US 5,874,473 A · Substituted cycloalkanecarboxylic acid derivatives as matrix metalloprotease inhibitors

##STR373## wherein (a) each 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;

alkenyl of 2-10 carbons;

alkynyl of 2-10 carbons;

--(CH.sub.2).sub.p Q, wherein

p is 0 or an integer 1-4, and

-alkenyl-Q, wherein

said alkenyl moiety comprises 2-4 carbons;

and

Q is selected from the group consisting of aryl of 6-10 carbons, heteroaryl comprising 4-9 carbons and at least one N, O, or 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.2).sub.2, --SO.sub.2 N(R.sup.2).sub.2, --C(O)R.sup.2, --N(R.sup.2).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.2).sub.2, --CHN.sub.4, --OR.sup.4, and --SR.sup.4 ;

wherein

R.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;

or

arylalkyl in which the aryl portion contains 6-10 carbons and the alkyl portion contains 1-4 carbons;

or

heteroaryl-alkyl in which the heteroaryl portion comprises 4-9 carbons and at least one N, O, or 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;

or

arylalkyl in which the aryl portion contains 6-10 carbons and the alkyl portion contains 1-4 carbons;

or

heteroaryl-alkyl in which the heteroaryl portion comprises 4-9 carbons and at least one N, O, or 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, or 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;

--(CH.sub.2).sub.s X wherein s is 2-3 and X is halogen;

or --C(O)R.sup.2 ;

and with the proviso that unsaturation in a moiety which is attached to Q or which is encompassed by Q is separated from any N, O, or S of Q by at least one carbon atom, and

x is 0, 1, or 2;

(b) D represents ##STR374## (c) e is 2 or 3;

(d) R.sup.14 is *--(CH.sub.2).sub.t R.sup.7 wherein

t is 0 or an integer of 1-4;

and

R.sup.7 is selected from the group consisting of ##STR375## 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, or S heteroatom;

wherein

Y represents O or S;

R.sup.1, R.sup.2, and R.sup.3 are as defined above;

and

u is 0, 1, or 2;

or

--(CH.sub.2).sub.v ZR.sup.8 wherein

v is 0 or an integer of 1 to 3;

and

Z represents ##STR376## 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, or S heteroatom;

arylalkyl wherein the aryl portion contains 6 to 12 carbons and the alkyl portion contains 1 to 4 carbons;

and

heteroaryl-alkyl wherein the aryl portion comprises 4-9 carbons and at least one N, O, or S heteroatom and the alkyl portion contains 1-4 carbons;

and

--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, or 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, or S heteroatom, and the alkyl portion contains 1-4 carbons;

and with the provisos that

when R.sup.8 is --C(O)R.sup.9, Z is S or O;

and

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 with the further proviso that

aryl or heteroaryl portions of any of said T or R.sup.14 groups optionally may bear up to two substituents selected from the group consisting of --(CH.sub.2).sub.y C(R.sup.11)(R.sup.12)OH, --(CH.sub.2).sub.y OR.sup.11, --(CH.sub.2).sub.y SR.sup.11, --(CH.sub.2).sub.y S(O)R.sup.11, --(CH.sub.2).sub.y S(O).sub.2 R.sup.11, --(CH.sub.2).sub.y SO.sub.2 N(R.sup.11).sub.2, --(CH.sub.2).sub.y N(R.sup.11).sub.2, --(CH.sub.2).sub.y N(R.sup.11)COR.sup.12, --OC(R.sup.11).sub.2 O-- in which both oxygen atoms are connected to the aryl ring, --(CH.sub.2).sub.y COR.sup.11, --(CH.sub.2).sub.y CON(R.sup.11).sub.2, --(CH.sub.2).sub.y CO.sub.2 R.sup.11, --(CH.sub.2).sub.y OCOR.sup.11, -halogen, --CHO, --CF.sub.3, --NO.sub.2, --CN, and --R.sup.12,

wherein

y is 0-4;

R.sup.11 represents H or alkyl of 1-4 carbons;

and

R.sup.12 represents alkyl of 1-4 carbons;

and

(e) G represents --M, ##STR377## wherein M represents --CO.sub.2 H, --CON(R.sup.11).sub.2, or --CO.sub.2 R.sup.12 ;

and

R.sup.13 represents any of the side chains of the 19 noncyclic naturally occurring amino acids;

and pharmaceutically acceptable salts thereof.

Substituted cycloalkanecarboxylic acid derivatives as matrix metalloprotease inhibitors

Life of this patent

Substituted cycloalkanecarboxylic acid derivatives as matrix metalloprotease inhibitors

Life of this patent

Abstract

Claims16