Arylsulfonyl hydroxamic acid derivatives as MMP and TNF inhibitors

A compound of the formula ##STR11## or the pharmaceutically acceptable salt thereof, wherein X is carbon;

• Y is sulfer, or oxygen;
• R.sup.1, R.sup.2 R.sup.3, R.sup.4, R.sup.7, R.sup.8 and R.sup.9 are selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted by (C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkylthio, (C.sub.1 -C.sub.6)alkoxy, trifluoromethyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)arylamino, (C.sub.6 -C.sub.10)arylthio, (C.sub.6 -C.sub.10)aryloxy, (C.sub.5 -C.sub.9)heteroarylamino, (C.sub.5 -C.sub.9)heteroarylthio, (C.sub.5 -C.sub.9)heteroaryloxy, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.3 -C.sub.6)cycloalkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl(hydroxymethylene), piperazinyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkoxy, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)acylthio, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkylsulfinyl, C.sub.6 -C.sub.10)arylsulfinyl, (C.sub.1 -C.sub.6)alkylsulfonyl, (C.sub.6 -C.sub.10)arlysulfonyl, amino, (C.sub.1 -C.sub.6)alkylamino or ((C.sub.1 -C.sub.6)alkyl).sub.2 amino;
• (C.sub.2 -C.sub.6)alkenyl, (C.sub.6 -C.sub.10)aryl(C.sub.2 -C.sub.6)alkenyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.6 -C.sub.10)aryl(C.sub.2 -C.sub.6)alkynyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkylthio, (C.sub.1 -C.sub.6)alkoxy, trifluoromethyl, (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.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)arylamino, (C.sub.6 -C.sub.10)arylthio, (C.sub.6 -C.sub.10)aryloxy, (C.sub.5 -C.sub.9)heteroarylamino, (C.sub.5 -C.sub.9)heteroarylthio, (C.sub.5 -C.sub.9)heteroaryloxy, (C.sub.3 -C.sub.6)cycloalkyl, (C.sub.1 -C.sub.6)alkyl(hydroxymethylene), piperidyl, (C.sub.1 C.sub.6)alkylpiperidyl, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)acylthio, (C.sub.1 -C.sub.6)acyloxy, R.sup.13 (C.sub.1 C.sub.6)alkyl wherein R.sup.13 is (C.sub.1 -C.sub.6)acylpiperazino, (C.sub.6 -C.sub.10)arylpiperazino, (C.sub.5 -C.sub.9)heteroarylpiperazino, (C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl(C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)arylpiperidyl(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)acylpiperidyl;
• or a group of the formula ##STR12## wherein n is 0 to 6:
• Z is hydroxy, (C.sub.1 -C.sub.6)alkoxy of NR.sup.14 R.sup.15 wherein R.sup.14 and R.sup.15 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted by (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 -C.sub.10)aryl(C.sub.6 -C.sub.10)aryl or (C.sub.3 C.sub.6)cycloalkyl;
• piperidyl, (C.sub.1 -C.sub.6)alkylpiperidyl, (C.sub.6 -C.sub.10)arylpiperidyl, (C.sub.5 -C.sub.9)heteroarylpiperidyl, (C.sub.1 -C.sub.6)acylpiperidyl, (C.sub.6 -C.sub.10)aryl, (C.sub.5 -C.sub.9)heteroaryl, (C.sub.6 C.sub.10)aryl(C.sub.6 -C.sub.10)aryl, (C.sub.3 -C.sub.6)cycloalkyl, R.sup.16 (C.sub.2 -C.sub.6)alkyl, (C.sub.1 -C.sub.5)alkyl(CHR.sup.16)(C.sub.1 -C.sub.6)alkyl wherein R.sup.16 is hydroxy, (C.sub.1 -C.sub.6)acyloxy, (C.sub.1 -C.sub.6)alkoxy, piperazino, (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, (C.sub.1 -C.sub.6)acylpiperazino, (C.sub.1 -C.sub.6)alkylpiperazino, (C.sub.6 -C.sub.10)aryl(C.sub.1 C.sub.6)alkylpiperazino, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino;
• R.sup.17 (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.5)alkyl(CHR.sup.17)(C.sub.1 -C.sub.6)alkyl wherein R.sup.17 is piperidyl or (C.sub.1 -C.sub.6)alkylpiperidyl;
• and CH(R.sup.18)COR.sup.19 wherein R.sup.18 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.5 -C.sub.9)heteroaryl(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)alkyamino(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.20 R.sup.21 NCO(C.sub.1 -C.sub.6)alkyl or R.sup.20 OCO(C.sub.1 -C.sub.6)alkyl 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, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl and (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl;
• and R.sup.19 is R.sup.22 O or R.sup.22 R.sup.23 N wherein R.sup.22 and R.sup.23 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.1 -C.sub.6)alkyl and (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl;
• or R.sup.14 and R.sup.15, or R.sup.20 and R.sup.21, or R.sup.22 and R.sup.23 may be taken together to form an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (C.sub.1 -C.sub.6)acylpiperazinyl, (C.sub.1 -C.sub.6)alkylpiperazinyl, (C.sub.6 -C.sub.10)arylpiperazinyl, (C.sub.5 -C.sub.9)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, (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.6)acyl or (C.sub.1 -C.sub.6 )alkoxy carbamoyl;
• or R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4, may be taken together to form a carbonyl;
• or R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4, or R.sup.7 and R.sup.8 may be taken together to form a (C.sub.3 -C.sub.6)clycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula ##STR14## wherein R.sup.24 is hydrogen, (C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, (C.sub.5 -C.sub.9)heteroaryl(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkylsulfonyl;
• and
• Ar is (C.sub.6 C.sub.10 )aryl or (C.sub.5 -C.sub.9)heteroaryl, each of which may be optionally substituted by (C.sub.1 C.sub.6)alkyl, one or two (C.sub.1 -C.sub.6)alkoxy, (C.sub.6 -C.sub.10)aryloxy or (C.sub.5 -C.sub.9)heteroaryloxy;
• with the proviso that R.sup.7 is other than hydrogen only when R.sup.8 is other than hydrogen;
• with the proviso that R.sup.3 is other than hydrogen only when R.sup.4 is other than hydrogen;
• with the proviso that R.sup.2 is other than hydrogen only when R.sup.1 is other than hydrogen;
• with the proviso that when R.sup.1, R.sup.2 and R.sup.9 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 R.sup.3, R.sup.4, R.sup.7 and R.sup.8, are independently a substituent comprising a heteroatom, the heteroatom cannot be directly bonded to the 3- or 5-positions.