US 5,854,277 A · Thiophenebutanoic acid derivatives as matrix metalloprotease inhibitors

##STR372## 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)p.sub.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 ##STR373## (c) R.sup.6 contains at least two carbon atoms and is selected from the group consisting of:

alkyl of 1-10 carbons;

aryl of 6-10 carbons;

heteroaryl comprising 4-9 carbons and at least one N, O, or 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, or S heteroatom, and the alkyl portion contains 1-8 carbons;

alkenyl of 2-10 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, or 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, or S heteroatom and the alkynyl portion contains 2-5 carbons;

--(CH.sub.2).sub.t R.sup.7 wherein

t is 0 or an integer of 1-5;

and

R.sup.7 is selected from the group consisting of ##STR374## 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;

and

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

v is 0 or an integer of 1 to 4;

and

Z represents ##STR375## 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;

--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.6 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

(d) G represents --M, ##STR376## 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.

Thiophenebutanoic acid derivatives as matrix metalloprotease inhibitors

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Thiophenebutanoic acid derivatives as matrix metalloprotease inhibitors

Life of this patent

Abstract

Claims14