Arylsulfonylamino hydroxamic acid derivatives
First Claim
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1. A compound of the formula ##STR9## or the pharmaceutically acceptable salts thereof, wherein n is 1 to 6:
- X is hydroxy, (C1 -C6)alkoxy or NR1 R2 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl, (C6 -C10)aryl(C1 -C6)alkyl, (C6 -C10)aryl(C6 -C10)aryl, (C6 -C10)aryl(C6 -C10)aryl(C1 -C6)alkyl, (C3 -C6)cycloalkyl, (C3 -C6)cycloalkyl(C1 -C6)alkyl, R5 (C2 -C6)alkyl, (C1 -C5)alkyl(CHR5)(C1 -C6)alkyl wherein R5 is hydroxy, (C1 -C6)acyloxy, (C1 -C6)alkoxy (C1 -C6)acylamino, (C1 -C6)alkylthio, (C6 -C10)arylthio, (C1 -C10)alkylsulfinyl, (C6 -C10)arylsulfinyl, (C1 -C6)alkylsulfoxyl, (C6 -C10)arylsulfoxyl, amino, (C1 -C6)alkylamino, ((C1 -C6)alkyl)2 amino; and
CH(R7)COR8 wherein R7 is hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl, (C1 -C6)alkylthio(C1 -C6)alkyl, (C6 -C10)arylthio(C1 -C6)alkyl, (C1 -C6)alkylsulfinyl(C1 -C6)alkyl, (C6 -C10)arylsulfinyl(C1 -C6)alkyl, (C1 -C6)alkylsulfonyl(C1 C6)alkyl, (C6 -C10)arylsulfonyl(C1 -C6)alkyl, hydroxy(C1 -C6)alkyl, amino(C1 -C6)alkyl, (C1 -C6)alkylamino(C1 -C6)alkyl, ((C1 -C6)alkyl)2 amino(C1 -C6)alkyl, R9 R10 NCO(C1 -C6)alkyl or R9 OCO(C1 -C6)alkyl wherein R9 and R10 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, and (C6 -C10)aryl(C1 -C6)alkyl and R8 is R11 O or R11 R12 N wherein R11 and R12 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, and (C6 -C10)aryl(C1 -C6)alkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, trifluoromethyl, trifluoromethyl(C1 -C6)alkyl, (C1 -C6)alkyl (difluoromethylene), (C1 -C3)alkyl(difluoromethylene)(C1 -C3)alkyl, (C6 -C10)aryl, (C6 -C10)aryl(C1 -C6)alkyl, (C6 -C10)aryl(C6 -C10)aryl, (C6 -C10)aryl(C6 -C10)aryl(C1 -C6)alkyl (C3 -C6)cycloalkyl,(C3 -C6)cycloalkyl(C1 -C6)alkyl, hydroxy(C1 -C6)alkyl, (C1 -C6)acyloxy(C1 -C6)alkyl, (C1 -C6)alkoxy(C1 -C6)alkyl, (C1 -C6)acylamino(C1 -C6)alkyl, (C6 -C10)aryl (C1 -C6)alkoxy(C1 -C6)alkyl, (C1 -C6)alkylthio(C1 -C6)alkyl, (C6 -C10)arylthio(C1 -C6)alkyl, (C1 -C6)alkylsulfinyl(C1 -C6)alkyl, (C6 -C10)arylsulfinyl(C1 -C6)alkyl, (C1 -C6)alkylsulfonyl(C1 -C6)alkyl, (C6 -C10)arylsulfonyl(C1 -C6)alkyl, amino(C1 -C6)alkyl, (C1 -C6)alkylamino(C1 -C6)alkyl, (C1 -C6)alkylamino)2 (C1 -C6)alkyl, R13 CO(C1 -C6)alkyl wherein R13 is R20 O or R20 R21 N wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, or (C6 -C10)aryl(C1 -C6)alkyl;
or R3 and R4 or R20 and R21 may be taken together to form a (C3 -C6)cycloalkyl, oxacyclohexyl, or thiocyclohexyl;
andAr is (C6 -C10)aryl, (C1 -C6)alkyl(C6 -C10)aryl, (C1 -C6)alkoxy (C6 -C10)aryl, ((C1 -C6)alkoxy)2 (C6 -C10)aryl, or (C6 -C10)aryloxy(C6 -C10)aryl;
with the proviso that when either R1 or R2 is CH(R7)COR8 wherein R7 and R8 are as defined above, the other R1 or R2 is hydrogen, (C1 -C6)alkyl or benzyl.
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Abstract
A compound of formula (I), wherein n, X, R3, R4 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##
213 Citations
13 Claims
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1. A compound of the formula ##STR9## or the pharmaceutically acceptable salts thereof, wherein n is 1 to 6:
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X is hydroxy, (C1 -C6)alkoxy or NR1 R2 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl, (C6 -C10)aryl(C1 -C6)alkyl, (C6 -C10)aryl(C6 -C10)aryl, (C6 -C10)aryl(C6 -C10)aryl(C1 -C6)alkyl, (C3 -C6)cycloalkyl, (C3 -C6)cycloalkyl(C1 -C6)alkyl, R5 (C2 -C6)alkyl, (C1 -C5)alkyl(CHR5)(C1 -C6)alkyl wherein R5 is hydroxy, (C1 -C6)acyloxy, (C1 -C6)alkoxy (C1 -C6)acylamino, (C1 -C6)alkylthio, (C6 -C10)arylthio, (C1 -C10)alkylsulfinyl, (C6 -C10)arylsulfinyl, (C1 -C6)alkylsulfoxyl, (C6 -C10)arylsulfoxyl, amino, (C1 -C6)alkylamino, ((C1 -C6)alkyl)2 amino; and
CH(R7)COR8 wherein R7 is hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl, (C1 -C6)alkylthio(C1 -C6)alkyl, (C6 -C10)arylthio(C1 -C6)alkyl, (C1 -C6)alkylsulfinyl(C1 -C6)alkyl, (C6 -C10)arylsulfinyl(C1 -C6)alkyl, (C1 -C6)alkylsulfonyl(C1 C6)alkyl, (C6 -C10)arylsulfonyl(C1 -C6)alkyl, hydroxy(C1 -C6)alkyl, amino(C1 -C6)alkyl, (C1 -C6)alkylamino(C1 -C6)alkyl, ((C1 -C6)alkyl)2 amino(C1 -C6)alkyl, R9 R10 NCO(C1 -C6)alkyl or R9 OCO(C1 -C6)alkyl wherein R9 and R10 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, and (C6 -C10)aryl(C1 -C6)alkyl and R8 is R11 O or R11 R12 N wherein R11 and R12 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, and (C6 -C10)aryl(C1 -C6)alkyl;R3 and R4 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, trifluoromethyl, trifluoromethyl(C1 -C6)alkyl, (C1 -C6)alkyl (difluoromethylene), (C1 -C3)alkyl(difluoromethylene)(C1 -C3)alkyl, (C6 -C10)aryl, (C6 -C10)aryl(C1 -C6)alkyl, (C6 -C10)aryl(C6 -C10)aryl, (C6 -C10)aryl(C6 -C10)aryl(C1 -C6)alkyl (C3 -C6)cycloalkyl,(C3 -C6)cycloalkyl(C1 -C6)alkyl, hydroxy(C1 -C6)alkyl, (C1 -C6)acyloxy(C1 -C6)alkyl, (C1 -C6)alkoxy(C1 -C6)alkyl, (C1 -C6)acylamino(C1 -C6)alkyl, (C6 -C10)aryl (C1 -C6)alkoxy(C1 -C6)alkyl, (C1 -C6)alkylthio(C1 -C6)alkyl, (C6 -C10)arylthio(C1 -C6)alkyl, (C1 -C6)alkylsulfinyl(C1 -C6)alkyl, (C6 -C10)arylsulfinyl(C1 -C6)alkyl, (C1 -C6)alkylsulfonyl(C1 -C6)alkyl, (C6 -C10)arylsulfonyl(C1 -C6)alkyl, amino(C1 -C6)alkyl, (C1 -C6)alkylamino(C1 -C6)alkyl, (C1 -C6)alkylamino)2 (C1 -C6)alkyl, R13 CO(C1 -C6)alkyl wherein R13 is R20 O or R20 R21 N wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, or (C6 -C10)aryl(C1 -C6)alkyl; or R3 and R4 or R20 and R21 may be taken together to form a (C3 -C6)cycloalkyl, oxacyclohexyl, or thiocyclohexyl; and Ar is (C6 -C10)aryl, (C1 -C6)alkyl(C6 -C10)aryl, (C1 -C6)alkoxy (C6 -C10)aryl, ((C1 -C6)alkoxy)2 (C6 -C10)aryl, or (C6 -C10)aryloxy(C6 -C10)aryl; with the proviso that when either R1 or R2 is CH(R7)COR8 wherein R7 and R8 are as defined above, the other R1 or R2 is hydrogen, (C1 -C6)alkyl or benzyl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
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13. A method of preparing a compound of the formula ##STR10## or the pharmaceutically acceptable salts hereof, wherein n is 1 to 6;
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X is hydroxy, (C1 -C6)alkoxy or NR1 R2 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl, (C6 -C10)aryl(C1 C6)alkyl, (C6 -C10)aryl(C6 -C10)aryl, (C6 -C10)aryl(C6 -C10)aryl(C1 -C6)alkyl, (C3 -C6)cycloalkyl, (C3 -C6)cycloalkyl(C1 -C6)alkyl, R5 (C2 -C6)alkyl, (C1 -C5)alkyl(CHR5)(C1 -C6)alkyl wherein R5 is hydroxy, (C1 -C6)acyloxy, (C1 -C6)alkoxy, (C1 -C6)acylamino, (C1 -C6)alkylthio, (C6 -C10)arylthio, (C1 -C6)alkylsulfinyl, (C6 -C10)arylsulfinyl, (C1 -C6)alkylsulfoxyl, (C6 -C10)arylsulfoxyl, amino, (C1 -C6)alkylamino, ((C1 -C6)alkyl)2 amino; and
CH(R7)COR8 wherein R7 is hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl, (C1 -C6)alkylthio(C1 -C6)alkyl, (C6 -C10)arylthio(C1 -C6)alkyl, (C1 -C6)alkylsulfinyl(C1 -C6)alkyl, (C6 -C10)arylsulfinyl(C1 -C6)alkyl, (C1 -C6)alkylsulfonyl(C1 -C6)alkyl, (C6 -C10)arylsulfonyl(C1 -C6)alkyl, hydroxy(C1 -C6)alkyl, amino(C1 -C6)alkyl, (C1 -C6)alkylamino(C1 -C6)alkyl, ((C1 -C6)alkyl3 amino(C1 -C6)alkyl, R9 R10 NCO(C1 -C6)alkyl or R9 OCO(C1 -C6)alkyl wherein R9 and R10 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, and (C6 -C10)aryl(C1 -C6)alkyl; and
R8 is R11 O or R11 R12 N wherein R11 and R12 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, and (C6 -C10)aryl(C1 -C6)alkyl;R3 and R4 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, trifluoromethyl, trifluoromethyl(C1 -C6)alkyl, (C1 -C6)alkyl (difluoromethylene), (C1 -C3)alkyl(difluoromethylene)(C1 -C3)alkyl, (C6 -C10)aryl, (C6 -C10)aryl(C1 -C6)alkyl, (C6 -C10)aryl(C6 -C10)aryl, (C6 -C10)aryl(C6 -C10)aryl(C1 -C6)alkyl, (C3 -C6)cycloalkyl, (C3 -C6)cycloalkyl(C1 -C6)alkyl, hydroxy(C1 -C6)alkyl, (C1 -C6)acyloxy(C1 -C6)alkyl, (C1 -C6)alkoxy(C1 -C6)alkyl, (C1 -C6)acylamino(C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkoxy(C1 -C6)alkyl, (C1 -C6)alkylthio(C1 -C6)alkyl, (C6 -C10)arylthio(C1 -C6)alkyl, (C1 -C6)alkylsulfinyl(C1 -C6)alkyl, (C6 -C10)arylsulfinyl(C1 -C6)alkyl, (C1 -C6)alkylsulfonyl(C1 -C6)alkyl, (C6 -C10)arylsulfonyl(C1 -C6)alkyl, amino(C1 -C6)alkyl, (C1 -C6)alkylamino(C1 -C6)alkyl, ((C1 -C6)alkylamino2 (C1 -C6)alkyl, R13 CO(C1 -C6)alkyl wherein R13 is R20 O or R20 R21 N wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, or (C6 -C10)aryl(C1 -C6)alkyl; or R3 and R4, or R20 and R21 may be taken together to form a (C3 -C6)cycloalkyl, oxacyclohexyl, or thiocyclohexyl, and Ar is (C6 -C10)aryl, (C1 -C6)alkyl(C6 -C10)aryl, (C1 -C6)alkoxy(C6 -C10)aryl, ((C1 -C6)alkoxy)2 (C6 -C10)aryl, or (C6 -C10)aryloxy(C6 -C10)aryl; with the proviso that when either R1 or R2 is CH(R7)COR8 wherein R7 and R8 are as defined above, the other of R1 or R2 is hydrogen, (C1 -C6)alkyl, or benzyl;
comprising reacting a compound of the formula ##STR11## wherein n, X, R3, R4 and Ar are as defined above with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenztriazole and hydroxylamine.
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Specification
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Current AssigneePfizer Inc.
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Original AssigneePfizer Inc.
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InventorsRobinson, Ralph P., Rizzi, James P.
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Primary Examiner(s)Ramsuer, Robert W.
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Application NumberUS08/894,873Time in Patent Office540 DaysField of Search562/623, 562/430, 560/13, 514/575US Class Current514/575CPC Class CodesA61P 1/02 Stomatological preparations...A61P 1/04 for ulcers, gastritis or re...A61P 17/00 Drugs for dermatological di...A61P 19/00 Drugs for skeletal disordersA61P 19/02 for joint disorders, e.g. a...A61P 29/00 Non-central analgesic, anti...A61P 31/02 Local antisepticsA61P 31/04 Antibacterial agentsA61P 31/18 for HIVA61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 37/04 ImmunostimulantsA61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...C07C 311/29 having the sulfur atom of a...C07D 207/12 Oxygen or sulfur atomsC07D 213/40 Acylated substituent nitrog...C07D 241/08 with oxygen atoms directly ...C07D 295/185 from aliphatic carboxylic a...
