Derivatives of peptides, the method of production thereof, pharmaceutical composition, inhibiting the human leukocyte elastase

 

(57) Abstract:

Usage: in pharmacology and medicine as inhibitors of elastase of human leukocytes. The essence of the invention: derivatives of peptides f-crystals I. Receiving lead by oxidation of the derived peptide f-crystals II, followed, if necessary, sulfonamideubul compounds, where R3- carboxy or ester group, converting the ester group of carboxylic acid to the corresponding carboxypropyl by hydrolysis. The pharmaceutical composition inhibiting the human leukocyte elastase, containing as active principle derived peptide I in the amount of 100 μg to 250 mg per dosage unit and a pharmaceutically acceptable carrier. The structure of the compounds of formulas I and II are indicated in the text description. 3 S. p. f-crystals, 2 tab.

Derivatives of the peptides of General formula

< / BR>
where R1is lower alkyl;

R2- lower alkyl, C6H5CH2OCONH(CH2)2C6H5SO2NH(CH2)4C6H5- X - R3- A - or R3AN(R6) CH (R5)CO, where A is OCO, CO, SO2, NHCO;

R3- C6H4(CH2)nwhere n= 0, 1, 2, 4, 2-NH2-5-Cl-phenyl, -C6H4OH, -CCH2, HOOC - C6H4(CH2)mwhere m = 1, 2, 4-CH3OC6H4- , 4-HOOC - C6H4- CH = CH-, 4-C2H5OOC - C6H4CH = CH-, 4-C2H5OOC - C6H4OCH2- C2H5OOCC6H4(CH2)2, 4-(H2NCOCH2) - C6H4O (CH2)3- , HOOC(CH2)2-, H3COOC-(CH2)2-, (C1- C4)-alkyl, CH3O(CH2)2O(CH2)2-, Z-isomer H2NCONHCOCH=CH-, 1-C2H5OOC-cyclopentyl, 1-HOOC-cyclopentyl-, H3C-O-(CH2)2O(CH2)2-, 1-substituted-, 2-(1-substituted)-ethyl-, 1-naphthyl, (1-naphthyl-SO2NHCO)C6H4-, (1-naphthyl-SO2NHCO)CH2CH2-, 4-ndimethylacetamide-C6H4(OCH2)k-, k= 0, 1, 2-(2-oxopyrrolidin)-ethyl-, 4-(CH3SO2NHCO)phenyl-, 2-(morpholinoethyl)-, 2-(2-pyridyl)-ethyl-, 2-(thienyl)-C1- C2-alkyl-, T,-SO2NHCO(CH2)2, where T is lower alkyl, phenyl, 1-substituted, 4-WC6H4SO2NHCOC6H4-, W is hydrogen, NO2, Br, Cl, 4-(4-Cl - C6H4SO2NHCO)C6H4(CH2)2-, 4-(4-Cl - C6H4SO2NHCO)C6H4CH = CH -, 4-(4-Br-C6H4SO2NH)CH2C6H4COC6H-, C6H5CH2OCO(CH2)2-.

2. The method of obtaining derivatives of the peptides of General formula

< / BR>
where R1is lower alkyl;

R2- lower alkyl, C6H5CH2OCO NH(CH2)2C6H5SO2NH(CH2)4C6H5-; X = R3- A - or R3AN(R6)CH(R5) CO -, where A - OCO -, CO, SO2, NHCO;

R3- C6H4(CH2)n, where n= 0, 1, 2, 4; 2-NH2-5-Cl-phenyl-, -C6H4OH, -C6H4COOH, 4-F-phenyl, 2, 4-di-Cl-phenyl, C1- C2-alkyl, OCOC6H4H3COOC-C6H4CH2-, HOOC - C6H4(CH2)m, where m = 1, 2, 4-CH3OC6H4-, 4-HOOC-C6H4-CH = CH -, 4-C2H5OOC-C6H4CH = CH -, 4-C2H5OOC-C6H4-OCH2- C2H5OOCC6H4(CH2)2,

4-(H2NCOCH2) - C6H4O (CH2)3-, HOOC (CH2)2-, H3COOC(CH2)2- C1- C4-alkyl, CH3O(CH2)2O(CH2)2-, Z-isomer H2NCONHCOCH = CH-, 1-C2H5OOC-cyclopentyl -, 1-HOOC-cyclopentyl, H3C-O-(CH2)2O(CH2)2-, 1-substituted-, 2-(1-substituted)-ethyl-, 1-naphthyl-, (1-naphthyl-SO23SO2NHCO)phenyl, 2-(morpholinoethyl)-, 2-(2-pyridyl)-ethyl-, 2-(thienyl)-C1- C2-alkyl, T-SO2NHCO(CH2)2, where T is lower alkyl, phenyl, 1-substituted, 4-WC6H4SO2NHCOC6H4-, W is hydrogen, NO2, Br, Cl; 4-(4-Cl-C6H4SO2NHCO)C6H4(CH2)2-, 4-(4-Cl-C6H4SO2NHCO)C6H4CH = CH-, 4-(4-Br-C6H4SO2NH)CH2C6H4COC 6H4-;

R4= R6is hydrogen;

R5- butyl, C6H5CH2OCONH(CH2)4- C6H5CH2OCO(CH2)2-,

characterized in that a derivative of the peptide of General formula

< / BR>
where the radicals have the above values,

subjected to oxidation, followed, if necessary, sulfonamideubul compounds, where R3- carboxypropyl, or ester group, or conversion of the ester group of carboxylic acid to the corresponding carboxypropyl by hydrolysis.

3. The pharmaceutical composition inhibiting the human leukocyte elastase, containing the active principle and a pharmaceutically acceptable carrier, characterized in that, as sports is B> - lower alkyl, C6H5-CH2OCONH(CH2)2C6H5SO2NH(CH2)4- C6H5-,

X = R3- A - or R3AN(R6)CH(R5)CO, where A is OCO, CO, SO2, NHCO;

R3- C6H4(CH2)nwhere n= 0, 1, 2, 4, 2- NH2- 5 - Cl-phenyl, -C6H4OH, -C6H4COOH, 4-F-phenyl, 2, 4-di-Cl-phenyl, C1- C2-alkyl-OCOC6H4-, H3COOC - C6H4CH2-, HOOC - C6H4(CH2)m- where m = 1, 2, 4-CH3OC6H4-, 4-HOOC-C6H4CH = CH -, 4-C2H5OOC - C6H4CH = CH-, 4-C2H5OOC - C6H4OCH2- C2H5OOCC6H4(CH2)2-, -(H2NCOCH2)C6H4O(CH2)3-, HOOC(CH2)2-, H3COOC - (CH2)2- C1- C4-alkyl, CH3O(CH2)2O(CH2)2-, Z-isomer H2NCONHCOCN = CH -, 1-C2H5OOC-cyclopentyl-,

1-HOOC-cyclopentyl-, H3C-O- (CH2)2O(CH2)2-, 1-substituted-, 2-(1-substituted)-ethyl-, 1-naphthyl, (1-naphthyl-SO2NHCO)-C6H4-, (1-naphthyl-SO2NHCO)CH2CH2-, 4-ndimethylacetamide-C6H4(OCH2)k-, k= 0, 1, 2-(2-oxopyrrolidin)-ethyl, 4-(C2)2, where T is lower alkyl, phenyl, 1-substituted, 4-W-C6H4- SO2NHCOC6H4-, W is hydrogen, NO2, Br, Cl, 4-(4-Cl-C6H4SO2NHCO)C6H4(CH2)2-, 4-(4-Cl - C6H4SO2NCO)C6H4CH = CH -, 4-(4Br-C6H4SO2NH)CH2C6H4COC6H4;

R4= R6is hydrogen;

R5-butyl, C6H5CH2OCONH(CH2)4- C6H5CH2OCO(CH2)2-,

in the amount of 100 μg to 250 mg per dosage unit.

 

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