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US 6,150,379 AGranted
Compounds and compositions as anticoagulants
AssigneeAxys Pharmaceuticals, Inc.
InventorsPaul R. Fatheree, Thomas E. Jenkins, Martin S. Linsell, Sean G. Trapp, Erik J. Verner, Wendy B. Young
Life of this patent
Estimating the term…
Abstract
The present invention relates to novel biheterocyclic derivatives which are factor Xa inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.
Claims6
A compound of Formula I:
- ##STR9## in which:
- n2 is 1, 2 or 3;
- n3 is 1, 2, 3 or 4;
- n4 is 1 or 2;
- A together with B form a fused heterobicyclic radical having 8 to 12 annular atoms, wherein each ring has 5 to 7 annular atoms, said annular atoms are selected from C, N, NR.sup.5,O and S, wherein R.sup.5 is R.sup.6 or X.sup.6 R6.sup.a, wherein X.sup.6 is a linking group containing 1 to 12 contiguous linking atoms and R.sup.6 and R.sup.6a independently represent hydrogen, (C.sub.6-14)aryl, cyclo(C.sub.3-14)alkyl, hetero(C.sub.5-14)aryl, heterocyclo(C.sub.3-14)alkyl, hetero(C.sub.8-14)polycycloaryl or (C.sub.9-14)polycycloaryl, wherein said R.sup.6 and X.sup.6 R.sup.6a groups optionally are substituted with 1 to 5 substituents independently selected from (C.sub.1-6)alkyl, (C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, (C.sub.1-6)alkylcarbamoyl, di(C.sub.1-6)alkylcarbamoyl, (C.sub.1-6)alkyloxy, (C.sub.1-6)alkyloxycarbonyl, (C.sub.1-6)alkylsulfinyl, (C.sub.1-6)alkylsulfonyl, (C.sub.1-6)alkylthio, amino, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto, perhalo(C.sub.1-3)alkyl, perhalo(C.sub.1-3)alkyloxy, uriedo and (C.sub.1-3)alkylimino;
- ring C represents a heteromonocyclic or fused heteropolycyclic ring having 5 to 18 annular atoms, wherein each ring has 5 to 7 annular atoms, said annular atoms are selected from C, N, NR.sup.5, O and S, wherein R.sup.5 is as defined above;
- X.sup.3 represents a carbon atom;
- R.sup.1 is amidino;
- each R.sup.2 is independently hydrogen, (C.sub.1-3)alkyl, (C.sub.1-3)alkyloxy, (C.sub.1-3)alkylsulfonyl, (C.sub.1-3)alkylthio, carboxy, halo, (C.sub.2-12)heteroalkyl, hydroxy, mercapto or nitro;
- each R.sup.3 is independently hydrogen, cyano, halo, nitro, perhalo(C.sub.1-3)alkyl or perhalo(C.sub.1-3)alkyloxy;
- and
- R.sup.4 independently at each occurance represents C.sub.4-12 alkyl substituted with 1 to 5 substituents independently selected from (C.sub.1-6)alkyl, (C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, (C.sub.1-6)alkylcarbamoyl, di(C.sub.1-6)alkylcarbamoyl, (C.sub.1-6)alkyloxy, (C.sub.1-6)alkyloxycarbonyl, (C.sub.1-6)alkylsulfinyl, (C.sub.1-6)alkylsulfonyl, (C.sub.1-6)alkylthio, amino, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto, perhalo(C.sub.1-3)alkyl, perhalo(C.sub.1-3)alkyloxy, uriedo and (C.sub.1-3)alkylimino, R.sup.7 or X.sup.7 R.sup.7a, wherein X.sup.7 is a linking group having 1 to 12 contiguous linking atoms and R.sup.7 and R.sup.7a independently at each occurance represent (C.sub.6-14)aryl, cyclo(C.sub.3-14)alkyl, hetero(C.sub.5-14)aryl, heterocyclo(C.sub.3-14)alkyl, hetero(C.sub.8-14)polycycloaryl or (C.sub.9-14)polycycloaryl, and wherein said R.sup.7 and X.sup.7 R.sup.7a groups optionally are substituted with 1 to 5 substituents independently selected from (C.sub.1-6)alkyl, (C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, (C.sub.1-6)alkylcarbamoyl, di(C.sub.1-6)alkylcarbamoyl, (C.sub.1-6)alkyloxy, (C.sub.1-6)alkyloxycarbonyl, (C.sub.1-6)alkylsulfinyl, (C.sub.1-6)alkylsulfonyl, (C.sub.1-6)alkylthio, amino, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto, perhalo(C.sub.1-3)alkyl, perhalo(C.sub.1-3)alkyloxy, uriedo and (C.sub.1-3)alkylimino;
- and the individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
10 more elements
A method of treating a disease in an animal in which factor Xa activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount a of compound of Formula I:
- ##STR11## in which:
- n2 is 1, 2 or 3;
- n3 is 1, 2, 3 or 4;
- n4 is 1 or 2;
- A together with B forms a fused heterobicyclic radical having 8 to 12 annular atoms, wherein each ring has 5 to 7 annular atoms, said annular atoms are selected from C, N, NR.sup.5, O and S, wherein R.sup.5 is R.sup.6 or X.sup.6 R6.sup.a, wherein X.sup.6 is a linking group containing 1 to 12 contiguous linking atoms and R.sup.6 and R.sup.6a independently represent hydrogen, (C.sub.6-14)aryl, cyclo(C.sub.3-14)alkyl, hetero(C.sub.5-14)aryl, heterocyclo(C.sub.3-14)alkyl, hetero(C.sub.8-14)polycycloaryl or (C.sub.9-14)polycycloaryl, wherein said R.sup.6 and X.sup.6 R.sup.6a groups optionally are substituted with 1 to 5 substituents independently selected from (C.sub.1-6)alkyl, (C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, (C.sub.1-6)alkylcarbamoyl, di(C.sub.1-6)alkylcarbamoyl, (C.sub.1-6)alkyloxy, (C.sub.1-6)alkyloxycarbonyl, (C.sub.1-6)alkylsulfinyl, (C.sub.1-6)alkylsulfonyl, (C.sub.1-6)alkylthio, amino, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto, perhalo(C.sub.1-3)alkyl, perhalo(C.sub.1-3)alkyloxy, uriedo and (C.sub.1-3)alkylimino;
- ring C represents a heteromonocyclic or fused heteropolycyclic ring having 5 to 18 annular atoms, wherein each ring has 5 to 7 annular atoms, said annular atoms are selected from C, N, NR.sup.5, O and S, wherein R.sup.5 is as defined above;
- X.sup.3 represents a carbon atom;
- R.sup.1 is amidino;
- each R.sup.2 is independently hydrogen, (C.sub.1-3)alkyl, (C.sub.1-3)alkyloxy, (C.sub.1-3)alkylsulfonyl, (C.sub.1-3)alkylthio, carboxy, halo, (C.sub.2-12)heteroalkyl, hydroxy, mercapto or nitro;
- each R.sup.3 is independently hydrogen, cyano, halo, nitro, perhalo(C.sub.1-3)alkyl or perhalo(C.sub.1-3)alkyloxy;
- and
- R.sup.4 independently at each occurance represents C.sub.4-12 alkyl substituted with 1 to 5 substituents independently selected from (C.sub.1-6)alkyl, (C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, (C.sub.1-6)alkylcarbamoyl, di(C.sub.1-6)alkylcarbamoyl, (C.sub.1-6)alkyloxy, (C.sub.1-6)alkyloxycarbonyl, (C.sub.1-6)alkylsulfinyl, (C.sub.1-6)alkylsulfonyl, (C.sub.1-6)alkylthio, amino, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto, perhalo(C.sub.1-3)alkyl, perhalo(C.sub.1-3)alkyloxy, uriedo and (C.sub.1-3)alkylimino,
- R.sup.7 or X.sup.7 R.sup.7a, wherein X.sup.7 is a linking group having 1 to 12 contiguous linking atoms and R.sup.7 and R.sup.7a independently at each occurance represent (C.sub.6-14)aryl, cyclo(C.sub.3-14)alkyl, hetero(C.sub.5-14)aryl, heterocyclo(C.sub.3-14)alkyl, hetero(C.sub.8-14)polycycloaryl or (C.sub.9-14)polycycloaryl, and wherein said R.sup.7 and X.sup.7 R.sup.7a groups optionally are substituted with 1 to 5 substituents independently selected from (C.sub.1-6)alkyl, (C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, (C.sub.1-6)alkylcarbamoyl, di(C.sub.1-6)alkylcarbamoyl, (C.sub.1-6)alkyloxy, (C.sub.1-6)alkyloxycarbonyl, (C.sub.1-6)alkylsulfinyl, (C.sub.1-6)alkylsulfonyl, (C.sub.1-6)alkylthio, amino, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto, perhalo(C.sub.1-3)alkyl, perhalo(C.sub.1-3)alkyloxy, uriedo and (C.sub.1-3)alkylimino;
- and the individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
11 more elements
Dependencies are inferred from the claim text.