RU2053228C1 - Peptide derivatives, method of their synthesis, pharmaceutical composition inhibiting human leukocyte elastase activity - Google Patents

Peptide derivatives, method of their synthesis, pharmaceutical composition inhibiting human leukocyte elastase activity Download PDF

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RU2053228C1
RU2053228C1 SU4024099A RU2053228C1 RU 2053228 C1 RU2053228 C1 RU 2053228C1 SU 4024099 A SU4024099 A SU 4024099A RU 2053228 C1 RU2053228 C1 RU 2053228C1
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nhco
phenyl
hooc
alkyl
ooc
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Хавен Бергесон Скотт
Дьюк Эдвардс Филип
Энтони Шварц Джон
Шоу Эндрю
Моррис Стейн Марк
Эми Трейнор Диане
Алан Вилдонгер Ричард
Джон Воланин Дональд
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Ай-Си Ай Америказ Инк.
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Priority claimed from GB858501523A external-priority patent/GB8501523D0/en
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Abstract

FIELD: organic chemistry. SUBSTANCE: products: peptide derivatives of the formula (I). Synthesis is carried out by oxidation of peptide derivative of the formula (II) followed by if necessary sulfoamination of compound where R3 - carboxy- or ester-group, conversion of carboxylic acid ester-group to the corresponding carboxy-group by hydrolysis. Pharmaceutical composition inhibiting human leukocyte elastase activity has derivatives of peptide (I) as an active substance at the dose 100-250 mg per unit and pharmaceutically acceptable carrier. Structure of compounds of the formulas (I) and (II) is given in description text. Synthesized compounds were used in pharmacology. EFFECT: improved method of synthesis. 4 cl, 2 tbl

Claims (3)

Производные пептидов общей формулы
Figure 00000001

где R1 - низший алкил;
R2 - низший алкил, C6H5CH2OCONH(CH2)2, C6H5SO2NH(CH2)4, C6H5 -; X - R3 - A - или R3 - AN(R6) CH (R5)CO, где A - OCO, CO, SO2, NHCO;
R3 - C6H4(CH2)n, где n = 0, 1, 2, 4, 2-NH2-5-Cl-фенил, -C6H4OH, -C6H4COOH, 4-F-фенил, 2,4-ди-Cl-фенил, C1 - C2-алкил, OCOC6H4, H3COOC - C6H4CH2, HOOC - C6H4(CH2)m, где 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)-алкил, CH3O(CH2)2O(CH2)2-, Z-изомер H2NCONHCOCH=CH-, 1-C2H5OOC-циклопентил, 1-HOOC-циклопентил-, H3C-O-(CH2)2O(CH2)2-, 1-адамантил-, 2-(1-адамантил)-этил-, 1-нафтил, (1-нафтил-SO2NHCO)C6H4 -, (1-нафтил-SO2NHCO)CH2CH2 -, 4-ацетамид-C6H4(OCH2)k -, k = 0, 1, 2-(2-оксопирролидинил)-этил-, 4-(CH3SO2NHCO)фенил-, 2-(морфолиноэтил)-, 2-(2-пиридил)-этил-, 2-(тиенил)-C1 - C2-алкил-, T-SO2NHCO(CH2)2, где T - низший алкил, фенил, 1-адамантил, 4-WC6H4SO2 NHCOC6H4-, W - водород, NO2, Br, Cl, 4-(4-Cl - C6H4 SO2NHCO)C6H4(CH2)2 -, 4-(4-Cl - C6H4SO2NHCO)C6H4CH = CH -, 4-(4-Br-C6H4SO2NH)CH2C6H4COC6H4 -;
R4 = R6 - водород;
R5 - бутил, C6H5 CH2OCONH(CH2)4-, C6H5CH2OCO(CH2)2 -.Derivatives of peptides of the general formula
Figure 00000001

where R 1 is lower alkyl;
R 2 is lower alkyl, C 6 H 5 CH 2 OCONH (CH 2 ) 2 , C 6 H 5 SO 2 NH (CH 2 ) 4 , C 6 H 5 -; X is R 3 - A - or R 3 - AN (R 6 ) CH (R 5 ) CO, where A is OCO, CO, SO 2 , NHCO;
R 3 - C 6 H 4 (CH 2 ) n , where n = 0, 1, 2, 4, 2-NH 2 -5-Cl-phenyl, -C 6 H 4 OH, -C 6 H 4 COOH, 4 -F-phenyl, 2,4-di-Cl-phenyl, C 1 - C 2 -alkyl, OCOC 6 H 4 , H 3 COOC - C 6 H 4 CH 2 , HOOC - C 6 H 4 (CH 2 ) m where m = 1, 2, 4-CH 3 OC 6 H 4 -, 4-HOOC - C 6 H 4 - CH = CH-, 4-C 2 H 5 OOC - C 6 H 4 CH = CH-, 4 -C 2 H 5 OOC - C 6 H 4 OCH 2 -, C 2 H 5 OOCC 6 H 4 (CH 2 ) 2 , 4- (H 2 NCOCH 2 ) - C 6 H 4 O (CH 2 ) 3 -, HOOC (CH 2 ) 2 -, H 3 COOC- (CH 2 ) 2 -, (C 1 - C 4 ) -alkyl, CH 3 O (CH 2 ) 2 O (CH 2 ) 2 -, Z-isomer H 2 NCONHCOCH = CH-, 1-C 2 H 5 OOC-cyclopentyl, 1-HOOC-cyclopentyl-, H 3 CO- (CH 2 ) 2 O (CH 2 ) 2 -, 1-adamantyl-, 2- (1-adamantyl ) -ethyl-, 1-naphthyl, (1-naphthyl-SO 2 NHCO) C 6 H 4 -, (1-naphthyl-SO 2 NHCO) CH 2 CH 2 -, 4-acetamide-C 6 H 4 (OCH 2 ) k -, k = 0, 1, 2- (2-oxopyrrolidinyl) -ethyl-, 4- (CH 3 SO 2 NHCO) phenyl-, 2- (morpholinoethyl) -, 2- (2-pyridi l) ethyl, 2- (thienyl) -C 1 - C 2 -alkyl-, T-SO 2 NHCO (CH 2 ) 2 , where T is lower alkyl, phenyl, 1-adamantyl, 4-WC 6 H 4 SO 2 NHCOC 6 H 4 -, W - hydrogen, NO 2 , Br, Cl, 4- (4-Cl - C 6 H 4 SO 2 NHCO) C 6 H 4 (CH 2 ) 2 -, 4- (4- Cl - C 6 H 4 SO 2 NHCO) C 6 H 4 CH = CH -, 4- (4-Br-C 6 H 4 SO 2 NH) CH 2 C 6 H 4 COC 6 H 4 -;
R 4 = R 6 is hydrogen;
R 5 is butyl, C 6 H 5 CH 2 OCONH (CH 2 ) 4 -, C 6 H 5 CH 2 OCO (CH 2 ) 2 -. 2. Способ получения производных пептидов общей формулы
Figure 00000002

где R1 - низший алкил;
R2 - низший алкил, C6H5CH2OCO NH(CH2)2, C6H5SO2NH(CH2)4, C6H5-; X = R3 - A - или R3 - AN(R6)CH(R5) CO -, где A - OCO -, CO, SO2, NHCO;
R3 - C6H4(CH2)n, где n = 0, 1, 2, 4; 2-NH2-5-Cl-фенил-, -C6H4OH, -C6H4COOH, 4-F-фенил, 2, 4-ди-Cl-фенил, C1 - C2-алкил, OCOC6H4, H3COOC-C6H4CH2 -, HOOC - C6H4(CH2)m, где 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-алкил, CH3O(CH2)2O(CH2)2-, Z-изомер H2NCONHCOCH = CH-, 1-C2H5OOC-циклопентил -, 1-HOOC-циклопентил, H3C-O-(CH2)2O(CH2)2 -, 1-адамантил-, 2-(1-адамантил)-этил-, 1-нафтил-, (1-нафтил-SO2NHCO)C6H4 -, (1-нафтил-SO2NHCO)CH2CH2 -, 4-ацетамид-C6H4(OCH2)k -, k = 0, 1, 2-(2-оксопирролидинил)-этил-, 4-(CH3SO2NHCO)фенил, 2-(морфолиноэтил)-, 2-(2-пиридил)-этил-, 2-(тиенил)-C1 - C2-алкил, T-SO2 NHCO(CH2)2, где T - низший алкил, фенил, 1-адамантил, 4-WC6H4SO2NHCOC6H4-, W - водород, NO2, Br, Cl; 4-(4-Cl-C6H4SO2 NHCO)C6H4(CH2)2 -, 4-(4-Cl-C6H4SO2NHCO)C6H4CH = CH-, 4-(4-Br-C6H4SO2NH)CH2C6H4COC 6H4-;
R4 = R6 - водород;
R5 - бутил, C6H5CH2OCONH(CH2)4-, C6H5CH2OCO(CH2)2 -,
отличающийся тем, что производное пептида общей формулы
Figure 00000003

где радикалы имеют указанные значения,
подвергают окислению с последующим, в случае необходимости, сульфонамидированием соединения, где R3 - карбоксигруппа, или сложноэфирная группа, или превращением сложноэфирной группы карбоновой кислоты в соответствующую карбоксигруппу путем гидролиза.2. A method of obtaining derivatives of peptides of the General formula
Figure 00000002

where R 1 is lower alkyl;
R 2 is lower alkyl, C 6 H 5 CH 2 OCO NH (CH 2 ) 2 , C 6 H 5 SO 2 NH (CH 2 ) 4 , C 6 H 5 -; X = R 3 - A - or R 3 - AN (R 6 ) CH (R 5 ) CO -, where A is OCO -, CO, SO 2 , NHCO;
R 3 is C 6 H 4 (CH 2 ) n, where n = 0, 1, 2, 4; 2-NH 2 -5-Cl-phenyl-, -C 6 H 4 OH, -C 6 H 4 COOH, 4-F-phenyl, 2, 4-di-Cl-phenyl, C 1 - C 2 -alkyl, OCOC 6 H 4 , H 3 COOC-C 6 H 4 CH 2 -, HOOC - C 6 H 4 (CH 2 ) m, where m = 1, 2, 4-CH 3 OC 6 H 4 -, 4-HOOC- C 6 H 4 -CH = CH -, 4-C 2 H 5 OOC-C 6 H 4 CH = CH -, 4-C 2 H 5 OOC-C 6 H 4 -OCH 2 -, C 2 H 5 OOCC 6 H 4 (CH 2 ) 2 ,
4- (H 2 NCOCH 2 ) - C 6 H 4 O (CH 2 ) 3 -, HOOC (CH 2 ) 2 -, H 3 COOC (CH 2 ) 2 -, C 1 - C 4 -alkyl, CH 3 O (CH 2 ) 2 O (CH 2 ) 2 -, Z-isomer of H 2 NCONHCOCH = CH-, 1-C 2 H 5 OOC-cyclopentyl -, 1-HOOC-cyclopentyl, H 3 CO- (CH 2 ) 2 O (CH 2 ) 2 -, 1-adamantyl-, 2- (1-adamantyl) -ethyl-, 1-naphthyl-, (1-naphthyl-SO 2 NHCO) C 6 H 4 -, (1-naphthyl-SO 2 NHCO) CH 2 CH 2 -, 4-acetamide-C 6 H 4 (OCH 2 ) k -, k = 0, 1, 2- (2-oxopyrrolidinyl) ethyl, 4- (CH 3 SO 2 NHCO) phenyl , 2- (morpholinoethyl) -, 2- (2-pyridyl) -ethyl-, 2- (thienyl) -C 1 - C 2 -alkyl, T-SO 2 NHCO (CH 2 ) 2 , where T is lower alkyl, phenyl, 1-adamantyl, 4-WC 6 H 4 SO 2 NHCOC 6 H 4 -, W is hydrogen, NO 2 , Br, Cl; 4- (4-Cl-C 6 H 4 SO 2 NHCO) C 6 H 4 (CH 2 ) 2 -, 4- (4-Cl-C 6 H 4 SO 2 NHCO) C 6 H 4 CH = CH-, 4- (4-Br-C 6 H 4 SO 2 NH) CH 2 C 6 H 4 COC 6 H 4 -;
R 4 = R 6 is hydrogen;
R 5 - butyl, C 6 H 5 CH 2 OCONH (CH 2 ) 4 -, C 6 H 5 CH 2 OCO (CH 2 ) 2 -,
characterized in that the peptide derivative of the General formula
Figure 00000003

where the radicals have the indicated meanings,
subjected to oxidation, followed by, if necessary, sulfonamidation of the compound, where R 3 is a carboxy group or an ester group, or by conversion of the ester group of a carboxylic acid into the corresponding carboxy group by hydrolysis. 3. Фармацевтическая композиция, ингибирующая эластазу человеческих лейкоцитов, содержащая активное начало и фармацевтически приемлемый носитель, отличающаяся тем, что в качестве активного начала она содержит производные пептидов общей формулы
Figure 00000004

где R1 - низший алкил;
R2 - низший алкил, C6H5-CH2OCONH(CH2)2, C6H5SO2NH(CH2)4-, C6H5 -,
X = R3 - A - или R3 - AN(R6)CH(R5)CO, где A - OCO, CO, SO2, NHCO;
R3 - C6H4(CH2)n, где n = 0, 1, 2, 4, 2- NH2 - 5 - Cl-фенил, -C6H4OH, -C6H4COOH, 4-F-фенил, 2, 4-ди-Cl-фенил, C1 - C2-алкил-OCOC6H4 -, H3COOC - C6H4CH2 -, HOOC - C6H4(CH2)m -, где 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-алкил, CH3O(CH2)2O(CH2)2-, Z-изомер H2NCONHCOCN = CH -, 1-C2H5OOC-циклопентил-,
1-HOOC-циклопентил-, H3C-O- (CH2)2O(CH2)2 -, 1-адамантил-, 2-(1-адамантил)-этил-, 1-нафтил, (1-нафтил-SO2NHCO)-C6H4-, (1-нафтил-SO2NHCO)CH2CH2 -, 4-ацетамид-C6H4(OCH2)k -, k = 0, 1, 2-(2-оксопирролидинил)-этил, 4-(CH2SO2NHCO)фенил, 2-морфолиноэтил, 2-(2-пиридил)-этил-, 2-(тиенил)-C1 - C2-алкил, T - SO2NHCO(CH2)2, где T - низший алкил, фенил, 1-адамантил, 4-W -C6H4 - SO2NHCOC6H4 -, W - водород, NO2, Br, Cl, 4-(4-Cl-C6H4SO2NHCO)C6H4(CH2)2 -, 4-(4-Cl - C6H4SO2NCO)C6H4CH = CH -, 4-(4Br-C6H4SO2NH)CH2C6H4COC6H4;
R4 = R6 - водород;
R5-бутил, C6H5CH2OCONH(CH2)4 -, C6H5CH2OCO(CH2)2 -,
в количестве 100 мкг - 250 мг на дозируемую единицу.3. A pharmaceutical composition that inhibits human leukocyte elastase, containing an active principle and a pharmaceutically acceptable carrier, characterized in that it contains derivatives of peptides of the general formula as an active principle
Figure 00000004

where R 1 is lower alkyl;
R 2 is lower alkyl, C 6 H 5 -CH 2 OCONH (CH 2 ) 2 , C 6 H 5 SO 2 NH (CH 2 ) 4 -, C 6 H 5 -,
X = R 3 - A - or R 3 - AN (R 6 ) CH (R 5 ) CO, where A is OCO, CO, SO 2 , NHCO;
R 3 - C 6 H 4 (CH 2 ) n , where n = 0, 1, 2, 4, 2 - NH 2 - 5 - Cl-phenyl, -C 6 H 4 OH, -C 6 H 4 COOH, 4 -F-phenyl, 2, 4-di-Cl-phenyl, C 1 - C 2 -alkyl-OCOC 6 H 4 -, H 3 COOC - C 6 H 4 CH 2 -, HOOC - C 6 H 4 (CH 2 ) m -, where m = 1, 2, 4-CH 3 OC 6 H 4 -, 4-HOOC-C 6 H 4 CH = CH -, 4-C 2 H 5 OOC - C 6 H 4 CH = CH- , 4-C 2 H 5 OOC - C 6 H 4 OCH 2 -, C 2 H 5 OOCC 6 H 4 (CH 2 ) 2 -, - (H 2 NCOCH 2 ) C 6 H 4 O (CH 2 ) 3 - , HOOC (CH 2 ) 2 -, H 3 COOC - (CH 2 ) 2 -, C 1 - C 4 -alkyl, CH 3 O (CH 2 ) 2 O (CH 2 ) 2 -, Z-isomer H 2 NCONHCOCN = CH -, 1-C 2 H 5 OOC-cyclopentyl-,
1-HOOC-cyclopentyl-, H 3 CO- (CH 2 ) 2 O (CH 2 ) 2 -, 1-adamantyl-, 2- (1-adamantyl) -ethyl-, 1-naphthyl, (1-naphthyl-SO 2 NHCO) -C 6 H 4 -, (1-naphthyl-SO 2 NHCO) CH 2 CH 2 -, 4-acetamide-C 6 H 4 (OCH 2 ) k -, k = 0, 1, 2- (2 -oxopyrrolidinyl) ethyl, 4- (CH 2 SO 2 NHCO) phenyl, 2-morpholinoethyl, 2- (2-pyridyl) ethyl, 2- (thienyl) -C 1 - C 2 -alkyl, T - SO 2 NHCO (CH 2 ) 2 , where T is lower alkyl, phenyl, 1-adamantyl, 4-W -C 6 H 4 - SO 2 NHCOC 6 H 4 -, W is hydrogen, NO 2 , Br, Cl, 4- ( 4-Cl-C 6 H 4 SO 2 NHCO) C 6 H 4 (CH 2 ) 2 -, 4- (4-Cl - C 6 H 4 SO 2 NCO) C 6 H 4 CH = CH -, 4- ( 4Br-C 6 H 4 SO 2 NH) CH 2 C 6 H 4 COC 6 H 4 ;
R 4 = R 6 is hydrogen;
R 5 -butyl, C 6 H 5 CH 2 OCONH (CH 2 ) 4 -, C 6 H 5 CH 2 OCO (CH 2 ) 2 -,
in the amount of 100 μg - 250 mg per dosage unit.
SU4024099 1985-01-22 1986-01-21 Peptide derivatives, method of their synthesis, pharmaceutical composition inhibiting human leukocyte elastase activity RU2053228C1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB858501524A GB8501524D0 (en) 1985-01-22 1985-01-22 Tetrapeptide derivatives
GB8501524 1985-01-22
GB8501523 1985-01-22
GB858501523A GB8501523D0 (en) 1985-01-22 1985-01-22 Tripeptide derivatives

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MD1929C2 (en) * 2001-07-19 2002-11-30 Олег БАЕВ Process for obtaining of matured spirituous distillates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Европейский патент 0124317, кл. C 07C103/52, опублик. 1981 г. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MD1929C2 (en) * 2001-07-19 2002-11-30 Олег БАЕВ Process for obtaining of matured spirituous distillates

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