US 5,886,043 AGranted

Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors

AssigneeBayer Aktiengesellschaft

InventorsHarold Clinton Eugene Kluender, Brian Richard Dixon, Michael Christopher VanZandt, Scott McClelland Wilhelm, Donald John Wolanin, William Harrison Bullock

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Abstract

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to 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 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.

Claims16

Dependent claims

Compounds having matrix metalloprotease inhibitory activity and the generalized formula:

##STR368## 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 ##STR369## (c) R.sup.6 is selected from the group consisting of:
aryl, provided that x is 1 or 2;
arylalkyl;
heteroaryl-alkyl;
aryl-substituted alkenyl;
heteroary-substituted alkenyl;
aryl-substituted alkynyl;
heteroaryl-substituted alkynyl;
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, ##STR370## 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.

30 more elements

Compounds having matrix metalloprotease inhibitory activity and the generalized formula:

##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).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 ##STR373## (c) R.sup.6 is selected from the group consisting of:
aryl of 6-10 carbons, provided that x is 1 or 2;
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;
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;
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;
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, ##STR374## 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.

61 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/866,778Filed 30 May 1997 · continuation
Priority: 15 Nov 1994
Granted: 23 Mar 1999
Term ends: Not estimatedThe source records don’t support an estimate.

Classification93 codes

C07D 207/08
Having no double bonds between ring members or between ring members and non-ring members: with hydrocarbon radicals, substituted by hetero atoms,…
A61K 31/4035
Condensed with carbocyclic rings, e.g. carbazole: isoindoles, e.g. phthalimide
A61K 31/47
Having six-membered rings with one nitrogen as the only ring hetero atom: quinolines; Isoquinolines
A61P 35/00
Antineoplastic agents