US 5,859,047 AGranted

Substituted 4-biarylbutyric acid derivatives as matrix metalloprotease inhibitors

AssigneeBayer Aktiengesellschaft

InventorsHarold Clinton Eugene Kluender, David Ross Brittelli, William Harrison Bullock, Kerry Jeanne Combs, Brian Richard Dixon, Michael Christopher VanZandt, Scott McClelland Wilhelm, Donald John Wolanin

Life of this patent

Estimating the term…

patentgrep

Loading patent…

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 substituted 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.

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 contains at least two carbon atoms and is selected from the group consisting of:
alkyl of 4-10 carbons, provided that x is 1 or 2;
alkenyl;
alkynyl;
and
trialkylsilyl-substituted alkyl;
and with the further proviso that
aryl or heteroaryl portions of any of said T 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.

29 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 contains at least two carbon atoms and is selected from the group consisting of:
alkyl of 4-10 carbons, provided that if said alkyl group is located on the alpha carbon relative to said D unit, then x is 1 or 2;
alkenyl of 2-10 carbons;
alkynyl of 2-10 carbons;
and
--(CH.sub.2).sub.w SiR.sup.10.sub.3 wherein
w is an integer of 1 to 3;
and
R.sup.10 represents alkyl of 1 to 2 carbons;
and with the further proviso that
aryl or heteroaryl portions of any of said T 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: 08/866,798Filed 30 May 1997 · continuation
Priority: 15 Nov 1994
Granted: 12 Jan 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