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US 6,204,268 B1Granted
Selective factor Xa inhibitors
AssigneeCOR Therapeutics, Inc.
InventorsRobert M. Scarborough, Bing-Yan Zhu, Ting Su
Life of this patent
Estimating the term…
Abstract
Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.
Claims19
A compound having the formula:
- wherein:
- R1 is selected from the group consisting of H, C1-6alkyl, C3-8cycloalkyl, C1-3alkylaryl, C1-3alkyl-C3-8cycloalkyl and aryl and R2 is H, or R1 and R2 are taken together to form a carbocyclic ring;
- m is an integer from 0-2;
- n is an integer from 0-6;
- k is 0;
- p is 0;
- q is 1;
- r is an integer from 0-4;
- s is an integer from 0-1;
- t is an integer from 0-4;
- A is selected from the group consisting of R3, —NR3R4,
- where R3, R4, R5 and R6 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R7 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R5 or R6 to form a 5-6 membered ring;
- and R8 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R6 to form a 5-6 membered ring;
- Q is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C2-6alkenylaryl, aryl, and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- D is selected from the group consisting of a direct link, —CO—, —SO2—, —O—CO—, —NR9—SO2— and —NR9—CO—, where R9 is selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- X is O or H2;
- Y is O or H2;
- K is selected from the group consisting of R28O— and R29R30N—, where R28, R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, C0-3alkylaryl, C0-3alkylC3-8cycloalkyl, C0-3alkylheterocycle;
- and where R29 and R30 can be taken together to form a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- E is selected from the group consisting of a direct link, C3-8cycloalkyl, aryl, and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- G is selected from the group consisting of R10, —NR10R11,
- where R10, R11, R12 and R13 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R14 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R12 or R13 to form a 5-6 membered ring;
- and R15 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R13 to form a 5-6 membered ring;
- with the proviso that when G is R10, then E must contain at least one N atom;
- W is selected from the group consisting of H,
- where R16 and R17 are independently selected from the group consisting of H, C1-3alkyl and aryl;
- and Z is selected from the group consisting of H, —COOR18, —CONR18R19, —CF3, —CF2CF3 and a group having the formula:
- where:
- R18 and R19 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl;
- U is selected from the group consisting of —O—, —S—, —N— and —NH—;
- and
- V is selected from the group consisting of —O—, —S—, —N— and —NH—;
- with the proviso that at least one of U or V is —N— or —NH—;
- R20 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo, C2-6alkenylheterocyclo, —CF3 and —CF2CF3;
- J is selected from the group consisting of —S—, —SO—, —SO2—, —O— and —NR21—, where R21 is selected from the group consisting of H, C1-6alkyl and benzyl;
- and
- L is selected from the group consisting of:
- a C6-10 heterocyclic ring system substituted by R24 and R25 and containing 1-4 heteroatoms selected from N, S and O;
- where d is an integer from 0-2;
- R22 and R23 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, —COOR26, —CONR26R27, —CN and —CF3;
- R24 and R25 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, —NO2, —NR26R27, —NR26COR27, —OR26, —OCOR26, —COOR26, —CONR26R27, —CN, —CF3, —SO2NR26R27 and C1-6alkyl-OR26;
- and
- R26 and R27 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl;
- and all pharmaceutically acceptable salts and optical isomers thereof.
43 more elements
A method for inhibiting the coagulation of biological samples, comprising the administration of the compound having the formula:
- wherein:
- R1 is selected from the group consisting of H, C1-6alkyl, C3-8cycloalkyl, C1-3alkylaryl, C1-3alkyl-C3-8cycloalkyl and aryl and R2 is H, or R1 and R2 are taken together to form a carbocyclic ring;
- m is an integer from 0-2;
- n is an integer from 0-6;
- k is 0;
- p is 0;
- q is 1;
- r is an integer from 0-4;
- s is an integer from 0-1;
- t is an integer from 0-4;
- A is selected from the group consisting of R3, —NR3R4,
- where R3, R4, R5 and R6 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R7 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R5 or R6 to form a 5-6 membered ring;
- and R8 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R6 to form a 5-6 membered ring;
- Q is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C2-6alkenylaryl, aryl, and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- D is selected from the group consisting of a direct link, —CO—, —SO2—, —O—CO—, —NR9—SO2— and —NR9—CO—, where R9 is selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- X is O or H2;
- Y is O or H2;
- K is selected from the group consisting of R28O— and R29R30N—, where R28, R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, C0-3alkylaryl, C0-3alkylC3-8cycloalkyl, C0-3alkylheterocycle;
- and where R29 and R30 can be taken together to form a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- E is selected from the group consisting of a direct link, C3-8cycloalkyl, aryl, and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- G is selected from the group consisting of R10, —NR10R11,
- where R10, R11, R12 and R13 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R14 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R12 or R13 to form a 5-6 membered ring;
- and R15 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R13 to form a 5-6 membered ring;
- with the proviso that when G is R10, then E must contain at least one N atom;
- W is selected from the group consisting of H,
- where R16 and R17 are independently selected from the group consisting of H, C1-3alkyl and aryl;
- and Z is selected from the group consisting of H, —COOR18, —CONR18R19, —CF3, —CF2CF3 and a group having the formula:
- where:
- R18 and R19 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl;
- U is selected from the group consisting of —O—, —S—, —N— and —NH—;
- and
- V is selected from the group consisting of —O—, —S—, —N— and —NH—;
- with the proviso that at least one of U or V is —N— or —NH—;
- R20 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo, C2-6alkenylheterocyclo, —CF3 and —CF2CF3;
- J is selected from the group consisting of —S—, —SO—, —SO2—, —O— and —NR21—, where R21 is selected from the group consisting of H, C1-6alkyl and benzyl;
- and
- L is selected from the group consisting of:
- a C6-10 heterocyclic ring system substituted by R24 and R25 and containing 1-4 heteroatoms selected from N, S and O;
- where d is an integer from 0-2;
- R22 and R23 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, —COOR26, —CONR26R27, —CN and —CF3;
- R24 and R25 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, —NO2, —NR26R27, —NR26COR27, —OR26, —OCOR26, —COOR26, —CONR26R27, —CN, —CF3, —SO2NR26R27 and C1-6alkyl-OR26;
- and
- R26 and R27 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl;
- and all pharmaceutically acceptable salts and optical isomers thereof.
43 more elements
Dependencies are inferred from the claim text.