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US 5,863,949 AGranted
Arylsulfonylamino hydroxamic acid derivatives
AssigneePfizer Inc.
InventorsRalph P. Robinson, James P. Rizzi
Life of this patent
Estimating the term…
Abstract
A compound of formula (I), wherein n, X, R.sup.3, R.sup.4 and Ar are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. ##STR1##
Claims13
A compound of the formula ##STR9## or the pharmaceutically acceptable salts thereof, wherein n is 1 to 6:
- X is hydroxy, (C.sub.1 -C.sub.6)alkoxy or NR.sup.1 R.sup.2 wherein R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.3 -C.sub.6)cycloalkyl(C.sub.1 -C.sub.6)alkyl, R.sup.5 (C.sub.2 -C.sub.6)alkyl, (C.sub.1 -C.sub.5)alkyl(CHR.sup.5)(C.sub.1 -C.sub.6)alkyl wherein R.sup.5 is hydroxy, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkoxy (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)alkylthio, (C.sub.6 -C.sub.10)arylthio, (C.sub.1 -C.sub.10)alkylsulfinyl, (C.sub.6 -C.sub.10)arylsulfinyl, (C.sub.1 -C.sub.6)alkylsulfoxyl, (C.sub.6 -C.sub.10)arylsulfoxyl, amino, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino;
- and CH(R.sup.7)COR.sup.8 wherein R.sup.7 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl(C.sub.1 C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)alkyl, R.sup.9 R.sup.10 NCO(C.sub.1 -C.sub.6)alkyl or R.sup.9 OCO(C.sub.1 -C.sub.6)alkyl wherein R.sup.9 and R.sup.10 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, and (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl and R.sup.8 is R.sup.11 O or R.sup.11 R.sup.12 N wherein R.sup.11 and R.sup.12 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, and (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl;
- R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, trifluoromethyl, trifluoromethyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl (difluoromethylene), (C.sub.1 -C.sub.3)alkyl(difluoromethylene)(C.sub.1 -C.sub.3)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl (C.sub.3 -C.sub.6)cycloalkyl,(C.sub.3 -C.sub.6)cycloalkyl(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino).sub.2 (C.sub.1 -C.sub.6)alkyl, R.sup.13 CO(C.sub.1 -C.sub.6)alkyl wherein R.sup.13 is R.sup.20 O or R.sup.20 R.sup.21 N wherein R.sup.20 and R.sup.21 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, or (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl;
- or R.sup.3 and R.sup.4 or R.sup.20 and R.sup.21 may be taken together to form a (C.sub.3 -C.sub.6)cycloalkyl, oxacyclohexyl, or thiocyclohexyl;
- and
- Ar is (C.sub.6 -C.sub.10)aryl, (C.sub.1 -C.sub.6)alkyl(C.sub.6 -C.sub.10)aryl, (C.sub.1 -C.sub.6)alkoxy (C.sub.6 -C.sub.10)aryl, ((C.sub.1 -C.sub.6)alkoxy).sub.2 (C.sub.6 -C.sub.10)aryl, or (C.sub.6 -C.sub.10)aryloxy(C.sub.6 -C.sub.10)aryl;
- with the proviso that when either R.sup.1 or R.sup.2 is CH(R.sup.7)COR.sup.8 wherein R.sup.7 and R.sup.8 are as defined above, the other R.sup.1 or R.sup.2 is hydrogen, (C.sub.1 -C.sub.6)alkyl or benzyl.
4 more elements
A method of preparing a compound of the formula ##STR10## or the pharmaceutically acceptable salts hereof, wherein n is 1 to 6;
- X is hydroxy, (C.sub.1 -C.sub.6)alkoxy or NR.sup.1 R.sup.2 wherein R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.3 -C.sub.6)cycloalkyl(C.sub.1 -C.sub.6)alkyl, R.sup.5 (C.sub.2 -C.sub.6)alkyl, (C.sub.1 -C.sub.5)alkyl(CHR.sup.5)(C.sub.1 -C.sub.6)alkyl wherein R.sup.5 is hydroxy, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)alkylthio, (C.sub.6 -C.sub.10)arylthio, (C.sub.1 -C.sub.6)alkylsulfinyl, (C.sub.6 -C.sub.10)arylsulfinyl, (C.sub.1 -C.sub.6)alkylsulfoxyl, (C.sub.6 -C.sub.10)arylsulfoxyl, amino, (C.sub.1 -C.sub.6)alkylamino, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino:
- and CH(R.sup.7)COR.sup.8 wherein R.sup.7 is hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl.sub.3 amino(C.sub.1 -C.sub.6)alkyl, R.sup.9 R.sup.10 NCO(C.sub.1 -C.sub.6)alkyl or R.sup.9 OCO(C.sub.1 -C.sub.6)alkyl wherein R.sup.9 and R.sup.10 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, and (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl:
- and R.sup.8 is R.sup.11 O or R.sup.11 R.sup.12 N wherein R.sup.11 and R.sup.12 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, and (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl;
- R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, trifluoromethyl, trifluoromethyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl (difluoromethylene), (C.sub.1 -C.sub.3)alkyl(difluoromethylene)(C.sub.1 -C.sub.3)alkyl, (C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.3 -C.sub.6)cycloalkyl(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acyloxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)acylamino(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylthio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfinyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylsulfonyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylsulfonyl(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkylamino.sub.2 (C.sub.1 -C.sub.6)alkyl, R.sup.13 CO(C.sub.1 -C.sub.6)alkyl wherein R.sup.13 is R.sup.20 O or R.sup.20 R.sup.21 N wherein R.sup.20 and R.sup.21 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, or (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl;
- or R.sup.3 and R.sup.4, or R.sup.20 and R.sup.21 may be taken together to form a (C.sub.3 -C.sub.6)cycloalkyl, oxacyclohexyl, or thiocyclohexyl,
- and
- Ar is (C.sub.6 -C.sub.10)aryl, (C.sub.1 -C.sub.6)alkyl(C.sub.6 -C.sub.10)aryl, (C.sub.1 -C.sub.6)alkoxy(C.sub.6 -C.sub.10)aryl, ((C.sub.1 -C.sub.6)alkoxy).sub.2 (C.sub.6 -C.sub.10)aryl, or (C.sub.6 -C.sub.10)aryloxy(C.sub.6 -C.sub.10)aryl;
- with the proviso that when either R.sup.1 or R.sup.2 is CH(R.sup.7)COR.sup.8 wherein R.sup.7 and R.sup.8 are as defined above, the other of R.sup.1 or R.sup.2 is hydrogen, (C.sub.1 -C.sub.6)alkyl, or benzyl;
- comprising reacting a compound of the formula ##STR11## wherein n, X, R.sup.3, R.sup.4 and Ar are as defined above with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenztriazole and hydroxylamine.
6 more elements
Dependencies are inferred from the claim text.