Patent ID: 6288063
Filing Date: 2001-09-11
Classification: C07C,C07D

Abstract:
Compounds having matrix metalloprotease inhibitory activity and the generalized formula:(T).sub.x A--B--D--E--Gwherein(a) (T).sub.x A represents substituted or unsubstituted aromatic moiety ##STR110##whereineach T represents a substituent group, independently selected from the group consisting of:the halogens --F, --Cl, --Br, and --I;alkyl of 1-10 carbons;haloalkyl of 1-10 carbons;haloalkoxy of 1-10 carbons;alkenyl of 2-10 carbons;alkynyl of 2-10 carbons;--(CH.sub.2).sub.p Q, whereinp is 0 or an integer 1-4,-alkenyl-Q, whereinsaid alkenyl moiety comprises 2-4 carbons, and-alkynyl-Q, whereinsaid alkynyl moiety comprises 2-7 carbons; andQ is selected from the group consisting of aryl of 6-10 carbons, heteroaryl comprising 4-9 carbons and at least one N, O, S heteroatom, --CN, --CHO, --NO.sub.2, --CO.sub.2 R.sup.2, --OCOR.sup.2, --SOR.sup.3, --SO.sub.2 R.sup.3, --CON(R.sup.4).sub.2, --SO.sub.2 N(R.sup.4).sub.2, --C(O)R.sup.2, --N(R.sup.4).sub.2, --N(R.sup.2)COR.sup.2, --N(R.sup.2)CO.sub.2 R.sup.3, --N(R.sup.2)CON(R.sup.4).sub.2, --CHN.sub.4, --OR.sup.4, and --SR.sup.4 ;whereinR.sup.2 represents H;alkyl of 1-6 carbons;aryl of 6-10 carbons;heteroaryl comprising 4-9 carbons and at least one N, O, or S heteroatom; orarylalkyl in which the aryl portion contains 6-10 carbons and the alkyl portion contains 1-4 carbons; orheteroaryl-alkyl in which the heteroaiyl portion comprises 4-9 carbons and at least one N, O, S heteroatom and the alkyl portion contains 1-4 carbons;R.sup.3 represents alkyl of 1-4 carbons;aryl of 6-10 carbons;heteroaryl comprising 4-9 carbons and at least one N, O, or S heteroatom; orarylalkyl in which the aryl portion contains 6-10 carbons and the alkyl portion contains 1-4 carbons; orheteroaryl-alkyl in which the heteroaryl portion comprises 4-9 carbons and at least one N, O, S heteroatom and the alkyl portion contains 1-4 carbons;R.sup.4 represents H;alkyl of 1-12 carbons;aryl of 6-10 carbons;heteroaryl comprising 4-9 carbons and at least one N, O, or S heteroatom;arylalkyl in which the aryl portion contains 6-10 carbons and the alkyl portion contains 1-4 carbons;heteroaryl-alkyl in which the heteroaryl portion comprises 4-9 carbons and at least one N, O, S heteroatom and the alkyl portion contains 1-4 carbons;alkenyl of 2-12 carbons;alkynyl of 2-12 carbons;--(C.sub.q H.sub.2q O).sub.r R.sup.5 wherein q is 1-3; r is 1-3; and R.sup.5 is H provided q is greater than 1, or alkyl of 1-4 carbons, or phenyl;alkylenethio terminated with H, alkyl of 1-4 Carbons, or phenyl;alkyleneamino terminated with H, alkyl of 1-4 carbons, or phenyl;--(CH.sub.2).sub.s X wherein s is 1-3 and X is halogen;--C(O)OR.sup.2 ; or--C(O)R.sup.2 ;and with the provisos that a) when two R.sup.4 groups are situated on a nitrogen, they may be joined by a bond to form aheterocycle, and b) unsaturation in a moiety which is attached to Q or which is part of Q is separated from any N, O, S of Q by at least one carbon atom, andx is 0, 1, or 2;(b) B represents an optionally substituted ring ##STR111##bearing 0-2 substituents T;(c) D represents ##STR112##in which R.sup.2 is defined as above and each R.sup.2 may be the same or different;(d) E represents a chain of n carbon atoms bearing m substituents R.sup.6, wherein said R.sup.6 groups are independent substituents, or constitute spiro or nonspiro rings in which a) two groups R.sup.6 are joined, and taken together with the chain atom(s) to which said two R6 group(s) are attached, and any intervening chain atoms, constitute a 3-7 membered ring, or b) one group R.sup.6 is joined to the chain on which said one group R.sup.6 resides, and taken together with the chain atom(s) to which said R6 group is attached, and any intervening chain atoms, constitutes a 3-7 membered ring; and whereinn is 2 or 3;m is an integer of 1-3;each group R.sup.6 is independently selected from the group consisting of:fluorine;hydroxyl, with the proviso that a single carbon may bear no more than one hydroxyl substituentheteroaryl comprising 4-9 carbons and at least one N, O, S heteroatom;arylalkyl wherein the aryl portion contains 6-10 carbons and the alkyl portion contains 1-8 carbons;heteroaryl-alkyl wherein the heteroaryl portion comprises 4-9 carbons and at least one N, O, S heteroatom, and the alkyl portion contains 1-8 carbons;aryl-alkenyl wherein the aryl portion contains 6-10 carbons and the alkenyl portion contains 2-5 carbons;heteroaryl-alkenyl wherein the heteroaryl portion comprises 4-9 carbons and at least one N, O, S heteroatom and the alkenyl portion contains 2 -5 carbons;alkynyl of 2-10 carbons;aryl-alkynyl wherein the aryl portion contains 6-10 carbons and the alkynyl portion contains 2-5 carbons;heteroaryl-alkynyl wherein the heteroaryl portion comprises 4-9 carbons and at least one N, O, S heteroatom and the alkynyl portion contains 2-5 carbons;--(CH.sub.2).sub.t R.sup.7 whereint is 0 or an integer of 1-5; andR.sup.7 is selected from the group consisting of ##STR113## ##STR114##and corresponding heteroaryl moieties in which the aryl portion of an aryl-containing R.sup.7 group comprises 4-9 carbons and at least one N, O, S heteroatom;whereinY represents O or S;R.sup.1 represents H or alkyl of 1-3 carbons;R.sup.2 and R.sup.3 are as defined above; andu is 0, 1, or 2; and--(CH.sub.2).sub.v ZR.sup.8 whereinv is 0 or an integer of 1 to 4, with the proviso that when R.sup.8 is heteroaryl, v is an integer of 1-4; andZ represents ##STR115##R.sup.8 is selected from the group consisting of:alkyl of 1 to 12 carbons;aryl of 6 to 10 carbons;heteroaryl comprising 4-9 carbons and at least one N, O, S heteroatom;arylalkyl wherein the aryl portion contains 6 to 12 carbons and the alkyl portion contains 1 to 4 carbons;heteroaryl-alkyl wherein the aryl portion comprises 4-9 carbons and at least one N, O, S heteroatom and the alkyl portion contains 1-4 carbons;--C(O)R.sup.9 wherein R.sup.9 represents alkyl of 2-6 carbons, aryl of 6-10 carbons, heteroaryl comprising 4-9 carbons and at least one N, O, S heteroatom, or arylalkyl in which the aryl portion contains 6-10 carbons or is heteroaryl comprising 4-9 carbons and at least one N, O, S heteroatom, and the alkyl portion contains 1-4 carbons;and with the provisos thatwhen R.sup.8 is --C(O)R.sup.9, Z is S or O;when Z is O, R.sup.8 may also be --(C.sub.q H.sub.2q O).sub.r R.sup.5 wherein q, r, and R.sup.5 are as defined above; and--(CH.sub.2).sub.w SiR.sup.10.sub.3 whereinw is an integer of 1 to 3; andR.sup.10 represents alkyl of 1 to 2 carbons;and with the proviso thataryl or heteroaryl portions of any of said T or R.sup.6 groups optionally may bear up to two substituents selected from the group consisting of --(CH.sub.2).sub.y C(R.sup.4)(R.sup.3)OH, --(CH.sub.2).sub.y OR.sup.4, --(CH.sub.2).sub.y SR.sup.4, --(CH.sub.2).sub.y S(O)R.sup.4, --(CH.sub.2).sub.y S(O).sub.2 R.sup.4, --(CH.sub.2).sub.y SO.sub.2 N(R.sup.4).sub.2, --(CH.sub.2).sub.y N(R.sup.4).sub.2, --(CH.sub.2).sub.y N(R.sup.4)COR.sup.3, --OC(R.sup.4).sub.2 O-- in which both oxygen atoms are connected to the aryl ring, --(CH.sub.2).sub.y COR.sup.4, --(CH.sub.2).sub.y CON(R.sup.4).sub.2, --(CH.sub.2).sub.y CO.sub.2 R.sup.4, --(CH.sub.2).sub.y OCOR.sup.4, -halogen, --CHO, --CF.sub.3, --NO.sub.2, --CN, and --R.sup.3, whereiny is 0-4; andR.sup.3 and R.sup.4 are defined as above; and any two R.sup.4 which are attached to one nitrogen may be joined to form a heterocycle;(e) G represents ##STR116##in which R.sup.3 is defined as above; and with the proviso that when G is ##STR117##each R.sup.6 is an independent substituent;and pharmaceutically acceptable salts and prodrugs thereof.