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US 4,066,773 AGranted
N.sup.2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
AssigneesMitsubishi Chemical Industries Limited, Shosuke Okamoto
InventorsShosuke Okamoto, Akiko Hijikata, Ryoji Kikumoto, Yoshikuno Tamao, Kazuo Ohkubo, Tohru Tezuka, Shinji Tonomura
Life of this patent
Estimating the term…
Abstract
N.sup.2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof have been found to be effective as pharmaceutical agents for the inhibition and suppression of thrombosis in mammals.
Claims6
An N.sup.2 -arylsulfonyl-L-argininamide having the formula (I):
- ##STR823## or a pharmaceutically acceptable salt thereof, wherein R is ##STR824## wherein R.sub.1 is --COOR.sub.3 wherein R.sub.3 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.12 aralkyl or 5-indanyl;
- each R.sub.2 independently is hydrogen, C.sub.1 -C.sub.10 alkyl, phenyl, C.sub.1 -C.sub.5 alkoxy, C.sub.2 -C.sub.6 alkoxycarbonyl, or carboxy;
- n is an integer of 1 to 4, R.sub.1 is substituted into the piperidine ring at the 2 to 3 position;
- and R.sub.2 is substituted into the piperidine ring at the 2, 3, 4, 5 or 6 position;
- and Ar is naphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C.sub.1 -C.sub.10 alkyl and C.sub.2 -C.sub.20 dialkylamino,
- and at least one substituent selected from the group consisting of C.sub.1 -C.sub.10 alkoxy, sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.10 aralkyl, carbonyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydoxyalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy, or mixtures thereof;
- naphthyl substituted with at least one C.sub.1 -C.sub.5 alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof;
- naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof;
- 5. 6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof;
- C.sub.7 -c.sub.12 aralkyl, 9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxyphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl or isoindolinyl, group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.2 -C.sub.20 dialkylamino, sulfoamino, carbamoy, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, metcapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C;hd 1-C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof;
- naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, .alpha.s-indacenyl, s-indacenyl, acenaphthylenyl, phenylcarbonylphenyl, phenoxyphenyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, isobenzothienyl, oxanthrenyl, thianthrenyl, dibenzofuranyl, dibenzothienyl, phenoxathiinyl, indolyl, IH-indazolyl, 1,8-naphthyridinyl, carbazolyl, or benzimidazolyl group, any of which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.2 -C.sub.20 dialkylamino, sulfoamino, carbamoyl, C.sub.3 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.2 -C.sub.20 dialkylamino, sulfoamic, carbamoyl, C.sub.3 -C.sub.10 N,N-dalkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 ;l hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof.
8 more elements
An N.sup.2 -arylsulfonyl-L-argininamide having the formula (I):
- ##STR825## or a pharmaceutically acceptable salt thereof, wherein R is ##STR826## wherein R.sub.1 is --COOR.sub.3 wherein R.sub.3 is hydrogen, C.sub.1 -C.sub.10 alkyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.12 aralkyl or 5-indanyl;
- each R.sub.2 independently is hydrogen, C.sub.1 -C.sub.10 alkyl, phenyl, C.sub.1 -C.sub.5 alkoxy, C.sub.2 -C.sub.6 alkoxycarbonyl, or carboxy;
- n is an integer of 1 to 4, R.sub.1 is substituted into the piperidine ring at the 2 or 3 position;
- and R.sub.2 is substituted into the piperidine ring at the 2, 3, 4, 5 or 6 position;
- and Ar is naphthyl substituted with at least one subitituent selected from the group consisting of halo, nitro, cyano, hydroxy, C.sub.1 -C.sub.10 alkyl and C.sub.2 -C.sub.10 dialkylamino,
- and at least one substituent selected from the group consisting of C.sub.1 -C.sub.10 alkoxy, sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy, or mixtures thereof;
- naphthyl substituted with at least one C.sub.1 -C.sub.5 alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 hydroxylalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof;
- naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, .sub.C.sub.2 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydroxylakyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof;
- 5. 6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxcarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof;
- C.sub.7 -c.sub.12 aralkyl-9,10-dihydroanthryl, 5,6,7,8-tetrahydroanthyryl, 9,10-dihydrophenanthryl, 1,2,3,4,5,6,7,8-octahydrophenanthryl, indenyl, indanyl, fluorenyl, acenaphthenyl, phenylthiophenyl, 1,2-ethylenedioxyphenyl, chromanyl, isochromanyl, 2,3-dihydrogenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-ethylenedioxynaphthyl, xanthenyl, thioxanthenyl, 1,2-trimethylenedioxylphenyl, 2H-chromenyl, 3,4-dehydro-1-isochromanyl, 4H-chromenyl, indolinyl or isoindolinyl, any of wich is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.2 -C.sub.20 dialkylamino, sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof;
- a phenyl which is unsubstituted or substituted with one or more groups selected from the group consisting of halo, nitro, cyano, hydroxy, C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.2 -C.sub.20 dialkylamino, sulfoamino, carbamoyl, C.sub.3 -C.sub.10 N,N-dialkylcarbamoyl, amino, C.sub.1 -C.sub.10 alkylamino, mercapto, C.sub.1 -C.sub.10 alkylthio, C.sub.7 -C.sub.12 aralkyl, carboxyl, C.sub.2 -C.sub.10 alkoxycarbonyl, C.sub.2 -C.sub.10 carboxyalkyl, C.sub.1 -C.sub.10 acylamino, C.sub.2 -C.sub.10 alkylcarbonyl, C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C.sub.1 -C.sub.5 alkoxy or mixtures thereof.
8 more elements
Dependencies are inferred from the claim text.