US 5,861,427 A · Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors

Abstract

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them treat a variety of physiological conditions. The compounds of the invention have the generalized formula ##STR1## wherein each T is a substituent group; x is 0, 1, or 2; the group D represents ##STR2## the group R6 represents a variety of possible substituent groups on the carbon chain between D and G, and the group 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 ; and R.sup.13 represents any of the side chains of the 19 noncyclic naturally occurring amino acids.

Compounds having matrix metalloprotease inhibitory activity and the generalized formula:

##STR369## wherein (a) T represents a substituent group, independently selected from the group consisting of halogen;
alkyl;
haloalkyl;
alkenyl;
alkynyl;
--(CH.sub.2).sub.p Q wherein p is 0 or an integer of 1-4;
-alkenyl-Q wherein said alkenyl moiety comprises 2-4 carbons;
wherein Q is selected from the group consisting of aryl, heteroaryl, --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, --COR.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, --OR.sup.4, and --SR.sup.4 ;
wherein R.sup.2 represents H, alkyl, aryl, heteroaryl, arylalkyl, or heteroaryl- alkyl;
R.sup.3 represents alkyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl;
and R.sup.4 represents H, alkyl, aryl, heteroaryl, arylalkyl, heteroaryl-alkyl, alkenyl, alkynyl, haloalkyl, acyl, or alkyleneoxy or polyalkyleneoxy terminated with H, alkyl, or phenyl;
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 ##STR370## (c) R.sup.6 contains at least two carbon atoms and is --(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
*N-phthalimidoyl;
*N-(1 ,2-naphthalenedicarboximidoyl);
*N-(2,3-naphthalenedicarboximidoyl);
* N-(1,8-naphthalenedicarboximidoyl);
*N-indoloyl;
*N-(2-pyrrolodinonyl);
*N-succinimidoyl;
*N-maleimidoyl;
*3-hydantoinyl;
*1,2,4-urazolyl;
*amido;
*urethane;
*urea;
and
*nonaromatic substituted or unsubstituted heterocycles containing and connected through a N atom, and comprising one additional 0 or S;
and
*amino;
*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;
with the proviso that when R.sup.7 is a nonaromatic heterocycle or an amino group, and t is 0, then x is 1 or 2;
and
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 lower alkyl;
and
R.sup.12 represents lower alkyl;
and
(d) G represents --M, ##STR371## 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.

44 more elements

Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors

Life of this patent

Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors

Life of this patent

Abstract

Claims16