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US 5,399,585 AGranted
Carboxamides and sulfonamides compounds which have useful pharmaceutical utility
AssigneeHoffmann-La Roche Inc.
InventorsLeo Alig, Albrecht Edenhofer, Marcel Muller, Arnold Trzeciak, Thomas Weller
Life of this patent
Estimating the term…
Abstract
Novel carboxamides and sulfonamides are described having of the formula R.sup.1 --A--(W).sub.a --X--(CH.sub.2).sub.b --(Y).sub.c --B--Z--COOR(I), in which R.sup.1, A, W, X, Y, B, Z, R, a, b and c are as provided in the description. These compounds are useful in the treatment of thromboses, apoplexy, myocardial infarct, inflammations, arteriosclerosis as well as in the treatment and prevention of tumors. These novel compounds are prepared by eliminating the protective groups in corresponding compounds with protected amidino or guanidino groups.
Claims19
A compound of the formula
- R.sup.1 --A--(W).sub.a --X--(CH.sub.2).sub.b --(Y).sub.c --B--Z--COOR(I)
- in which
- A is ##STR3## B is ##STR4## W is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.3 --, --CH.sub.2 CH(CH.sub.3)--, --COCH.sub.2 --, --CH(OH)CH.sub.2 -- or --CH.sub.2 COCH.sub.2 --;
- X is --CONR.sup.2 --, --NR.sup.2 CO--, --SO.sub.2 NR.sup.2 -- or --NR.sup.2 SO.sub.2 --;
- Y is --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 O--, --OCH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH--, --C(Q.sup.1, Q.sup.2)--CO(CH.sub.2).sub.4 --, --CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, --CH(CH.sub.3)CH.sub.2 CH.sub.2 --, --CH.sub.2 COCH.sub.2 --, --C(Q.sup.1,Q.sup.2)--CH(OH)--, --C(Q.sup.1,Q.sup.2)-- CH(SSCH.sub.3)--, --CH(CH.sub.2 OH)CH.sub.2 or --CH(COOR)CH.sub.2 --, wherein the carbonyl groups may be in the form of oxime, oxime ether, ketal or thioketal or enol ether and the hydroxyl groups may be in the form of lower alkyl ether, di(lower alkyl)amino-lower-alkyl ether or of ester of lower alkanecarboxylic acids;
- Z is --OCH.sub.2 --, --NR.sup.6 CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.sub.2 --, --CH.dbd.CH-- or --C(CH.sub.3).dbd.CH--;
- R is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl;
- Q.sup.1 and Q.sup.2 are hydrogen or lower alkyl or form, together with the C atom to which they are bonded, a 3- to 6-membered saturated ring;
- R.sup.1 is amidino or guanidino;
- R.sup.2 is hydrogen, lower alkyl, phenyl-lower-alkyl, phenyl-lower-alkyl which is substituted in the phenyl moiety by amino, amidino or --COOR, or a radical --CH.sub.2 COOR or --Y--B--X--COOR;
- R.sup.3 is hydrogen, lower alkyl, lower alkoxy, halogen, lower carbalkoxy, amino, lower alkylamino, di-lower-alkylamino or amidino;
- R.sup.4 is hydrogen, lower alkyl, lower alkoxy, halogen, lower carbalkoxy, amino, lower alkylamino, di-lower-alkyl-amino or a radical --Z--COOR or --CH.dbd.CH(CH.sub.2).sub.n COOR;
- R.sup.6 is hydrogen, lower alkyl or benzyl;
- n is an integer of 0-4;
- a, c and d each are 0 or 1;
- b is an integer of 0-2, where a and b are 0 when c is 1, and c is 0 when a or b is different from 0;
- or the physiologically acceptable salts thereof.
14 more elements
A pharmaceutical composition comprising a compound of the formula
- R.sup.1 --A--(W).sub.a --X--(CH.sub.2).sub.b (Y).sub.c--B--Z--COOR(I)
- in which
- A is ##STR5## B is ##STR6## W is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.3 --, --CH.sub.2 CH(CH.sub.3)--, --COCH.sub.2 --, --CH(OH)CH.sub.2 -- or --CH.sub.2 COCH.sub.2 --;
- X is --CONR.sup.2 --, --NR.sup.2 CO--, --SO.sub.2 NR.sup.2 -- or --NR.sup.2 SO.sub.2 --;
- Y is --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 O--, --OCH.sub.2 --, --CH (CH.sub.3)CH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH--, --C(Q.sup.1, Q.sup.2)--CO(CH.sub.2).sub.d --, --CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, --CH(CH.sub.3)CH.sub.2 CH.sub.2 --, --CH.sub.2 COCH.sub.2 --, --C(Q.sup.1,Q.sup.2)--CH(OH)--, --C(Q.sup.1,Q.sup.2)-- CH(SSCH.sub.3)--, --CH(CH.sub.2 OH)CH.sub.2 -- or --CH(COOR)CH.sub.2 --, wherein the carbonyl groups may be in the form of oxime, oxime ether, ketal or thioketal or enol ether and the hydroxyl groups may be in the form of lower alkyl ether, di(lower alkyl)amino-lower-alkyl ether or of ester of lower alkanecarboxylic acids;
- Z is --OCH.sub.2 --, --NR.sup.6 CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.sub.2 --, --CH.dbd.CH-- or --C(CH.sub.2).dbd.CH--;
- R is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl;
- Q.sup.1 and Q.sup.2 are hydrogen or lower alkyl or form, together with the C atom to which they are bonded, a 3- to 6-membered saturated ring;
- R.sup.1 is amidino or guanidino;
- R.sup.2 is hydrogen, lower alkyl, phenyl-lower-alkyl, phenyl-lower-alkyl which is substituted in the phenyl moiety by amino, amidino or --COOR, or a radical --CH.sub.2 COOR or --Y--B--X--COOR;
- R.sup.3 is hydrogen, lower alkyl, lower alkoxy, halogen, lower carbalkoxy, amino, lower alkylamino, di-lower-alkylamino or amidino;
- R.sup.4 is hydrogen, lower alkyl, lower alkoxy, halogen, lower carbalkoxy, amino, lower alkylamino, di-lower-alkyl-amino or a radical --Z--COOR or --CH.dbd.CH(CH.sub.2).sub.n COOR;
- R.sup.6 is hydrogen, lower alkyl or benzyl;
- n is an integer of 0-4;
- a, c and d each are 0 or 1;
- b is an integer of 0-2, where a and b are 0 when c is 1, and c is 0 when a or b is different from 0;
- or the physiologically acceptable salts thereof;
- together with one or more excipients or carriers.
15 more elements
A method of treating thromboses, apoplexy, myocardial infarct, inflammations and arteriosclerosis comprising administering an effective amount of a compound of the formula
- R.sup.1 --A--(W).sub.a --X--(CH.sub.2).sub.b --(Y).sub.c --B--Z--COOR(I)
- in which
- A is ##STR7## B is ##STR8## W is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.3 --, --CH.sub.2 CH(CH.sub.3)--, --COCH.sub.2 --, --CH(OH)CH.sub.2 -- or --CH.sub.2 COCH.sub.2 --;
- W is --CONR.sup.2 --, --NR.sup.2 CO--, --SO.sub.2 NR.sup.2 -- or --NR.sup.2 SO.sub.2 --;
- Y is --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 O--, --OCH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH--, C(Q.sup.1, Q.sup.2)--CO(CH.sub.2).sub.d --, --CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, --CH(CH.sub.3)CH.sub.2 CH.sub.2 --, --CH.sub.2 COCH.sub.2 --, --C(Q.sup.1,Q.sup.2)--CH(OH)--, --C(Q.sup.1, Q.sup.2)-- CH(SSCH.sub.3)--, --CH(CH.sub.2 OH)CH.sub.2 -- or --CH(COOR)CH.sub.2 --, wherein the carbonyl groups may be in the form of oxime, oxime ether, ketal or thioketal or enol ether and the hydroxyl groups may be in the form of lower alkyl ether, di(lower-alkyl)amino-lower-alkyl ether or of ester of lower alkanecarboxylic acids;
- is --OCH.sub.2 --, --NR.sup.6 CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH(CH.sub.3)CH.sub.2 --, --CH.sub.2 --, --CH.dbd.CH-- or --C(CH.sub.3).dbd.CH--;
- R is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl;
- Q.sup.1 and Q.sup.2 are hydrogen or lower alkyl or form, together with the C atom to which they are bonded, a 3- to 6-membered saturated ring;
- R.sup.1 is amidino or guanidino;
- R.sup.2 is hydrogen, lower alkyl, phenyl-lower-alkyl, phenyl-lower-alkyl which is substituted in the phenyl moiety by amino, amidino or --COOR, or a radical --CH.sub.2 COOR or --Y--B--X--COOR;
- R.sup.3 is hydrogen, lower alkyl, lower alkoxy, halogen, lower carbalkoxy, amino, lower alkylamino, di-lower-alkylamino or amidino;
- R.sup.4 is hydrogen, lower alkyl, lower alkoxy, halogen, lower carbalkoxy, amino, lower alkylamino, di-lower-alkyl-amino or a radical -Z-COOR or --CH.dbd.CH(CH.sub.2).sub.n COOR;
- R.sup.6 is hydrogen, lower alkyl or benzyl;
- n is an integer of 0-4;
- a, c and d each are 0 or 1;
- b is an integer of 0-2, where a and b are 0 when c is 1, and c is 0 when a or b is different from 0;
- or the physiologically acceptable salts thereof.
14 more elements
Dependencies are inferred from the claim text.