Back to results
US 5,886,024 AGranted
Thiophene-containing butonic acid derivatives as matrix metalloprotease inhibitors
AssigneeBayer Aktiengesellschaft
InventorsHarold Clinton Eugene Kluender, Guenter Hans Herbert Heinz Benz, William Harrison Bullock
Life of this patent
Estimating the term…
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 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.
Claims14
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 heteroarylalkyl;
- 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;
- aryl;
- heteroaryl;
- arylalkyl;
- heteroaryl-alkyl;
- alkenyl;
- aryl-substituted alkenyl;
- heteroaryl-substituted alkenyl;
- alkynyl;
- aryl-substituted alkynyl;
- heteroaryl-substituted alkynyl;
- --(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 O 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
- --(CH.sub.2).sub.v ZR.sup.8 wherein v is 0 or an integer of 1-4,
- Z represents ##STR370## and R.sup.8 is selected from the group consisting of:
- alkyl;
- aryl;
- heteroaryl;
- arylalkyl;
- and
- heteroaryl-alkyl;
- and
- --C(O)R.sup.9 wherein R.sup.9 represents alkyl of at least two carbons, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl;
- 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 alkyleneoxy or polyalkyleneoxy terminated with H, alkyl, or phenyl;
- 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.
69 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 1-10 carbons;
- aryl of 6-10 carbons;
- heteroaryl comprising 4-9 carbons and at least one N, O, or S heteroatom;
- 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;
- alkenyl of 2-10 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;
- alkynyl of 2-10 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;
- --(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 ##STR374## 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;
- --(CH.sub.2).sub.v ZR.sup.8 wherein
- v is 0 or an integer of 1 to 4;
- and
- Z represents ##STR375## 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;
- and
- 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;
- --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.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, ##STR376## 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.
88 more elements
Dependencies are inferred from the claim text.