US 5,789,434 A · Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors

Abstract

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The presently claimed compounds have the generalized formula ##STR1## in which each T represents a substituent group; x is 0, 1, or 2; D represents ##STR2## .delta. is 0 or 1; U' represents O, S, or N, with the proviso that when U' is N, then .delta.=0, and when U' is O or S, then .delta.=1; R.sup.14 is any of a variety of substituent groups; and G represents M, ##STR3## in which M represents --CO.sub.2 H, --CON(R.sup.11).sub.2, or --CO.sub.2 R.sup.12, R.sup.11 represents H or an alkyl group, R.sup.12 represents an alkyl group, and R.sup.13 represents any of the side chains of the 19 noncyclic naturally occurring amino acids; and pharmaceutically acceptable salts thereof.

Compounds having matrix metalloprotease inhibitory activity and the generalized formula:

##STR461## 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 ##STR462## (c) .delta. is 0 or 1;
and U' represents O, S, or N, with the proviso that
when U' is N, then .delta.=0, and
when U' is O or S, then .delta.=1;
(d) R.sup.14 is selected from the group consisting of:
COR.sup.2 ;
CO.sup.2 R.sup.3 ;
CON(R.sup.2).sub.2 ;
alkyl of 1-9 carbons;
aryl of 6-10 carbons;
arylalkyl wherein the aryl portion contains 6-10 carbons and the alkyl portion contains 1-7 carbons;
alkenyl of 2-9 carbons;
aryl-alkenyl wherein the aryl portion contains 6-10 carbons and the alkenyl portion contains 2-4 carbons;
alkynyl of 2-9 carbons;
aryl-alkynyl wherein the aryl portion contains 6-10 carbons and the alkynyl portion contains 2-4 carbons;
--(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 ##STR463## 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 ##STR464## 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;
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, ##STR465## 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.

92 more elements

Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors

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Derivatives of substituted 4-biarylbutyric acid as matrix metalloprotease inhibitors

Life of this patent

Abstract

Claims10