Arylsulfonyl hydroxamic acid derivatives as MMP and TNF inhibitors
First Claim
Patent Images
1. A compound of the formula ##STR11## or the pharmaceutically acceptable salt thereof, wherein X is carbon;
- Y is sulfer, or oxygen;
R1, R2 R3, R4, R7, R8 and R9 are selected from the group consisting of hydrogen, (C1 -C6)alkyl optionally substituted by (C1 -C6)alkylamino, (C1 -C6)alkylthio, (C1 -C6)alkoxy, trifluoromethyl, (C6 -C10)aryl, (C5 -C9)heteroaryl, (C6 -C10)arylamino, (C6 -C10)arylthio, (C6 -C10)aryloxy, (C5 -C9)heteroarylamino, (C5 -C9)heteroarylthio, (C5 -C9)heteroaryloxy, (C6 -C10)aryl(C6 -C10)aryl, (C3 -C6)cycloalkyl, hydroxy(C1 -C6)alkyl, (C1 -C6)alkyl(hydroxymethylene), piperazinyl, (C6 -C10)aryl(C1 -C6)alkoxy, (C5 -C9)heteroaryl(C1 -C6)alkoxy, (C1 -C6)acylamino, (C1 -C6)acylthio, (C1 -C6)acyloxy, (C1 -C6)alkylsulfinyl, C6 -C10)arylsulfinyl, (C1 -C6)alkylsulfonyl, (C6 -C10)arlysulfonyl, amino, (C1 -C6)alkylamino or ((C1 -C6)alkyl)2 amino;
(C2 -C6)alkenyl, (C6 -C10)aryl(C2 -C6)alkenyl, (C5 -C9)heteroaryl(C2 -C6)alkenyl, (C2 -C6)alkynyl, (C6 -C10)aryl(C2 -C6)alkynyl, (C5 -C9)heteroaryl(C2 -C6)alkynyl, (C1 -C6)alkylamino, (C1 -C6)alkylthio, (C1 -C6)alkoxy, trifluoromethyl, (C1 -C6)alkyl (difluoromethylene), (C1 -C3)alkyl(difluoromethylene)(C1 -C3)alkyl, (C6 -C10)aryl, (C5 -C9)heteroaryl, (C6 -C10)arylamino, (C6 -C10)arylthio, (C6 -C10)aryloxy, (C5 -C9)heteroarylamino, (C5 -C9)heteroarylthio, (C5 -C9)heteroaryloxy, (C3 -C6)cycloalkyl, (C1 -C6)alkyl(hydroxymethylene), piperidyl, (C1 C6)alkylpiperidyl, (C1 -C6)acylamino, (C1 -C6)acylthio, (C1 -C6)acyloxy, R13 (C1 C6)alkyl wherein R13 is (C1 -C6)acylpiperazino, (C6 -C10)arylpiperazino, (C5 -C9)heteroarylpiperazino, (C1 -C6)alkylpiperazino, (C6 -C10)aryl(C1 -C6)alkylpiperazino, (C5 -C9)heteroaryl(C1 -C6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1 -C6)alkylpiperidyl, (C6 -C10)arylpiperidyl, (C5 -C9)heteroarylpiperidyl, (C1 -C6)alkylpiperidyl(C1 -C6)alkyl, (C6 -C10)arylpiperidyl(C1 -C6)alkyl, (C5 -C9)heteroarylpiperidyl(C1 -C6)alkyl or (C1 -C6)acylpiperidyl;
or a group of the formula ##STR12## wherein n is 0 to 6;
Z is hydroxy, (C1 -C6)alkoxy of NR14 R15 wherein R14 and R15 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl optionally substituted by (C1 -C6)alkylpiperidyl, (C6 -C10)arylpiperidyl, (C5 -C9)heteroarylpiperidyl, (C6 -C10)aryl, (C5 -C9)heteroaryl, (C6 -C10)aryl(C6 -C10)aryl or (C3 C6)cycloalkyl;
piperidyl, (C1 -C6)alkylpiperidyl, (C6 -C10)arylpiperidyl, (C5 -C9)heteroarylpiperidyl, (C1 -C6)acylpiperidyl, (C6 -C10)aryl, (C5 -C9)heteroaryl, (C6 C10)aryl(C6 -C10)aryl, (C3 -C6)cycloalkyl, R16 (C2 -C6)alkyl, (C1 -C5)alkyl(CHR16)(C1 -C6)alkyl wherein R16 is hydroxy, (C1 -C6)acyloxy, (C1 -C6)alkoxy, piperazino, (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, (C1 -C6)acylpiperazino, (C1 -C6)alkylpiperazino, (C6 -C10)aryl(C1 C6)alkylpiperazino, (C5 -C9)heteroaryl(C1 -C6)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino;
R17 (C1 -C6)alkyl, (C1 -C5)alkyl(CHR17)(C1 -C6)alkyl wherein R17 is piperidyl or (C1 -C6)alkylpiperidyl; and
CH(R18)COR19 wherein R18 is hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl, (C5 -C9)heteroaryl(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)alkyamino(C1 -C6)alkyl, ((C1 -C6)alkyl)3 amino (C1 -C6)alkyl, R20 R21 NCO(C1 -C6)alkyl or R20 OCO(C1 -C6)alkyl wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl and (C5 -C9)heteroaryl(C1 -C6)alkyl; and
R19 is R22 O or R22 R23 N wherein R22 and R23 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl and (C5 -C9)heteroaryl(C1 -C6)alkyl;
or R14 and R15, or R20 and R21, or R22 and R23 may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (C1 -C6)acylpiperazinyl, (C1 -C6)alkylpiperazinyl, (C6 -C10)arylpiperazinyl, (C5 -C9)heteroarylpipctazinyl or a bridged diazabicycloalkyl ring selected from the group consisting of ##STR13## wherein r is 1, 2 or 3;
m is 1 or 2;
p is 0 or 1; and
Q is hydrogen, (C1 -C3)alkyl, (C1 -C6)acyl or (C1 -C6 )alkoxy carbamoyl;
or R1 and R2, or R3 and R4, may be taken together to form a carbonyl;
or R1 and R2, or R3 and R4, or R7 and R8 may be taken together to form a (C3 -C6)clycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula ##STR14## wherein R24 is hydrogen, (C1 -C6)acyl, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl, (C5 -C9)heteroaryl(C1 -C6)alkyl or (C1 -C6)alkylsulfonyl; and
Ar is (C6 C10 )aryl or (C5 -C9)heteroaryl, each of which may be optionally substituted by (C1 C6)alkyl, one or two (C1 -C6)alkoxy, (C6 -C10)aryloxy or (C5 -C9)heteroaryloxy;
with the proviso that R7 is other than hydrogen only when R8 is other than hydrogen;
with the proviso that R3 is other than hydrogen only when R4 is other than hydrogen;
with the proviso that R2 is other than hydrogen only when R1 is other than hydrogen;
with the proviso that when R1, R2 and R9 are a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 2 or 6-positions;
with the proviso that when one or more of the group consisting of R3, R4, R7 and R8, are independently a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 3- or 5-positions.
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Abstract
A compound of the formula ##STR1## wherein R1, R2 R3, R4 R5, R6, R7, R8, R9 and Ar are as defined above, useful in the treatment of a condition seiected from the group consisting of arthritis, cancer, tisuue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other disease characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases involving the production of TNF.
219 Citations
11 Claims
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1. A compound of the formula ##STR11## or the pharmaceutically acceptable salt thereof, wherein X is carbon;
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Y is sulfer, or oxygen; R1, R2 R3, R4, R7, R8 and R9 are selected from the group consisting of hydrogen, (C1 -C6)alkyl optionally substituted by (C1 -C6)alkylamino, (C1 -C6)alkylthio, (C1 -C6)alkoxy, trifluoromethyl, (C6 -C10)aryl, (C5 -C9)heteroaryl, (C6 -C10)arylamino, (C6 -C10)arylthio, (C6 -C10)aryloxy, (C5 -C9)heteroarylamino, (C5 -C9)heteroarylthio, (C5 -C9)heteroaryloxy, (C6 -C10)aryl(C6 -C10)aryl, (C3 -C6)cycloalkyl, hydroxy(C1 -C6)alkyl, (C1 -C6)alkyl(hydroxymethylene), piperazinyl, (C6 -C10)aryl(C1 -C6)alkoxy, (C5 -C9)heteroaryl(C1 -C6)alkoxy, (C1 -C6)acylamino, (C1 -C6)acylthio, (C1 -C6)acyloxy, (C1 -C6)alkylsulfinyl, C6 -C10)arylsulfinyl, (C1 -C6)alkylsulfonyl, (C6 -C10)arlysulfonyl, amino, (C1 -C6)alkylamino or ((C1 -C6)alkyl)2 amino;
(C2 -C6)alkenyl, (C6 -C10)aryl(C2 -C6)alkenyl, (C5 -C9)heteroaryl(C2 -C6)alkenyl, (C2 -C6)alkynyl, (C6 -C10)aryl(C2 -C6)alkynyl, (C5 -C9)heteroaryl(C2 -C6)alkynyl, (C1 -C6)alkylamino, (C1 -C6)alkylthio, (C1 -C6)alkoxy, trifluoromethyl, (C1 -C6)alkyl (difluoromethylene), (C1 -C3)alkyl(difluoromethylene)(C1 -C3)alkyl, (C6 -C10)aryl, (C5 -C9)heteroaryl, (C6 -C10)arylamino, (C6 -C10)arylthio, (C6 -C10)aryloxy, (C5 -C9)heteroarylamino, (C5 -C9)heteroarylthio, (C5 -C9)heteroaryloxy, (C3 -C6)cycloalkyl, (C1 -C6)alkyl(hydroxymethylene), piperidyl, (C1 C6)alkylpiperidyl, (C1 -C6)acylamino, (C1 -C6)acylthio, (C1 -C6)acyloxy, R13 (C1 C6)alkyl wherein R13 is (C1 -C6)acylpiperazino, (C6 -C10)arylpiperazino, (C5 -C9)heteroarylpiperazino, (C1 -C6)alkylpiperazino, (C6 -C10)aryl(C1 -C6)alkylpiperazino, (C5 -C9)heteroaryl(C1 -C6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1 -C6)alkylpiperidyl, (C6 -C10)arylpiperidyl, (C5 -C9)heteroarylpiperidyl, (C1 -C6)alkylpiperidyl(C1 -C6)alkyl, (C6 -C10)arylpiperidyl(C1 -C6)alkyl, (C5 -C9)heteroarylpiperidyl(C1 -C6)alkyl or (C1 -C6)acylpiperidyl;or a group of the formula ##STR12## wherein n is 0 to 6;
Z is hydroxy, (C1 -C6)alkoxy of NR14 R15 wherein R14 and R15 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl optionally substituted by (C1 -C6)alkylpiperidyl, (C6 -C10)arylpiperidyl, (C5 -C9)heteroarylpiperidyl, (C6 -C10)aryl, (C5 -C9)heteroaryl, (C6 -C10)aryl(C6 -C10)aryl or (C3 C6)cycloalkyl;
piperidyl, (C1 -C6)alkylpiperidyl, (C6 -C10)arylpiperidyl, (C5 -C9)heteroarylpiperidyl, (C1 -C6)acylpiperidyl, (C6 -C10)aryl, (C5 -C9)heteroaryl, (C6 C10)aryl(C6 -C10)aryl, (C3 -C6)cycloalkyl, R16 (C2 -C6)alkyl, (C1 -C5)alkyl(CHR16)(C1 -C6)alkyl wherein R16 is hydroxy, (C1 -C6)acyloxy, (C1 -C6)alkoxy, piperazino, (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, (C1 -C6)acylpiperazino, (C1 -C6)alkylpiperazino, (C6 -C10)aryl(C1 C6)alkylpiperazino, (C5 -C9)heteroaryl(C1 -C6)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino;
R17 (C1 -C6)alkyl, (C1 -C5)alkyl(CHR17)(C1 -C6)alkyl wherein R17 is piperidyl or (C1 -C6)alkylpiperidyl; and
CH(R18)COR19 wherein R18 is hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl, (C5 -C9)heteroaryl(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)alkyamino(C1 -C6)alkyl, ((C1 -C6)alkyl)3 amino (C1 -C6)alkyl, R20 R21 NCO(C1 -C6)alkyl or R20 OCO(C1 -C6)alkyl wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl and (C5 -C9)heteroaryl(C1 -C6)alkyl; and
R19 is R22 O or R22 R23 N wherein R22 and R23 are each independently selected from the group consisting of hydrogen, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl and (C5 -C9)heteroaryl(C1 -C6)alkyl;or R14 and R15, or R20 and R21, or R22 and R23 may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (C1 -C6)acylpiperazinyl, (C1 -C6)alkylpiperazinyl, (C6 -C10)arylpiperazinyl, (C5 -C9)heteroarylpipctazinyl or a bridged diazabicycloalkyl ring selected from the group consisting of ##STR13## wherein r is 1, 2 or 3; m is 1 or 2; p is 0 or 1; and Q is hydrogen, (C1 -C3)alkyl, (C1 -C6)acyl or (C1 -C6 )alkoxy carbamoyl; or R1 and R2, or R3 and R4, may be taken together to form a carbonyl; or R1 and R2, or R3 and R4, or R7 and R8 may be taken together to form a (C3 -C6)clycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula ##STR14## wherein R24 is hydrogen, (C1 -C6)acyl, (C1 -C6)alkyl, (C6 -C10)aryl(C1 -C6)alkyl, (C5 -C9)heteroaryl(C1 -C6)alkyl or (C1 -C6)alkylsulfonyl; and Ar is (C6 C10 )aryl or (C5 -C9)heteroaryl, each of which may be optionally substituted by (C1 C6)alkyl, one or two (C1 -C6)alkoxy, (C6 -C10)aryloxy or (C5 -C9)heteroaryloxy; with the proviso that R7 is other than hydrogen only when R8 is other than hydrogen; with the proviso that R3 is other than hydrogen only when R4 is other than hydrogen; with the proviso that R2 is other than hydrogen only when R1 is other than hydrogen; with the proviso that when R1, R2 and R9 are a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 2 or 6-positions; with the proviso that when one or more of the group consisting of R3, R4, R7 and R8, are independently a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 3- or 5-positions. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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Specification
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Current AssigneePfizer Inc.
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Original AssigneePfizer Inc.
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InventorsRizzi, James P., Piscopio, Anthony
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Primary Examiner(s)Ramsuer, Robert W.
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Application NumberUS08/930,665Time in Patent Office469 DaysField of Search544/131, 544/139, 514/237.5US Class Current544/131CPC Class CodesA61P 1/02 Stomatological preparations...A61P 19/02 for joint disorders, e.g. a...A61P 31/04 Antibacterial agentsA61P 31/12 AntiviralsA61P 31/18 for HIVA61P 35/00 Antineoplastic agentsA61P 37/04 ImmunostimulantsA61P 43/00 Drugs for specific purposes...C07D 211/96 Sulfur atomC07D 241/04 having no double bonds betw...C07D 241/08 with oxygen atoms directly ...C07D 295/24 Oxygen atoms
