbylamine)-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)- acetic acid (receipt see example 14) was dissolved in 20 ml of dichloromethane. To the solution add 3 ml triperoxonane acid and the reaction mixture stirred for 2 days at room temperature. For processing, the reaction mixture was concentrated under reduced pressure. To completely remove triperoxonane acid residue is repeatedly mixed, depending on the circumstances, with toluene in an amount of 2 ml) and again evaporated. The thus obtained crude product is purified by flash chromatography on silicone 1:1 and then pure ethyl acetate. After concentration of the eluate under reduced pressure to obtain 1.26 g of the target compound as amorphous solid. IR-spectrum (in the form of tablets with KBr): 3365, 2942, 1726, 1652 cm-1.

Example 16: Benzyl ester 3-(1-/2'-)tert.-butoxycarbonyl)- 4'-phenyl-butyl/cyclopentane-1-carbylamine)-2,3,4,5-tetrahydro-2-oxo - 1H-1-benzazepin-1-acetic acid.

A). of 10.5 g of tert.-Butyl ether complex 3-amino-2,3,4,5 - tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt see example 1)), of 8.25 g of the hydrate p-toluenesulfonic acid and 20.1 ml of benzyl alcohol contribute in 174 ml of toluene. The reaction mixture is boiled for 4 hours with a water separator, and initially precipitated sludge slowly dissolves. Then the toluene is removed under reduced pressure and the remaining residue is stirred with methyl tert.-butyl ether and then filtered. The thus obtained solid residue was dissolved in dichloromethane and the solution is alkalinized by adding an aqueous solution of sodium carbonate under ice cooling. Then separate the dichloromethane phase is washed with water, dried over sodium sulfate and evaporated. The resulting crude product for cleaning is recrystallized from methyl tert. - butyl ether. ASS="ptx2">

B). 12.8 g Videolooking product is injected into the interaction from 13.7 g of 1-/2'-(tert. -butoxycarbonyl)-4'- phenyl-butyl-cyclopentane-1-carboxylic acid (receipt see example 5 (B)) as described in example 3 In) method. The reaction mixture is treated as described in example 3). Obtain 19.3 g of target compound with so pl. 118-123oC.

Example 17: Benzyl ester 3-/1-(2'-carboxy-4 - phenyl-butyl)cyclopentane-1-carbylamine/-1,3,4,5-tetrahydro-2-oxo - 1H-1-benzazepin-1-acetic acid.

15 g of Benzyl ether complex 3-(1-/2'-(tert-butoxycarbonyl)- 4'-phenylbutyl/cyclopentane-1-carbylamine)-2,3,4,5 - tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid (receipt see example 16) being in communication with 56 ml trifter-acetic acid as described in example 6 method. The reaction mixture is treated as described in example 6, and the resulting crude product is crystallized from methyl tert.butyl ether. Get to 13.1 g of target compound with so pl. 86-90oC.

Example 18: Benzyl ester 3-(1-/2'-(tert.-butyl - carbonylcontaining)-4'-phenylbutyl/cyclopentane-1 - carbonylative)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1 - acetic acid.

2 g of ester Benzyl 3-/1-(2'-carbox what I see example 17) with the exclusion of moisture dissolved in 20 ml of anhydrous dichloromethane. To the solution add and 0.46 ml of triethylamine and 0.1 g of dimethylaminopyridine. Then, under ice cooling, was added dropwise a solution of 0.5 g chlormethiazole ether pavlinovoi acid in 3 ml of anhydrous dichloromethane. The reaction mixture is then stirred for 2 days at room temperature. For processing, the reaction mixture was making water, the organic phase is separated, washed with aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and concentrate under reduced pressure. Remaining as a residue the crude product is purified by flash chromatography on 150 g of silica gel, and as the eluting means a mixture of n-hexane with ethyl acetate composition: first, 7:3 and then 1:1. Obtain 1.1 g of pure benzyl ester 3-(1-/2' - (pivaloyloxymethyl)-4'-phenyl-butyl/ cyclopentane-1-carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1 - benzazepin-1-acetic acid in the form of a solid foam with a melting 71-78oC.

Example 19: 3-(1-/2'-(Pivaloyloxymethyl)-4'- phenyl-butyl/cyclopentane-1-carbylamine)-2,3,4,5-tetrahydro-2 - oxo-1H-1-benzazepin-1-acetic acid.

1.0 g of ester Benzyl 3-(1-/2'-n-1-acetic acid (see getting example 18) was dissolved in 100 ml of ethanol. The solution is mixed with 0.5 g of the catalyst is 5% palladium-on-charcoal grill. Then hydronaut for 3 hours under hydrogen pressure of 5 bar. For processing, is filtered from the catalyst, and the filtered solution is evaporated. The resulting residue is dried at 80oC and reduced pressure. Obtain 0.7 g of the target compound as a glassy product.

IR-spectrum (in the form of tablets with KBr): 3410, 1750, 1660 cm-1.

As described in the above examples of ways you can also get listed in table 1 the compounds of formula (I):

Example I Tablets containing (3S,2'R)-3-(1-/2'- (etoxycarbonyl)-4'-phenyl-butyl/cyclopentane-1-carbylamine) -2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

To prepare tablets of the following composition per tablet, mg:

(3S, 2'R)-3-(1-/2'-(Etoxycarbonyl)-4'-phenyl-butyl/cyclopentane - 1-carbylamine)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1 - acetic acid - 20

Corn starch - 60

Milk sugar - 135

Gelatin (10% solution) - 6

Biologically active ingredient, corn starch and the lactose concentrate with 10% gelatin solution. Pasta rathmell the second granulate is passed through a machine for grinding in a blender mixed with the following other auxiliary substances, mg:

Talc - 5

Magnesium stearate - 5

Corn starch - 9

and then pressed into tablets weighing 240 mg

Example II: Solution for injection containing (3S,2'R)-3-/1- (2'-carboxy-4'-phenyl-butyl)cyclopentane-1-carbylamine-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid.

Prepare a solution for injection the following composition, per 5 ml, mg:

(3S,2'R)-3-/1-(2'-Carboxy-4'-phenyl-butyl)-cyclopentane-1 - carbylamine/-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-acetic acid - 10

Na2HPO47H2O - 43,24

NaH2PO42H2O - 7,72

NaCl - 30,0

Purified water - 4948,0

Solids dissolve in water, the solution is sterilized and portions, depending on the circumstances, 5 ml poured into ampoules.

1. Derivatives benzazepin, benzoxazepin and benzothiazepin-N-acetic acids of the General formula I

< / BR>
where R1denotes the (lower)alkoxy(lower)alkyl group, a lower CNS residue which is substituted by lower CNS group, phenyl(lower)alkyl group or phenyloxy(lower)alkyl group, which, if necessary, in the phenyl ring may be substituted by lower alkyl, lower alkoxyl or halogen, or naphthyl(lower)alkyl is UP> denotes hydrogen or halogen;

R4denotes hydrogen or forming biolabeling ester group;

R5denotes hydrogen or forming biolabeling ester group,

and physiologically tolerated salts of the acids of formula I.

2. Derivatives under item 1 of the formula I, where R4and/or R5denote forming biolabeling ester group.

3. Derivatives PP. 1 and 2 of the formula I, where forming biolabeling ester group is a lower alkyl group, if necessary substituted in the phenyl ring by lower alkyl or associated with 2 adjacent carbon atoms of the lower alkalinous chain phenyl or phenyl(lower) alkyl group, in particular phenyl, benzyl or indanyl; if necessary substituted in the dioxolane ring by lower alkyl DIOXOLANYL group, in particular (2,2-dimethyl-1,3-dioxolane-4-yl)methyl; or if necessary replaced in oxymethylene the group of lower alkyl (C2-C6)-alkanoyloxy group.

4. Derivatives PP.1 - 3 of formula I, wherein R4means forming biolabeling ester group, and R5represents hydrogen.

1means fenetylline group or naphthylethylene group, and R2denotes hydrogen.

7. Drug, providing an inhibitory effect on neutral endopeptidase-based active agents and conventional additives, characterized in that the active substance it contains a pharmacologically effective amount of a derivative according to paragraphs.1 - 6 of formula I and a conventional pharmaceutical excipients and/or carriers.

8. The method of obtaining derivatives of benzazepin, benzoxazepin-and benzothiazepin-N-acetic acids of the General formula I

< / BR>
where R1denotes the (lower)alkoxy(lower)alkyl group, a lower CNS residue which is substituted by lower CNS group, phenyl(lower)alkyl group or phenyloxy(lower)alkyl group, which if necessary can be substituted in the phenyl ring by lower alkyl, lower alkoxyl or halogen, or naphthyl(lower)alkyl group;

A - denotes CH2, O or S;

R2denotes hydrogen or halogen;

R3denotes hydrogen or halogen;

R4denotes hydrogen or forming biolabeling ester group;

< / BR>
where R1has the above value,

R4ameans for protective acidic function group

or their reactive derivatives enter into interaction with amines of General formula III

< / BR>
where R2, R3and a have the above meaning,

R5ameans for protective acidic function group

obtaining the amides of General formula IV

< / BR>
where R1, R2, R3, R4a, R5aand a have the above meaning,

in the compounds of formula IV, simultaneously or in any sequence to each other, otscheplaut protective for acid function group R4aand R5aif they are not desired, forming a complex biolabeling ester group, and optionally, depending on the circumstances, the released acid group etherification with alcohol of General formula V or a corresponding reactive derivative of General formula Va

R6- HE (Y); R6- X

where R6is a form biolabeling ester group;

X denotes tsepliaeva reactive group,

and the resulting acid of the formula I

 

Same patents:

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

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

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

CHY5ororwhere Y3, Y5have the specified values;

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

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

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

CHY5ororwhere Y3, Y5have the specified values;

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