US 5,886,022 AGranted

Substituted cycloalkanecarboxylic acid derivatives as matrix metalloprotease inhibitors

AssigneeBayer Aktiengesellschaft

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

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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 g roup; x is 0, 1, or 2; the group D represents ##STR2## the subscript "e" is 2 or 3; the group R.sup.14 represents a variety of possible substituent groups of the cycloalkyl ring between D and G; the subscript "k" is 0-2; 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 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, 0, or S of Q by at least one carbon atom;
and
x is 0, 1, or 2;
(b) D represents ##STR369## (c) e is 2 or 3;
(d) R.sup.14 is independently selected from the group consisting of:
alkyl of 1-9 carbons;
arylalkyl wherein the alkyl portion contains 1-7 carbons and the aryl portion contains 6-10 carbons;
alkenyl of 2-9 carbons;
aryl-substituted alkenyl wherein the alkenyl portion contains 2-4 carbons and the aryl portion contains 6-10 carbons;
alkynyl of 2-9 carbons;
aryl-substituted alkynyl wherein the alkynyl portion contains 2-4 carbons and the aryl portion contains 6-10 carbons;
and
aryl of 6-10 carbons;
and
k is 0-2;
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 lower alkyl;
and
R.sup.12 represents lower alkyl;
and
(e) 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.

35 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) e is 2 or 3;
(d) R.sup.14 is independently selected from the group consisting of:
alkyl of 1-9 carbons;
arylalkyl wherein the alkyl portion contains 1-7 carbons and the aryl portion contains 6-10 carbons;
alkenyl of 2-9 carbons;
aryl-substituted alkenyl wherein the alkenyl portion contains 2-4 carbons and the aryl portion contains 6-10 carbons;
alkynyl of 2-9 carbons;
aryl-substituted alkynyl wherein the alkynyl portion contains 2-4 carbons and the aryl portion contains 6-10 carbons;
and
aryl of 6-10 carbons;
and
k is 0-2;
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, ##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.

64 more elements

Dependencies are inferred from the claim text.