Derivatives of the peptides or their pharmaceutically acceptable salt, a method of obtaining derivatives of the peptides and pharmaceutical composition

 

(57) Abstract:

Use in medicine for the treatment and prevention endotheliumderived diseases such as hypertension. The essence of the invention: derivatives of the peptides of General formula I: R1-A-CH2(R2)-CON(R7)-CH2)(R3)- CON(R6)-CO(R4R5where R1is hydrogen or acyl; R2- lower alkyl, aryl(lower)alkyl, (C3- C7) cycloalkyl (ness.) alkyl, heterocyclic (lower)alkyl, in which the heterocyclic group is unsaturated 5,6-membered heterophilically group containing 1-2 nitrogen atom, optionally substituted imino-protective group; R3- heterocyclic (lower) alkyl, heterocyclic group may be unsaturated condensed 9-membered group containing 1 nitrogen atom and optionally substituted with a suitable Deputy selected from (ness.)the alkyl and aminosidine groups, aryl (ness.) alkyl; R4- H, aryl (ness.) alkyl, (ness.) alkyl, amino (ness.) alkyl, substituted or unsecured, carboxy (lower) alkyl, protected or unprotected heterocyclic (ness.) alkyl, and heterocyclic group may be unsaturated 5-6-membered ring containing 1 or 2 carboxy, substituted carboxy, carboxy (lower) alkyl, unprotected or protected; R6- H, heterocyclic (ness.) alkyl, where the heterocyclic group is a saturated 6-membered heterocycle with one nitrogen atom; R7- H or (ness.) alkyl; A Is-O-, NH, (ness.) alkylamino, lower alkylene, or their pharmaceutically acceptable salts, method of producing compounds of the formula I consists in the condensation of 2 fragments of R1ACH2(R2)COOH and R7NHCH(R3)CON(R6) CH(R4R5and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a peptide derivative of formula I in an effective amount. 3 s and 5 C. p. F.-ly, 1 table.

The invention relates to new peptide compound and its pharmaceutically acceptable salts, namely to a new peptide compound and its pharmaceutically acceptable salts, which have pharmacological activity, for example endothelialisation and so forth, to methods for their preparation, to pharmaceutical compositions containing them and method of using them therapeutically in the treatment and prevention endotheliopathy diseases such as hypertension and so forth.

Cell salt, which have pharmacological activity, for example endothelialisation and so on.

The aim of the invention is to create ways to get the specified peptide compounds and salts thereof.

Another objective of the invention to provide a pharmaceutical composition containing as an active ingredient specified peptide compound or its pharmaceutically acceptable salt.

Another aim of the invention is to provide a method of use of these substances for the treatment and prevention endotheliopathy diseases such as hypertension and the like.

The desired compound of the invention can be represented by the following General formula I:

< / BR>
where R1hydrogen or acyl;

R2lower alkyl, optionally substituted ar(lower)alkyl, cyclo(lower)alkyl(lower)alkyl or by selecting substituted heterocyclic (lower) alkyl;

R3the choice of the substituted heterocyclic (lower)alkyl or by selecting substituted ar(lower)alkyl;

R4hydrogen or selection substituted lower alkyl;

R5carboxy, substituted carboxy, carboxy(lower)alkyl or substituted carboxy(lower)alkyl-O-, -NH-, lower alkylamino or lower alkylene, provided that when R2denotes the (S)-isobutyl, R3denotes N-(dichlorobenzenesulfonyl)indole-3-ylmethyl, R4denotes methyl, R5denotes methoxycarbonyl, R6denotes hydrogen, R7represents hydrogen and A represents-NH-, then the partial formula

< / BR>
has the absolute configuration

< / BR>
In particular, the compound represented by the following formula I', is more suitable as an antagonist of endothelin and so forth:

< / BR>
where R1, R2, R3, R4, R5, R6, R7and A have the above values.

In addition, compound I, having the strongest activity, can be represented by the following formula:

< / BR>
where R1, R4, R5, R7and A have the above significance, and Rc2denotes lower alkyl and Rc3denotes the N-substituted indolylmethane.

In accordance with the invention, a new peptide compound I and its salt can be obtained by methods that are listed in the following diagrams:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R1, R2, R3tion-protected amino group;

R1bacyl, substituted amino group;

R1cacyl;

R2aand R3aeach indicates a protected imino containing heterocyclic(lower)alkyl, optionally substituted by suitable substituent(s);

R4aprotected amino(lower)alkyl or protected imino containing heterocyclic(lower)alkyl, optionally substituted by suitable substituent(s);

R2band R3beach represents imino containing heterocyclic(lower)alkyl, optionally substituted by suitable substituent(s);

R4amino(lower)alkyl or imino containing heterocyclic(lower)alkyl, optionally substituted by suitable substituent(s);

R4cprotected carboxy(lower)alkyl;

R4acarboxy(lower)alkyl;

R5aprotected carboxy or protected carboxy(lower)alkyl;

R5bcarboxy or carboxy(lower)alkyl;

R5ccarboxy or esterified carboxy;

R5d/aminirovanie carboxy.

Some of the starting compounds used in the above methods, are new and can be the floor and accepted way:

< / BR>
< / BR>
where R1, R2, R3, R4, R5, R6, R7and a have the above meanings;

R8aminosidine group;

R9protected carboxy.

In this specification, amino acids, peptides, protective groups, condensing agents and so on are indicated by abbreviations according to IUPAC-IUB Commission on biological terminology), which are customarily used in this field of technology.

In addition, unless anything else, amino acids and their residues (when shown under such reductions) imply L-configuration compounds and residues, whereas the D-configuration compounds and residues shown in attachment D-.

Suitable pharmaceutically acceptable salts of the target compound I may be conventional non-toxic salts and include an acid additive salt such as a salt of an organic acid, such as acetate, triptorelin, maleate, tartrate, fumarate, methanesulfonate, bansilalpet, formate, toluensulfonate and so forth, salt of an inorganic acid such as hydrochloride, bromohydrin, iodohydrin, sulfate, nitrate, phosphate, and so forth, or a salt with a base, for example an amino acid such as arginine, asparagine and so forth, salt, alkaline earth metal, for example potassium salt, magnesium salt, and so forth, ammonium salt, salt with organic base, for example, salt of trimethylamine, salt, triethylamine salt of pyridine, picoline salt, salt dicyclohexylamine, salt N,N'-dibenziletilendiaminom and so on.

In the above and subsequent descriptions of suitable examples and illustrations of the various definitions that fall in the scope of the invention is explained in more detail as follows.

The term "lower" means 1-6, preferably 1-4 carbon atoms, and the term "higher" implies more than 6, preferably 7 to 12 carbon atoms, unless stated otherwise.

Suitable "acyl" may include aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s), originating from acids, such as carboxylic, carbonic, carbamino, sulphonic acid.

The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic acyl, for example, carbarnoyl, lower alkanoyl, for example formyl, acetyl, propionyl, butyryl, isobutyryl, 3,3-dimethylbutyryl, 4,4-dimethylvaleric, valeryl, from whom, propanesulfonyl and so on, the lowest alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl and so on, the lowest alkanoyl, such as acryloyl, methacryloyl, crotonoyl and so on, (C3-C7) cycloalkylcarbonyl, such as cyclohexanecarbonyl and so on, (C3-C7)cycloalkyl(lower)alkanoyl, such as cyclohexylethyl and so forth, amidino protected carboxyterminal, such as lower alkoxyalkyl, such as methoxyl, amoxil, tert-butoxyl and so on, C3-C7-cycloalkylcarbonyl, such as cyclohexyloxycarbonyl and so forth, (heterocyclic acyl) (lower)alkanoyl, and specified heterocyclic acyl is the same as mentioned below, for example morpholinoethyl(lower)alkanoyl, for example 3-morpholinobutyrophenone and so on, the lowest or highest allylcarbamate, such as methylcarbamoyl, ethylcarbitol, propellerblades, isopropylcarbamate, butylcarbamoyl, 2 - methylbutanoyl, intercalator, 1,3-dimethylbutylamino, exaltabitur, heptylcarbinol, octigabay, noninternal and so forth, di(lower)allylcarbamate, for example, N-methyl-N-ethylcarbamate, dimethylcarbamoyl, diethylcarbamoyl, ciproelavil and so forth, C3-C7-cycloalkylcarbonyl, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, cyclohexylcarbonyl and so forth, N-lower alkyl-N-(C3-C7)cycloalkylcarbonyl, for example N-methyl-N-cyclopropylamino, N-methyl-N-cyclohexylcarbonyl, N-ethyl-N-cyclohexylcarbonyl, N-propyl-N-exaltabitur and so forth, di(C3-C7)cyclohexylcarbonyl, such as dicyclopropyl, dicyclopentadienyl, dicyclohexylcarbodimide and so forth, N-[di(lower)allylcarbamate(C3-C7) cycloalkyl]carbarnoyl, for example N-(1-(or 4-)dimethylcyclohexyl)carbarnoyl, and so on), N- [di(lower)allylcarbamate (lower)alkyl(C3- C7)cycloalkyl] carbarnoyl, for example, N-[1-(or 4-) (dimethylcarbamoyl)-cyclohexyl] carbarnoyl, and so forth, N- [carbarnoyl(lower)-alkyl] carbarnoyl, for example N-(1-carbarnoyl-2 - methylbutyl)-carbarnoyl, and so forth, N-[N-(lower) allylcarbamate(lower)-alkyl] carbarnoyl, for example N-N-(1-isopropylcarbamate-2-methylbutyl)carbarnoyl, and so on), N-[N,N-lower alkalescency(lower)alkyl]carbarnoyl, for example N-[2-methyl-1-(piperidinylcarbonyl)butyl] carbarnoyl, and so forth, N -[N,N-di-(NCDs who carbamoyl)ethyl]carbarnoyl, N-[(dimethylcarbamoyl)-2-methylpropyl] carbarnoyl, N-[2,2-dimethyl-1- (dimethylcarbamoyl)propyl] carbarnoyl, N-[2-methyl-1-(dimethylcarbamoyl) butyl] carbarnoyl, N-[2-methyl-1-(diethylcarbamoyl)butyl] carbarnoyl, N-[3-methyl-1-(dimethylcarbamoyl)butyl] carbarnoyl, N-(1-dimethylcarbamoyl)carbarnoyl, and so forth, N-(lower)alkyl-N-[N,N-di(lower)allylcarbamate](lower) allylcarbamate, for example N-methyl-N-[1-dimethylcarbamoyl--2-methylbutyl] -carbarnoyl, N-methyl-N-[dimethylcarbamoyl-3-methylbutyl] -carbarnoyl, and so forth, N-[N-(lower)cycloalkylcarbonyl-(lower)alkyl] carbarnoyl, for example N-(1-cyclohexylcarbonyl)-2-methyl-butyl)carbarnoyl and so on and so forth.

The aromatic acyl may include (C6- C10)aroyl, for example benzoyl, toluoyl, xyloyl, naphtol and so on, (C6-C10)arenesulfonyl, for example benzazolyl, toil and so on, (C6-C10)arylcarbamoyl, such as phenylcarbamoyl, trikarbonil and so on, (C6-C10)aryloxyalkyl, for example phenylacetyl and so forth, and the like.

Heterocyclic acyl, in which the specified heterocyclic group may be such that is mentioned below, may include heterocyclicamines, such as furoyl, thenoyl 2- (or 3 - or 4-) piribedil, thiomorpholine, indolocarbazole and so on, the lowest or highest alkylaminocarbonyl, such as aziridine-1-ylcarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidine-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl, octahydrate-1-ylcarbonyl, tetrahydrocannabinol, tetrahydroisoquinolinium, digidropiridinovym, tetrahydropyrimidines and so forth, heterocyclic carbarnoyl, in which the specified heterocyclic group may be one which is mentioned below, such as pyridylcarbonyl, piperidinylcarbonyl, hexahydro-1H-isopinocampheol and so forth, and the like.

The aliphatic acyl substituted with aromatic group (or groups) may include (C6-C10ar(lower)alkanoyl, such as phenyl(lower)alkanoyl, such as phenylacetyl, phenylpropionyl, phenylhexanoic, naphthylacetyl and so on, (C6-C10)-ar(lower)alkoxycarbonyl, such as phenyl(lower)alkoxycarbonyl, such as benzyloxycarbonyl, ventilatsioonil and so on, phenoxy(lower)alkanoyl, such as phenoxyacetyl, phenoxypropionyl and so on, (C6-C10ar(lower) alkoxyaryl, such as phenyl(lower)alkoxyaryl, for example benzyloxy and so on, (C-C10ar (lower)alkylsulfonyl, for example benzylmethyl and so forth, and the like.

Aliphatic acyl, substituted heterocyclic group(s) may include heterocyclic (lower) alkanoyl in which the specified heterocyclic group may be one which is mentioned below, such as titilate, imidazolylalkyl, ferilizer, tetrazolate, thiazoleacetic, cialiserectile, tanypodinae, thiadiazolidine, pyridylacetic and so on), heterocyclic (lower)-allylcarbamate in which the specified heterocyclic group may be one which is mentioned below, such as pyridylmethylamine, morfolinoetilrutin, and so forth, and the like.

These acyl groups may be further substituted by one or more, preferably 1 to 3 suitable substituents, such as hydroxy, lower alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and so forth, halogen, for example chlorine, bromine, iodine, fluorine, carbarnoyl, oxo, di(lower)allylcarbamate, amino, protected amino, such as lower alkanolamine, for example, formamido, acetamido, propionamido and so forth, the lower alkoxycarbonyl, such as tertbutoxycarbonyl sulfonyl, toil and so forth, ar(lower) alkyl such as benzyl, and so forth, lower alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and so forth, carboxy, protected carboxy, mentioned below, carboxy(lower) alkyl, for example carboxymethyl, carboxyethyl and so forth, protected carboxy(lower)alkyl, for example tert-butoxycarbonylmethyl and so on).

Suitable examples of the above-mentioned acyl groups which are substituted by one or more, preferably 1 to 3 suitable substituents may be halophenol (lower)alkanoyl, for example 2-chlorophenylacetyl and so forth, (AMINOPHENYL) (lower)alkanoyl, for example 4-aminophenylacetic and so forth, [(lower alkoxycarbonyl)phenyl] (lower)alkanoyl, for example 4-(tert-butoxycarbonylamino) phenylacetyl and so forth, amino (lower) alkanoyl, for example 2-amino-3 - methylpentanol and so forth, (lower alkoxycarbonyl) (lower)alkanoyl, for example 2-(tert-butoxycarbonylamino)-3-methylpentanol and so on, the lowest alkanoyl, substituted by suitable substituent(s) such as phenyl, amino, lower alkoxycarbonyl and so forth, for example 2-amino-2-phenylacetyl, 2-(tert-butoxycarbonylamino)-2-phenylacetyl and so forth, di(lower)alkylpiperidines, for example, 4-(dimethylcarbamoyl)-piperidine-1-ylcarbonyl and so forth, [di(lower)allylcarbamate] pyrrolidinylcarbonyl, for example 2-(dimethylcarbamoyl)-pyrrolidin-1-ylcarbonyl and so on, piperazinylcarbonyl, substituted by suitable substituent(s) such as lower alkyl, oxo, and so forth, for example 4-methyl-3-oxo-2-(1-methylpropyl " piperazine-1-ylcarbonyl and so forth, N-(lower)-alkyl-N-[hydroxy(lower)alkyl]carbarnoyl, for example N-methyl-N-(2-hydroxyethyl)carbarnoyl, and so forth, N- [hydroxy(lower)alkyl]carbarnoyl, for example N-[1-(hydroxymethyl)-3 - methylbutyl]carbarnoyl, and so forth, N-[(C3-C7) cycloalkyl-(lower) alkyl]carbarnoyl, for example N-(cyclohexylmethyl)-carbarnoyl, and so forth, N-[carboxy(lower)alkyl]carbarnoyl, for example N-(1-carboxy-2-methylbutyl)carbarnoyl, and so forth, N-[(lower)alkoxycarbonyl(lower)alkyl] carbarnoyl, for example N-(1-methoxycarbonyl-2-methylbutyl) carbarnoyl, and so forth, (oxytetracycline) carbarnoyl, in which the specified heterocyclic group may be one which is mentioned below, for example, [oxo(hexahydro-1H-azepine)]carbarnoyl, such as E-caprolactam-3-yl and so on, N-[N-(lower)alkoxycarbonylmethyl] carbarnoyl, for example N-(N - ethoxycarbonylpyrimidine-4-yl)carbarnoyl, and so forth is N-[1-(N,N-dimethylcarbamoyl)-1-phenylmethyl] carbarnoyl, N-[1-(N, N - dimethylcarbamoyl)-1-cyclohexylmethyl]carbarnoyl, and so forth, N-[hydroxy(C3-C7)cycloalkyl]carbarnoyl, for example N-(4-hydroxycyclohexyl)carbarnoyl, and so forth, N-(lower)alkoxyalkanols, for example N-(4 - methoxyphenyl)-carbarnoyl, and so forth, N-(lower alkanolamine)carbarnoyl, for example N-(2-methylpropylamine)carbarnoyl, and so forth.

Preferred examples of the acyl may be carbarnoyl, lower alkanoyl, for example formyl, acetyl, propionyl, butyryl, isobutyryl, 3,3 - dimetional, 4,4-dimethylvaleric, valeryl, isovaleryl, pivaloyl, hexanoyl, 3-methylallyl and so on, the lowest alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t - butoxycarbonyl and so on, the lowest alkanoyl, such as acryloyl, methacryloyl, crotonoyl and so on, (C3-C7-cycloalkylcarbonyl, such as cyclohexanecarbonyl and so on, (C3-C7) cycloalkyl(lower)alkanoyl, such as cyclohexylethyl and so on, C3-C7-cycloalkylcarbonyl, such as cyclohexyloxycarbonyl and so on, morpholinoethyl(lower)alkanoyl, for example 3-morpholinobutyrophenone and so on, the lowest or highest allylcarbamate, such as methylcarbamoyl, 1,3-denationalisation, exaltabitur, heptylcarbinol, oxycarbonyl, noninternal and so forth, di(lower)allylcarbamate, for example N-methyl-N-ethylcarbamate, dimethylcarbamoyl, diethylcarbamoyl, dipropylamino, diisopropylamino, dibutylamino, Diisobutylene, digoxigenin and so on, C3-C7-cycloalkylcarbonyl, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, cyclohexylcarbonyl and so forth, N-lower alkyl-N-(C3- C7)cycloalkylcarbonyl, for example N-methyl-N-cyclopropylamino, N-methyl-N - cyclohexylcarbonyl, N-ethyl-N-cyclohexylcarbonyl, N-propyl-N-exaltabitur and so forth, di(C3- C7)cyclohexylcarbonyl, such as dicyclopropyl, dicyclopentadienyl, dicyclohexylcarbodimide and so forth, N-[di-(lower)allylcarbamate(C3-C7) cycloalkyl] carbarnoyl, for example N-(1- (or 4-)-dimethylcyclohexyl) carbamoyl and so forth, N-[di(lower)allylcarbamate(lower) alkyl(C3-C7-cycloalkyl] carbarnoyl, for example N-[1-(or 4-) (dimethylcarbamoyl)cyclohexyl] carbarnoyl, and so forth, N-[carbarnoyl(lower)alkyl] carbarnoyl, for example N-(1-carbarnoyl-2-methylb-2 - methylbutyl)carbarnoyl, and so forth, N-[N,N-lower alkalescency(lower)alkyl] carbarnoyl, for example N-[2-methyl-1- (piperidinylcarbonyl)butyl] carbarnoyl, and so forth, N-[N, N-di(lower allylcarbamate(lower)alkyl]carbarnoyl, for example N- (dimethylcarbamoyl)carbarnoyl, N-[1-(or 2-) (dimethylcarbamoyl)ethyl] carbarnoyl, N-[1-(dimethylcarbamoyl)-2-methylpropyl] carbarnoyl, N-[2,2-dimethyl-1- (dimethylcarbamoyl)propyl]carbarnoyl, N-[2-methyl-1- (dimethylcarbamoyl)butyl] carbarnoyl, N-[2-methyl-1-(diethylcarbamoyl)butyl] carbarnoyl, N-[3-methyl-1-(dimethylcarbamoyl)butyl] carbarnoyl, N-(1-dimethylcarbamoyl)carbarnoyl, and so forth, N-(lower)-alkyl-N-[N,N-di(lower)allylcarbamate] (lower)allylcarbamate, for example N-methyl-N-(1-dimethylcarbamoyl-2-methylbutyl)carbarnoyl, N-methyl-N-(1-dimethylcarbamoyl-3-methylbutyl-carbarnoyl, and so forth, N-[N-(lower) cycloalkylcarbonyl(lower)alkyl] carbarnoyl, for example N-(1-cyclohexylcarbonyl-2-methylbutyl)carbarnoyl, and so on, (C6-C10)aroyl, for example benzoyl, toluoyl, xyloyl, naphtol and so on, (C6-C10) arylcarbamoyl, such as phenylcarbamoyl, trikarbonil and so on, (C6-C10)aryloxyalkyl, for example phenylacetyl and so on, furoyl, thenoyl, 2-(or 3-, or 4-)-pyridylcarbonyl, thiazolidinones, thiadiazolidine, tetras aminocarbonyl, for example, aziridine-1-ylcarbonyl, azetidin-1-ylcarbonyl-pyrrolidin-1-ylcarbonyl, piperidine-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl, octahydrate-1-ylcarbonyl, tetrahydrocannabinol, tetrahydropyrimidines and so on, pyridylcarbinol, piperidinylcarbonyl, hexahydro-1H-isopinocampheol, (C6-C10ar(lower)alkanoyl, such as phenyl(lower)alkanoyl, such as phenylacetyl, phenylpropionyl, phenylhexanoic, naphthylacetyl and so on, (C6-C10ar(lower)alkoxycarbonyl, such as phenyl(lower)alkoxycarbonyl, such as benzyloxycarbonyl, ventilatsioonil and so on, (C6-C10ar(lower)alkoxyaryl, such as phenyl(lower)alkoxyaryl, for example benzyloxy and so on, (C6-C10ar(lower)alkanoyl, such as phenyl(lower)alkanoyl, such as cynnamoyl and so on, (C6-C10ar(lower)alkylsulfonyl, for example bansilalpet, and so on, titilate, imidazolylalkyl, ferilizer, tetrazolate, thiazoleacetic, thiadiazolyl, tanypodinae, thiadiazolidine, pyridylacetic, pyridylmethylene, morpholinoethyl, halophenol(lower)alkanoyl, for example 2 - chlorophenylacetyl and so forth, (AMINOPHENYL)(lower)Alka is 4- (tertbutoxycarbonyl)phenylacetyl and so forth, amino(lower)-alkanoyl, for example 2-amino-3-methylpentanol, and so forth, (lower alkoxycarbonyl)(lower)alkanoyl, for example 2-(tert-butoxycarbonylamino)-3-methylpentanol and so on, the lowest alkanoyl, substituted by suitable substituent(s) such as phenyl, amino, lower alkoxycarbonyl, for example 2-amino-2-phenylacetyl, 2-(tert-butoxycarbonylamino)-2-phenylacetyl and so forth, di(lower)alkylpiperidines, for example 2,6-(or 3,5-)dimethylpiperidin-1-ylcarbonyl and so forth, [di(lower)allylcarbamate] piperidinylcarbonyl, for example 4- (dimethylcarbamoyl)piperidine-1-ylcarbonyl and so forth, [di(lower)allylcarbamate] pyrrolidinylcarbonyl, for example 2- (dimethylcarbamoyl)pyrrolidin-1-ylcarbonyl and so on, piperazinylcarbonyl, substituted by suitable substituent (substituents), for example lower alkyl, oxo, and so forth, for example 4-methyl-3 - oxo-2-(1-methylpropyl)piperazine-1-ylcarbonyl, and so forth, N-(lower)alkyl-N-[hydroxy(lower)alkyl] carbarnoyl, for example N-methyl-N-(2-hydroxyethyl)-carbarnoyl, and so forth, N- [hydroxy(lower)alkyl] carbarnoyl, for example N-[1-(hydroxymethyl)-3 - methylbutyl]carbarnoyl, and so forth, N-[(C3-C7) cycloalkyl(lower)alkyl]carbarnoyl, for example N-(cyclohexylmethyl)carbarnoyl and so toxicarol(lower)alkyl] carbarnoyl, for example, N-(1-methoxycarbonyl-2-methylbutyl)carbarnoyl, and so forth, (oxytetracycline)carbarnoyl, such as [oxo(hexahydro-1H - azepine)]-carbarnoyl (for example, E-caprolactam-3-yl and so on, N-[N-(lower)alkoxycarbonylmethyl] carbarnoyl, for example N-(N-ethoxycarbonylpyrimidine-4-yl)carbarnoyl, and so forth, N-[N-N-di (lower)allylcarbamate(lower)alkyl] carbarnoyl, substituted by phenyl or cyclo (lower)alkyl, for example N-[1-(N,N - dimethylcarbamoyl)-1-phenylmethyl]carbarnoyl, N-[1-(N, N-dimethylcarbamoyl)-1-cyclohexylmethyl] carbarnoyl, and so forth, N-[hydroxy(C3-C7) cycloalkyl] carbarnoyl, for example N-(4-hydroxycyclohexyl)carbarnoyl, and so forth, N-(lower)alkoxyphenyl)carbarnoyl, for example N-/4 - methoxyphenyl)carbarnoyl, and so forth, N-(lower alkanolamine)carbarnoyl, for example N-(2-methylpropylamine)carbarnoyl and so on and so forth.

Suitable "lower alkyl" may include remotemachine or branched lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and so forth, where the most preferred example is isobutyl, 1-methylpropyl, n-butyl, and 2,2-dimethylpropyl for R2and methyl for R7.

Suitable "lower alkylene" can, pentamethylene, hexamethylene and so forth, where the most preferred example is methylene.

Suitable "protected carboxy" may include esterified carboxy and aminirovanie carboxy as mentioned above. "Esterified carboxy" may be those mentioned below.

Suitable examples of parts of ester esterified carboxy may be difficult to lower alkilany ether such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentalogy ether, hexyl ether, and so forth, which may have at least one suitable substituent(s), such as complex lower alkanoyloxy(lower) alkilany ether, such as complex acetoxymethyl ether complex propionylacetate ether complex butyrylacetate ether complex veterinarinary ether complex pivaloyloxymethyl ether complex hexaniacinate ether, complex 1- (or 2-or 3-, or 4-) acetoxyvalerenic ether complex of 1-(or 2-) propionylacetate ether complex of 1-(or 2-or 3-) propionoxypiperidine ether complex of 1-(or 2-) butyrylacetate ether complex of 1-(or 2-) isobutyrylacetate ether, slouchily ether, complex 2-ethylbutyraldehyde ether complex 3,3-dimethylbutylamino ether complex of 1-(or 2-) pentanedinitrile ether and so on, aroyl (lower) alkilany ester, such as benzoyl (lower) alkilany ether, for example finacialy ether, and so forth, complex lower alkanesulfonyl (lower) alkilany ether, for example 2-mutilative ether and so forth, complex mono (or di or three ) halo (lower) alkyl ester, for example 2-iodoethylene ether, 2,2,2-trichlorethylene ether and so on, complex lower alkoxycarbonyl (lower) alkilany ether, for example methoxycarbonylmethylene ether, ethoxycarbonylmethylene ether, propoxycarbazone ether, tert-butoxycarbonyloxyimino ether, 1-(or 2-) methoxycarbonylmethylene ether, 1-(or 2-) ethoxycarbonylmethylene ether, 1-(or 2-) isopropoxycarbonyloxymethyl ether and so forth, complex thalidomide (lower), alkilany ether or complex (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) (lower) alkilany ether, for example (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl - methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl) ethyl ester, and so forth, complex lower alkenilovyh ether, such as vinyl ether, allyl ether and so on; the Chille) alkilany ether, which may have at least one suitable substitute, such as benzyl ether, 4-methoxybenzyloxy ether, 4-nitrobenzyloxy ether, finitely ether, trailovic ether, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4 - dimethoxybenzyl ether, 4-hydroxy-3,5-di-t-butylbenzylamine ether and so forth, complex arrowy ester which may have at least one suitable substituent(s) such as phenyl ether, 4-hlorfenilovy ether, tallowy ether, tert-BUTYLPEROXY ether, Kilroy ether, comenjoy ether and so forth, complex palinology ether and so on.

Preferred specific examples thus esterified carboxy may be the lowest alkoxycarbonyl, phenyl(substituted) alkoxycarbonyl and benzoyl (lower) alkoxycarbonyl, and the most preferred may be methoxycarbonyl, etoxycarbonyl, benzyloxycarbonyl and ventilatsioonil.

Suitable "carboxy(lower)alkyl" means aforementioned lower alkyl, which is substituted by carboxy, where preferred examples include carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl for R5.

Suitable "protected carboxy(lower)alkyl" means you inim an example would be the low alkoxycarbonyl(lower)alkyl, phenyl(lower)alkoxycarbonyl(lower) alkyl and benzoyl(lower)alkoxycarbonyl, and more preferable examples are methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropionyl, ethoxycarbonylbutyl, ventilatsioonile, ventilatsioonile, ventilatsioonile and ventilatsioonohuniisutid for R5.

The "aminirovanie" carboxy" may refer to the referenced below.

Suitable examples liderando carboxy include carbarnoyl; mono (or di) (lower)allylcarbamate, where the lower alkyl group may be one which is mentioned below, such as methylcarbamoyl, ethylcarbitol, isopropylcarbamate, butylcarbamoyl, 3-methylbutanoyl, isobutylbarbituric, intercalator, dimethylcarbamoyl, diethylcarbamoyl and so on, and furthermore, the specified lower alkyl can be substituted by the group consisting of carboxy, protected carboxy, for example lower Alcoceber, such as methoxycarbonyl, ethoxycarbonyl and so forth, ar(lower)alkoxycarbonyl, preferably phenyl(lower)alkoxycarbonyl, such as benzyloxycarbonyl, and so on, aroyl(lower)alkoxycarbonyl, preferably a benzoyl (lower)alkoxycarbonyl, dust, mentioned below, for example saturated or unsaturated 5 - or 6-membered heterophilically group containing 1 to 4 nitrogen atom, for example pyridyl, pyrrolidinyl and so on, with the specified heterocyclic group may be substituted by suitable substituent(s) such as oxo, carboxy, protected carboxy and carbamoyl, such as oxopyrrolidin substituted carboxy, lower alkoxycarbonyl, for example 2-oxo-5-carboxy-pyrrolidinyl, 2-oxo-5-carbamoylbiphenyl and so on; C3-C7-cycloalkyl, optionally substituted by carboxy or protected carboxy, for example lower alkoxycarbonyl, such as carboxylicacid, ethoxycarbonylmethoxy and so forth; (C3-C7)cycloalkylcarbonyl, such as cyclohexylcarbonyl and so on; carbarnoyl, substituted amino or di(lower)alkylamino, for example N-aminocarbonyl, N- (dimethylamino)carbarnoyl, and so on; -N(optional substituted heterocyclic)carbarnoyl, where the heterocyclic part is the same as mentioned above, for example saturated or unsaturated 5 - or 6-membered heterophilically group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atom, unsaturated 5 - or 6 - membered heterophilically group, soderzhashy 1 to 2 sulfur atom and 1 to 3 nitrogen, each of these heterocyclic groups may be substituted by suitable substituent(s) such as hydroxy, protected hydroxy, halogen, lower alkoxy, lower alkyl, amino, nitro and cyano, such as diazolidinyl, benzothiazolylthio, morpholinomethyl N-(lower alkylthiomethyl)carbarnoyl, such as methylthiazolyldiphenyl and so on; the lowest alkylaminocarbonyl, such as pyrrolidin-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl and so forth, and the specified alkylen on the choice of substituted carboxy or substituted by carboxy, for example lower alkoxy carbonyl, for example, carboxymyoglobin-1-ylcarbonyl, (methoxycarbonyl)pyrrolidin-1-ylcarbonyl, (etoxycarbonyl)-1-ylcarbonyl, and so forth, or the specified alkylen choice broken by another heteroatom(s) such as nitrogen, oxygen or sulfur, such as morpholinomethyl and so on; the lowest alkylsulfonyl, such as methylsulfonylamino and so on; arenesulfonyl, such as benzoylphenyl and so on and so forth.

Preferred specific examples thus liderando carboxy can be: carbarnoyl; mono-(or di -) lower alkyl carbarnoyl, for example methylol, dimethylcarbamoyl, diethylcarbamoyl and so on; N-(lower)alkyl-N- [carboxy(lower)alkyl] carbamoyl, for example N-methyl-N-(carboxymethyl)carbarnoyl, and so forth; N- (lower)alkyl-N-[protected carboxy(lower) alkyl] carbarnoyl, such as N-(lower)alkyl-N-[lower alkoxycarbonyl(lower)alkyl] carbarnoyl, for example N - methyl-N-(methoxycarbonylmethyl) carbarnoyl, and so on; N-[carboxy (lower)alkyl] carbarnoyl, for example N-(carboxymethyl)carbarnoyl, N-(2 - carboxyethyl)carbarnoyl, N-(3-carboxypropyl)carbarnoyl, N-(4 - carboxybutyl)carbarnoyl, N-(5-carboxypentyl)carbarnoyl, N-(1-carboxyethyl)carbarnoyl, N-(1-carboxy-2-methylpropyl)carbarnoyl, N-(1-carboxy-3-methylbutyl)carbarnoyl, N-(1,2-dicarboxyethyl)carbarnoyl, and so forth; N-[protected carboxy (lower) -alkyl]carbarnoyl, such as N-[lower alkoxycarbonyl(lower)alkyl] carbarnoyl, for example N- (methoxycarbonylmethyl)carbarnoyl, N-(2-methoxycarbonylethyl)carbarnoyl, N-(3-methoxycarbonylpropionyl)carbarnoyl, N-(4-ethoxycarbonylbutyl) carbarnoyl, N-(5-methoxycarbonylmethyl)carbarnoyl, N-[1,2 - bis(methoxycarbonyl)ethyl] carbarnoyl, and so forth, N-[ar(lower)-alkoxycarbonyl(lower)alkyl] carbarnoyl, preferably N-[phenyl(lower) alkoxycarbonyl(lower)alkyl] carbamoyl, for example N- (benzyloxycarbonylamino)carbarnoyl, N -(5-benzyloxycarbonylamino)carbamoyl and so forth, N- [aroyl(lower)alkoxy] (lower)alkyl} carbarnoyl, preferably a benzoyl(lower)alkoxy(lower) allylcarbamate, for example N- (ventilatsioonile)carbarnoyl, N-(2-ventilatsioonile)carbarnoyl, N- (3-ventilatsioonile)carbarnoyl, N-(4-ventilatsioonohuniisutid) carbarnoyl, N-(5-peaceconditionality) carbarnoyl, N-(1-phenacyloxy)carbarnoyl, N-(1-phenacyloxy-2-methylpropyl)carbarnoyl, N-(1-phenacyloxy-3-methylbutyl)carbarnoyl, and so forth; N-[carboxy(lower)alkyl]carbarnoyl, substituted aryl, for example N-[carboxy(lower)alkyl]carbarnoyl, substituted phenyl or naphthyl, for example N-(1-carboxy-2-phenylethyl)-carbarnoyl, and so forth; N-protected carboxy(lower)allylcarbamate, substituted aryl, for example N-{ [lower alkoxycarbonyl](lower)alkyl}carbamoyl, substituted phenyl or naphthyl, for example N-(1-ethoxycarbonyl-2 - phenylethyl)carbarnoyl, and so forth; N-[carboxy(lower)alkyl] carbamoyl, substituted heterocyclic group, such as pyrrolidon, pyrrolidino, imidazolines, pyrazolines, pyridium and its N-oxide, pirimidinom, pyrazinium, pyridazinyl, triazolyl, 2H-1,2,3-triazolium and so on, tetrazolium and dihydrotriazines, such as the military heterocyclic group, such as N-[lower alkoxycarbonyl(lower)alkyl] carbarnoyl, replaced by Petroliam, pyrrolidino, imidazolium, pyrazolyl, pyridium and its N-oxide, pirimidinom, pyrazinium, pyridazinyl, triazolyl, tetrazolyl or dihydrotriazines, for example N-[1-etoxycarbonyl-2-(pyridin-2 - yl)ethyl]carbarnoyl, and so forth; N-aryl(lower)allylcarbamate, for example N-benzylcarbamoyl and so on; N-[carboxy(C3-C7) cycloalkyl](lower)alkyl} carbarnoyl, for example N-(4 - carboxylatomethyl)carbamoyl and so on; N-{[protected carboxy(C3-C7) cycloalkyl](lower)alkyl} carbamoyl, such as N-{[lower alkoxycarbonyl (C3-C7) cycloalkyl](lower)-alkyl}carbarnoyl, such as N-{[lower alkoxycarbonyl(C3- C7)cycloalkyl](lower)alkyl}carbarnoyl, for example N- (4-ethoxycarbonylphenyl)carbarnoyl, and so forth; N- [heterocyclic(lower)alkyl] carbarnoyl, and specified heterocyclic group is azetidinol, pyrrolidinium, imidazolidinyl, piperidinyl, pyrazolidine and piperazinil, for example N-[pyrrolidinyl(lower)alkyl] carbarnoyl, for example N-[2-(pyrrolidin-1-yl)ethyl] carbarnoyl, and so forth, and the specified heterocyclic group may be sammenligne, substituted by carboxy, lower alkoxycarbonyl or carbamoyl, for example 2-oxo-5-carboxypropyl, 2-oxo-5-ethoxycarbonylpyrimidine, 2-oxo-5-carbamoylbiphenyl and so forth; (C3- C7) cycloalkylcarbonyl, such as cyclohexylcarbonyl and so on; carbarnoyl, substituted amino or di (lower)alkylamino, for example N-aminocarbonyl, N-(dimethylamino)carbarnoyl, and so forth; N- (optional substituted heterocyclic)carbarnoyl, and heterocyclic part is thiazolyl, 1,2-thiazolyl, thiazolyl, thiadiazolyl, diazolidinyl, benzothiazolyl, benzotriazolyl, morpholinyl, such as diazolidinyl, benzothiazolylthio and morpholinylcarbonyl and so on, with each of these heterocyclic groups may be substituted by lower alkyl, for example N-(lower alkylthiomethyl)carbarnoyl, for example methylthiazolyl and so on; the lower alkylaminocarbonyl, such as pyrrolidin-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl and so on; the lower alkylaminocarbonyl, substituted by carboxy or protected carboxy, for example lower alkoxycarbonyl, for example 2-carboxypropyl-1-ylcarbonyl, 2-(methoxycarbonyl)pyrrolidin-1-ylcarbonyl, 2-(etoxycarbonyl)-pyrrolidin-1-ylcarbonyl morpholinoethyl and so on; lowest alkylsulfonyl, such as methylsulfonylamino and so forth; (C6-C10) arenesulfonyl, such as benzensulfonamidelor and so on and so forth.

Suitable "for choosing substituted heterocyclic(lower) alkyl" means the above lower alkyl, substituted saturated or unsaturated, magiclink or polycyclic heterocyclic group containing at least one heteroatom, such as oxygen, sulfur, and so forth.

Preferred heterocyclic part may be a heterocyclic group as unsaturated 3 to 8-membered, preferably 5 - or 6-membered, heterophilically group containing 1 to 4 nitrogen atom, for example pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, such as 1H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and so on, dihydrotriazine, for example 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.); unsaturated 3 to 8-membered, preferably 5 - or 6-membered heterophilically group containing 1 to 4 nitrogen atom, for example azetidine, pyrrolidine, imidazolidine, piperidine, pyrazolidine, peperonata, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl, tetrasulphides, tetrachloropyridine, for example tetrazolo(1,5-C)pyridazinyl, and so on, dihydrotriazine and so on; unsaturated 3 to 8-membered, preferably 5 - or 6-membered heterophilically group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atom, for example oxazolyl, isoxazolyl, oxadiazolyl, for example 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-occationaly and so on; unsaturated 3 to 8-membered, preferably 5 - or 6-membered, heterophilically group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atom, for example morpholyl and so on; unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atom, for example benzoxazolyl, benzoxadiazole and so on; unsaturated 3 to 8-membered, preferably 5 - or 6-membered heterophilically group containing 1 to 2 sulfur atom and 1 to 3 nitrogen atom, for example thiazolyl, 1,2-thiazolyl, thiazolyl, thiadiazolyl, for example 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, and so on; unsaturated 3 to 8-membered, preferably 5 - or 6-membered, heterophilically group containing 1 2 6-membered, heterophilically group containing a sulfur atom, such as thienyl and so on; unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 2 sulfur atom and 1 to 3 nitrogen atom, for example benzothiazolyl, benzothiadiazole, and the like; and the specified heterocyclic group may be substituted by one or more, preferably one or two substituent(s) such as hydroxy; protected hydroxy, in which the hydroxyl group is protected common hydroxyamino group, such as acyl, three(lower)alkylsilane, for example tert-butyldimethylsilyloxy and so forth, and the like; halogen, for example chlorine, bromine, iodine and fluorine; lower alkoxy which may be remotemachine or branched alkoxy, such as methoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and so forth, more preferably, C1-C4-alkoxy, such as methoxy and the like; lower alkyl mentioned above, more preferably C1-C4-alkyl, such as methyl and the like; amino; nitro; -cyano and so on.

And also, when specified heterocyclic group has at its ring imino-part (s), last(s) may be replaced by a suitable substitute is owned by the group, referred to below, more preferably lower alkanoyl oxycarbonyl, for example formyl, and so forth, arenesulfonyl, such as tosyl and so on and so forth.

The preferred example according to the choice of the substituted heterocyclic(lower) alkyl" may be lower alkyl, substituted unsaturated 5 - or 6-membered heterophilically group containing 1 to 4 nitrogen atom, such as pyridyl(lower) alkyl, imidazolyl(lower)alkyl, and so forth, lower alkyl, substituted unsaturated condensed 7 to 12-membered heterocyclic group containing 1 to 5 nitrogen atoms, such as indolyl(lower)alkyl and the like; lower alkyl, substituted unsaturated 5 - or 6-membered heterophilically group, containing 1 to 2 sulfur atom and 1 to 3 nitrogen atom, such as TESOL(lower)alkyl, and so forth, and the specified heterocyclic group may be substituted by suitable substituent(s) such as lower alkyl, for example methyl, ethyl, propyl, isobutyl and so on, the lowest alkanoyl, for example formyl, and so on, (C6-C10) arenesulfonyl, such as tosyl and so on and so forth.

More preferable example may be: pyridyl(lower)alkyl, such as 2-(or 3-, or 4-)pyridylmethyl and so forth; they shall ethyl and so on; thiazolyl(lower)alkyl, such as thiazol-3-ylmethyl and so on; N(lower)alkyl (e.g., 1-tosylamide-3-ylmethyl and so on); -N-(lower) alcoholiday(lower)alkyl, for example N-formylindole-3-ylmethyl and so on); -N-(lower)acylinder(lower)alkyl, for example N-methyl(or ethyl or propyl or isobutyl)indole-3-ylmethyl and so on, for R3and pyridyl(lower)alkyl, for example 2-pyridylmethyl and so on; imidazolyl(lower)alkyl, for example imidazol-1(or 3)ylmethyl and so forth, and-N-arenas-sulfanilamidnyi(lower)alkyl, for example 1-tosylamide-3-ylmethyl and so on, for R2and most preferably, -indolyl(lower)alkyl, N-(lower)alcoholiday(lower)alkyl and N- (lower)acylinder(lower)alkyl for R3and pyridyl(lower)alkyl and imidazolyl(lower)alkyl and imidazolyl(lower) alkyl for R2.

Suitable "ar(lower)alkyl" may include C6- C10-ar-(lower) alkyl such as phenyl(lower)alkyl (e.g. benzyl, phenethyl, and so forth), tolyl(lower)alkyl, xylyl(lower)alkyl, naphthyl (lower)alkyl, for example naphthylmethyl and so forth, and the like, where the specified ar(lower)alkyl may be substituted by suitable substituent(s), such that the/P> A preferred example for the choice of the substituted ar(lower) alkyl may be phenyl(lower)alkyl and naphthyl(lower)alkyl, most preferably benzyl and naphthylmethyl for R2and benzyl for R3.

Suitable "lower alkylamino" means aminogroup, the above-mentioned substituted lower alkyl and the most preferable example may be methylimino.

Suitable "cyclo(lower)alkyl(lower)alkyl" means aforementioned lower alkyl, substituted C3-C7is cyclo(lower) alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and so forth, and the most preferable example may be C4-C6is cyclo(lower)alkyl, most preferred is cyclohexylmethyl.

Suitable "for choosing substituted lower alkyl" may include the above-mentioned lower alkyl, for example methyl, ethyl, isopropyl, butyl, isobutyl, and so forth, which for choosing substituted by suitable substituent(s), such as by selecting a substituted heterocyclic group, referred to below, for example pyridyl, thiazolyl, imidazolyl, N-tosylimines and so on; C6-C10-aryl, mentioned below, for example phenyl, naphthyl and so ewenny carboxy, as mentioned above, such as benzyloxycarbonyl and so on and so forth.

The preferred example according to the choice of the substituted lower alkyl" may be lower alkyl, for example isopropyl, isobutyl, and so forth, pyridyl(lower)alkyl, such as 2-(or 3, or 4-)pyridylmethyl, 2-(2-pyridyl)ethyl, and so on, thiazolyl(lower)alkyl, for example 3-triazolylmethyl and so on, imidazolyl(lower)alkyl, such as 2-(or 3-)imidazolines and so on, the N-protected imidazolyl(lower)-alkyl, such as N- (arenesulfonyl)imidazolyl(lower)alkyl, for example N-tolyl-2-(or 3-) imidazolines and so on, C6-C10ar(lower) alkyl such as phenyl(lower)alkyl, for example benzyl, naphthylmethyl and so forth, amino(lower)alkyl, for example, 4-aminobutyl and so forth, protected amino(lower)alkyl, such as C6-C10ar(lower)alkoxycarbonyl, for example 4- (benzyloxycarbonylamino)butyl, and so forth, carboxy(lower)alkyl, for example carboxymethyl, 2-carboxyethyl and so forth, protected carboxy(lower)alkyl, such as C6-C10ar(lower)alkoxycarbonyl(lower)alkyl, for example benzyloxycarbonylamino, 2-benzyloxycarbonylation and so on and so forth.

The most preferable example of "you the 3-triazolylmethyl, 2-(or 3-) imidazolidinyl, N-tosyl-2-(or 3-)-imidazolidinyl, benzyl, naphthylmethyl, 4-aminobutyl, 4-(benzyloxycarbonylamino)butyl, carboxymethyl, 2-carboxyethyl, benzyloxycarbonylation and 2-benzyloxycarbonylamino for R4and 2-millimeter and 2-(2-pyridyl)ethyl for R6.

Suitable "choice of the substituted heterocyclic group" may include the same heterocyclic part that mentioned above, for example pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl and so forth, tetrazolyl, for example 1H-tetrazolyl, 2H-tetrazolyl and so on, dihydrotriazine, for example 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl and so forth, thiazolyl, 1,2-thiazolyl, thiazolyl, thiadiazolyl, for example 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, and so on, with the specified heterocyclic group selection locked by the same substituents, which are mentioned above, e.g. imino-protective group, for example by arenesulfonyl and so on.

Suitable "aryl" may include C6- C10-aryl, such as phenyl, tolyl, xylyl, cumenyl, naphthyl, and so forth, Prica group protected amino or protected imino may include acyl, mentioned above, in this preferred example can be lower alkanoyl, (C6- C10ar (lower)alkoxycarbonyl and (C6-C10) arenesulfonyl, and the most preferable example may be benzyloxycarbonyl.

Suitable "aminosteroid heterocyclic(lower)alkyl, optionally substituted by suitable substituent(s)" means a connection provided for "optional substituted heterocyclic(lower)alkyl" mentioned above, and heterocyclic ring contains aminogroup (-NH-), for example, indolyl(lower)alkyl, imidazolyl(lower)alkyl, and so forth.

Suitable "protected aminosteroid heterocyclic(lower)alkyl, optionally substituted by suitable substituent (Vice)" means the aforementioned "aminosteroid heterocyclic(lower)alkyl, optionally substituted by suitable substituent(s)", aminogroup protected traditional imidazolidine group mentioned below.

"Acyl, substituted protected amino group" stands for acyl residues, which are explained above, and he substituted protected amino as mentioned above.

"Acyl, substituted amino group" denotes acyl, stated that the Deputy is presented in the chemistry of peptides, those who presented for aminosidine groups in protected Amina.

The preferred options for each definition can be represented as follows:

R1denotes acyl, such as carbarnoyl, organic carbon, organic coal, organic sulfonovy or organic carbimidoyl acyl, for example lower alkanoyl, for example acetyl, propionyl, 3,3-dimethylbutyryl, pivaloyl, 4-methylpentanol and so on; amino(lower)alkanoyl, for example 2-amino-3-methylpentanol and so on; protected amino(lower)alkanoyl, for example, acylamino(lower)alkanoyl, such as lower alkoxycarbonyl(lower)alkanoyl, for example 2-tert-butoxycarbonylamino-3-methylpentanol and so forth, C3-C7-cycloalkenyl(lower)alkanoyl, for example, 2-(3-cyclohexylurea)-3-methylpentanol and so on; the lower alkoxycarbonyl, for example tert-butoxycarbonyl and so on; C3-C7-cycloalkyl(lower)alkanoyl, such as cyclohexylethyl and so on; C3-C7-cycloalkylcarbonyl, such as cyclohexylcarbonyl and so on; C3-C7- cycloalkylcarbonyl, such as cyclohexyloxycarbonyl and so on; aroyl, such as C6-C10for example Ben is eniluracil, 1 - or 2-naphthylacetyl, 3-phenylpropionyl and so on; aminosilanes ar(lower)alkanoyl, for example aminosilanes, for example aminosilanes (C6-C10ar(lower) alkanoyl, such as aminosilanes phenyl(lower)alkanoyl, for example 2-amino-2-phenylacetyl and so on; protected aminosilanes ar(lower)alkanoyl, for example acylaminoalkyl (C6- C10ar(lower)alkanoyl, such as lower alkoxycarbonylmethyl phenyl(lower)alkanoyl, for example 2-(4-tert-butoxy-carbonylmethyl)acetyl, 2-tertbutoxycarbonyl-2-phenylacetyl and so on; galour(lower)alkanoyl, for example, halo (C6- C10ar(lower)alkanoyl, such as halophenol(lower)alkanoyl, for example 2-course)acetyl and the like; ar(lower)alkanoyl, for example, C6-C10ar(lower)alkanoyl, such as phenyl(lower)alkanoyl, such as cynnamoyl and so on; acilglycerol, such as C6-C10-acilglycerol, such as phenylglyoxylic and so forth; ar(lower)alkylglycerol, such as C6-C10ar(lower)alkylglycerol, such as benzylpenicilloyl and so on; pyridylcarbonyl, for example 2-, or 3-, or 4-pyridylcarbonyl and so on; tetrahydropyrimidine, for example 1,2,3,6-tetrahedral next; tetrahydroisoquinolines, for example 1,2,3,4-tetrahydroquinolin-2-ylcarbonyl and so on; morpholinylcarbonyl, such as morpholinomethyl and so on; thiomorpholine, such as thiomorpholine and so on; indolocarbazole, for example 2-indolocarbazole and so on; piperazinylcarbonyl, substituted by 1-3 substituents selected from oxo and lower alkyl, such as 4-methyl-2-(1-methylpropyl)-3-oxopiperidin-1-ylcarbonyl and so on; pyridyl(lower)alkanoyl, for example 2-, or 3-, or 4-pyridylacetic and so on; morpholinylcarbonyl(lower)alkanoyl, for example, 3- (morpholinomethyl) propionyl and so forth; ar(lower)alkylsulfonyl, for example, C6-C10ar(lower) alkylsulfonyl, such as phenyl(lower)alkylsulfonyl, for example benzylmethyl and so on; N - or N, N-di(lower or higher)allylcarbamate, such as N - or N,N-di(C1-C10)allylcarbamate, such as isopropylcarbamate, 2-methylbutanoyl, heptylcarbinol, dimethylcarbamoyl, diethylcarbamoyl, dipropylamino, diisopropylamino; dibutylbarbituric, Diisobutylene and so on; hydroxy(lower)allylcarbamate, for example, 1-hydroxymethyl-3-methylbutanoyl and so on; carboxy(lower)allylcarbamate, for example 1-carbon carboxy(lower)allylcarbamate, such as low alkoxycarbonyl(lower)allylcarbamate, for example 1-methoxycarbonyl-2 - methylbutanoyl and so forth, carbarnoyl(lower)allylcarbamate, for example 1-carbarnoyl-2-methylbutanol and so on; [N - or N,N - di(lower)allylcarbamate] (lower)allylcarbamate, for example 1-isopropylcarbamate-2-methylbutanoyl, dimethylcarbamodithioato, 1-(dimethylcarbamoyl) ethylcarbitol, 2- (dimethylcarbamoyl)ethylcarbitol, 1-(dimethylcarbamoyl)-2-methylpropanol, 1- (dimethylcarbamoyl)-2,2-dimethylpropylene, 1-(dimethylcarbamoyl)-3-methylbutanol, 1- (diethylcarbamoyl)-2-methylbutanol, 1-(dimethylcarbamoyl)intercalator and so on; N-lower alkyl-N-[hydroxy(lower)alkyl] carbarnoyl, for example N-(2-hydroxyethyl)-N-methylcarbamoyl and so on; N-lower alkyl-N-[di(lower)allylcarbamate(lower)alkyl] carbarnoyl, for example N-[1-dimethylcarbamoyl-2-methylbutyl)-N-methylcarbamoyl, N-(1-dimethylcarbamoyl-3-methylbutyl] -N-methylcarbamoyl and so on; the lowest or highest alkylaminocarbonyl, such as C3-C10-alkylaminocarbonyl, such as pyrrolidin-1-ylcarbonyl, piperidine-1-ylcarbonyl, 3,5 - or 2,6-dimethylpiperidin-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl, octahydrate-1-ylcarbonyl and carbonyl, 4-(dimethylcarbamoyl)piperidine-1 - ylcarbonyl and so on; N-lower alkyl-N-(C3-C7)cycloalkylcarbonyl, such as N-cyclohexyl-N-methylcarbamoyl and so on; mono - or di(C3-C7)cycloalkylcarbonyl, such as cyclohexylcarbonyl, dicyclohexylcarbodimide and so on; hydroxy - or di(lower)allylcarbamate - or di(lower)allylcarbamate (lower)alkyl-substituted (C3-C7) cycloalkylcarbonyl, for example 4 - hydroxycyclohexanone, 1 - or 4-(dimethylcarbamoyl)cyclohexylcarbonyl, 1 - or 4-(dimethylcarbamoyl) cyclohexylcarbonyl and so on; C3-C7- cycloalkyl(lower)allylcarbamate, such as cyclohexyloxycarbonyl and so forth; di(lower)allylcarbamate-substituted C3-C7-cycloalkyl (lower)allylcarbamate, for example, [1-cyclohexyl-1- (dimethylcarbamoyl) methyl]carbarnoyl, and so forth; di(lower)allylcarbamate-substituted ar(lower)allylcarbamate, such as di(lower)allylcarbamate-substituted phenyl(lower)allylcarbamate, for example, [1-phenyl-1-(dimethylcarbamoyl)methyl] carbarnoyl, and so forth; arylcarbamoyl, preferably C6-C10-arylcarbamoyl, in which the aryl group may be substituted by 1-3 substituents selected from halogen, NISS toxigenicity and so on; pyridylcarbinol and so on; N-protected piperidinylcarbonyl, for example N-arylpiperazines, such as N-lower alkoxycarbonylmethyl, for example 1 - ethoxycarbonylpyrimidine-4-ylcarbonyl and so on; morpholinyl(lower)allylcarbamate, for example 2-(morpholino)ethylcarbamate and so on; the lower alkanolamines, for example 3-isobutyrylacetate and so on; the lowest alkylaminocarbonyl, for example piperidine-1-ylcarbonyl and so on; N-(C3-C7) cycloalkylcarbonyl(lower) allylcarbamate, for example 1 - cyclohexylcarbonyl-2-methylbutanol and so on; the lower alkylaminocarbonyl (lower)allylcarbamate, for example 1-(piperidine-1-ylcarbonyl)-2-methylbutanol, and so on; pyridyl(lower)allylcarbamate, for example 2-pyridylmethylamine and so forth, or oxo-substituted hexahydrobenzylcarbonate, for example 2-oxo-hexahydro-1H-azepin-3-ylcarbonyl and so on; in particular N,N - di(lower)allylcarbamate; mono - or di(C3- C7)cycloalkylcarbonyl; N-(lower)alkyl-N-(C3- C7)cycloalkylcarbonyl; N-(lower)alkyl-N-[di(lower)allylcarbamate (lower)alkyl] carbarnoyl; C6-C10-arylcarbamoyl; the lowest or highest alkylaminocarbonyl, such as C3-Clower alkyl, for example butyl, isobutyl, 1-methylpropyl, 2,2-dimethylpropyl and so on; in particular isobutyl;

R3represents indolyl(lower)alkyl, for example 3-indoleacetic and so on; N-(lower)acylinder (lower)alkyl, for example 1-methyl-3-indoleacetic, 1-ethyl-3-indoleacetic, 1-propyl-3-indoleacetic, 1-isobutyl-3-indoleacetic and so on; N-arylindole(lower)alkyl, such as N- (lower)alcoholiday(lower)alkyl, for example 1-formyl-3-indoleacetic and so forth, or ar(lower)alkyl, such as C6-C10ar(lower)alkyl, for example benzyl, 1 - or 2-naphthylmethyl and so forth, in particular N-(lower)acylinder(lower)alkyl such as 1-methyl-3-indoleacetic;

R4denotes hydrogen, lower alkyl, for example isopropyl, isobutyl and the like; amino(lower)alkyl, such as 4-aminobutyl and so on; protected amino (lower)alkyl, for example, acylamino(lower)alkyl such as mono - or di - or triphenyl(lower)alkoxycarbonyl (lower)alkyl, such as 4-benzyloxycarbonylamino and so on; carboxy (lower)alkyl, for example carboxymethyl, 2-carboxyethyl and so on; protected carboxy (lower)alkyl, for example, esterified carboxy(lower)alkyl, such as mono - or di - or triphenyl(lower)alkyl, UB> ar(lower)alkyl, for example benzyl, 1 - or 2-naphthyl, and so forth; pyridyl(lower)alkyl, for example 2 - or 3 - or 4-pyridylmethyl and so on; imidazolyl (lower)alkyl, for example 1H-4 - imidazolidinyl and so on; or thiazolyl(lower)-alkyl, such as 4-triazolylmethyl and so on; in particular, C6-C10ar(lower)alkyl such as benzyl; or pyridyl(lower)alkyl, such as 2-pyridylmethyl;

R5represents carboxy; esterified carboxy, such as lower alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl and so forth, ar(lower)alkoxycarbonyl, such as mono - or di - or triphenyl(lower)alkoxycarbonyl, such as benzyloxycarbonyl and so on, propyl(lower)alkoxycarbonyl, such as benzoyl(lower)alkoxycarbonyl, such as pencil and so on; aminirovanie carboxy, such as carbarnoyl, N - or N, N-di(lower)allylcarbamate, such as methylcarbamoyl, ethylcarbitol, propellerblades, isopropylcarbamate, butylcarbamoyl, N,N-dimethylcarbamoyl, N, N-diethylcarbamoyl and so on, the lowest allylcarbamate substituted by one or two substituents selected from carboxy and protected carboxy, preferably esterified carboxy, more preferably lower alkoxycarbonyl metilcarbamat, 1 - or 2-carboxyethylgermanium, 4-carboximetilkrahmal, 5-carboximetilkrahmal, 1-carboxy-2-methylpropanol, 1-carboxy-3 - methylbutanoyl, 1,2-dicarboxyethyl, benzyloxycarbonylamino, 2-benzyloxycarbonylamino, 1 - or 2-ventilatsioonisusteemi, 4-ventilatsioonisusteemi, 5-ventilatsiooniprobleemid, 1-methoxycarbonyl-2-methylpropanol, 1-methoxycarbonyl-3 - methylbutanoyl, 1,2-bis-(methoxycarbonyl)ethylcarbamate and so forth, N-(lower) alkyl-N-[carboxy - or protected carboxy (preferably esterified carboxy, more preferably lower alkoxycarbonyl) (lower)alkyl]carbarnoyl, for example N - methyl-N-(carboxymethyl)carbarnoyl, N-methyl-N-(methoxycarbonylmethyl)carbarnoyl, and so forth, ar(lower)allylcarbamate, for example, C6-C10ar(lower)allylcarbamate, such as phenyl(lower)allylcarbamate, such as benzylcarbamoyl, and so forth, carboxy - or protected carboxy, preferably esterified carboxy, substituted ar(lower)allylcarbamate, such as carboxy or lower alkoxycarbonyl - substituted phenyl(lower) allylcarbamate, such as 1-carboxy-2-phenylethanol, 1-etoxycarbonyl-dalee, N-[carboxy - or protected carboxy - substituted C3-C7cycloalkyl(lower)alkyl/carbarnoyl, for example, carboxy (C3-C7) cycloalkyl(lower)alkyl]carbarnoyl, for example 4 - carboxyethylpyrrole and so forth, esterified carboxy - substituted C3-C7cycloalkyl(lower)allylcarbamate, such as lower alkoxycarbonyl (C3-C7)cycloalkyl(lower)allylcarbamate, for example, 4-(etoxycarbonyl) cyclohexyloxycarbonyl and so on, arylcarbamoyl, such as lower alkylsulfonyl, such as methylsulfonylamino and so on, arylcarbamoyl, for example, C6-C10arylcarbamoyl, such as vinylsulfonylacetamido and so forth, carboxy - or protected carboxy (preferably esterified carboxy)-substituted pyridyl (lower)allylcarbamate, such as carboxy or lower alkoxycarbonyl-substituted pyridyl (lower)allylcarbamate, for example 1-carboxy-2-(2-pyridyl) ethylcarbitol, 1-etoxycarbonyl-2-(pyridyl)ethylcarbamate and so on, the lowest alkylaminocarbonyl, such as pyrrolidin-1-ylcarbonyl, piperidine-1-ylcarbonyl and so on, the lowest alkylaminocarbonyl, substituted by carboxy or substituted carbon-carboxypropyl-1-ylcarbonyl, 2-ethoxycarbonylpyrimidine-1-ylcarbonyl and so forth, [lower alkylamino(lower)alkyl] carbarnoyl, substituted by one or two substituents selected from carboxy, protected carboxy, preferably esterified carboxy, more preferably lower alkoxycarbonyl, and carbamoyl, for example 2-(2-carboxy-5-oxopyrrolidin-1-yl)ethylcarbamate, 2-(2-etoxycarbonyl-5-oxopyrrolidin-1-yl)ethylcarbamate, 2-(2-carbarnoyl-5-oxopyrrolidin-1-yl)ethylcarbitol and so on, morpholinoethyl, morpholinomethyl and so on, pyridylcarbonyl, for example 2 - pyridylcarbinol and so on, thiazolecarboxamide, for example 2-thiazolecarboxamide and so on, the lowest alkyldimethylammonium, such as 5-(lower)alkyl-1,3,4 - thiadiazolidine, for example 5-methyl-1,3,4-thiadiazolidine and so on, benzothiazolylthio, for example 2-benzothiazolylthio and so on, morpholinyl(lower)allylcarbamate, for example 2-morpholinoethyl and so forth, pyridyl(lower)alkylaryl, for example 2-pyridylmethylamine and so on, carbazoyl, for example, 3,3 - dimethylcarbamoyl and so forth, carboxy(lower) alkyl, for example carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl and so forth, or protected carboxy(NCDs is, for example methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3 - methoxycarbonylpropionyl, 4-ethoxycarbonylbutyl and so on, aroyl(lower)alkoxycarbonyl (lower)alkyl, for example ventilatsioonile, 2-ventilatsioonide, 3 - ventilatsioonile, 4-ventilatsioonohuniisutid and so on; in particular carboxy; lower alkoxycarbonyl or carbonyl; N - or N,N-di(lower) allylcarbamate;

R6denotes hydrogen or pyridyl(lower)alkyl, for example 2-pyridylmethyl, 2(2-pyridyl)ethyl, and so on; especially hydrogen;

R7denotes hydrogen or lower alkyl, for example methyl or so forth, in particular hydrogen;

And indicates the lowest alkylene, for example methylene, and so on; -O-; -NH-; or lower alkylamino, such as methylamino and so forth, in particular methylene or-NH-.

Method 1.

The desired compound I or its salt can be obtained by reacting the compound (II) or its reactive derivative at carboxypropyl, or its salt, with a compound III or rationalplanm at the amino group or its salt.

Suitable reactive derivative at the amino group of compound III may include Schiff's base type imino or its tautomeric someid, the ketone or the like; a derivative Silla formed by reacting compound III with compound silila, such as bis(trimethylsilyl)ndimethylacetamide, mono(trimethylsilyl)acetamide", she bis(trimethylsilyl)urea or the like; a derivative formed by reacting compound III with phosphorus trichloride or phosphoenol, and the like.

Suitable salt of the compound III and its reactive derivative can be referred to as acid additive salts, as for the compounds I.

Suitable reactive derivative at carboxypropyl connection I can include galvanized, acid anhydride, activated amide, an activated ester, and so forth. Suitable examples of the reactive derivatives may be an acid chloride, acid azide, mixed acid anhydride with an acid such as substituted phosphoric acid, for example dialkylphosphinate acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, galizana phosphoric acid and so on, dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, acid, such as methanesulfonate and so on, aliphatic carbonbaseunit acid, pentane acid, isopentane acid, 2-ethylmalonate acid, trichloroacetic acid, and so forth, or aromatic carboxylic acid, such as benzoic acid and the like; symmetric acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester, such as complex cinematology ether complex methoxymethyl ether, dimethylaminomethylene [(CH3)2+N CH-] ester, complex vinyl ether complex propargilovyh ether complex p-nitrophenyloctyl ether complex of 2,4-dinitrophenolate ether complex trichloranisole ether complex pentachlorphenol ether complex methylphenylene ether complex phenylazophenyl ether, phenyl complex tiefer, complex p-nitroaniline tiefer, complex p-crazily tiefer, complex carboxymethylate tiefer, complex pyranyloxy ether complex pyridiniumyl ether complex piperidinyl ether complex 8-hinolinovy ether and so forth, or an ester with N-hydroxidealuminum, for example N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and so forth, and the like. These reactive, praise salts of compound (II) and its reactive derivative can be the salt of the base, such as a salt of an alkali metal such as sodium salt, potassium salt, and so forth, salt, alkaline earth metal, e.g. calcium salt, magnesium salt, and so forth, ammonium salt, salt with organic base, such as salt, trimethylamine salt of triethylamine salt of pyridine, picoline salt, salt dicyclohexylamine, salt N,N'-dibenziletilendiaminom and so forth, and the like.

The reaction is usually carried out in a conventional solvent such as water, an alcohol, such as methanol, ethanol and so forth, acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These traditional solvents can be used in a mixture with water.

In this reaction, when compound II is used in the form of a free acid or in the form of its salt, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinobutyrophenone, N-cyclohexyl-N'-(4-diethylaminoethoxy) carbodiimide, N,N'-diethylcarbamoyl, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3 - dimetil-H-cyclohexylamin, ethoxyacetylene, 1-alkoxy-1-chloroethylene, trialkylphosphites, etiloleat, isopropylpalmitate, phosphorus oxychloride (chlorine phosphoryl), phosphorus trichloride, diphenylphosphoryl, thionyl chloride, oxalicacid, lower alkylsulfonate, such as ethylchloride, isopropylcarbamate and so forth, triphenylphosphine, 2-ethyl-7-gidroksibenzotriazola salt, 2-ethyl-5-(m-sulfophenyl)isoxazoline hydrochina intramolecular salt, N - hydroxybenzotriazole, 1-(p-chlorobenzenesulfonate)-6-chloro-1H - benzotriazol; the so-called reagent Vilsmeier obtained by reacting N, N-dimethyformamide with thionyl chloride, phosgene, trichloromethyl-chloroformate, phosphorus oxychloride, and so forth, and the like.

The reaction can also be carried out in the presence of inorganic or organic bases such as bicarbonate of an alkali metal, three(lower)alkylamine, pyridine, N-(lower)alkalifying, N,N - di(lower)alkylbenzene or the like.

The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

Method 2.

The desired compound Ib or its salt can be obtained by reacting compound Ia elinam derived from carboxypropyl, or its salt.

Suitable salts of the compounds Ia and its reactive derivative can be those described in respect of compound III. Suitable salts of the compounds IV and its reactive derivative can be those described in respect of compound (II). Suitable salts of the compounds Ib can be those described in connection I.

If the acyl symbol "R1" has origin from karbinovykh acid source compound IV is usually used in the form of isocyanates.

This reaction can be performed basically as in method 1, and therefore the reaction mode and reaction conditions, such as reactive derivatives, solvents, reaction temperature and so forth, this reaction can be borrowed from the description of the method 1.

Method 3:

The desired compound I or its salt can be obtained by reacting compound V or its reactive derivative at carboxypropyl, or salts thereof, with the compound VI or its reactive derivative at the amino group or its salt.

Suitable salts of the compounds V and its reactive derivative can be taken from the description link the project for compounds I and III, respectively.

This reaction can be performed basically as described for method 1, and therefore the reaction mode and reaction conditions, such as reactive derivatives, solvents, reaction temperature and so forth, this reaction can be borrowed from the description of the method 1.

Method 4.

The target connection Id or its salt can be obtained by subjecting compound Ic or its salt reaction off carboxyamide group in R5a.

Suitable salts of the compounds Ic and Id can be borrowed from the description of the compounds I.

This reaction is carried out in accordance with the traditional method, such as solvolysis, including hydrolysis, repair or the like.

The solvolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base may include an inorganic base and organic base, such as alkali metal, e.g. sodium, potassium, and so forth, alkaline earth metal, such as magnesium, calcium and so forth, hydroxide, or carbonate, or bicarbonate, as well as hydrazine, trialkylamine, such as trimethylamine, triethylamine and so on, picoline, 1,5-diazabicylo the acid may include an organic acid, for example formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid and so forth; inorganic base, for example hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, bromovalerate, hydrogen fluoride, and so forth.

Reaction off using a Lewis acid such as triglossia acid, such as trichloroacetic acid, triperoxonane acid and so forth, is preferably carried out in the presence of cation-capture agents, such as anisole, phenol and so on.

The reaction is usually carried out in a solvent such as water, alcohol such as methanol, ethanol and so forth, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamid, their mixture, or any other solvent which does not adversely impact on the conduct of the reaction. As a solvent it is also possible to use a liquid base or acid. The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating.

The repair method is applicable for the cleavage reaction may include chemical voices.com recovery are a combination of metal, e.g. tin, zinc, iron and so forth, or a metallic compound, such as chromium chloride, chromium acetate, and so forth, and organic or inorganic acids, for example formic acid, acetic acid, propionic acid, triperoxonane acid, p-toluenesulfonic acid, hydrochloric acid, Hydrobromic acid, and so forth.

Suitable catalysts used in catalytic reduction are conventional catalysts such as platinum catalysts, such as spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, and so forth, palladium catalysts, e.g. spongy palladium, palladium black, palladium oxide, palladium carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, and so forth, Nickel catalysts, for example, the recovered Nickel, Nickel oxide, skeletal Nickel catalyst for hydrogenation, and so forth, cobalt catalysts, for example, the recovered cobalt, skeletal cobalt hydrogenation catalyst and so on, metal catalysts, such as reduced iron, skeletal iron ka is Aligator hydrogenation and so forth, and things like that.

Recovery is usually carried out in a conventional solvent which does not adversely impact on the conduct of the reaction, such as water, methanol, ethanol, propanol, N,N-dimethylformamide or a mixture thereof. In addition, in the case of the above acid in liquid form in a chemical recovery, it can be used as solvent. In addition, the suitable solvent used in the catalytic reduction may be the above-mentioned solvent, and other traditional solvents, such as simple diethyl ether, dioxane, tetrahydrofuran, and so forth, and mixtures thereof. The reaction temperature of this recovery is not critical and the reaction is usually carried out under conditions of from cooling to heating.

Method 5.

The desired connection If or its salt can be obtained by subjecting compound Ie or its salt reaction off imino - or aminosidine group (s) in R7a.

Suitable salts of the compounds Ie and If can be borrowed from the description of the compounds I.

This reaction removal can be done in the traditional way known in the chemistry of peptides, such as solvol>Method 6.

The desired compound Ih or its salt can be obtained by subjecting compound Ig or its salt reaction off aminosidine group in R1a.

Suitable salts of the compounds Ig and Ih can be found in the description of the compounds I.

This reaction removal can be done in traditional chemistry of peptides way, the details of which can be found in the description of the method 4.

Method 7.

The desired compound Ij or its salt can be obtained by reacting the compound (Ii) or its reactive derivative at carboxypropyl, or its salt, optionally substituted amine or its salt.

Suitable salts of the compound (Ii) and its reactive derivative can be found in the description of compound (II).

Suitable salts of the compounds Ij can be found in the description of the compounds I.

Suitable choice of substituted amines mean amines, which can form the above-mentioned aminirovanie carboxy R5areceived in connection Ij.

This reaction can be performed basically as described in method 1, and therefore the reaction mode and reaction conditions, such as the reactive derivative, the solution is LASS="ptx2">

Compound Ig or its salt can be obtained by acylation of the amino group in R1b/compound Ih or its salts.

Suitable salts of the compounds Ig and Ih can be the same as that described for compound I.

Suitable allermuir agent used in this reaction may be traditional allerease agent, which is able to introductionat acyl group mentioned above, such as carboxylic acid, carbonic acid, acid and their reactive derivatives, such as galoyanized carboxylic acid, acid anhydride, activated amide, an activated ester, and so forth. A preferred example of such a reactive derivative may be an acid chloride, bromohydrin, mixed acid anhydride with an acid such as substituted phosphoric acid, for example dialkylphosphinate acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, galizana phosphoric acid and so on, dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, ester of carbonic acid, such as methylcarbonate, ethylcarbonate, propylmalonate and so on, aliphatic carboxylic to the trichloroacetic acid and so forth, aromatic carboxylic acid, for example benzoic acid, and so forth, a symmetric acid anhydride, an activated acid amide with a heterocyclic compound containing aminopentyl, such as imidazole, 4-substituted imidazole, dimethylpyrazole, triazole and tetrazole, activated ester, such as complex p-nitrophenyloctyl ether complex of 2,4-dinitrophenolate ether complex trichloranisole ether complex pentachlorphenol ether complex methylphenylene ether complex phenylazophenyl ether, phenyl complex tiefer, complex p-nitrophenyloctyl tiefer, complex p-crazily tiefer, complex carboxymethylate tiefer, or an ester of N-hydroxidealuminum, such as N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole and so forth, and the like.

This reaction can be performed in the presence of organic or inorganic bases, such as alkali metal, e.g. lithium, sodium, potassium, and so forth, alkaline earth metal, e.g. calcium, and so forth, alkali metal hydride, for example sodium hydride, and so forth, hydride alkaline earth metal, for example a hydride is part metal, for example, calcium hydroxide, and so forth, a carbonate of an alkali metal, for example sodium carbonate, potassium carbonate and so on, bicarbonate of an alkali metal, e.g. sodium bicarbonate, potassium bicarbonate, and so forth, alkali metal alkoxide, such as sodium methylate, sodium ethylate, trebuchet potassium and so on, albanova acid alkali metal, for example sodium acetate, and so forth, trialkylamine, for example, triethylamine and so on, the connection pyridine such as pyridine, lutidine, picoline, 4-dimethylaminopyridine and so on) quinoline and the like.

In that case, if allerease agent is used in free form or in the form of its salt, the reaction is preferably carried out in the presence of a condensing agent such as a carbodiimide compound, for example N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N-(4-diethylaminoethoxy)carbodiimide, N, N'-diethylcarbamoyl, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide and so on, the connection ketenimine (for example, N,N'-carbonylbis(2-Mei), pentamethylene-N-cyclohexylamine, diphenylmethan-N-cyclohexylamine and so forth, the compounds of the olefin or acetylene simple ester, for example ethoxyacetylene, beta Harvin is sulfonyloxy)-6-chloro-1H-benzotriazole and so forth, the combination of trialkylphosphine or triphenylphosphine and carbon tetrachloride, disulfide or diisodecylphthalate, such as diethyldithiocarbamate and so on, the connection of phosphorus, such as etiloleat, isopropylpalmitate, phosphorylchloride, phosphorus trichloride, and so forth, thionyl chloride, oxalicacid, N-ethylbenzothiazoline salt, N-ethyl-5-phenylisoxazole-3-sulfonate, a reagent (referred to as "reagent Vilsmeier"), formed by the interaction of the amide compounds such as N,N-di(lower) alkylborane, for example, dimethylformamide and so on, N-methylformamide and so on with the connection of halogen, such as thionyl chloride, phosphorylchloride, phosgene or the like.

The reaction is usually carried out in a conventional solvent which does not adversely impact on the conduct of the reaction, for example water, acetone, dichloromethane, alcohol, for example methanol, ethanol and so forth, tetrahydrofuran, pyridine, N,N-dimethylformamide, and so forth, and mixtures thereof.

The reaction temperature is not critical influence and the reaction is usually carried out under conditions of from cooling to heating.

Method 9.

The desired compound Ia or its salt can be obtained by subjecting spline can be performed in the traditional way in the chemistry of peptides, such as solvolysis, recovery and the like, and the details of this method can be found in the description of the method 4.

Method 10.

The desired compound Il or its salt can be obtained by subjecting compound Ik or its salt reaction off carboxyamide group in R4c< / BR>
Suitable salts of the compounds Ik and Il can be found in the description of the compounds I.

This reaction removal can be done in traditional chemistry of peptides way, such as solvolysis, restore, and so on, and the details of this method can be found in the description of the method 4.

Method 11.

The desired connection In or its salt can be obtained by subjecting compound Im or its salt reaction off aminosidine group in R3a< / BR>
Suitable salts of the compounds and Im In can be found in the description of the compounds I.

This reaction removal can be done in the traditional way in the chemistry of peptides, such as solvolysis, recovery and the like, and the details of this method can be found in the description of the method 4.

Method 12.

Search Ip connection or its salt can be obtained by subjecting compound Io or its salt reaction removal of amino - or connection I.

This reaction removal can be done in the traditional way in the chemistry of peptides, such as solvolysis, recovery and the like, and the details of this method can be found in the description of the method 4.

The compound obtained above ways, you can select and clear the traditional method, such as spraying, recrystallization, column chromatography, pereosazhdeniya or the like. The desired compound I can be converted into its salt by a common way. A method of obtaining a new source of compounds is explained in more detail below.

Method 1 (stage 1).

Compound IIIa or its salt can be obtained by reacting compound VII or its reactive derivative at carboxypropyl, or salts thereof, with the compound VI or its reactive derivative at the amino group or its salt. Suitable salts of the compounds VII and its reactive derivative can be found in the description of compound II. Suitable salts of the compounds VIII and its reactive derivative can be found in the description of compound III. This reaction can be performed basically as described for method 1, and therefore the reaction mode and reaction conditions, nab the Aichi in method 1.

Stage 2.

Compound II or its salt can be obtained by subjecting the compound IIIa or its salt reaction off aminosidine group, R8in the traditional way, which is described with regard to method 4.

Method 2.

Stage 1.

Compound IX or its salt can be obtained by reacting the compound (II) or its reactive derivative at carboxypropyl, or its salt, an amino group, or its salt.

Suitable salts of the compounds IX can be found in the description of the compounds I. This reaction can be performed basically as described for method 1, and therefore the reaction mode and reaction conditions, such as reactive derivatives, solvents, reaction temperature and so forth, this reaction can be found in method 1.

Stage 2.

Compound V or its salt can be obtained by subjecting compound IX or its salt reaction off carboxyamide group, R9in the traditional way, such as that given in respect of mode 4.

It should be noted that the connection I and other compounds can include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and which have pharmacological activity, such as endothelialisation activity, such as a relaxation activity of the blood vessel and so on, and are suitable for therapeutic treatment and prevention endotheliopathy diseases such as hypertension, heart disease, such as angina pectoris, cardiomyopathy, myocardial infarction or the like, cerebral attack, as cerebral arterial spasm, cerebral ischemia, cerebrovascular convulsion or the like, postnataly cerebral spasm after subarachnoid hemorrhage, asthma, such as bronchostenosis or the like, kidney failure, such as acute renal failure, renal failure, caused by taking drugs, such as cisplatin, cyclosporine and so on, the failure of the peripheral circulation, such as Raynaud's disease, i.e., symmetrical gangrene, Buerger's disease, and so forth, arteriosclerosis, diabetic nephropathy, diabetic retinopathy, shock, such as hemorrhagic shock, shock caused by endotoxin and so on, hemangioendothelioma, orginate after re-perfusion, such as after organ transplantation and tissue, percutaneous transluminal to the STV circulation after surgery, ulcers, irritable bowel syndrome (mucous colitis), dysuria, retinopathy, dysmenorrhea, premature labor, threatening abortion, glaucoma, complications after surgery, PTCA, and so forth.

For therapeutic purposes peptide compound I and its pharmaceutically acceptable salt according to the invention can be used in the form of pharmaceutical preparation containing one of these compounds as an active ingredient in a mixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, pills, granules, solution, suspension, emulsion, sublingual tablet, suppository, ointment, spray, tincture, ophthalmic solutions, Vasilina candle, and the like. If desired, these drugs can be included excipients, stabilizers, wetting and emulsifying agents, buffer solutions and other commonly used additives.

The dose of compound I varies depending on the age and condition of the patient, however, in the case of intravenous administration, a daily dose of 0.01 to 100 mg Yunogo ingredient per 1 kg of body weight of the patient (person), in the case of oral administration a daily dose of 0.1 to 100 mg of active ingredient per 1 kg of body weight of a person prescribed for the treatment endotheliopathy diseases.

To illustrate the usefulness of the desired compound I shows the data of pharmacological tests of some typical compounds of the General connection I.

Test I.

Method of labeled atoms with radioactive ligand.

1. Test connection:

a. Compound a (compound of example 7-2).

b. Compound B (compound of example 296).

c. Connection C (compound of example 325).

d. Compound D (compound of example 319).

e. Compound E (compound of example 379).

2. Test method.

a. Obtaining crude membrane receptor.

Pork aorta obtained from PEL-Freeze Biologicals (USA) and maintained at a temperature of -80oC before use. Porcine aorta (50 g) was thawed and released from adipose tissue, cut with scissors and then homogenized by Poltrona (Brinkmann PT-20, the maximum speed of 3 10) in 100 ml buffer (0.25 M sucrose, 10 mm Tris-HCl, 0.1 mm etc). The homogenate was centrifuged at 10,000 g for 20 min at a temperature of 4 is the temperature value 4oC, after which the precipitation is considered as the crude membrane fraction. The precipitate after centrifugation resuspended in 25 ml of buffer solution (50 mm Tris-HCl, 100 mm NaCl, 5 mm MgCl2of 1.5 μg/ml of phenylmethylsulfonyl (PMSF), 120 μg/ml bacitracin, 12 μg/ml leupeptin, 6 μg/ml chinastone, 0,1 bovine serum albumin (BSA), pH 7.5). The membrane fraction aortic maintained at a temperature of -80oC until use.

b. Method for determining 125I-endothelin-1-binding ability.

1252-Endothelin-1 (1,67 10-11M) (Amersham, Japan; specific activity of 2000 cubic inches/mmol) and incubated with 50 μl of the membrane of the aorta obtained in buffer solution at room temperature (20 of the 22oC) for 60 min in a final volume of 250 μl. After incubation the incubation mixture is filtered through glass fiber filter GF/C (pre-treated with 0.1-polyethylenimine for 3 h before use), using the harvester cells (Brandel M-24S). Then the filters are washed ten times with a total volume of 3 ml of wash buffer (50 mm Tris-HCl, pH 7.5) at 0oC. the Filters read in the count of gamma rays (Packard Auto Gamma Model 5660).

3. The results and the rabbit or the contractile response to endothelin.

1. Test connection: connection A.

2 test Method.

Thoracic aorta isolated from freshly slaughtered male rabbits, albino (age 11 weeks) and cut into 25 mm strips with dinadiawan inner shell. After removal of adipose tissue, these arterial segments with a width of 2 mm and a length of 25 mm is suspended in 25 ml of cells to organs filled with a solution of Krebs-ringer (113 mm NaCl, 4.8 mm KCl, 2.2 mm CaCl2, 1.2 mm MgCl2, 25 mm NaHCO3, 1.2 mm KH2PO4, 5.5 mm glucose), maintaining the temperature of the 37oC, and fill 95 O2/5 CO2. Pre-loading of 0.5 g carried out after conditioning the aorta by injecting increasing concentrations of KCl. Reduction measure in the form of increase in the value of the isometric pressure.

The test connection is facing in relation to the contractile response of the aorta of rabbits induced by endothelin (3,210-9M). Synthetic endothelin derived from the Peptide Institute Inc. (Osaka, Japan). The test compound is added after the reaction to the contraction induced by endothelin.

3. The results of the test.

The activity of the test compounds expressed the table. 2.

Test 3.

Effect on endothelin-1-Pressor response.

1. Test connection: connection A.

2. Test method.

The wistar rats weighing 200-250 g anaesthetize simple ether and abdominal aorta kanyoro plastic tube through the femoral artery and vein for measurement of blood pressure and intravenous injection of endothelin-1. Animals localize to recover for 3 h and tied in each cell. Blood pressure is directly recorded by a pressure sensor (RT-200T, manufactured by Nihon KOHDEN) and record on the recorder (CWT685G, manufactured by Nihon KOHDEN). Get Pressor response to intravenous injection of endothelin-1 (3,2 mg/kg). This dose produces prolonged Pressor response, which lasts more than 1 h

Effect of intravenous infusion of test compounds investigated in rats after 20 min after the start of intravenous endothelin-1.

3. The results of the test.

The potency of the test compounds on rats expressed by the following indicator:

++: fully antagonistically (almost 100);

+: moderately antagonistically (50);

-: no effect.

The toxicity study with repeated oral administration in two weeks.

1. Test method.

Five rats of sprag-Dole in each group received oral investigational compound (mg/kg) once daily for 14 days.

2. The analyzed compound: sodium salt of the compound of example 16.

3. The results of the test.

Within two weeks of pronounced changes were observed.

The results of the test is found to illustrate the invention in detail. In the examples the following abbreviations are used, which are introduced in addition to the abbreviations adopted by the IUPAC-IUB:

Ac Acetyl

Boc Tert-butoxycarbonyl

BU Butyl

Bzl Benzyl

DMF Dimethylformamide

DMSO Dimethylsulfoxide

Et Ethyl

HOBT (N-hydroxybenzotriazole

Me Methyl

NMM N-methylmorpholine

Pac Pencil

D-Pya D-(2-pyridyl)alanine

D-4Pya D-(4-pyridyl)alanine

TFA Triperoxonane acid

TEA Triethylamine

TS or ToS Toil

WSCD 1-ethyl-3(3-dimethylaminopropyl)carbodiimide

Z Benzyloxycarbonyl

DMAP Dimethylaminopyridine

Recipe 1-1. To a mixture of Boc-D-Trp(CH3)-OH (1,59 g) HClH-D-Phe-OCH3(1.08 g) and HOBT (0,81 g) in DMF (20 ml) was added under cooling in an ice bath WSCD (0,93 g). After stirring for 2 h at room temperature the mixture was evaporated in vacuum and the residue was dissolved in ethyl acetate (50 ml). The solution is then washed with 0.5 and hydrochloric acid (20 ml), water (20 ml), saturated sodium bicarbonate solution (20 ml) and water (twice 20 ml), dried over magnesium sulfate and evaporated in vacuum. The residue is triturated with ether, to deliver Boc-D-Trp (CH3)-Phe-OCH3(1.45 g). So pl. 95-96oC; Rf0,83 (CHCl3: MeOH 9:1).

Division 1-2. A solution of Boc-D-Trp is centered in vacuum and dissolved in 4 B.C. HCl in 1,4-dioxane (10 ml). The resulting solution was concentrated in vacuum. The residue is triturated with ether, resulting in the HClH-D-Trp-(CH3)-D-Phe-OCH3(1,09 g). So pl. 188-192oC; Rfor =0.51 (CHCl3:MeOH 9:1).

Division 1-3. To the mixture TSOHH-L-Leu-OBzI (14.5 g) and TEA (12 ml) in dichloromethane (300 ml), cooled in an ice bath, was added dropwise fenetylline (4,7 ml). After stirred for 10 min at the same temperature and the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (300 ml). The solution was washed 1 N. HCl (100 ml), water (100 ml), 1 M aqueous solution of sodium bicarbonate (100 ml) and brine (twice 100 ml), dried over magnesium sulfate and evaporated, resulting in the N-phenacetin-L-Leu-OBzl (14 g). The product received without additional purification was used in the next stage. Rf0,50 (CHCl3:MeOH 9:1)

Recipe 1-4. A solution of N-phenacetin-L-Leu-OBzI (14 g) in methanol (140 ml) was subjected to hydrogenation for 2 hours at 10-Mr. palladium on coal (1.4 g) under hydrogen pressure of 3 ATA. After removal of catalyst by filtration, the filtrate was concentrated in vacuum. The residue is triturated with diisopropyl ether, resulting in the N-phenacetin-L-Leu-OH (7.7 g). So pl. 135-136oC; Rf0,17 (CHCl3:MeOH 9,1).

CHCl3:MeOH 9:1).

Recipe 2-2. HClH-D-Trp(CH3)-D-Phe-OBzT was obtained quantitatively in the same manner as in the case of recipe 1-2. So pl. 147-150oC; Rf0,57 (CHCl3:MeOH 9:1).

Recipe 3-1. Boc-L-Leu-OH (1.30 grams), HClH-D-Trp(CH3)-OBzI (1,76 g), WSCD (950 mg) and HOBT (827 mg) in DMF (30 ml) was subjected to interact with the 5oC during the night in the same way as described in recipe 1-1, receiving the Boc-L-Leu-D-Rp (CH3)-OBzI (2,48 g). So pl. 124-126oC; Rf0,87 (CHCl3:MeOH 9:1).

Recipe 3-2. Boc-L-Leu-Trp (CH3-OBzI in MeOH (50 ml) and water (1 ml) was subjected to hydrogenation at 10-Mr. palladium on charcoal, in the same manner as described in recipe 1-4, receiving the Boc-L-Leu-D-Trp (CH3)-OH (1,95 g). So pl. 64-67oC; Rf0,57 (CHCl3:MeOH:AcOH 16:1:1).

Recipe 4-1. N-phenacetin-L-Leu-D-Trp(CH3)-OBrI (5,96 g) was obtained from N-phenacetin-L-Leu-OH (2,96 g), HClH-D-Trp(CH3)-OBzI,(3,9 g), HOBT (1.68 g) and WSCD (1,93 g) in the same manner as described in recipe 1-1. So pl. 152-155oC; Rf0,72 (CHCl3:MeOH 9:1).

Recipe 4-2. To a solution of N-phenacetin-L-Leu-D-Trp(CH3)-OBzI (5.9 g) in a mixture of methanol (60 ml), acetic acid (60 ml) and DMF (100 ml) was added 10 cent palladium on charcoal (0.6 g). The mixture was stirred for 5 h under hydrogen pressure of 3 ATA and room template, receiving the N-phenacetin-L-Leu-D-trp(CH3)-OH (4,69 g). So pl. 76-79oC; Rf0,50 (CHCl3:MeOH:AcOH 16:1:1).

Division 5. Boc-D-Trp(CH3)-ON (6.0 g), D-Pya-OC2H52HCl (5,54 g), WSCD (3.51 g), HOBT (3,05 g) and tea (2,09 g) was subjected to interaction in DMF (200 silt) in the same manner as in the case of recipe 1-1, receiving the Boc-D-Trp(CH3)-D-Pya-OC2H5(6,18 g). So pl. 99-101oC; Rf0,67 (CHCl3: MeOH 9:1).

Division 6. The reaction between Boc-D-Trp (CH3)-D-Pya-OC2H5(4,50 g), TFA (50 ml) and anisole (5 ml) was performed in the same manner as described in recipe 1-2. The result has been 2HClH-D-Trp (CH3)-D-Pya-OC2H5(4.15 g). So pl. 81-83oC, Rf0,22 (CHCl3:MeOH:AcOH 8:1:1).

Recipe 7. To a solution of (S)-- benzyloxycarbonyl-j-methylbutylamine (1.50 g) in ethyl acetate (60 ml) was added at room temperature, hexahydro-1H-azepin (722 mg). After stirring for 30 min at the same temperature, the solution was washed successively with 5 HCI, 1 M sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo, resulting in the benzyl ester of N-(hexahydro-IH-azepin-I-ylcarbonyl)-L-leucine (of 2.06 g) in the form of crystallites is methyl-N,N-dimethylmethyleneammonium (0.20 g), (S)-alpha-benzyloxycarbonyl-j-metalbulletin.com (0.25 g) and TEA (0.1 ml) in ethyl acetate (10 ml) was performed in the same manner as described in recipe 7, receiving the N-[(1S)-2,2-dimethyl-1-(N, N-dimethylcarbamoyl)propyl]carbarnoyl] -L-L-OBzI(0.40 g). Rfof 0.59 (hexane:EtOAc 2:1).

Recipe 9. The reaction between (S)-a-benzyloxycarbonyl-g-metalbulletin.com (500 mg) and octahydrate (275 mg) was performed in the same manner as described in recipe 7, receiving the N-(octahydrate-1-ylcarbonyl)-L-Leu-OBZI(680 mg). So pl. 87-89oC; Rf0,65 (n-hexane:EtOAc 1:1).

Recipe 10. The reaction between (2S)-2-amino-3,3-dimethyl-N,N-dimethylmethyleneammonium (0.25 g), benzyl ester (2S)-2-chlorocarbonyl-4-methylvaleramide acid (0.36 g) and tea (0.31 g) in ethyl acetate (10 ml) was performed in the same manner as described in example 4-1, receiving the benzyl ester of (2S)-2-[N-[(S)-2,2-dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoylated] -4 - methylvaleramide acid (0,44 g). Rf0,41 (hexane:EtOAc 2: 1).

Recipe 11. The reaction between (2R)-2-carboxymethyl-4-methylvalerate (1.35 g) hexahydro-1H-azepine (0,610 g) and WSCDHCI (1.18 g) in methylene chloride (30 ml) was performed in the same manner as described in recipe 1-1, receiving as a result of (2R)-2-(hexahydro-1H-azepin is to restore the appropriate gasoline ethers, conducted in the same manner as described in recipe 4-2, received the following connections:

1) N-[(1S)-2,2-dimethyl-1-(N, N - dimethylcarbamoyl-)propyl]carbarnoyl]-L-Leu-OH; Etc., 90-93oC; Rf0,50 (CHCI3: MeON:AcOH 16:1:1);

2) (2S)-2-[N-[(1S)-2,2-dimethyl-1-(N, N - dimethylcarbamoyl) propyl]carbanilate]-4-methylvaleramide acid; So pl. 146-148oC; Rf0,20 (CHCI3:MeOH 9:1);

3) N-(hexahydro-1H-azepin-1 - ylcarbonyl)-L-Leu-OH; Rf0,40 (benzene:EtOAc:AcOH 20:20:1);

4) N-(octahedral-1-ylcarbonyl)-L-Leu-OH; Rf0,45(benzene: EtOAc: AcOH 20:20:1).

Recipe 13. The interaction of the corresponding parent compounds with 2HClH - D-Pya-OC2H5in the presence of NMM conducted in the same manner as described in recipe 1-1, were obtained the following compounds:

Boc-D-Trp(ISO-C4H9)-D-Pya-OC2H5; So pl. 60-62oC; Rf0,62 (CHCl3:MeOH 9: 1);

2) Boc-D-Trp(CHO)-D-Pya-OC2H5; So pl. 131-134oC; Rf0,60 (CHCl3:MeOH 9: 1);

3) Boc-D-Trp(C2H5)-D-Pya-OC2H5; So pl. 64-67oC; Rf0,60 (CHCl3:MeOH 9: 1);

4) Boc-D-Trp(n-C3H7)-D-Pya-OC2H5; So pl. 62-63oC; Rf0,60 (CHCl3:MeOH 9: 1).

Recipe 14. By removing tertbutoxycarbonyl groups from the respective is 1-2, were obtained the following compounds:

1) 2HClH-D-Trp(ISO-C4-H9)-D-Pya-OC2H5; Rf0,09 (CHCl3:MeOH 9:1);

2) 2HClH-D-Trp(CHO)-D-Pya-OC2H5; Rf0,15 (CHCl3: MeOH 9:1);

3) HCIH-D-Trp(C2H5)-D-Pya-OC2H5; Rf0,15 (CHCl3:MeOH 9:1);

4) HClH-D-Trp(n-C3H7)-D-Pya-OC2H5; Rf0,13 (CHCl3:MeON 9:1).

Division 15. By reacting (S)-a-benzyloxycarbonyl-g - methylbutylamine with the corresponding amines conducted in the same manner as described in recipe 7, were obtained the following compounds:

N-(thiomorpholine)-L-Leu-OBzI; So pl. 89-91oC; Rf0,53 (n-hexane: AcOEt 1:1);

2) N-(1,2,3,4-tetrahydroisoquinoline-2-ylcarbonyl)-L-Leu-S; Rf0,71 (n-hexane:AcOEt 1:1);

3) N-(1,2,3,4-tetrahydroquinolin-I-ylcarbonyl)-L-Leu-BOzI; Rf0,62 (n-hexane:AcOEt 2:1);

4) N-(N,N-dibutylamino)-L-Leu-BOzI; Rf0,70 (n-hexane:AcOEt 2:1);

5) N-(N,N-dipropylamino)-L-Leu-zI; Rf0.69 (n-hexane:AcOEt 2:1);

6) N-(N-heptylcarbinol)-L-Leu-BOzI; Rf0,63 (n-hexane-AcOEt 2:1);

7) N-(N,N-diisobutylamine)-L-Leu-OBzI; Rf0,76 (n-hexane:AcOEt 2:1);

8) N-(N-cyclohexyl-N-methylcarbamoyl)-L-Leu-BOzI; Rf0,82 (n-hexane:AcOEt 1:1);

9) N - [4-(N, N-dimethylcarbamoyl) piperidinylcarbonyl]-L-Leu-BO)-2-(N,N-dimethylcarbamoyl) pyrrolidin-1-ylcarbonyl]-L-Leu-OBzI; Rf0,47(CHCl3:MeON 9:1);

12) N-[(2R)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1 - ylcarbonyl]-L-Leu-BOzI; Rf0,51 (CHCl3:MeOH 9:1);

13) N-[1-(N, N-dimethylcarbamoyl) cyclohexylcarbonyl]-L - Leu-OBzI; So pl. 145-148oC; Rf0,61 (CHCl3:MeOH 9:1);

14) N-[(1S,2S)-2-(N,N-diethylcarbamoyl)-2-methylbutanoyl]-L-Leu-OBzI; Rf0,31 (n-hexane:AcOEt 2:1);

15) N-(1,2,3,6-tetrahydropyridine-1-ylcarbonyl)-L-Leu-OBzI; Rf0,49 (n-hexane AcOEt 2:1);

16) N-(2,6-dimethylpiperidino)-L-Leu-OBzI; So pl. 81-83oC; Rf0,53 (n-hexane:AcOEt 2:1);

17) N-(3,5-dimethylpiperidino)-L-Leu-OBzI; Rf0,60 (n-hexane:AcOEt 2:1);

18) N-(N,N-dicyclohexylcarbodimide)-L-Leu-OBzI; So pl. 100-103oC; Rf0,80 (n-hexane:AcOEt 2:1);

19) N-(N,N-diethylcarbamoyl)-L-Leu-OBzI; Rf0,45 (H-hexane:AcOEt 2:1);

20) N-(N,N-diisopropylamino)-L-Leu-OBzI; Rf0,65 (n-hexane:AcOEt 2: 1);

21) N-[N-methyl-N-[(1S)-3-methyl-1-(N,N-dimethylcarbamoyl)-butyl]carbarnoyl] -L-Leu-OBzI; So pl. 183-187oC; Rf0,38 (CHCl3:MeOH:AcOH 16:1:1);

22)N-[(1S)-1-(N, N-dimethylcarbamoyl)intercalator] -L-Leu OBzI; So pl. 133-136oC; Rf0,59 (n-hexane:AcOEt 2:1);

23) N-[N-methyl-N-[1S,2S)-1-(N,N-dimethoxybenzoyl)-2-methylbutyl]carbarnoyl]-L-Leu-OBzI; Rf0,60 (n-hexane-AcOEt 2:1);

24) N-[(1S)-1-N,N-dimethylcarbamoyl) ethylcarbamate)]-L-Leu OBzI; Rf0,55 (n-hexa is e (11 ml) was added at room temperature cyclohexylamine (0.40 g). After stirring for 10 min the solvent drove under reduced pressure and the residue was dissolved in ethyl acetate (30 ml). The solution is successively washed with 1 N. HCl, water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuum. The solid residue triturated with hexane, to deliver benzyl-(2S)-2-cyclohexylcarbonyl-4-methylvalerate (0.45 g). So pl. 89-90oC; Rf0,70 (n-hexane: AcOEt 2:1).

Recipe 17. By reacting benzyl-(2S)-2-chlorocarbonyl-4-methylvalerate with the corresponding amines conducted in the same manner as described in recipe 16, were obtained the following compounds:

1) benzyl(2S)-4-methyl-2-[(2S)-2 - methylbutanoate] valerate; So pl. 48-49oC; Rf0.69 (n-hexane:AcOEt 2:1);

2) benzyl-(2S)-4-methyl-2-[(1S,2S)-2 - methyl-1-(N,N-dimethylcarbamoyl) butylcarbamoyl]valerate; Rf0,91 (CHCl3:MeOH 9:1);

3) benzyl-(2)-4-methyl-2-[(1R,2S)-2 - methyl-1-(N,N-dimethylcarbamoyl) butylcarbamoyl]valerate; Rf3,36 (n-hexane:AcOEt 2:1);

4) benzyl-(2S)-4-methyl-2-[(1S)-2-methyl-1-(N, N-dimethylcarbamoyl) propylboronic]valerate; Rf0,66 (n-hexane:AcOEt 2:1);

5) benzyl-(2S)-4-methyl-2-[(1S)-3-methyl-1-(N, N-dimethylcarbamoyl) butylcarbamoyl]valerate; Rf0,67 (UB> 0,36 (n-hexane:AcOEt 2:1);

7) benzyl-(2S)-4-methyl-2-[1S,2S)-1-carbarnoyl-2 - methylbutanoate] valerate; So pl. 140-141oC; Rf0,13 (n-hexane:AcOEt 2:1);

8) benzyl-(2S)-2-[1S, 2S)-1-(isopropylcarbamate)-2 - methylbutanoate]-4-methylvalerate; So pl. 90-92oC; Rf0,67 (n-hexane:AcOET 2:1);

9) benzyl-2(S)-4-methyl-2-(piperidinecarboxylate)-valerate; Rf0,70 (n-hexane:AcOEt 2:1);

10) benzyl-(2S)-2-[(1S, 2S)-1- (cyclohexylcarbonyl)-2-methylbutanoate]-4-methylvalerate; So pl. 98-100oC; Rf0,55 (n-hexane: AcOEt 2:1);

11) benzyl-(2S)-2-(hexahydro-1-n - azepin-1 ylcarbonyl)-4-methylvalerate; Rf0,78 (n-hexane:AcOEt 2:1);

12) benzyl-(2S)-2-(1,2,3,4-tetrahydroisoquinoline-2-ylcarbonyl)-4-methylvalerate; Rf0,68 (n-hexane:AcOEt 2:1).

Recipe 18. To a solution of benzyl-(2R)-2-carboxymethyl-4-methylvalerate (527 mg) and cyclohexylamine (238 mg) in methylene chloride (10 ml) was added at room temperature WSCDHCl (460 mg). After stirring overnight the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (30 ml). The solution is washed with 5% HCl, water, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuum. The residue is triturated with n-hexane, obtaining the result benzyl-(2R)-2-(cycle is of n 19. The reaction between benzyl-(2R)-2-carboxymethyl-4-methylvalerate (320 mg), octahydrate (165 mg) and WSCDHCl (280 mg) in methylene chloride (20 ml) was performed in the same manner as described in recipe 18. The result has been benzyl-(2R)-2-(octahydrate-1-ylcarbonyl)-4-methylvalerate (378 mg). Rf0.83 (benzene:AcOEt:AcOH 20:20:1).

Recipe 20. By restoring the corresponding benzyl ethers in the presence of 10-aqueous palladium on coal carried out in the same manner as described in recipe 1-4, the following connections:

1) N-(1,2,3,4-tetrahydroisoquinoline-2-ylcarbonyl)-L-Leu-OH; So pl. 93-85oC; Rf0,32 (benzyl:AcOEt:AcOH 20:20:1);

2) N-(1,2,3,4-tetrahydroquinolin-1-ylcarbonyl)-L-Leu-OH; Rf0,46 (benzyl: AcOEt:AcOH 20:20:1);

3) N-(N,N-dibutylamino)-L-Leu-OH; So pl. 121-123oC; Rf0,51 (benzene: AcOEt:AcOH 20:20:1);

4) N-(N,N-dipropylamino)-L-Leu-OH; Rf0,41 (benzene:AcOEt:AcOH 20:20: 1);

5) N-(N-heptylcarbinol)-L-Leu-OH; Rf0,48 (benzene:AcOEt:AcOH 20:20:1);

6) N-(N, N-diisobutylamine)-L-Leu-OH; So pl. 116-118oC; Rf0,39 (benzene:AcOEt:AcOH 20:20:1);

7) N-(N-cyclohexyl-N-methylcarbamoyl)-L-Leu-OH; Rf0,51 (benzene:AcOEt-AcOH 20:20:1);

8) N-[4-(N, N-dimethylcarbamoyl) piperidinylcarbonyl] -L-Leu-OH; Rf0,10 (CHCl3:MeOH:AcOH 16:1:1);

9) N-(2-pyridylcarbonyl)-L-Leu-OH; (CHCl3:MeOH:AcOH 16:1:1);

11) N-[(2R)-2-(N,N-dimethylcarbamoyl)pyrrolidin-1 - ylcarbonyl)-L-Leu-OH; Rf0,34 (CHCl3:MeOH:AcOH 16:1:1);

12) N-[1-(N, N-dimethylcarbamoyl) cyclohexylcarbonyl]-L-Leu-OH; So pl. 191-192oC; Rf0,35 (CHCl3:MeOH:AcOH 16:1:1);

13) N-[(1S,2S)-1-(N,N-dimethylcarbamoyl)-2 - methylbutanoyl]-L-Leu-OH; Rf0,35 (CHCl3:MeOH:AcOH 16:1:1);

14) N-(2,6-dimethylpiperidino)-L-Leu-OH; Rf0,53(CHCl3:MeOH:AcOH 16:1:1);

15) N-(3,5-dimethylpiperidino)-L-Leu-OH; Rf0,53 (CHCl3:MeOH:AcOH) 16:1:1;

16) N-(N, N-dicyclohexylcarbodimide)-L-Leu-OH; So pl. 62-73oC; Rf0,50 (CHCl3:MeOH:AcOH 16:1:1);

17) N-(N,N-diethylcarbamoyl)-L-Leu-OH; So pl. 106-107oC; Rf0,36 (CHCl3: MeOH:AcOH 16:1:1);

18) N-(N,N-diisopropylamino)-L-Leu-OH; Rf0,38 (CHCl3:MeOH:AcOH 16: 1:1);

19) N-[(N-methyl-N-[(1S)-3-methyl-1-(N, N - dimethylcarbamoyl)-butyl]carbarnoyl]-L-Leu-OH; Rf0,38 (CHCl3:MeOH:AcOH 16:1:1);

20) N-[(1S)-1-(N, N-dimethylcarbamoyl)intercalator] -L-Leu-OH; So pl. 155-160oC; Rf0,34 (CHCl3:MeOH:AcOH 16:1:1);

21) N-[N-methyl-N-[(1S,2S)-1-(N,N-dimethylcarbamoyl)-2 - methylbutyl]carbarnoyl]-L-Leu-OH; Rf0,52 (CHCl3:MeOH:AcOH 16:1:1);

22) N-[(1S)-1-(N, N-dimethylcarbamoyl)ethylcarbamate)] -L-Leu-OH; Rf0,46 (CHCl3:MeOH:AcOH 16:1:1);

23) (2S)-2-cyclohexylcarbonyl-4-methylvaline the slot; Rf0,40 (CHCl3:MeOH 9:1);

25) (2S)-4-methyl-2-[(1S,2S)-1-(N,N-dimethylcarbamoyl)butylcarbamoyl]- valeric acid; Rf0,50 (CHCl3:MeOH:AcOH 16:1:1);

26) (2S)-4-(methyl-2-[(12 )-2-methyl-1-(N,N - dimethylcarbamoyl)-butylcarbamoyl]-valeric acid; Rf0,33 (CHCl3:MeOH:AcOH 16:1:1);

27) (2S)-4-methyl-2-[(1S)-2-methyl-1-(N,N-dimethylcarbamoyl)- propylgallate]-valeric acid; Rf0,31 (CHCl3MeOH:AcOH 16:1:1);

28) (2S)-4-iutil-2-[(1S)-3-methyl-1-(N,N-dimethylcarbamoyl)- butylcarbamoyl]valeric acid; Rf0,35 (CHCl3:MeOH:AcOH 16:1:1);

29) (2S)-4-methyl-2-[(1S,2S)-4-carbarnoyl-2-methylbutanoate]- valeric acid; So pl. 170-175oC; Rf0,50 (CHCl3:MeOH:AcOH 16:1:1);

30) (2S)-2-[(1S, 2S)-1-(isopropylcarbamate)-2 - methylbutanoate] -4-methylvaleramide acid; So pl. 179-180oC; Rf0,37 (CHCl3:MeOH:AcOH 16: 1:1);

31) (2S)-4-methyl-2-(piperidinecarboxylate)-valeric acid; Rf0,56 (CHCl3:MeOH:AcOH 16:1:1);

32) (2S)-2-[(1S,2S)-1-(cyclohexylcarbonyl)-2 - methylbutanoate] -4-methylvaleramide acid; So pl. 193-195oC; Rf0,43 (CHCl3:MeOH:AcON 16: 1:1);

33) (2S)-2-(hexahydro-1H-azepin-1 ylcarbonyl)-4-methylvaleramide acid; So square 86-88oC; Rf0,53 (benzene:AcOEt:AcOH 20:20:1);
35) (2R)-2-(cyclohexylcarbonyl)-4-methylvaleramide acid; So square 86-88oC; Rf(benzene:AcOEt:AcOH 20:20:1);

36) (2R)-2-(octahydrate-1-ylcarbonyl)-4-methylvaleramide acid; So pl. 79-81oC; Rf0,56 (benzene:AcOEt:AcOH 20:20:1);

37) N-cyclopentanecarbonyl-L-Leu-OH; So pl. 105-108oC; Rf0,32 (CHCl3: MeOH 9:1);

38) N[1-(N,N-dimethylcarbamoyl) cyclohexylcarbonyl]-L-Leu-OH; Rf0,35 (CHCl3:MeOH:AcOH 16:1:1);

39) N-cyclohexylcarbonyl-L-Leu-D-Trp(CH3-OH); So pl. 202-206oC; Rf0,51 (CHCl3:MeOH:AcOH 8:1:1);

40) N-(piperidinylcarbonyl)-L-Leu-OH; So pl. 185-187oC; Rf 0,70 (CHCl3: MeOH 9:1);

41) N-[(2S)-2-methylbutanoyl]-L-Leu-OH; Rf0,22 (CHCl3:MeOH:AcOH 8: 1:1);

42) N-(2-pyridylmethylene)-L-Leu-OH; So pl. 183-185oC; Rf0,23 (CHCl3:MeOH:AcOH 8:1:1);

43) H-[(1S,2S)-1-(N,N-dimethylcarbamoyl)-2 - methylbutanoyl]-L-Leu-OH; So pl. 185-187oC; Rf0,27 (CHCl3:MeOH:AcOH 8:1:1).

Recipe 21. To a solution of N-(1,2,3,6-tetrahydropyran-1-ylcarbonyl)-L-Leu-OBzI (0,58 g) in MeOH (6 ml) was added at room temperature 1 N. NaOH (3.5 ml). After 1 h the mixture was acidified using 1 N. HCl (5 ml) and the solvent was removed by distillation in vacuum. The residue was dissolved in ethyl acetate (20 ml) and washed with water (20 ml) and brine (20 ml). Organic with the 1-ylcarbonyl)-L-Leu-OH (0.31 g) as oily liquid. Rf0,41 (CHCl3:MeOH:AcOH 16:1:1).

Recipe 22. By hydrolysis of the corresponding benzyl esters 1 N. NaOH carried out in the same manner as described in recipe 21, received the following connections:

1) N-(thiomorpholine)-L-Leu-OH; Rf0,31 (benzene:AcOEt:AcOH 20:20: 1);

2) (2S)-2-[(1S, 2S)-1-piperidinylcarbonyl)-2-methylbutanoate] - 4-methylvaleramide acid; Rf0,47 (CHCl3:MeOH:AcOH 16:1:1).

Division 23. L-Leu-OH (10.0 g) was dissolved in water (150 ml) containing concentrated sulfuric acid (3.2 ml), at 0oC. To the resulting solution was added dropwise over 1 h a solution of sodium nitrite (7.9 g) in water (50 ml). The mixture was saturated with sodium chloride and subjected to extraction with ethyl acetate (500 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuum. The solid residue triturated with hexane, obtaining as a result of (2S)-2-hydroxy-4-methylvaleramide acid (6,51 g). So pl. 70 72oC; Rf0,80 (n-BuOH:AcOH:H2O 4:1:1).

Recipe 24. To a stirred solution of (2S)-2-hydroxy-4 - methylvaleramide acid (5.0 g) and benzylbromide (4,95 ml) in DMF (50 ml) was added at room temperature potassium carbonate (3.13 g). After stirring for 12 h the solvent is kept in vacuum. The remainder of the Rast is over magnesium sulfate and concentrated in vacuum. The remainder in the form of an oily liquid was subjected to purification using column chromatography on silica gel, using as eluent a mixture of Aksana and ethyl acetate. The result was obtained benzyl(2S)-2-hydroxy-4-methylvalerate (8,2 g) as a colorless oily liquid. Rf0,67 (CHCl3:MeOH:AcOH 16:1:1).

Division 25. To a solution of benzyl-(2S)-2-hydroxy-4 - methylvalerate (1,00 g) in tetrahydrofuran (20 ml) was added at room temperature trichloromethylcarbonate (0,55 ml). The solution was heated for 11 hours under reflux, after which the solvent is kept at atmospheric pressure, resulting in the (2S)-2-chlorocarbonyl-4-methylvalerate (1.26 g) as oily liquid. Rf0,81 (n-hexane-AcOEt 2:1).

Division 26. A solution of benzyl-(2R)-2-tertbutoxycarbonyl-4-methylvalerate (3,40 g) in TFA (60 ml) was stirred for 1 h while cooling in a water bath. After distillation, TFA received benzyl-(2R)-2 - carboxymethyl-4-methylvalerate (2,72 g) as oily liquid. Rf0,73 (benzene:AcO0Et:AcOH 20:20:1).

Division 27. By reacting the corresponding starting compounds with phenylisocyanate in Et3N or HMM, carried out in the same manner as described in recipe 7, were obtained the following compounds:siarbaloi-L-Leu-D-Trp (CH3)- BZI; So pl. 190-193oC; Rf0,74(CHCl3:MeOH 9:1).

Division 28. By interacting TSOHH-L-Leu-OBzI with appropriate amines in the presence of trichloromethylcarbonate carried out in the same manner as described in example 72, received the following connections:

1) N-[I-(N,N-dimethylaminocarbonylmethyl) cyclohexylcarbonyl]-L - Leu-OBzI; Rf0,70 (CHCl3:MeOH 9:1);

2) N-[(1S, 2S)-1-(N, N-dimethylcarbamoyl)-2-methylbutanoyl]-L-Leu-OBzI; So pl. 95-98oC; Rfof 0.32 (n-hexane:AcOEt 1:1);

3) N-(piperidinylcarbonyl)-L-Leu-OBzI; Rf0,43 (n-hexane:AcOEt 1:1);

4) N-(2-pyridylmethylene)-L-Leu-OBzI; Rf0,50(AcOEt);

5) N-[(2)-2-methylbutanoyl] -L-Leu-OBzI; So pl. 73-75oC; Rf0,29 (n-hexane:AcOEt 3:1).

Recipe 29. 1) Mix TSOHH-L-Leu-OBzI (12.0 g), ethyl acetate (150 ml) and IM sodium bicarbonate solution (150 ml) was stirred at room temperature for 20 minutes the Organic phase after separation was washed in 1 M sodium bicarbonate solution and saturated aqueous sodium chloride and then dried over magnesium sulfate. To the resulting solution was added a 4 n solution of hydrogen chloride in ethyl acetate (15.3 ml) and stirred the mixture for 5 minutes, cooling it with ice. After removal of solvent received HClH-L-Leu-OBzI of trichloromethylcarbonate (3.6 ml) in toluene (7,6 ml) and the mixture was stirred for 2 h at 120oC, and then filtered. After removal of the solvent from the filtrate, the residue was dissolved in toluene (152 ml). The resulting solution was evaporated, resulting in the (S)-a-benzyloxycarbonyl-g-methylbutadiene (7,58 g).

3) To a solution of the obtained product in ethyl acetate (114 Il) was added under ice cooling, hexahydro-1H-azepin (3.5 g) and the mixture was stirred at the same temperature for 30 minutes the resulting solution was washed with 5% HCl, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride, then dried over magnesium sulfate. After removal of the solvent was obtained N-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-OBZI (9,96 g). Rf0,71 (n-hexane:EtOAc 2:1).

4) To a solution of N-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-OBzI (9.0 g) in ethanol (69 ml) was added 10% palladium on coal (0,692 g) and spent catalytic reduction for 30 min under hydrogen pressure of 3 ATA. Thereafter, the catalyst was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (138 ml), the solution washed with 5% HCl and saturated aqueous sodium chloride and dried. After removal of solvent the residue was recrystallized from ethyl acetate and hexane, obtaining as a result of N-(hexahydro-1H-azepin-1-elkware Boc-D-Trp-OH (15.0 g) in DMF (150 ml) was added under ice cooling tertbutoxide potassium (13.8 g) and methyliodide (10.5 g). After stirring for 30 minutes under ice cooling and for 15 min at room temperature the reaction mixture was poured into a cooled ice 0,24 N. HCl and subjected to extraction with ethyl acetate. The extract is washed with 5% NaHSO3and saturated aqueous sodium chloride. After removal of the solvent was obtained residue, which was recrystallized from diisopropyl ether. In the received Boc-D-Trp (CH3)-OH (9,18 g). Rf0,61 (CHCl3:MeOH 8:2).

2) To a solution of the obtained product (6,84 g) in dichloromethane (137 ml) was added at -30oC NMM (2.17 g) and isobutylparaben (with 2.93 g). To the mixture was added at -15 10oC 2HClH-D-Pya - OC2H5(6.0 g) and at -20oC NMM (4,54 g), after which the mixture was stirred at this temperature for 30 minutes Then washed with 1 M sodium bicarbonate solution and saturated aqueous sodium chloride and was treated with charcoal. The solvent was removed by evaporation and the residue was recrystallized from ethyl acetate and hexane, obtaining the resulting Boc-D-Trp(CH3)-D-Pya-OC2H5(7,88 g). So pl. 99-101oC; Rf0,80 (CHCl3:MeOH 9:1); (2D3) +26,5oC (C=1,0; MeOH).

3) To a solution of the obtained product (7.8 g) in ethyl acetate (61,7 ml) dobie hours at room temperature. The target product was collected by decantation and trituration with ethyl acetate. The result has been 2HClH-D-Tp(CH3)-D-Pya-OC2H5(7,4 g).

Recipe 31-1. By interaction of N-Boc - NN-methyl-Nin-methyl-D-Trp-OH (0.65 g), 2HClH-D-Pya-OEt (0.52 g), HOBt (0.32 g) WSCD (0.36 g) Et3N (0.20 g) and DMF (20 silt) carried out in the same manner as described in recipe 1-1), received N-Boc-NN-methyl-Nin-methyl-D-Trp-D-Pya-OEt (0,78 g). Rf0,81 (CHCl3:MeOH 9:1).

Recipe 31-2. By reacting Boc-D-Trp(CHO)-OH (2.0 g), 2HClH-D-Pya-OEt (0.16 g), WSCD (1,03 g), HOBt (0,90 g),NMM (0,61 g) and DMF (20 ml), carried out in the same manner as described in recipe 1-1, received Boc-D-Trp(CHO)-D-Pya-OEt (2,23 g). So pl. 136-137oC; Rfof 0.65 (ethyl acetate).

Recipe 31-3. To a solution of Boc-D-Trp(CHO)-OH (0,79 g) and N-methylmorpholine (0,13 ml) in methyl chloride (20 ml) was added at -15oC dropwise isobutylparaben (0,31 ml). After 15 min to the prepared solution was added at -30oC N-methylmorpholin (0,13 ml) and HClH-D-Gly(OBzI)-OPac (0.85 grams). After stirring for one hour the mixture was washed with 0.5 M hydrochloric acid (10 ml), water (10 ml) and 1 M solution of sodium bicarbonate (10 ml), dried over magnesium sulfate and concentrated in vacuum. The solid residue of RAM:methanol 9:1).

Recipe 31-4. Boc-D-Trp(CHO)-D-Phe-OPac was obtained in the same manner as in the case of recipe 1-1. So pl. 142 146oC; Rfto 0.78 (chloroform:methanol 9:1).

Recipe 31-5. By reacting Boc-D-Trp(CHO)-OH (1.0 g), HClH-AIa-OPac (0,81 g), HOBT (0,49 g), WSCD (0.56 g) and DMF (10 ml), carried out in the same manner as described in recipe 1-1, received Boc-D-Trp(CHO)-bAla-OPac (3.15 g). So pl. 153 155oC; Rfof 0.58 (chloroform:methanol 9:1).

Recipe 31-6. By reacting Boc-D-Trp(CHO)-OH (10.0 g), HClH-beta-Ala-OMe (to 4.41 g), HOBt (4,47 g), WSCD (5,14 g) and DMF (100 ml), carried out in the same manner as described in recipe 1-1, received Boc-D-Trp (CHO)-beta-Ala-Ome (8,77 g). So pl. 134-135oC; Rf0,54 (CHCl3:MeOH 9:1).

Recipe 31-7. By reacting Boc-D-Phe-OH (265 mg), 2HClH-D-Pya-OEt(267 mg), HOBt(0.16 g), WSCD(0,19 g), N-methylmorpholine (0.10 g) and DMF (6 ml), carried out in the same manner as described in recipe 1-1, received Boc-D-Phe-D-Pya-OEt (0.32 g). So pl. 97-99oC; Rf0,58 (CHCl3:MeOH 9: 1).

By removal of tertbutoxycarbonyl groups from the respective parent compounds, carried out in the same manner as described in recipe 1-2, were obtained the following compounds.

Recipe 32-1. HClH-D-Trp(Me)-L-Leu-OBz1; So pl. 85-90oC; Rf0,27 (CHCl3:MeOH 9:1).

Recipe 32-2. 2HCl; f0,16 (CHCl3:MeOH:AcOH 8:1: 1, vol.).

Recipe 32-4. HClH-D-Trp(CHO)-D-Glu-(OBzI)-OPac; So pl. 80-89oC; Rfof 0.50 (chloroform:methanol 9:1).

Recipe 32-5. HClH-D-Trp(CHO)-D-Phe-OPac; So pl. 185oC (Razlog.); Rfof 0.37 (chloroform:methanol:acetic acid 16:1:1).

Recipe 32-6. HClH-D-Trp(CHO)-b Ala-OPac; So pl. 157-164oC; Rfto 0.17 (chloroform:methanol:acetic acid 16:1:1).

Recipe 32-7. HClH-D-Trp(CHO)-Ala-OMe; So pl. 168-169oC; Rfof 0.53 (10% MeOH in CHCl3).

Recipe 32-8. 2HClH-D-Phe-D-Pya-OEt; Rf0,12 (10% MeOH in CHCl3).

By reacting (S)-a - benzyloxycarbonyl-g-methylbutylamine with the corresponding amines, carried out in the same way as it is written in recipe 7, were obtained the following compounds.

Recipe 33-1. N-(pyrrolidin-1-ylcarbonyl)-L-Leu-OBzI; Rfof 0.14 (EtOAc: hexane 1:2).

Division 33-2. N-(piperidine-1-ylcarbonyl)-L-Leu-OBzI; So pl. 75-76oC; Rfa 0.27 (EtOAc:hexane 1:2).

Recipe 33-3. N-[(2S)-4-methyl-2-(1-methylpropyl)-3-oxopiperidin-1-ylcarbonyl]L-Leu-OBzI; Rfof 0.13 (EtOAc:hexane 1:1, vol.).

Recipe 33-4. N-[{ (1S)-1-(N, N-dimethylcarbamoyl)-1-cyclohexylmethyl} carbarnoyl]-L-Leu-OBzI; Rfof 0.26 (EtOAc: hexane 1:1, vol.).

Recipe 33-5. N[{(1S)-1-(N,N-dimethylcarbamoyl)-1-f is mailmeter)cyclohexyl} carbarnoyl]-L-Leu-OBzI; Rfof 0.25 (ethyl acetate).

Recipe 33-7. N[{CIS-5 - (N,N-dimethylcarbamoyl)cyclohexyl]carbarnoyl}-L-Leu-OBzI; Rf0,34 (ethyl acetate).

Recipe 33-8. N-(N,N-dimethylcarbamoyl)carbarnoyl-L-Leu-OBzI; Rfto 0.23 (ethyl acetate).

Recipe 33-9. N-[{2-(N,N-dimethylcarbamoyl)ethyl}carbarnoyl]-L-Leu-OBzI; Rfof 0.33 (ethyl acetate).

Recipe 33-10. N-[(TRANS-4-oxocyclohexyl)carbarnoyl]-L-Leu-OBzI; So pl. 169-171oC; Rfof 0.53 (ethyl acetate).

Recipe 33-11. N-[{(1S)-1-(oxymethyl)-3-methylbutyl} carbarnoyl]-L-Leu-OBzI; Rf0,38 (n-hexane:ethyl acetate 1:1).

Recipe 33-12. N-[{ 2-morpholino)ethyl} carbarnoyl] -L-Leu-OBzI; Rf0,46 (CHCl3:MeOH:AcOH 8:2:1).

Recipe 33-13.

N-(E-caprolactam-3-ylcarbonyl)-L-Leu-OBzI; So pl. 148-150oC; Rfof 0.52 (ethyl acetate).

Recipe 33-14. N-(N'-isobutyrylacetate)-L-Leu-OBzI; So pl. 93-96oC, Rf0,16 (n-hexane:ethyl acetate 1:1).

Recipe 33-15. N-[(1-ethoxycarbonylpyrimidine-4-yl)carbarnoyl]-L-Leu-OBzI; Rfof 0.35 (n-hexane:ethyl acetate 1:1).

By removal of benzyl groups from the corresponding starting compound, carried out in the same manner as described in recipe 1-4 were obtained the following compounds.

Recipe 34-1. N-(pyrrolidin-1-licarb in CHCl3).

Recipe 34-3. N-(2-chlorpheniramol)-L-Leu-OH; Rf0,20 (10% MeOH in CHCl3).

Recipe 34-4. N-(o-chlorophenylacetyl)-L-Leu-OH; So pl. 145-146oC; Rf0,21 (10% MeOH in CHCl3).

Recipe 34-5. (2R)-2-[{(1S)-1-(N,N-dimethylcarbamoyl)-2,2-dimethylpropyl} carbarnoyl]-methyl-4-methylvaleramide acid; Rf0,43 (10% MeOH in CHCl3).

Recipe 34-6. N-[(2S)-4-methyl-2-(1-methylpropyl)-3 - oxopiperidin-1-ylcarbonyl]-L-Leu-OH; So pl. 180oC (Razlog.); Rf0,20 (10% MeOH in CHCl3).

Recipe 34-7. N-[{(1S)-1-(N,N-dimethylcarbamoyl)-1-cyclohexylmethyl} carbarnoyl]-L-Leu-OH; So pl. 210-211oC; Rf0,20 (10% MeOH in CHCl3).

Recipe 34-8. N-[{(1S)-1-(N,N-dimethylcarbamoyl)-1-phenylmethyl} carbarnoyl] -L-Leu-OH; Rf0,38 (CHCl3:MeOH:AcOH 16:1:1, vol.).

Recipe 34-9. N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methyl-Leu-OH; Rf0,58 (benzene:ethyl acetate:acetic acid 20:20:1, by vol.).

Recipe 34-10. N-[{CIS-4-(N,N-dimethylcarbamoyl)cyclohexyl} carbarnoyl]-L-Leu-OH; Rf0,57 (CHCl3:MeOH:AcOH 8:1:1).

Recipe 34-11. N-[{CIS-4-(N,N-dimethylcarbamoyl)cyclohexyl} carbarnoyl] -L-Leu-OH; Rf0,52 (CHCl3:MeOH:AcOH 8:1:1).

Recipe 34-12. N-(N,N-dimethylcarbamoyl)carbarnoyl-L-Leu-OH; Rf0,73 (CHCl3:MeOH:AcOH 8:2:1).

f0,77 (CHCl3:MeOH:AcOH 8:2:1).

Recipe 34-15. N-[N-(2-oxyethyl)-N-methylcarbamoyl] -L-Leu-OH; Rf0,65 (CHCl3-MeOH:AcOH 8:1:1).

Recipe 34-16. N-[{(1S)-(1-oxymethyl)-3-methylbutyl} carbarnoyl]-L-Leu-OH; Rf0,68 (benzene:ethyl acetate:acetic acid 20:20:1).

Recipe 34-17. N-[2-(morpholino)ethyl carbarnoyl]-L-Leu-OH; Rf0,21 (CHCl3: MeOH:AcOH 8:2:1).

Recipe 34-18. N-(E-caprolactam-3-ylcarbonyl)-L-Leu-OH; Rf0,67 (CHCl2: MeOH-AcOH 8:2:1).

Recipe 34-19. N-(N'-isobutyrylacetate)-L-Leu-OH; Rf0,45 (CHCl3:MeOH:AcOH 8:1:1).

Recipe 34-20. N-[(1-ethoxycarbonylpyrimidine-4-yl)carbarnoyl]-L-Leu-OH; Rf0,48 (CHCl3:MeOH-AcOH 8:1:1).

Division 35. Carrying out the reaction between hexahydro-1H-azepine (0.3 g), (S)-a-benzyloxycarbonyl-g-dimethylbutadiene (0,48 g) and EtOAc (10 ml) in the same manner as described in recipe 7, was obtained N-(hexahydro-1H)-azepin-1-ylcarbonyl)-g - methyl-L-Leu-OH. The resulting product, 10% Pd on C (60 mg), MeOH (10 ml) and H2O (1 ml) was subjected to interact in the same way as described in recipe 1-4). The result was obtained N-(hexahydro-1H-azepin-1-ylcarbonyl)-gamma-methyl-L-Leu-OH (0,43 g). So pl. 64 66oC; Rf0,20 (10 MeOH in CHCl3).

Recipe 36-1.Kim the same way as described in the recipe 1-1, received Boc-D-I-Nal-methanesulfonamide (0,63 g). Rf0,48 (10 MeOH in CHCl3).

Recipe 36 2. Carrying out the reaction between Boc-D-Phe-OH (0.20 g), methanesulfonamide (0,79 mg), DMAP (0.11 g), WSCDHCl (0.17 g) and DMF (4 ml) in the same manner as described in this recipe 1-1, received Boc-Phe-methanesulfonamide (0.21 g). So pl. 73 75oC; Rf0,80 (CHCl3MeOH:AcOH 8:1:1, vol.).

Recipe 36-3. Carrying out the reaction between Boc-D-Phe-OH (0.20 g), benzosulfimide (0,13 g), DMAP (0.11 g), WSCDHCl (0.17 g) and CH2Cl2(4 ml) in the same manner as described in recipe 1-1, received Boc-D-Phe-benzosulfimide (0.32 g); Rf0,83 (CHCl3:MeOH:AcOH 8:1:1, vol.).

Recipe 36-4. Carrying out the reaction between Boc-D-Pya-OH (0.20 g), diethylamine (66 ml), HOBt (0.12 g), WSCDHCl (0.17 g) and DMF (2 ml) in the same manner as described in recipe 1-1, received Boc-D-Pya-diethylamid (45 mg). So pl. 133 135oC; Rfof 0.32 (EtOAc).

Recipe 37-1. Carrying out the reaction between Boc-D-I-Nal-methanesulfonamide (0,60 g), 4 N. HCl-EtOAc (10 ml) and EtOAc (3 ml) in the same manner as described in recipe 1-2, received HClH-D-I-Nal-methanesulfonamide. So pl. 250oC (Razlog.); Rf0,42 (CHCl3:MeOH:AcON 8:2:1, vol.).

Division 37-2. Carrying out the reaction between Boc-D-Phe-methanesulfonamide (0,19 g) and 4 N. HCl EtOAc (10 ml) in the same way as the op is OH 8:1:1, vol.).

Division 37 3. Carrying out the reaction between Boc-D-Phe-benzosulfimide (0,30 g) and 4 n HCl-EtOAc (10 ml) in the same manner as described in recipe 1-2, received HClH-D-Phe-benzosulfimide (0,22 g). So pl. 230oC (Razlog.); Rf0,22 (CHCl3:MeOH:AcOH 8:1:1; vol.).

Recipe 37-4. Carrying out the reaction between Boc-D-Pya-diethylamide (45 mg) and 4 n HCl-EtOAc (1 ml) in the same manner as described in recipe 1-2, received 2HClH-D-Pya-diethylamin (41 mg); Rf0,18 (10% MeOH in CHCl3).

Recipe 38-1. Carrying out the reaction between o-chlorophenylalanine (1.54 g), ToSOHH-L-Leu-OBzI (3.94 g), N-methylmorpholine (1.1 g) and EtOAc (50 ml) in the same manner as described in recipe 7, was obtained N-(2-chlorpheniramol)-L-Leu-OBzI (4,30 g); Rf0,86 (10 MeOH in CHCl3).

Recipe 38-2. Carrying out the reaction between o-chlorophenylalanine acid (0.73 g), HClH-L-Leu-OBZI (1.0 g), WSCD (0.66 g) and CH2Cl2(20 ml) in the same manner as described in recipe 1-1 was obtained N-(o-chlorophenylacetyl)-L-Leu-OBzI (1.4 g); So pl. 75 77oC; Rf0,86 (10 MeOH in CHCl3).

Division 39. To a stirred solution of N-Boc-N-methylglycine (2.0 g) and HClH-L-Lle-OMe (2.0 g) in MeOH was added at room temperature cyanoborohydride sodium (0.87 g). After 30 min the solvent is kept in vacuum, the residue was dissolved in ethyl acetate (50 ml is ovale in vacuum. The residue was subjected to purification using column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane in a ratio of (1 3) (3 1). The result was obtained N-[2-(N-Boc-N-methylamino)ethyl] -L-Leu-OMe (1,67 g); Rf0,78 (EtOAc: hexane 2:1, vol.).

Division 40. Carrying out the reaction between N-[2-(N-Boc-N-methylamino)ethyl]-L-Leu-OMe (1.60 g) and 4 n HCl-EtOAc (20 ml) in the same manner as described in recipe 1-2, received 2HClN-[2-(N-methyl - amino)ethyl]-L-Ile-OMe (1.40 g). So pl. 148 150oC; Rf0,19 (10 MeOH in CHCl3).

Division 41. Dissolved 2HClN-[2-(N-methylamino)ethyl]-L-Ile-OMe (1.30 grams) 24 N. HN3-MeOH (20 ml) at room temperature and leave the solution to stand for 5 days. After that, the solvent is kept in vacuum and the residue was dissolved in EtOAc (30 ml). The solution was washed with sodium bicarbonate (20 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuum, obtaining as a result of (3S)-1-methyl-3-(1-methylpropyl)-2-oxopiperidin (0,69 g); Rf0,57 (10% MeOH in CHCl3).

Division 42. To a stirred suspension of Na-Boc-Nin-methyl-D-Trp-OH (1.0 g) and NaH (0.31 g, 60% in oil) in tetrahydrofuran was added at room temperature methyliodide (1,34 g). After 8 days, the mixture was evaporated in vacuum and the residue suspended in EtOAc (30 ml). Roume. The residue was subjected to purification using column chromatography on silica gel, using as eluent 20 g, 2% MeOH in CHCl3. In the received N-Boc-NN-methyl-Nin-methyl-D-Trp-OH (0,70 g).

Division 43. Fine powder of potassium carbonate (5.8 g) suspended in a solution of 2-(aminomethyl)pyridine (3.0 g) and ethylbromoacetate (3.1 ml) in dimethylformamide (30 ml). The mixture was stirred at room temperature overnight and then poured into ice-cold water, subjected to extraction with ethyl acetate (50 ml of 2), the organic layer was twice washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The residue was subjected to purification using column chromatography on silica gel, using as eluent a mixture of MeOH and CHCl3with a ratio of 1 to 99. The result was obtained N-(ethoxycarbonylmethyl)-N-(pyridine-2-ylmethyl)Amin (2.30 g); Rf0,27 (MeOH:CHCl31:19).

Division 44. A solution of 2-[2 (tertbutoxycarbonyl)ethyl]pyridine (2 g) in dimethylformamide (10 ml) was added at 0oC to a suspension of sodium hydride (0.54 g) in dimethylformamide (10 ml). The mixture was stirred for one hour at 0oC and for another hour at room temperature, after which he added is the atur. The solution was then poured into a saturated solution of ammonium chloride (50 ml) and the mixture was subjected to extraction with ethyl acetate (30 ml 2). The combined organic salt was washed with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuum. The residue was subjected to purification using column chromatography on silica gel, using as eluent a mixture of MeOH and CHCl3with a ratio of 1 to 99. The result was obtained 2-[2-{N-(tertbutoxycarbonyl)-N-(ethoxycarbonylmethyl) amino}ethyl]pyridine; Rf0,47 (CHCl3:MeOH 1:19).

Division 45. Carrying out the reaction between 2-[2-N-(tertbutoxycarbonyl)-N-(ethoxycarbonylmethyl) amino} ethyl] pyridine (430 mg), and 4 N. HCl-1,4 - dioxane (5 ml) in the same manner as described in recipe 1-2 was obtained N-(ethoxycarbonylmethyl)-N-[2-(pyridin-2 - yl)-ethyl]lindegaard (400 mg). Rf0,24 (MeOH:CHCl31:19).

Division 46. Carrying out the reaction between N-methyl-L-Leu-OBzI-hydrochloride (600 mg), trichloromethylcarbonate (0.54 ml) and hexamethyleneimine (877 mg) in the same manner as described in the writings 29-2 and 29-3, was obtained N- (hexahydro-1H-azepin-1-ylcarbonyl)-N-methyl-L-Leu-OBzI (515 mg); Rf0,44 (n-hexane:ethyl acetate 3:1).

Division 47. Carrying out the reaction between Boc-L-Asp(OBzI)-OH (1.0 g), 2-aminopyridine (0.35 g)UB>f
0,52 (CHCl3:MeOH:AcOH 16:1:1).

Division 48. In the same way as described in recipe 1-2, received H-L-ASp(OBzI)-2-pyridylamino. 2HCl. So pl. 170-178oC; Rfto 0.23 (chloroform:methanol:acetic acid 8:1:1).

Division 49. Carrying out the reaction between HClH-L-tert.-Leu-dimethylamide (0,22 g), benzyl-(2R)-2-(carboxymethyl)-4-methylvalerate (0,30 g), WSCD (0.21 g) and CH2Cl2(8 ml) in the same manner as described in recipe 1-1, received benzyl-(2R)-2- [{ (1S)-1-(N, N-dimethylpropyl carbarnoyl)methyl-4-methylvalerate (0.40 g); Rf0,71 (10% MeOH in CHCl3).

Example 1-1. To a mixture of N-phenylacetyl-L-Leu-OH (0.25 g), HClH-D-Trp-(CH3)-D-Phe-OCH3(0,48 g) and HOBT (0.16 g) in DMF (8 ml) was added under cooling in an ice bath WSCD (0,19 g). After stirring for 4.5 h at the same temperature and the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 ml). The solution was washed sequentially with 0.5 N. HCl (10 ml), saturated aqueous sodium bicarbonate (10 ml) and brine (10 ml), then dried over magnesium sulfate and concentrated in vacuum. The residue is triturated with ether, obtaining the target compound (0, 90 g). So pl. 185-188oC; Rf0,52 (CHCl3:MeOH 9:1).

Example 1-2. To a solution of N-phenylacetyl-L-Leu-D-Trp(CH3)-D-Phe-OCH3(the e and the mixture was acidified using 1 N. HCl (2 ml) and concentrated in vacuum. The residue was dissolved in ethyl acetate (20 ml) and the solution was washed with 0.5 N. HCl (10 ml) and brine (10 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuum. The residue is triturated with ether, obtaining the target compound (0.50 g). So pl. 177-185oC; FAB-MS m/z 598 (M + H)+; Rf0,52 (CHCl3:AcOH MeOH 16:1:1).

Example 2-1. Carrying out the reaction between 3-phenylpropenoic acid (33 mg), HClH-L-leu-D-Trp(CH3)-D-Phe-OBzI (0.12 g), HOBT (32 mg) and WSCD (37 mg) in DMF (2 ml) in the same manner as described in example 1-1, was received by the target connection (0,13 g). So pl. 218-220oC: Rf0,74 (CHCl3:MeOH 9:1).

Example 2-2. N-(3-phenylpropionyl)-L-Leu-D-Trp (CH3)-D-Phe-OBzI (0.1 g) in DMF (1.5 ml) was subjected to hydrolysis 1 N. NaOH (0.5 ml) in the same manner as described in example 1-2. The result has been the target compound (68 mg). So pl. 175-180oC; Rf0,51 (CHCl3:MeOH:AcOH 16:1:1); FAB-M M/z 611 (M + H)+.

Carrying out the reaction between cyclohexyloxy acid (31 mg), HClH-L-Leu-D-Trp (CH3)-D-Phe-OBzI (0.12 g), HOBT (32 mg) and WSCD (37 mg) in the same manner as described in example 1-1 were obtained target compound (0.12 g). So pl. 191-194oC; Rf0,74 (CHCl3:MeOH 9:1).

Example 3-2. Carrying out the reaction between N-cyclohexa the re 1-2, received target compound (63 mg). So pl. 225-228oC; Rf0,51 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z 603 (M + H)+.

Example 4-1. To a solution of HClH-L-Leu-D - Trp(CH3)-D-Phe-OBzI (120 mg) and Et3N (22 mg) in DMF (5 ml) was added at room temperature phenylisocyanate (26 mg). The mixture was stirred at the same temperature for 30 min, and then chased off the solvent, the residue was dissolved in AcOEt (20 ml) and the solution was washed successively with 5% HCl, 1 M aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride. Then it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ether, obtaining the target compound (115 mg). So pl. 222-224oC; Rf0,77 (CHCl3:MeOH 9:1).

Example 4-2. Conducting the hydrolysis of N-phenylcarbamoyl-L-Leu-D-Trp(CH3)-D-Phe-OBzI (115 mg) in DMF (2 ml) 1 N. NaOH (0.3 ml) in the same manner as described in example 1-2), received the target compound (93 mg). So pl. 248-251oC; Rf0,60 (CHCl3:MeOH:AcOH 16:1:1).

Example 5-1. Carrying out the reaction between HClH-L-Leu-D-Trp(CH3)-D-Phe-OBzI (300 mg), Et3N (50.2 mg) and cyclohexylsulfamate (68,2 mg) in DMF (10 ml) at room temperature for 30 min in the same manner as described in the example is rovada hydrolysis of N-cyclohexylcarbonyl-L-Leu-D-Trp-(CH3)-D-Phe-OBzI (300 mg) in DMF (10 ml) 1 N. NaOH (2.2 ml) at room temperature for 30 min in the same manner as described in example 1-2 was obtained target compound (246 mg). So pl. 219-221oC; Rf0,52 (CHCl3:MeOH:AcOH 16: 1:1).

Example 6-1. Carrying out the reaction between N - phenacetin-L-Leu-D-Trp(CH3)-OH (0.20 mg), HOBT (72 mg), WSCD (83 mg) and NMM (54 mg) in the same manner as described in example 3-3 was obtained target compound (0.21 g). So pl. 130 137oC; Rf0,51 (CHCl3:MeOH 9:1); FAB-MS m/z:626 (M + H)+.

Example 6-2. Carrying out the reaction between N - phenacetin-L-Leu-D-Trp(CH3)-D-Pya-OC2H5HCl (0.15 g) in DMF (2 ml) and 1 N. NaOH (1 ml) at 0oC for 20 min in the same manner as described in example 1-2 was obtained target compound (102 mg). So pl. 205oC (Razlog.); Rf0,33 (CHCl3:MeOH:AcOH 8:1:1); FAB-MS m/z:598 (M + H)+.

Example 7-1. Carrying out the reaction between 2HClH-L-Leu-D-Trp(CH3)-D-Pua-OC2H5(350 mg), Et3N (122 mg) and cyclohexylsulfamate (91 mg) in DMF (10 ml) at room temperature for 30 min in the same manner as described in example 4-1 was obtained target compound (284 mg). So pl. 216 218oC; Rf0,61 (CHCl3:MeOH 9:1).

Example 7-2. Carrying out the reaction between N-cyclohexylcarbonyl-L-Leu-D-Trp(CH3)-D-Pya-OC2is ANO in example 1-2, received target compound (125 mg). So pl. 207 210oC; Rf0,45 (CHCl3: MeOH:AcOH 8:1:1).

Example 8 1. Carrying out the reaction between N-phenylacetyl-L-Leu-D-Trp(CH3)-OH (90 mg), HClH-D-Phe-OEt (46 mg), WSCD (33 mg) and HOBT (27 mg) in DMF (2 ml) over night at the 5oC, in the same manner as described in example 1-1 were obtained target compound (87 mg). So pl. 207-209oC; Rf0,38(CHCl3:AcOEt 3: 1).

Example 8-2. Carrying out the reaction between N-phenacetin-L-Leu-D-Trp(CH3)-D-Phe-OEt (64 mg) in DMSO (2 ml) and 1 N. NaOH (0.2 ml) at room temperature for 2 h in the same manner as described in example 1-2 was obtained target compound (48 mg). So pl. 172 - 175oC; Rf0,30 (CHCl3:MeOH 5:1).

Example 9. To a solution of N-cyclohexylcarbonyl-L-Leu-D-Trp(CH3)-D-Pya-OC2H5(920 mg) in DMF (20 ml) was added at room temperature 1 N. NaOH (7.3 ml). After 10 min, to the mixture was added 1 N. HCl (8.5 ml) and the solution was evaporated in vacuum. The residue was dissolved in 1 N. HCl (50 ml) and water (200 ml) and transferred into a column with "Diaion HP-20" (trade name, produced by Mitsubishi Chemical Industries). Elution was carried out MeOH (300 ml). The eluate was concentrated in vacuo. The residue (750 mg) was dissolved in 1 N. NaOH (1,24 ml) and was lioresallioresal, obtaining the target compound as a white powder (remail)propyl]carbarnoyl-L-Leu-OH (0.28 g), H-D-Trp(CH3)-D-Pya-OC2H5): of 0.82 (3H, d, J 6.0 Hz), of 0.87 (3H, d, J 6.0 Hz) and 1.15 (3H, t, J 6.0 Hz), of 1.35 (2H, t, J 6.0 Hz), of 1.65 (1H, m), 2,58 (3H, s), 3,06 (3H, s), 3,1 3,3 (4H, m), 3,70 (3H, s) 4,06 (2H, q, J 6.0 Hz), 4,34 (1H, square J 6.0 Hz), and 4.75 (1H, d, J 10 Hz), the 4.90 (1H, square J 6.0 Hz), 5,13 (1 H, sq J 6.0 Hz), of 6.20 (1H, d, J 10.0 Hz), 6.48 in (1H, d, J 8.0 Hz), to 6.58 (1H, d, J 7.5 Hz), make 6.90 (1H, s), 6,95 7,30 (6H, m), 7,56 (1H, TD, J of 7.5, 2.0 Hz), the 7.65 (1H, d, J 7.5 Hz), 7,98 (1H, d, J 8.0 Hz), a 8.34 (1H, d, J 5.0 Hz).

Example 11. Carrying out a reaction between (2S)-2-[N-[(1S)- 2,2-dimethyl-1-(N,N-dimethylcarbamoyl] carbanilate]-4-methylvaleramide acid (0.15 g), H-D-Trp (CH3)-D-Pya - OC2H52HCl (0.24 g), HOBT (77 mg), WSCD (88 mg) and NMM (53 mg) in DMF (4 ml) in the same manner as described in example 1-1 were obtained target compound (0.33 g); Rf0,73(CHCl3:MeOH 9:1).

Example 12. Carrying out the reaction between N-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-OH (1.51 g), 2HClH-D-Trp(CH3)-D-Pya-OC2H5(2.50 g), WSCD (997 mg), HOBT (868 mg) and NMM (541 mg) in DMF (60 ml) in the same manner as described in example 1-1 were obtained target compound (2.16 g); Rf0,34 (ethyl acetate).

NMR (CDCl3d): of 0.82 (3H, d, J 6.0 Hz), is 0.84 (3H, d, J 6.0 Hz), of 1.18 (3H, t, J 7.5 Hz), 1,3 1,8 (11 H, m), 3,1 3,5 (7H, m), 3,68 (3H, s), 4,10 (2H, q, J 7.5 Hz), 4,10 (1H, W), 4,7 4,9 (3H, m), of 6.68 (1H, d, J 8.0 Hz), of 6.96 (1H, s), 7,0 is 7.3 (5H, m), and 7.5 (1H, TD, J of 8.0, 2.0 Hz), to 7.64 (2H, 1, J 8.0 Hz), of 8.28 (1H, d, J 5.0 Hz).

Example 13. Conducting the reaction/SUB>H5(1.54 g), WSCD (612 mg), HOBT (532 mg) and tea (332 mg) in DMF (30 ml) in the same manner as described in example 1-1, was received by the target connection (1,41 g); Rf0,43 (CHCI3:MeOH 9:1).

Example 14. Carrying out the reaction between N-(octahydrate-1-ylcarbonyl)-L-Leu-OH (191 mg), 2HCIH-D-Trp(CH3)-D-Pya-OC2H5(300 mg), WSCD (120 mg), HOBT (104 mg) and tea (65 mg) in DMF (20 ml) in the same manner as described in example 1-1 were obtained target compound (340 mg); Rf0,60 (CHCl3:MeOH 9:1).

Example 16. To a solution of N-(hexahydro-IH-azepin-1-ylcarbonyl)-L-Leu-D-Trp(CH3)-D-Pya-OC2H5(37 mg) in ethanol (740 ml) was added under cooling in an ice bath, 1 N. NaOH (146 ml). After stirring for 30 min to the reaction mixture were added 1 N. HCl (150 ml) and the solvent is kept in vacuum. The residue was dissolved in 1 N. HCl (500 ml) and water (5000 ml) and was passed through a chromatographic column Packed with a non-ionic adsorption resin "Diaion HP-20" (3 l). Elution was performed with methanol (10 l). The eluate was then concentrated in vacuo and the residue was recrystallized from n-hexane, obtaining the target compound (34,1 g). So pl. 113-118oC; Rf0,34 (CHCl3: MeOH:AcOH 8:1:1).

NMR (CDCl3d) to 0.89 (6H, d, J 5.0 Hz), 1,32 and 1.80 (11H, m), 3,11 (2H, d, J 6.0 Hz), 3,16-of 3.53 (6H, m), 3,78 H, d, J 5.0 Hz).

Example 17. Carrying out the reaction between N-(hexahydro-1H-azepin-1-ylcarbonyl) L-Leu-D-Trp(CH3)-D-Pya-OC2H5(1.35 g) and 1 n NaOH (6.4 ml) in ethanol (30 ml) in the same manner as described in example 9, was obtained target compound (1.08 g); Rf0,44 (CHCl3:MeOH:AcOH 8:1:1).

NMR (DMSO-d6d): to 0.74 (3H, d, J 3.0 Hz), of 0.79 (3H, d, J 3.0 Hz), 1,08-1,67 (11H, m), 2,72-of 3.12 (3H, m), 3,18-to 3.38 (5H, m), of 3.69 (3H, s), 4.09 to of 4.25 (2H, m), 4,28-4,43 (1H, m), between 6.08 (1H, d, J 8.5 Hz), 6,92-to 7.15 (4H, m), of 7.25 (1H, d, J 8.0 Hz), 7,49 to 7.62 (2H, m), of 7.69 (1H, d, J 8.5 Hz), 8,03 (1H, d, J 9.0 Hz), 8,40 (1H, d, J 4.0 Hz).

Example 18. Carrying out the reaction between N-[N - [(1S)-2,2-dimethyl-1-(N,N-dimethylcarbamoyl)propyl] carbarnoyl] -L-Leu - D-Trp(CH3)-D-Pya-OC2H5(0.31 g) and 1 N. NaOH (1.5 ml) in DMF in the same manner as described in example 9, was obtained target compound (0.25 g); Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

NMR (DMSO-d6d) 0,66 (6H, d, J 6.0 Hz), to 0.88 (9H, s), 1,0-1,3 (3H, m), 2,7-3,3 (4H, m), and 2.8 (3H, s), 3,68 (3H, s) 4,08 (1H, q, J 6.0 Hz), 4,20 (1H, q, J 5.0 Hz), to 4.38 (1H, m), 4,50 (1H, d, J 9.0 Hz), 6,37 (1H, d, J 9.0 Hz), 6.48 in (1H, d, J 7.5 Hz), 6,9-to 7.15 (4H, m), 7,2 (1H, d, J 7.5 Hz), 7,2 (1H, d, J 7.5 Hz), 7,45 and 7.6 (2H, m), 7,66 (1H, d, J 7.5 Hz), of 8.28 (1H, d, J 8.0 Hz), scored 8.38 (1H, d, J 4.0 Hz).

Example 19. Carrying out the reaction between N-[(2S)-2-[N-[(1S)-2,2-dimethyl-1-(N, N-dimethylcarbamoyl)propyl] carbanilate]-4-methylvinyl]-D-Trp(CH3)-D-Pya-OC2H5(0,30 g) UB> 0,20 (CHCl3: MeOH:AcOH 8:1:1).

NMR (DMSO-d6d)to 0.78 (6H, d, J 6.5 Hz), to 0.88 (9H, s), of 1.2-1.6 (3H, m), 2,7-3,4 (4H, m), and 2.83 (3H, s),3,05 (3H, s), 3,66 (3H, s), 4.16 the (H, q, J 6.0 Hz), 4,34-4,48 (2H, m), and 4.75 (1H, q, J 3.0 Hz) and 6.9 to 7.7 (1OH, m), 8,16 (1H, d, J 10 Hz), 8,40 (1H, d, J 4.0 Hz).

Examples 20. Carrying out the reaction between N=[(2R)-2-(hexahydro-1H-azepin-1-ylcarbonyl)-4-methylvinyl] -D-Trp(CH3)-D - Pya-OC2H5(1.10 g) and 1 N. NaOH (5.2 ml) in ethanol (20 ml) in the same manner as described in example 9, was obtained target compound (783 mg); Rf0,49 (CHCl3:MeOH:AcOH 8:1:1).

Example 21. Carrying out the reaction between N-(octahydrate-1-ylcarbonyl-L-Leu-D-Trp(CH3)-D-Pya-OC2H5(300 mg) and 1 n NaOH (2.4 ml) in ethanol (10 ml) in the same manner as described in example 9, was obtained target compound (210 mg); Rf0,68 (CHCl3:MeOH-AcOH 8:2:1).

NMR (DMSO-d6d): 0,75 (6H, d, J 5.5 Hz), 1,02 1,65 (16, m), 2,72 3,32 (5H, m), 3,68 (3H, s), 4,08 4.26 deaths (2H, m), 4,29 of 4.45 (1H, m), to 5.93 (1H, d, J 8.5 Hz), 6,92 to 7.18 (4H, m), 7,13 (1H, d, J 8.0 Hz), 7,32 (1H, d, J 9.0 Hz), of 7.48 of 7.69 (3H, m) of 7.97 (1H, d, J 9.0 Hz), scored 8.38 (1H, d, J 4.5 Hz).

Example 22. To a solution of N-(hexahydro-1H-azepin-1-ylcarbonyl-L-Leu-D-Trp(CH3-D-Pya-OC2H5(800 mg) in ethanol (10 ml) was added under cooling in an ice bath 4 n solution of hydrogen chloride in ethyl acetate (0.63 ml). After stirring for 5 mi the SUB>f0,64 (CHCl3:MeOH 9:1).

NMR (DMSO-d6d): of 0.71 (3H, d, J 5.0 Hz), of 0.77(3H, d, J 5.0 Hz), to 1.14(3H, t, J 6.0 Hz), 1,15 1,66 (11H, m), 2,82 (1H, q, J and 11.0 Hz), is 3.08 4,18 (8H, m), and 3.72 (3H, s) 4,08 (2H, q, J 7.5 Hz), 4,32 4,48 (1H, m), 4.63 to 4,80 (1H, m), 6,13 (1H, W), 7,02 (2H, t, J 7.0 Hz), 7,13 (1H, t, J 7.5 Hz), 7,37 (1H, d, J 8.0 Hz), EUR 7.57 (1H, d, J 7.5 Hz), 7,82 (2H, t, J 7.0 Hz), by 8.22 8,42 (2H, m), 8,78 (2H, d, J 5.0 Hz).

Example 23. Carrying out the reaction between N[(2R)-2-hexahydro-1H-azepin-1-ylcarbonyl)-4-methylvinyl] -D-Trp(CH3)-D-Pya-OC2H5(300 mg) and 4 N. a solution of hydrogen chloride in ethyl acetate (0,36 ml) in ethanol (10 ml) in the same manner as described in example 22 was obtained target compound (298 mg); Rf0,43 (CHCl3:MeOH 9:1).

Subjecting the corresponding starting compound II and III interaction in the same manner as described in example 1-1 were obtained target compound in accordance with examples 24 71.

Below are the physico-chemical properties of these target compounds.

Example 24. So pl. 193 195oC; Rf0,49 (CHCl3:MeOH 9:1).

Example 25. So pl. 186-189oC; Rf0,62 (CHCl3:MeOH 9:1).

Example 26. So pl. 181 183oC; Rf0,56(CHCl3:MeOH:AcOH 8:1:1).

Example 27. Rf0,49(CHCl3:CeOH 9:1).

Example 28. Rf0,77 (CHCl3:MeOH 9:1).

Example 32. So pl. 184 185oC; Rf0,54 (CHCl3:MeOH 9:1).

Example 33. Rf0,77 (CHCl3:MeOH 9:1).

Example 34. Rf0,43 (CHCl3:MeOH 9:1).

Example 35. Rf0,53 (CHCl3:MeOH 9:1).

Example 36. Rf0,36 (CHCl3:MeOH 9:1).

Example 37. So pl. 79 81oC; Rf0,60 (CHCl3:MeOH:AcOH 16:1:1).

Example 38. So pl. 69 71oC; Rf0,43 (CHCl3:MeOH).

Example 39. So pl. 54 55oC; Rf0,41 (CHCl3:MeOH 9:1).

Example 40. So pl. 100 105oC; Rf0,41 (CHCl3:MeOH 9:1).

Example 41. Rf0,53 (CHCl3:MeOH 9:1).

Example 42. Rf0,55 (CHCl3:MeOH 9:1).

Example 43. So pl. 62 68oC; Rf0,52 (CHCl3:MeOH 9:1).

Example 44. So pl. 60 67oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 45. Rf0,58 (CHCl3:MeOH 9:1).

Example 46. So pl. 80 83oC; Rf0,53 (CHCl3:MeOH 9:1).

Example 47. Rf0,55 (CHCl3:MeOH 9:1).

Example 48. Rf0,48 (CHCl3:MeOH 9:1).

Example 49. So pl. 140 142oC; Rf0,43 (CHCl3:MeOH 9:1).

Example 50. Rf0,52 (CHCl3:MeOH 9:1).

Example 51. So pl. 135-138oC; Rf0,31 (CHCl3:MeOH 9:; f0,50 (CHCl3:MeOH 9:1).

Example 54. So pl. 170-178oC; Rf0,48 (CHCl3:MeOH 9:1).

Example 55. So pl. 194-196oC; Rf0,45 (CHCl3:MeOH 9:1).

Example 56. So pl. 166-167oC; Rf0,70 (CHCl3:MeOH 9:1).

Example 57. So pl. 110-115oC; Rf0,59 (CHCl3:MeOH 9:1).

Example 58. So pl. 79-80oC; Rf0,79 (CHCl3:MeOH 9:1).

Example 59. So pl. 77-79oC; Rf0,52(CHCl3:MeOH 9:1).

Example 60. Rf0,36 (CHCl3:MeOH 9:1).

Example 61. Rf0,53 (CHCl3:MeOH 9:1).

Example 62. Rf0,53 (CHCl3:MeOH 9:1).

Example 63. So pl. 185-188oC; Rf0,53 (CHCl3:MeOH 9:1).

Example 64. So pl. 170-175oC; Rf0,58 (CHCl3MeOH 9:1).

Example 65. Rf0,71 (CHCl3:MeOH 9:1).

Example 66. So pl. 183 190oC; Rf0,60(CHCl3:MeOH 9:1).

Example 67. Rf0,70 (CHCL3:MeOH 9:1).

Example 68. Rf0,79 (CHCl3:MeOH 9:1).

Example 69. So pl. 159-161oC; Rf0,62 (CHCl3:MeOH 9:1).

Example 70. Rf0.51(CHCl3:MeOH 9:1).

Example 71. So pl. 148-150oC; Rf0,78 (CHCl3:MeOH 9:1).

Example 72. To a solution of HClH-L-Ile-OMe (135 mg) and Et3N (50.2 mg) in dry toluole 30 min, it was concentrated under reduced pressure. The residue was dissolved in DMF (10 ml) was added thereto at room temperature, the mixture HClH-L-Leu-D-Trp(CH3)-D-Phe-OBzI (300 mg) and Et3N (50.2 mg) in DMF (10 ml). After stirring the reaction mixture for one hour the solvent was removed in vacuum. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed successively with 5 HCl, 1 M sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ether, obtaining the target compound (324 mg). So pl. 184-186oC; Rf0,80 (CHCl3:MeOH 9:1).

Example 73. To a mixture of HClH-L-Leu-D-Trp(CH3)-D-Phe-OBzI (0.12 g), 4-pyridyloxy acid (38 mg) and NMM (24 mg) in DMF (2 ml) was added under cooling in an ice bath WSCD (37 mg). After stirring for 3 h at room temperature the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed sequentially with 0.5 N. HCl, water, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuum. The residue is triturated with ether, obtaining the target compound (107 mg). So pl. 122-125oC; Rf0,46 (CHCl3:MeOH 9:1).

Exposing sootvetstvetstvovat with examples 74 82.

Below are the physico-chemical properties of these target compounds.

Example 74. So pl. 105-110oC; Rf0,50 (CHCl3MeOH 9:1).

Example 75. So pl. 98-108oC; Rf0,65 (CHCl3MeOH 9:1).

Example 76. So pl. 173-175oC; Rf0,84 (CHCl3MeOH 9:1).

Example 77. So pl. 196 to 199oC; Rf0,79 (CHCl3:MeOH 9:1).

Example 78. So pl. 139-141oC; Rf0,60 (CHCl3:MeOH:AcOH 8:2:1).

Example 79. So pl. 90-96oC; Rf0,36 (CHCl3:MeOH 9:1).

Example 80. So pl. 206-209oC; Rf0,45 (CHCl3:MeOH 9:1).

Example 81. So pl. 124 to 128oC; Rf0,56 (CHCl3:MeOH 9:1).

Example 82. Rf0,64 (CHCl3:MeOH 9:1).

Example 83. To a mixture of benzylchloride (0.18 g) and HClN-L-Leu-D-Trp(CH3)-D-Pya-OC2H5(0.50 g) in DMF (10 ml) was added at 0oC Et3N (0,42 ml). After completion of the reaction, the solution was evaporated to dryness in a vacuum. The residue was dissolved in ethyl acetate and the solution was washed with 0.5 N. HCl, dried over magnesium sulfate and concentrated in vacuum. The solid residue triturated with ether, obtaining the target compound (0.29 grams). So pl. 98-100oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 84. Carrying out the reaction between morpholinylcarbonyl in example 83, received target connection. Rf0,45 (CHCl3MeOH 9:1).

Subjecting the corresponding parent compound Ia interaction with the derived isocyanate IV in the same manner as described in example 4-1 was obtained target compound in accordance with examples 85 91.

Below are the physico-chemical properties of these target compounds.

Example 85. So pl. 222-223oC; Rf0,79 (CHCl3:MeOH 9:1).

Example 86. So pl. 198-204oC; Rf0,49 (CHCl3:MeOH 9:1).

Example 87. So pl. 205-206oC; Rf0,46 (CHCl3: MeOH 9:1).

Example 88. So pl. 216-218oC; Rf0,45 (CHCl3:MeOH 9:1).

Example 89. So pl. 188-202oC; Rf0,53 (CHCl3:MeOH 9:1).

Example 90. So pl. 167-172oC; Rf0,53 (CHCl3:MeOH 9:1).

Example 91. So pl. 163-167oC; Rf0,53 (CHCl3:MeOH 9:1).

Example 92. To a mixture of N-cyclohexylcarbonyl-L-Leu-D-Trp(CH3)-OH (0.40 g), (H-D-4-Pya-OC2H52HCl (0.26 g), NMM (0.10 g) and HOBT (0.14 g) in DMF (8 ml) was added under cooling in an ice bath WSCD (0.16 g). After stirring at room temperature the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed sequentially with 0.5 N. HCl, water, saturated solution b is to deliver the target compound (0.45 g). So pl. 182-186C; Rf0,32 (CHCl3:MeOH: AcOH 16:1:1).

Through the cooperation of the parent compounds V and VI, conducted in the same manner as described in example 92, received the target compounds in accordance with examples 93 98.

Below are the physico-chemical properties of these target compounds.

Example 93. So pl. 170-173oC; Rf0,43 (CHCl3:MeOH 9:1).

Example 94. So pl. 181-182oC; Rf0,71 (CHCl3:MeOH 9:1).

Example 95. So pl. 197-198oC; Rf0,70 (CHCl3:MeOH 9:1).

Example 96. So pl. 115-123oC; Rf0,74 (CHCl3:MeOH 9:1).

Example 97. So pl. 148-156oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 98. So pl. 154-158oC; Rf0,51 (CHCl3:MeOH 9:1).

By hydrolysis of the corresponding ethyl ester (Ic) aqueous solution of NaOH conducted in the same manner as described in examples 1-2, 9, or 16, were obtained target compound in accordance with examples 99 145.

Below are the physico-chemical properties of these target compounds.

Example 99. So pl. 167-170oC; Rf0,44 (CHCl3:MeOH:AcOH 8:1:1).

Example 100. So pl. 173-178oC; Rf0,62 (CHCl3:MeOH:AcOH 8:1:1).

Example 101. So pl. 150-155oC; Rf0,69 (CHCl3:MeOH:AcOH 8:1:1).

Example 104. Rf0,66 (CHCl3:MeOH:AcOH 8:2:1).

Example 105. Rf0,78 (CHCl3:MeOH:AcOH 8:2:1).

Example 106. Rf0.57 (CHCl3:MeOH:AcOH 8:1:1).

Example 107. Rf0,52 (CHCl3:MeOH:AcOH 8:1:1).

Example 108. Rf0,72 (CHCl3:MeOH:AcOH 8:1:1).

Example 109. Rf0,56 (CHCl3:MeOH:AcOH 20:20:1).

Example 110. Rf0,32 (CHCl3:MeOH:AcOH 8:1:1).

Example 111. Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

Example 112. So pl. 150-155oC; Rf0,29 (CHCl3:MeOH:AcOH 8:2:1).

Example 113. Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

Example 114. Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

Example 115. Rf0,33 (CHCl3:MeOH:AcOH 8:1:1).

Example 116. Rf0,33 (CHCl3:MeOH:AcOH 8:1:1).

Example 117. Rf0,34 (CHCl3:MeOH:AcOH 8:1:1).

Example 118. Rf0,32 (CHCl3:MeOH:AcOH 8:1:1).

Example 119. Rf0,33 (CHCl3:MeOH:AcOH 8:1:1).

Example 120. Rf0,38 (CHCl3:MeOH:AcOH 8:1:1).

Example 121. Rf0,34 (CHCl3:MeOH:AcOH 8:1:1).

Example 122. Rf0,35 (CHCl3:MeOH:AcOH 8:1:1).

Example 123. Rf0,33 (CHCl3:MeOH:AcOH 8:1:1).

Example 124. Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

Example 125. Rf
0,30 (CHCl3:MeOH:AcOH 8:1:1).

Example 128. Rf0,32 (CHCl3:MeOH:AcOH 8:1:1).

Example 129. Rf0,29 (CHCl3:MeOH:AcOH 8:1:1).

Example 130. Rf0,33 (CHCl3:MeOH:AcOH 8:1:1).

Example 131. Rf0,29 (CHCl3:MeOH:AcOH 8:1:1).

Example 132. Rf0,33 (CHCl3:MeOH:AcOH 8:1:1).

Example 133. Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

Example 134. Rf0,37 (CHCl3:MeOH:AcOH 8:1:1).

Example 135. Rf0,46 (CHCl3:MeOH:AcOH 8:1:1).

Example 136. Rf0,24 (CHCl3:MeOH:AcOH 8:1:1).

Primer 137. Rf0,38 (CHCl3:MeOH:AcOH 8:1:1).

Example 138. Rf0,29 (CHCl3:MeOH:AcOH 8:1:1).

Example 139. Rf0,32 (CHCl3MeOH:AcOH= 8:1:1).

Example 140. Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

Example 141. Rf0,33 (CHCl3:MeOH:AcOH 8:1:1).

Example 142. Rf0,53 (CHCl3:MeOH:AcOH= 8:1:1).

Example 143. Rf0,57 (CHCl3:MeOH:AcOH 8:1:1).

Example 144. Rf0,50 (CHcl3:MeOH:AcOH 8:1:1).

Example 145. Rf0,62 (CHCl3:MeOH:AcOH 8:1:1).

NMR (DMSO-d6d): 0,54 (3H, d, J 6.0 Hz), of 0.64 (3H, d, J 6.0 Hz), 0,72-1,02 (2H, m), 1,10-1,72 (13H, m), 2,2 4,04-4,010 (1H, m), 4,24-and 4.40 (IH, m), 6,94-to 7.18 (4H, m), 7,20-7,42 (2H, m), 7,46-to 7.68 (3H, m), 8,30 (1H, d, J 7.5 Hz), to 8.41 (1H, d, J 4.0 Hz).

By hydrolysis is imarah 1-2, 9 or 16, were obtained target compound in accordance with examples 146-151.

Below are the physico-chemical properties of these target compounds.

Example 146. So pl. 120-124oC; Rf0,85 (CHCl3:MeOH:AcOH 8:1:1).

Example 147. So pl. 220-236oC; Rf0,16 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 598 (M + H)+.

Example 148. So pl. 214-218oC; Rf0,20 (CHCl3:MeOH:AcOH 16:1:1); FAB MS m/z: 598 (M + H)+.

Example 149. So pl. 174-180oC; Rf0,32 (CHCl3:MeOH:AcOH 16:1:1); FAB MS m/z: 598 (M + H)+.

Example 150. So pl. 194oC (Razlog.); Rf0,51 (CHCl3:MeOH:AcOH 16:1:1); FAB MS m/z 711 (M + H)+.

Example 151. So pl. 195oC (Razlog.); Rf0,51 (CHCl3:MeOH:AcOH 16:1:1); FAB MS m/z: 711 (M + H)+.

By hydrolysis of the corresponding ethyl esters (IC) aqueous solution of NaOH conducted in the same manner as described in examples 1-2, 9, or 16, were obtained target compound in accordance with examples 152-157.

Below are the physico-chemical properties of these target compounds.

Example 152. So pl. 127-145oC; Rf0,29 (CHCl3:MeOH:AcOH 8:2:1); FAB MS m/z 672 (M + H)+.

Example 153. Rf0,36 (CHCl3:MeOH:AcOH 8:1:1).

Example 154. Rf0,38 (CHCl3MeOH:AcOH 8:1:1).

Example 157. Rf0,45 (CHCl3:MeOH:AcOH 8:1:1).

Example 158. Isopropylcarbamate-L-Leu-D-Trp(CH3)-D-Phe-OBzI (60 mg) was subjected to interaction with 1 N. NaOH (2 ml) in DMF (2 ml) at room temperature for 30 min in the same manner as described in example 1-1/2. The result has been the target compound (48 mg). So pl. 211-213oC; Rf0,54 (CHCl3:MeOH:AcON 16:1:1).

By hydrolysis of the corresponding ethyl esters (IC) aqueous solution of NaOH conducted in the same manner as described in example 9, was obtained target compound in accordance with examples 159-166.

Below are the physico-chemical properties of these target compounds.

Example 159. So pl. >250oC; Rf0,12 (CHCl3:MeOH:AcON 16:1:1).

Example 160. So pl. >250oC; Rf0,10 (CHCl3: MeOH:AcOH 16:1:1).

Example 161. So pl. >250oC; Rf0,12 (CHCl3:MeOH:AcOH 16:1:1).

Example 162. So pl. >250oC; Rf0,13 (CHCl3:MeOH:AcOH 16:1:1).

Example 163. So pl. 245oC (Razlog.); RfCHCl3:MeOH:AcOH 16:1:1).

Example 164. So pl. >250oC; Rf0,13 (CHCl3:MeOH:AcOH 16:1:1).

Example 165. Rf0,37 (CHCl3:MeOH:AcOH 8:1:1).

Example 166. Rf0,33 (CHCl3:MeO the mayor the same way as described in example 1-2 or 16, were obtained target compound in accordance with examples 167-169.

Below are the physico-chemical properties of these target compounds.

Example 167. So pl. 171-174oC; Rf0,51 (CHCl3:MeON:AcOH 16:1:1:); FAB MS m/z: 563 (M + H)+.

Example 168. So pl. 165-175oC; Rf0,51 (CHCl3:MeOH:AcOH 16:1:1); FAB MS m/z: 549 (M + H)+.

Example 169. So pl. 132-135oC; Rf0,31 (CHCl3:MeOH:28% aqueous ammonia solution 65:25:4).

Example 170. Conducting the hydrolysis of N-phenacetin-L - Leu-D-Trp(CH3)-D-4-HCl 1 N. NaOH in the same manner as described in example 1-2, received the target connection. So pl. wing 112-116oC; Rf0,33 (CHCl3:MeOH:AcOH 8:1: 1); FAB MS m/z: 604 (C + H)+.

Example 171. Conducting the hydrolysis of N-cyclohexylcarbonyl-L-Leu-D-Trp (CH3)-D-Pya-OC2H5(0.25 g) 1 N. NaOH (1 ml) in DMF (3 ml) in the same manner as described in example 9, was obtained target compound (0.16 g). Rf0,36 (CHCI3: MeOH:AcOH 8:1:1).

Example 172. N-phenylacetyl-L-Leu-D-Trp(CHO)-D-Phe-OPac (0.20 g) was dissolved in a mixture of DMF (2 ml) and acetic acid (2 ml) and was added to the obtained solution at room temperature powder zinc (0.20 g). After stirring for 3 h at the same temperature CME is ivali over magnesium sulfate and concentrated in vacuum. The residue is triturated with ether, obtaining the target compound (0.16 g). So pl. 230oC(Razlog); Rf0,51 (CHCl3:MeOH:AcOH16:1:1); FAB MS m/z: 611.

Example 173. Carrying out the reaction between Boc-D-AlloIle-L-Leu-D-Trp (CHO)-D-Phe-OPac (0.16 g), zinc powder (0.16 g) and acetic acid (1.6 ml) in DMF (1.6 ml) in the same manner as described in example 172, received the target compound (0.11 g). So pl. 197oC (Razlog.); Rf0,49 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 707.

Example 174. A solution of N-[1(S)-methoxycarbonyl-2(S)-methylbutanoyl]-L-Leu-D-Trp(CH3)-D-Phe-OBzI (270 mg) in DMF (20 ml) and water (1 ml) was subjected to hydrogenation in the presence of 10-s Pd-fired when the hydrogen pressure of 3 ATA for one hour at room temperature. After this, the solution was filtered, the filtrate was concentrated in vacuo, the residue was recrystallized from ethyl acetate and ether, obtaining the target compound (198 mg). So pl. 210-212oC; Rf0,48 (CHCl3:MeOH:AcOH 16:1:1).

Example 175. Carrying out the reaction between N -[1(S) - methoxycarbonyl-2(S)-methylbutanoyl] -L-Leu-D-Trp(CH3)-D-Phe-OBzI (70 mg) and 1 N. NaOH (1 ml) in DMF (2 ml) in the same manner as described in example 1-2 was obtained target compound (50 mg). So pl. 221-225oC; Rf0,42 (CHCl3:MeOH:AcOH 16:1:1).

Example 176. To R is formate (0,13 ml). The solution was heated for 11 hours under reflux, after which drove the solvent in vacuo. The remainder in the form of an oily liquid was dissolved in DMF (10 ml) was added to a solution of 2HClH-Leu-D-Trp(CH3-D-Pya-OEt(0.50 g). the pH of the mixture using NMM (approximately 0.2 g) was set equal to about 7. After 10 minutes the solvent is kept in vacuum, the residue was dissolved in ethyl acetate (20 ml), the solution was washed successively 1 N. HCl, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuum. The solid residue triturated with ethyl ether, obtaining the target compound (0.29 grams). So pl. 128-130oC; Rf0,50(CHCl3:MeOH 9: 1).

Example 177. To a solution of N-phenylacetyl-L-Leu-D - Trp(CH3)-D-His(ToS)-OBzI (78 mg) in DMF was added at room temperature piridinkarboksamid (0.15 g). After stirring for 2 h the solvent is kept in vacuum, the residue was dissolved in ethyl acetate (20 ml), the solution washed with 1 M sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuum, obtaining the target compound (845 mg). So pl. 118-126oC; Rf0,28 (CHCl3:MeOH 9:1).

Example 178. Carrying out the reaction between Boc-D - phenylglycyl-L-leu-D-Trp(CH3)-D-Phe-OH (0.1 g), tenie (90 mg). So pl. 135-165oC; Rf0,20 (CHCl3:MeOH:AcOH 16:1:1:); FAB-MS m/z: 612 (M + H)+.

Example 179. Carrying out the reaction between Boc-L - phenylglycyl-L-Leu-D-Trp(CH3)-D-Phe-OH(0.11 g), TEA (1.5 ml) and anisole (0.2 ml) in the same manner as described in example 1-2 was obtained target compound (107 g). So pl. 145-170oC; Rf0,20 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 612 (M + H)+.

Example 180. By reacting the corresponding starting compounds II and III is carried out in the same manner as described in example 1-1, was received by the target connection. So pl. 197-202oC; Rf0,52 (CHCl3:MeOH 9:1).

By reacting the corresponding starting compounds II and III is carried out in the same manner as described in example 1-1, preferably in the presence of a suitable base, obtained target compound in accordance with examples 181-215.

Below are the physico-chemical properties of these target compounds.

Example 216. To a mixture of fenetylline (0.27 g) and HClH-L-Leu-D-Trp(CHO)-bAla-OPac (0.94 g) in DMF (10 ml ) was added at 0oC triethylamine (0.54 ml). After 30 min the solvent is kept in vacuum, the residue was dissolved in ethyl acetate (50 ml), the solution was washed with 0.5 n hydrochloric acid (30 ml), dried over magnesium sulfate and the concentrate is. pl. 163-171oC; Rfto 0.45 (chloroform:methanol 9:1).

By reacting the corresponding starting compounds Ia and IV, conducted in the same manner as described in example 73, received the target compounds in accordance with examples 217 244.

Below are the physico-chemical properties of these target compounds.

Example 217. So pl. 152-153oC; Rf0,48 (CHCl3:MeOH 9:1).

Example 218. So pl. 180-181,5oC; Rf0,57 (CHCl3:MeOH 9:1).

Example 219. So pl. 197-199oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 220. So pl. 76-79oC; Rf0,54 (CHCl3:MeOH 9:1).

Example 221. So pl. 154-160oC; Rf0,64 (CHCl3:MeOH 9:1).

Example 222. So pl. 98-103oC; Rf0,52 (CHCl3:MeOH 9:1).

Example 223. So pl. 171-174oC; Rf0,40 (CHCl3:MeOH 9:1).

Example 224. So pl. 150-153oC; Rf0,52 (CHCl3:MeOH 9:1).

Example 225. So pl. 170-172oC Rf0,53 (CHCl3:MeOH 9:1).

Example 226. So pl. 159-168oC Rf0,38 (CHCl3:MeOH 9:1).

Example 227. So pl. 77-88oC Rf0,52 (CHCl3:MeOH 9:1).

Example 228. So pl. 158-162oC Rf0,55 (CHCl3:MeOH 9:1).

Example 229. So pl. 191-193oC; Rf0,43 (SNL. 123-126oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 232. So pl. 145-146oC; Rf0,60 (CHCl3:MeOH 9:1).

Example 233. So pl. 168-170oC; Rf0,72 (CHCl3:MeOH 9:1).

Example 234. So pl. 180-183oC; Rf0,59 (CHCl3:MeOH 9:1).

Example 235. So pl. 196-204oC; Rf0,49 (CHCl3:MeOH 9:1).

Example 236. So pl. 221-226oC; Rf0,49 (CHCl3:MeOH 9:1).

Example 237. Rf0,47 (CHCl3:MeOH 9:1).

Example 238. So pl. 198-199oC; Rf0,65 (CHCl3:MeOH 9:1).

Example 239. So pl. 104-107oC; Rf0,59 (CHCl3:MeOH 9:1).

Example 240. So pl. 228-230oC; Rf0,57 (CHCl3:MeOH 9:1).

Example 241. So pl. 196 to 199oC; Rf0,53 (CHCl3:MeOH 9:1).

Example 242. So pl. 207-212oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 243. So pl. 186 to 190oC; Rf0,49 (CHCl3:MeOH 9:1).

Example 244. Rf0,49 (CHCl3:MeOH 9:1).

By reacting the corresponding starting compounds V and VI, conducted in the same manner as described in example 92, received the target compounds in accordance with examples 245 263.

Below are the physico-chemical properties of these target compounds.

Example 245. So PL..

Example 247. So pl. 143-147oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 248. So pl. 106-110oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 249. So pl. 116-119oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 250. So pl. 140-143oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 251. So pl. 156 to 160oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 252. So pl. 128-130oC; Rf0,76 (CHCl3:MeOH:AcOH 8:1:1).

Example 253. So pl. 120-130oC; Rf0,85 (CHCl3:MeOH:AcOH 8:1:1).

Example 254. So pl. 145-148oC; Rf0,88 (CHCl3:MeOH:AcOH 8:2:1).

Example 255. So pl. 165-167oC; Rf0,91 (CHCl3:MeOH:AcOH 8:2:1).

Example 256. Rf0,37 CHCl3:MeOH:AcOH 8:1:1).

Example 257. Rf0,56 (CHCl3:MeOH 19:1).

Example 258. Rf0,45 (CHCl3:MeOH 19:1).

Example 259. So pl. 69-70oC; Rf0,53 (CHCl3:MeOH 9:1).

Example 260. Rf0,45 (CHCl3:MeOH 19:1).

Example 261. Rf0,71 (CHCl3:MeOH 9:1).

Example 262. So pl. 120-130oC; Rf0,85 (CHCl3:MeOH:AcOH 8:1:1).

Example 263. So pl. 120-122oC; Rf0,72 (CHCl3:MeOH 9:1).

Below are the physico-chemical properties of these target compounds.

Example 264. To restorannom angle (30 mg) and ammonium formate (0.2 g). After 3 h, the suspension was filtered and the filtrate was evaporated in vacuum. The residue was dissolved in 1 N. hydrochloric acid (1 ml) and subjected to purification using column chromatography on "Diaion HP-20" (trade name, manufactured by: Mitsubishi Chemical Industries), using as eluent MeOH. After lyophilization received target connection (57.4 mg). So pl. 142 160oC; Rfof 0.26 (chloroform:methanol: 28 aqueous ammonia solution 5:3:1), FAB-MS m/z 578 (M+H).

Example 265. Carrying out the reaction between N-phenylacetyl-L-Leu-D-Trp(CHO)-beta-Ala-OH (0,38 g) and 1 N. NaOH in DMF (10 ml) in the same manner as described in example 1-2 was obtained target compound (0,23 g). So pl. 85 95oC; Rfof 0.48 (chloroform:methanol:acetic acid 16:1:1), FAB-MS m/z 578 (M+H).

Example 266. Carrying out the reaction between N-phenylacetyl-L-His(Tos)-D-Trp(CHO)-beta-Ala-OMe (0.32 g) and pyridinecarboxamide in DMF (6 ml) in the same manner as described in example 177, received the target compound (0.20 g). So pl. 160 166oC; Rfof 0.30 (10% MeOH in CHCl3).

Example 267. Carrying out the reaction between Boc-D-alloIle-L-Leu-D-Trp-D-Pya-OEt (2.0 g) and 4 N. HCl in dioxane (35 ml) in the same manner as described in example 1-2 was obtained target compound (1,82 g); Rf0,62 (CHCl3:MeOH:AcOH 8:2:1).

Example 268. Carrying out the reaction between Boc-D-alloIle-L-Leu-D-Trp(CHO)-D-Glu is (0,60 g). So pl. 85-100oC; Rfof 0.16 (chloroform:methanol:acetic acid 16:1:1); FAB-MS m/z 679 (M+H).

By interaction of the respective Races-ethers (IC), zinc powder, acetic acid and DMF conducted in the same manner as described in example 172, received the target compounds in accordance with examples 269 292 and 349.

The target compounds in accordance with examples 293 294, 297 330, 333 - 345, 347 348 and 350 355 were obtained by reacting the corresponding methyl, ethyl, benzyl or RAS-ethers (IC) with an aqueous solution of NaOH conducted in the same manner as described in examples 1-2, 9 and 16.

The target compounds in accordance with examples 295 296 331 332 were obtained by hydrogenation of the corresponding benzyl esters (IC), conducted in the same manner as described in recipe 1-4. Example 346

Carrying out the reaction between N-(e-caprolactam-3 enaminocarbonyl)-L-Leu-OH (298 mg), 2HClH-D-Trp(Me)-D-Pya-OEt (400 mg), WSCD (159 mg), HOBt (139 mg), Et3N (87 mg) and DMF (10 ml) in the same manner as described in example 1-1 were obtained target compound (411 mg).

Below are the physico-chemical properties of the target compounds in accordance with examples 269 355.

Example 269. So pl. 165-168oC; Rf0,52 (CHCl3:MeOH:AcOH 16:1:1).< pl. 150-153oC; Rf0,52 (CHCl3:MeOH:AcOH 16:2:1); FAB-MS m/z: 719 (M+H).

Example 272. So pl. 196 to 199oC; Rf0,52 (CHCl3:MeOH:AcOH 16:2:1); FAB-MS m/z: 719 (M+H).

Example 273. So pl. 90-100oC; Rf0,50 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z 649 (M+H).

Example 274. So pl. 140-148oC; Rf0,50 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 708 (M+H).

Example 275. So pl. 95-105oC; Rf0,44 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 670 (M+H).

Example 276. So pl. 183-185oC; Rf0,36 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 671 (M+H).

Example 277. So pl. 145-150oC; Rf0,46 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 664 (M+H).

Example 278. So pl. 205-207oC; Rf0,49 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 675 (M+H).

Example 279. So pl. 90-130oC; Rf0,41 (CHCl3:MeOH:AcOH 8:1:1).

Example 280. So pl. 89-120oC Rf0,40 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 678 (M+H).

Example 281. So pl. 145-150oC; Rf0,51 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z 663 (M+H).

Example 282. So pl. 165-170oC; Rf0,49 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 733 (M+H).

Example 283. So pl. 156 to 160oC; Rf0,47 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 733 (M+H).

Example 284. So pl. 165-200oC; Rf0,29 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 616 (M+H).

Example 285. So pl. 137-142oC; R16:1:1); FAB-MS m/z 658 (M+H).

Example 287. So pl. 111-128oC; Rf0,48 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z 673 (M+H).

Example 288. So pl. 80-108oC; Rf0,47 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 817 (M+H).

Example 289. So pl. 110-113oC; Rf0,49 (CHCl3:MeOH:AcOH 16:1:1).

Example 290. So pl. 196oC (dec. ); Rf0,52 (CHCl3:MeOH:AcOH 16:1:1); FAB-MS m/z: 535 (M+H).

Example 291. So pl. 165 to 169oC; Rf0,45 (CHCl3:MeOH:AcOH=16:1:1); FAB-MS m/z: 630 (M+H).

Example 292. Rf0,32 (CHCl3:MeOH:AcOH 8:1:1).

Example 293. Rf0,32 (CHCl3:MeOH:AcOH 8:1:1).

Example 294. Rf0,68 (CHCl3:MeOH:AcOH 8:2:1).

Example 295. So pl. 188-190oC; Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

Example 296. So pl. 202-205 areoC; Rf0,29 (CHCl3:MeOH:AcOH 8:1:1).

Example 297. Rf0,10 (CHCl3:MeOH:AcOH 8:1:1).

Example 298. Rf0,07 (CHCl3:MeOH:AcOH 8:1:1).

Example 299. Rf0,10 (CHCl3:MeOH:AcOH 8:1:1).

Example 300. Rf0,09 (CHCl3:MeOH:AcOH 8:1:1).

Example 301. Rf0,11 (CHCl3:MeOH:AcOH 8:1:1).

Example 302. Rf0,25 (CHCl3:MeOH:AcOH 8:1:1).

Example 303. Rf0,22 (CHCl3:MeOH:AcOH 16:1:1)

Example 304. Rf0,29 (CHCl3:MeOH:AcOH 8:1:1).

Example 305. Rf0,33 (CHCl

Example 308. Rf0,33 (CHCl3:MeOH:AcOH 8:2:1).

Example 309. Rf0,53 (CHCl3:MeOH:AcOH 8:1:1).

Example 310. Rf0,28 (CHCl3:MeOH:AcOH 8:2:1).

Example 311. Rf0,25 (CHCl3:MeOH:AcOH 8:1:1).

Example 312. Rf0,62 (CHCl3:MeOH:AcOH 8:2:1).

Example 313. Rf0,64 (CHCl3:MeOH:AcOH 8:2:1).

Example 314. Rf0,46 (CHCl3:MeOH:AcOH 8:2:1).

Example 315. So pl. 248oC (dec); Rf(CHCl3:MeOH:AcOH 8:1:1).

Example 316. Rf0,32 (CHCl3:MeOH:AcOH 8:1:1).

Example 317. So pl. 142-147oC; Rf0,34 (CHCl3:MeOH:AcOH 8:1:1).

Example 318. Rf0,31 (CHCl3:MeOH:AcOH 8:1:1).

Example 319. Rf0,37 (CHCl3:MeOH:AcOH 8:1:1).

Example 320. Rf0,37 (CHCl3:MeOH:AcOH 8:1:1).

Example 321. Rf0,20 (CHCl3:MeOH:AcOH 8:2:1).

Example 322. Rf0,32 (CHCl3:MeOH:AcOH 8:1:1).

Example 323. Rf0,36 (CHCl3:MeOH:AcOH 8:1:1).

Example 324. Rf0,36 (CHCl3:MeOH:AcOH 8:1:1).

Example 325. Rf0,36 (CHCl3:MeOH:AcOH 8:1:1).

Example 326. Rf0,54 (CHCl3:MeOH:AcOH 8:2:1).

Example 327. Rf0,54 (CHCl3:MeOH:AcOH 8:2:1).

Example 328. Rf0,53 (CHCl3:MeOH:AcOH 8:2:1).

Example 329. Rf0,53 (CHClRf0,27 (CHCl3:MeOH:AcOH 8:1:1).

Example 332. So pl. 200-210oC; Rf0,34 (CHCl3:MeOH:AcOH 8:1:1).

Example 333. So pl. 146-150oC; Rf0,74 (CHCl3:MeOH:AcOH 8:1:1).

Example 334. So pl. 138-141oC; Rf0,70 (CHCl3:MeOH:AcOH 8:1:1).

Example 335. So pl. 80-90oC; Rf0,42 (CHCl3:MeOH:AcOH 16:1:1); Rf0,72 (CHCl3:MeOH:AcOH 8:1:1).

Example 336. Rf0,61 (CHCl3:MeOH:AcOH 16:1:1).

Example 337. So pl. pp. 103 -- 110oC; Rf0,46 (CHCl3:MeOH:AcOH 16:1:1).

Example 338. So pl. 128-137oC; Rf0,47 (CHCl3:MeOH:AcOH 8:1:1).

Example 339. So pl. 105-115oC Rf0,48 (CHCl3:MeOH:AcOH 16:1:1).

Example 340. So pl. 133-136oC; Rf0,47 (CHCl3:MeOH:AcOH 8:1:1).

Example 341. So pl. 158-162oC; Rf0,42 (CHCl3:MeOH:AcOH 8:1:1).

Example 342. Rf0,64 (CHCl3:MeOH:AcOH 8:1:1).

Example 343. Rf0,56 (CHCl3:MeOH:AcOH 8:1:1).

Example 344. Rf0,30 (CHCl3:MeOH 9:1).

Example 345. Rf0,41 (CHCl3:MeOH:AcOH 8:2:1).

Example 346. So pl. 210-212oC; Rf0,44 (CHCl3:MeOH 9:1).

Example 347. Rf0,50 (CHCl3:MeOH:AcOH 8:2:1).

Example 348. So pl. 129-135oC; Rf0,37 (CHCl3:MeOH:AcOH 8:1:1).

Example 349. So the>MeOH:AcOH 8:2:1).

Example 351. So pl. 133-140oC; Rf0,52 (CHCl3:MeOH:AcOH 8:1:1).

Example 352. So pl. 208-210oC; Rf0,72 (CHCl3:MeOH:AcOH 8:1:1).

Example 353. So pl. 113-123oC; Rf0,72 (CHCl3:MeOH:AcOH 8:1:1).

Example 354. So pl. 160-164oC; Rf0,80 (CHCl3:MeOH:AcOH 8:1:1).

Example 355. Rf0,30 (CHCl3:MeOH:AcOH 8:1:1).

The target compounds in accordance with examples 356 374, 376 377, 380 - 382, 384 392 and 300 were obtained by reacting the carboxylic acid Ii with substituted amines conducted in the same manner as described in example 1-1.

The target compounds in accordance with examples 375, 378-379 and 393-399 were obtained by reacting the corresponding carboxylic acids or their ethyl esters Ii unsubstituted or substituted amines in the same manner as described in example 383.

Example 383. N-(hexahydro-1H-azepin-I-ylcarbonyl)-L-Leu-D-Trp(Mt)-D-Pya-OEt(0.20 g) was dissolved in 2,4 N. solution of ammonia in methanol (10 ml) and the mixture was left to stand for 3 days at room temperature. It was then concentrated in vacuo and the residue triturated with diethyl ether, obtaining the target compound (0.18 g).

Example 401. Carrying out the reaction between N-(exag
in MeOH (5 ml) in the same manner as described in example 383, received the target compound (42.7 mg).

Below are the physico-chemical properties of the target compounds in accordance with examples 356 401.

Example 356. So pl. 220-224oC; Rf0,47 (CHCl3:MeOH 9:1).

Example 357. So pl. 196-203oC; Rf0,36 (CHCl3:MeOH 9:1).

Example 358. Rf0,61 (CHCl3:MeOH 9:1).

Example 359. So pl. 140-145oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 360. Rf0,56 (CHCl3:MeOH 9:1).

Example 361. Rf0,60 (CHCl3:MeOH 9:1).

Example 362. Rf0,60 (CHCl3:MeOH 9:1).

Example 363. Rf0,58 (CHCl3:MeOH 9:1).

Example 364. Rf0,58 (CHCl3:MeOH 9:1).

Example 365. Rf0,53 (CHCl3:MeOH 9:1).

Example 366. Rf0,53 (CHCl3:MeOH 9:1).

Example 367. Rf0,52 (CHCl3:MeOH 9:1).

Example 368. Rf0,83 (CHCl3:MeOH:AcOH=8:2:1)

Example 369. Rf0,83 (CHCl3:MeOH:AcOH=8:2:1)

Example 370. Rf0,83 (CHCl3:MeOH:AcOH=8:2:1)

Example 371. Rf0,83 (CHCl3:MeOH:AcOH=8:2:1)

Example 372. Rf0,83 (CHCl3:MeOH:AcOH=8:2:1)

Example 373. So pl. 190-195oC; Rf0,72 (CHCl3:MeOH 9:1).

Example 374. So pl. 195-197o 0,44 (CHCl3:MeOH 9:1).

Example 377. So pl. 160-164oC; Rf0,49 (CHCl3:MeOH 9:1).

Example 378. Rf0,44 (CHCl3:MeOH 9:1).

Example 379. So pl. 200-203oC; Rf0,51 (CHCl3:MeOH 9:1).

Example 380. So pl. 76-78oC; Rf0,54 (CHCl3:MeOH 9:1).

Example 381. So pl. 75-78oC; Rf0,49 (CHCl3:MeOH 9:1).

Example 382. Rf0,64 (CHCl3:MeOH 9:1).

Example 383. So pl. 110-112oC; Rf0,50 (CHCl3:MeOH 9:1).

Example 384. So pl. 140-145oC; Rf0,64 (CHCl3:MeOH 9:1).

Example 385. Rf0,65 (CHCl3:MeOH 9:1).

Example 386. Rf0,62 (CHCl3:MeOH 9:1).

Example 387. Rf0,62 (CHCl3:MeOH 9:1).

Example 388. Rf0,62 (CHCl3:MeOH 9:1).

Example 389. Rf0,64 (CHCl3:MeOH 9:1).

Example 390. Rf0,45 (CHCl3:MeOH 9:1).

Example 391. So pl. 165-167oC; Rf0,48 (CHCl3:MeOH 9:1).

Example 392. So pl. 142-143oC; Rf0,50 (CHCl3:MeOH 9:1).

Example 393. So pl. 168oC; Rf0,46 (CHCl3:MeOH 9:1).

Example 394. So pl. 120-125oC; Rf0,47 (CHCl3:MeOH 9:1).

Example 395. So pl. 115-125oC; Rf0,47 (CHCl3:MeOH 9:1).

Example 396. So pl. SS="ptx2">

Example 398. So pl. 108-109oC; Rf0,34 (CHCl3:MeOH=19:1).

Example 399. So pl. 119-120oC; Rf0,28 (CHCl3:MeOH=19:1).

Example 400. Rf0,49 (CHCl3:MeOH 9:1).

Example 401. So pl. 195-197oC; Rf0,26 (CHCl3:MeOH 9:1).

Example 402. Carrying out the reaction between N-(hexahydro-IH-azepin-I-ylcarbonyl-L-Leu-D-Trp(Me)- OH (400 mg), N-(ethoxycarbonyl)-N-(pyridine-2-ylmethyl)amine (187 mg), HOBT (131 mg), WSLD-HCl (150 mg) and DMF (5 ml) in the same manner as described in example 1-1 were obtained target compound (554 mg). Rf0,37 (CHCl3:MeOH 20:1).

Example 403. Carrying out the reaction between N-(hexahydro-1H-azepin-1-ylcarbonyl-L-Leu-D-Trp(Me)- OH (400 mg), N-(ethoxycarbonylmethyl)-N-[2-(pyridin-2-yl)ethyl]unindividualized, HOBT (131 mg), WSCD (150 mg), N-methylmorpholine (98 mg) and DMF (5 ml) in the same manner as described in example 92, received the target compound (288 mg). Rf0,32 (CHCl3:MeOH 20:1).

Example 404. Carrying out the reaction between cyclohexylsulfamate (60 mg), 2HClH-D-alloIle-L-Leu-D-Trp(Me)-D-Pya-OEt (300 mg), Et3N (87 mg) and DMF (10 ml) in the same manner as described in example 4-1 was obtained target compound (260 mg).

So pl. 235-237oC; Rf0,45 (CHCl3:MeOH 9:1).

Example 405. The target connection with the release 90,8 received takings-L-Leu-D-Trp(CH3-D-Pya-OC2H5(1.70 g) in TFA (20 ml) and anisole (2 ml) was subjected to interaction at 0oC for one hour. The obtained product was subjected to interaction with 4 N. a solution of HCl in 1,4-dioxane in the same manner as described in recipe 1-2. The result has been the target compound (1.60 g). So pl. 141-145oC; Rf(CHCl3:MeOH 9:1).

The target compounds in accordance with examples 407 416 were obtained by cleavage tertbutoxycarbonyl groups from the respective parent compounds (1b) in their interaction with TFA and anisole as described in recipe 1-2.

Below are the physico-chemical properties of these target compounds.

Example 407 So pl. 146-156oC; Rf0,35 (CHCl3:MeOH 9:1).

Example 408. Rf0,26 (CHCl3:MeOH 9:1).

Example 409. Rf0,26 (CHCl3:MeOH 9:1).

Example 410. So pl. 86-103oC; Rf0,36 (CHCl3:MeOH 9:1).

Example 411. So pl. 76-102oC; Rf0,20 (CHCl3:MeOH:AcOH 16:1:1).

Example 412. So pl. 152-165oC; Rf0,32 (CHCl3:MeOH 9:1).

Example 413. Rf0,27 (CHCl3:MeOH 9:1).

Example 414. Rf0,26 (CHCl3:MeOH 9:1).

Example 415. So pl. 194-202oC; Rf0,26 (CHCl3:MeOH 9:1).

the particular by reacting the corresponding starting compounds with 4 N. a solution of hydrogen chloride in ethyl acetate, carried out in the same manner as described in example 22.

Below are the physico-chemical properties of these target compounds.

Example 417. So pl. 141-146oC; Rf0,86 (CHCl3:MeOH:AcOH 8:1:1); FAB-MS m/z: 678 (M+H).

Example 418. So pl. 103-120oC.

Example 419. Rf0,41 (CHCl3:MeOH 9:1).

Example 420. Rf0,44 (CHCl3:MeOH 9:1).

Example 421. Rf0,49 (CHCl3:MeOH 9:1).

Example 422. Rf0,44 (CHCl3:MeOH 9:1).

Example 423. Rf0,51 (CHCl3:MeOH 9:1).

Example 424. Rf0,65 (CHCl3:MeOH 9:1).

Example 425. So pl. 110-135oC; Rf0,50 (CHCl3:MeOH 9:1).

Example 426. So pl. 105-145oC; Rf0,49 (CHCl3:MeOH 9:1).

Compounds according to examples 427 429 were obtained by reacting the corresponding starting compounds II and III in the same manner as described in example 1-1.

Below are the physico-chemical properties of these target compounds.

Example 427. Rf0,44 (CHCl3:MeOH 9:1).

Example 428. Rf0,44 (CHCl3:MeOH 9:1).

Example 429. So pl. 110-112oC; Rf0,50 (CHCl3:MeOH 9:1).

SOEDINENIYa in the same way, as described in example 92.

Below are the physico-chemical properties of these target compounds.

Example 430. Rf0,44 (CHCl3:MeOH 9:1). Rf0,44 (CHCl3:MeOH 9:1).

Example 432. So pl. 110-112oC; Rf0,50 (CHCl3:MeOH 9:1).

The target compounds, which are described in the above examples, are given in table. 3.

In table. 3 configuration, followed by consoles-CIS - or TRANS-, does not mean the absolute configuration and the relative configuration. Other configurations mean absolute configuration.

1. Derivatives of the peptides of General formula I

< / BR>
where R1hydrogen or acyl;

R2lower alkyl, aryl(lower)alkyl, C3WITH7- cycloalkyl(lower)alkyl, heterocyclic(lower)alkyl, in which the heterocyclic group is unsaturated 5,6-membered heterophilically group containing 1 to 2 nitrogen atom and optionally substituted aminosidine group;

R3heterocyclic(lower)alkyl, and heterocyclic group may be unsaturated condensed 9-membered group containing 1 nitrogen atom and optionally substituted with a suitable substitute, choose from th alkyl, amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, heterocyclic(lower)alkyl, with the specified heterocyclic group is an unsaturated 5 to 6-membered heterophilically group containing 1 or 2 nitrogen atom or 1 sulphur atom and 1 nitrogen atom and optionally substituted aminosidine group;

R5carboxy, protected carboxy, carboxy(lower)alkyl, protected carboxy(lower)alkyl;

R6hydrogen, heterocyclic(lower)alkyl where the specified heterocyclic group is an unsaturated 6-membered heterophilically group containing 1 nitrogen atom;

R7hydrogen or lower alkyl;

A-O-, NH, lower alkylamino or lower alkylene, provided that when R2(S)-isobutyl, R3N- (dichlorobenzenesulfonyl)indole-3-ylmethyl, R4methyl, R5methoxycarbonyl, R6hydrogen, R7hydrogen and a-NH-, then the fragment formula

< / BR>
has the absolute configuration

< / BR>
or their pharmaceutically acceptable salts.

2. Connection on p. 1, which has an absolute configuration

< / BR>
3. Connection on p. 2, where R1carbarnoyl, saturated or unsaturated, acyclic is POI(s), aromatic acyl, or heterocyclic acyl, each of which is derived from organic carboxylic or organic coal or organic or organic sulphonic carbamino acid; R2lower alkyl, C6- C10-(ness.)alkyl, C3WITH7-cycloalkyl(NISS. )alkyl, or 5 - or 6-membered aromatic heterophilically(lower)alkyl, where the heterocyclic ring contains 1 or 2 nitrogen atom; R39-membered condensed with heterocyclic benzene(NISS. )alkyl, where the heterocyclic group contains 1 nitrogen atom and may be substituted by lower alkyl or organic carboxylic-acyl, or6- C10-ar(NISS. )alkyl; R4hydrogen, lower alkyl, C6- C10- ar(ness.)alkyl, amino(NISS. )alkyl, protected carboxy(ness.)alkyl, 5 - or 6-membered aromatic heterophilically(NISS. )alkyl, where the heterocyclic ring contains 1 or 2 nitrogen atom, or a 5 - or 6 - membered aromatic heterophilically(ness.)alkyl, where the heterocyclic ring contains 1 nitrogen atom and 1 sulfur atom; R5carboxy, esterified carboxy, selected from lower alkoxycarbonyl,6WITH10- ar(ness.)alkoxycarbonyl and C6WITHUrbanol, lower alkylcarboxylic substituted by one or two substituents selected from carboxy and protected carboxy, N-(ness.)alkyl-N- (carboxy - or protected carboxy(NISS. )allylcarbamate,6WITH10-ar(ness.)allylcarbamate, carboxy - or protected carboxy substituted C6WITH10- ar(ness.)allylcarbamate,3WITH7cycloalkylcarbonyl, N-[carboxy - or protected carboxy substituted C3WITH7- cycloalkyl(lower)alkyl] carbamoyl, lower alkylsulfonyl,6WITH10arylsulfonyl, carboxy - or protected carboxylester 5 - or 6-membered aromatic getelementsbyclassname (NISS. )allylcarbamate, where the heterocyclic ring contains 1 to 3 nitrogen atom; lower alkylaminocarbonyl, lower alkylaminocarbonyl, substituted by carboxy or protected carboxy, [lower alkylamino(ness.)alkyl]carbamoyl, substituted by 1 to 2 substituents selected from oxo, carboxy, protected carboxy and carbamoyl, morpholinoethyl, 5 - or 6-membered saturated heterogenities of carbamoyl, where the heterocyclic ring contains 1 nitrogen atom and 1 oxygen atom, 5 - or 6-membered aromatic heterodontosauridae of carbamoyl, where the heterocyclic ring contains 1 to 2 nitrogen atom and 1 sulfur atom and may be substituted by lower alkyl, 9 - or 10-membered condensed with benzene heterocyclic carbamoyl, where the heterocyclic ring contains 1 to 2 nitrogen atom and 1 sulfur atom, 5 - or 6-membered saturated getelementsbyclassname(ness.)allylcarbamate, where the heterocyclic ring contains 1 nitrogen atom and 1 oxygen atom, 5 - or 6-membered aromatic getelementsbyclassname (NISS. )alkylsulphonyl, where the heterocyclic ring contains 1 to 3 nitrogen atom, carbazole, di(lower)acylcarnitine, carboxy(NISS. )alkyl or protected carboxy(NISS. )alkyl; R6hydrogen or 6-membered aromatic heterophilically(lower)alkyl, in which the heterocyclic ring contains 1 nitrogen atom.

4. Connection on p. 3, where R1carbarnoyl, lower alkanoyl, amino(lower)alkanoyl, lower alkoxycarbonyl(lower)alkanoyl, lower alkoxycarbonyl,3WITH7-cycloalkenyl(lower)alkanoyl, lower alkoxycarbonyl,3WITH7- cycloalkyl(lower)alkanoyl,3WITH7- cycloalkylcarbonyl,3WITH7- cycloalkylcarbonyl, benzoyl, Naftoli, phenyl(lower)alkanoyl, naphthyl(lower)Alka is alieni(lower)alkanoyl, phenyl(lower)alkanoyl, phenylglyoxylic, phenyl(lower)alkylglycerol, pyridylcarbonyl, tetrahydromyrcenol, tetrahydroisoquinoline, morpholinylcarbonyl, thiomorpholine, indolocarbazole, piperazinylcarbonyl, substituted by 1 to 3 substituents selected from oxo and lower alkyl, pyridyl(lower)alkanoyl, morpholinylcarbonyl(lower)alkanoyl, phenyl(lower)alkylsulfonyl, N - or N, N-di(C1WITH10-allylcarbamate, hydroxy(lower)allylcarbamate, carboxy(lower)allylcarbamate, lower alkoxycarbonyl, (lower)allylcarbamate, carbarnoyl(lower)allylcarbamate, [N - or N, N - di(lower)allylcarbamate] (lower)allylcarbamate, N-lower alkyl-N-[hydroxy(lower)alkyl]carbarnoyl, N-lower alkyl-N-[di(lower)allylcarbamate(lower)alkyl]carbarnoyl,3- C10-alkylaminocarbonyl, di(lower)allylcarbamate(lower)alkylaminocarbonyl, N-lower alkyl-N-(C3WITH7)cycloalkylcarbonyl, mono - or di(C3- C7)cycloalkylcarbonyl, hydroxy-, or di (lower)allylcarbamate-or di(lower)allylcarbamate(lower)alkyl substituted (C3- C7)cycloalkylcarbonyl,3- C7-cycloalkyl(lower)allylcarbamate, di(lower)allylcarbosilane (3
- C7cycloalkylcarbonyl(lower)allylcarbamate, lower alkylaminocarbonyl(lower)allylcarbamate, pyridyl(lower)allylcarbamate or oxazolidinyl hexahydrobenzylcarbonate; R2lower alkyl; R3indolyl(lower)alkyl, N-(lower)acylinder(lower)alkyl, N-(lower)alcoholiday(lower)alkyl, phenyl (lower)alkyl or naphthyl(lower)alkyl; R4hydrogen, lower alkyl, amino(lower)alkyl, mono-, or di-, or triphenyl(lower)alkoxycarbonyl(lower) alkyl, carboxy(lower)alkyl, mono-, or di-, or triphenyl(lower) alkoxycarbonyl(lower)alkyl, phenyl(lower)alkyl, naphthyl(lower) alkyl, pyridyl(lower)alkyl, imidazolyl(lower)alkyl or thiazolyl (lower)alkyl; R5carboxy, lower alkoxycarbonyl, mono-, or di-, or triphenyl(lower)alkoxycarbonyl, benzoyl(lower)alkoxycarbonyl, carbarnoyl, N - or N,N-di(lower)allylcarbamate lowest allylcarbamate, substituted 1 2 replace the silt and benzoyl(lower)alkoxycarbonyl, N-(lower)alkyl-N-[carboxy - or lower alkoxycarbonyl(lower)alkyl]carbarnoyl, phenyl(lower)allylcarbamate, carboxy - or lower alkoxycarbonylmethyl phenyl(lower)allylcarbamate, C3- C7- cycloalkylcarbonyl, carboxy(C3< / BR>
WITH7)cycloalkyl(lower)allylcarbamate lowest alkylsulphonyl, phenylsulfonylacetate, carboxy - or lower alkoxycarbonylmethyl pyridyl(lower)allylcarbamate, lower alkylaminocarbonyl, lower alkylaminocarbonyl, substituted by carboxy or lower alkoxycarbonyl, (lower alkylamino(lower)alkyl)carbarnoyl, substituted by 1 to 2 substituents selected from carboxy, lower alkoxycarbonyl and carbamoyl, morpholinoethyl, morpholinylcarbonyl, pyridylcarbinol, diazolidinyl lowest alkyldimethylammonium, benzothiazolylthio, morpholinyl(lower)allylcarbamate, pyridyl(lower)alkylaryl, carbazoyl, di(lower)alkylaromatic, carboxy(lower)alkyl, lowest alkoxycarbonyl(lower)alkyl, or benzoyl(lower)alkoxycarbonyl(lower)alkyl; R6and R7the hydrogen.

5. Connection on p. 4, where R1N - or N,N-di(C1- C10)allylcarbamate, N-lower alkyl-N-(C3- C7)cycloalkyl ISSI)alkyl] carbarnoyl, phenylcarbamoyl, C3WITH10-alkylaminocarbonyl or N-(lower)alkyl-N-[hydroxy(lower)alkyl]carbarnoyl; R2lower alkyl; R3indolyl(lower)alkyl, N-(lower)alcoholiday(lower)alkyl or N- (lower)acylinder(lower)alkyl; R4pyridyl(lower)alkyl or phenyl(lower)alkyl; R5carboxy, lower alkoxycarbonyl, carbarnoyl, or N-or N, N-di(lower)allylcarbamate, And methylene or-NH-.

6. Connection on p. 5, where R1isopropylcarbamate, 2-methylbutanoyl, heptylcarbinol, dimethylcarbamoyl, diethylcarbamoyl, dipropylamino, diisopropylamino, dibutylamino, Diisobutylene, pyrrolidin-1-yl-carbonyl, piperidine-1-yl-carbonyl, 3,5 - or 2,6-dimethylpiperidin-1-yl-carbonyl, hexahydro-1H-azepin-1-yl-carbonyl or octahydrate-1-yl-carbonyl; R2isobutyl; R3- indole-Z-yl-methyl, N-formylindole-3-yl-methyl, N-methylindol-3-yl-methyl, N-ethylindole-3-yl-methyl, N-propional-3-yl-methyl or N-isobutylene-3-yl-methyl; R4pyridylmethyl or benzyl; R5- carboxy, methoxycarbonyl, etoxycarbonyl, carbarnoyl, methylcarbamoyl, ethylcarbitol, butylcarbamoyl, N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.

7. The method of obtaining derivatives of peptides obducat the interaction of compounds of General formula II

< / BR>
where R1, R2and A have the above values,

or reactivity derived from carboxypropyl, or its salt with a compound of General formula III

< / BR>
where R3R7have the specified values,

or its reactive derivative at the amino group or its salt, to obtain the compounds of General formula I

< / BR>
where R1R7and A have the above values,

or its salt,

and, if necessary, remove each protective group, followed by separation of the target product and obtaining the compounds of formula I in free form or in pharmaceutically acceptable salt.

8. Pharmaceutical composition having antagonistic activity on the endothelin comprising as an active ingredient derived peptide of formula I under item 1 or its pharmaceutically acceptable salt in an effective amount and a pharmaceutically acceptable carrier.

Priorities signs:

14.05.90 when R2isobutyl, R3- N-(lower)alkalinty-6-yl-methyl, R4benzyl, pyridylmethyl, And-NH-;

03.12.90 when R2isobutyl, R3- (lower)alkalinty-6-yl-methyl, R4benzyl, pyridylmethyl, And-O - or lower alkyl and the acyl, R4lower alkyl, ar(lower)alkyl, or optionally substituted heterocyclic (lower)alkyl, And-NH-, -O - or lower alkylene.

 

Same patents:

The invention relates to the field of Bioorganic chemistry, namely to a new 6-(moselhotel-L-prolyl - L-arginyl)aminonaphthalene-1-isobutylamino formula:

< / BR>
as a substrate for the determination of thrombin

The invention relates to the field of organic chemistry, in particular to the field of peptide synthesis, and can be used to remove temporary protective group, a carboxyl blocking function

The invention relates to boron-containing peptides, a new biologically active compounds that may find application in biochemistry as inhibitors trypsinogen serine proteases, such as thrombin, kallickrein plasma and plasmin

The invention relates to the field of Bioorganic chemistry, namely to new connections dibromide 6-(D-leucyl-L-prolyl-L-arginyl), aminonaphthalene-1-pentanitroaniline (1) and its benzyloxycarbonyl (Z) is the derivative (2)

The invention relates to medicine and can be used for the prevention and treatment of diseases in which appropriate stimulation of endogenous production of cytokines and hemopoietic factors
The invention relates to medicine, namely to psychiatry

The invention relates to new derivatives of acetic acid, hydrate, solvate and pharmaceutically acceptable salts, which can find application in the pharmaceutical industry

The invention relates to new biologically active peptide, inhibiting the hypersecretion of thyroid-stimulating hormone (TSH) and prolactin (PRL), caused by natural hypothalamic peptide with thyroliberin (tireotropin-releasing hormone, TRH)

FIELD: medicine, immunology, peptides.

SUBSTANCE: invention relates to a new composition of biologically active substances. Invention proposes the composition comprising of peptides of the formula: Arg-Gly-Asp and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys that elicits ability to inhibit the proliferative response for phytohemagglutinin, to induce the suppressive activity of mononuclear cells and ability of peptides to induce secretion of immunosuppressive cytokines of grouth-transforming factor-β1 and interleukin-10 (IL-10). The composition can be prepared by a simple procedure.

EFFECT: valuable biological properties of composition.

3 cl, 16 tbl, 9 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I): , wherein X means hydrogen atom, -OR1, -NR1R1' and -CHR1R1' wherein R1 and R1' are taken among the group: hydrogen atom, (C1-C6)-alkyl and acyl; (1) each R2 is taken independently among the group: hydrogen atom, (C1-C6)-alkyl; or (2) (a) R2 bound with carbon atom that is bound with X and Z1 and substitute R5 can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R2 bound with carbon atom that is bound with ring Ar can be bound with R7 to form ring condensed with ring Ar; each among Z1, Z2 and Z3 is taken independently from the following groups: -N(R3e)C(R3)(R3a)-, -C(R3)(R3a)N(R3e)-, -C(O)N(R3d)-, -N(R3d)C(O)-, -C(R3)(R3a)C(R3b)(R3c)-, -SO2N(R3d)- and -N(R3d)SO2- wherein each among R3, R3a, R3b and R3c, R3d, R3e when presents is taken independently among hydrogen atom and (C1-C6)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R4 and R4' are taken among hydrogen atom, (C1-C6)-alkyl and aryl; R5 represents 5 substitutes in phenyl ring J wherein each R5 is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR12, -N(R12)(R12'), (C1-C6)-alkyl, nitro-, aryl wherein R12 and R12' are taken among hydrogen atom and (C1-C6)-alkyl; or two substitutes R5 can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R6 and R6' are taken among hydrogen atom and (C1-C6)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R7 are substitutes at ring Ar wherein each R7 is taken among hydrogen, halogen atom, -NR13R13', (C1-C6)-alkyl and nitro- wherein R13 and R13' are taken among hydrogen atom and (C1-C6)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R8 and R8' are taken among hydrogen atom and (C1-C6)-alkyl; B is taken among -N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring and heterocycloalkyl ring wherein R14-R17, R20 and R21 are taken independently among hydrogen atom and (C1-C6)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R9' are taken among hydrogen atom and (C1-C6)-alkyl; R10 is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R11 wherein R11 is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R19)CH2C(O)NH2 wherein R19 represents (C1-C6)-alkyl, -NHCH2CH2OH and -N(CH3)CH2CH2OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: it is suggested to apply Pro-Gly-Pro tripeptide known as anticoagulant to keep stable norglycemia and stable normoinsulinemia in circulation at no side effects because the above-mentioned tripepetide is being natural human and animal metabolite.

EFFECT: higher efficiency of application.

3 cl, 5 ex, 2 tbl

FIELD: pharmaceutics.

SUBSTANCE: the set of components is suggested containing: (a) pharmaceutical preparation including low-molecular thrombin inhibitor or its pharmaceutically acceptable derivative in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier; and (b) pharmaceutical preparation including pre-medicine of low-molecular thrombin inhibitor or pharmaceutically acceptable derivative of this pre-medicine in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier, where components (a) and (b), each of them, should be taken in the form suitable to be introduced together; it is, also, suggested to apply this set of components for treating the state at which it is necessary or preferably to inhibit thrombin. The innovation enables to treat thrombotic states such as thrombosis of deep veins and pulmonary embolism.

EFFECT: higher efficiency of application.

30 cl, 1 tbl

FIELD: medicine, experimental medicine.

SUBSTANCE: one should introduce tripeptide Pro-Gly-Pro for laboratory animals as injections at the quantity of 0.09-1.0 mg/kg body weight, and, also, gelatin as fodder additive. The method suggested enables to suppress appetite, decrease the quantity of fodder intake that leads to decreased body weight as a result.

EFFECT: higher efficiency.

2 cl, 5 dwg, 5 ex

FIELD: medicine, chemistry of peptides, amino acids.

SUBSTANCE: invention relates to novel biologically active substances. Invention proposes the novel composition comprising peptides of the formula: H-Arg-Gly-Asp-OH and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys. The composition shows ability to inhibit proliferative activity of mononuclear cells, to induce suppressive activity and their ability for secretion of cytokines TNF-1β (tumor necrosis factor-1β) and IL-10 (interleukin-10 ).

EFFECT: simplified method for preparing composition, valuable medicinal properties of composition.

4 cl, 16 tbl, 9 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to a method for preparing foodstuff containing hypotensive peptides and it using as an anti-hypertensive agent that can be used as a foodstuff. Method involves stages for fermentation of casein-containing fermenting material with lactobacillus microorganism, nanofiltration of the prepared peptide-containing fermentation product and isolation of the product. Prepared product is used as an anti-hypertensive agent and as a foodstuff also. Invention provides preparing a foodstuff with the high content of hypotensive peptides enriched by bivalent ions.

EFFECT: improved preparing method of foodstuff.

22 cl, 1 dwg, 4 ex

Up!