N2 -arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof

Claim 2

An N 2 -arylsulfonyl-L-argininamide having the formula (I): ##STR823## or a pharmaceutically acceptable salt thereof, wherein R is ##STR824## wherein R 1 is --COOR 3 wherein R 3 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, C 7 -C 12 aralkyl or 5-indanyl; each R 2 independently is hydrogen, C 1 -C 10 alkyl, phenyl, C 1 -C 5 alkoxy, C 2 -C 6 alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R 1 is substituted into the piperidine ring at the 2 to 3 position; and R 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 1 -C 10 alkyl and C 2 -C 20 dialkylamino, and at least one substituent selected from the group consisting of C 1 -C 10 alkoxy, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 10 aralkyl, carbonyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydoxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy, or mixtures thereof; naphthyl substituted with at least one C 1 -C 5 alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof;

Claim 3

6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; C 7 -c 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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamino, carbamoy, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, metcapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C;hd 1-C 10 hydroxyalkyl, C 1 -C 10 haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, αs-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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamino, carbamoyl, C 3 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamic, carbamoyl, C 3 -C 10 N,N-dalkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 ;l hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof.

Claim 4

6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; C 7 -c 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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamino, carbamoy, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, metcapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C;hd 1-C 10 hydroxyalkyl, C 1 -C 10 haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; naphthoquinonyl, anthryl, phenanthryl, pentalenyl, heptalenyl, azulenyl, biphenylenyl, αs-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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamino, carbamoyl, C 3 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamic, carbamoyl, C 3 -C 10 N,N-dalkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 ;l hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof.

Claim 5

An N 2 -arylsulfonyl-L-argininamide having the formula (I): ##STR825## or a pharmaceutically acceptable salt thereof, wherein R is ##STR826## wherein R 1 is --COOR 3 wherein R 3 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, C 7 -C 12 aralkyl or 5-indanyl; each R 2 independently is hydrogen, C 1 -C 10 alkyl, phenyl, C 1 -C 5 alkoxy, C 2 -C 6 alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R 1 is substituted into the piperidine ring at the 2 or 3 position; and R 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 1 -C 10 alkyl and C 2 -C 10 dialkylamino, and at least one substituent selected from the group consisting of C 1 -C 10 alkoxy, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy, or mixtures thereof; naphthyl substituted with at least one C 1 -C 5 alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 hydroxylalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxylakyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof;

Claim 6

An N 2 -arylsulfonyl-L-argininamide having the formula (I): ##STR825## or a pharmaceutically acceptable salt thereof, wherein R is ##STR826## wherein R 1 is --COOR 3 wherein R 3 is hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, C 7 -C 12 aralkyl or 5-indanyl; each R 2 independently is hydrogen, C 1 -C 10 alkyl, phenyl, C 1 -C 5 alkoxy, C 2 -C 6 alkoxycarbonyl, or carboxy; n is an integer of 1 to 4, R 1 is substituted into the piperidine ring at the 2 or 3 position; and R 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 1 -C 10 alkyl and C 2 -C 10 dialkylamino, and at least one substituent selected from the group consisting of C 1 -C 10 alkoxy, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy, or mixtures thereof; naphthyl substituted with at least one C 1 -C 5 alkoxy and at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 hydroxylalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; naphthyl substituted with at least one substituent selected from the group consisting of sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxylakyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof;

Claim 7

6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxcarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; C 7 -c 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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C 1 -C 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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof.

Claim 8

6,7,8-tetrahydronaphthyl substituted with at least one substituent selected from the group consisting of halo, nitro, cyano, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxcarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof; C 7 -c 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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl, oxo and phenyl optionally substituted with at least one hydroxy, C 1 -C 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 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 2 -C 20 dialkylamino, sulfoamino, carbamoyl, C 3 -C 10 N,N-dialkylcarbamoyl, amino, C 1 -C 10 alkylamino, mercapto, C 1 -C 10 alkylthio, C 7 -C 12 aralkyl, carboxyl, C 2 -C 10 alkoxycarbonyl, C 2 -C 10 carboxyalkyl, C 1 -C 10 acylamino, C 2 -C 10 alkylcarbonyl, C 1 -C 10 hydroxyalkyl, C 1 -C 10 haloalkyl and phenyl optionally substituted with at least one hydroxy, C 1 -C 5 alkoxy or mixtures thereof.

Claim 9

The compound of claim 1, wherein said Ar group is substituted with at least one C 1 -C 5 alkoxy, C 1 -C 5 alkyl group or mixtures thereof.

Claim 10

The compound of claim 2, wherein said phenyl group is substituted with at least one C 1 -C 5 alkoxy group.

Claim 11

A method of inhibiting activity and suppressing activation of thrombin in vivo which comprises administering to a mammal a pharmaceutically effective amount of a compound of claim 1.

Claim 12

A method of inhibiting activity and suppressing activation of thrombin in vivo which comprises administering to a mammal a pharmaceutically effective amount of a compound of claim 2.