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US 6,333,321 B1Granted
Selective factor Xa inhibitors
AssigneeCOR Therapeutics, Inc.
InventorRobert Scarborough
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.
Claims54
A compound having the formula:
- wherein:
- R1 and R2 are independently selected from the group consisting of H, C1-6alkyl, C3-8cycloalkyl, C1-3alkylaryl, C1-3alkyl-C3-8cycloalkyl and aryl;
- R3 is H, C1-6alkyl or R2 and R3 are taken together to form a carbocyclic ring;
- q is an integer from 0-1;
- 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 R8, —NR8R9,
- where R8, R9, R10 and R11 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R12 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R10 or R11 to form a 5-6 membered ring;
- and R13 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R11 to form a 5-6 membered ring;
- D is selected from the group consisting of a direct link, C3-8cycloalkyl, C1-6alkenyl, C1-4alkenylaryl, aryl and 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, —CO—, —SO2—, —O—CO—, —NR14—SO2— and —NR14—CO—, where R14 is selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- G 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;
- J is selected from the group consisting of R15, —NR15R16,
- where R15, R16, R17 and R18 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R19 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R17 or R18 to form a 5-6 membered ring;
- and R20 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R18 to form a 5-6 membered ring;
- with the proviso that when J is R15, then G must contain at least one N atom;
- L is selected from the group consisting of R33, —NR33R34,
- where R33, R34, R35 and R36 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R37 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R35 or R36 to form a 5-6 membered ring;
- and R38 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R36 to form a 5-6 membered ring;
- M is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C1-6alkenyl, C1-6alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- Q is selected from the group consisting of H,
- where R21 and R22 are independently selected from the group consisting of H, C1-3alkyl and aryl;
- and T is selected from the group consisting of H, —COOR23, —CONR23R24, —CF3, —CF2CF3 and a group having the formula:
- where,
- R23 and R24 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl;
- U′ and U″ are independently selected from the group consisting of —O—, —S—, —N— and —NH—;
- with the proviso that at least one of U′ or U″ is —N— or —NH—;
- R25 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo C2-6alkenylheterocyclo, —CF3 and —CF2CF3;
- V is selected from the group consisting of —S—, —SO—, —SO 2, —O— and —NR26—, where R26 is selected from the group consisting of H, C1-6alkyl and benzyl;
- and W is selected from the group consisting of:
- a C6-10 heterocyclic ring system substituted by R29 and R30 and containing 1-4 heteroatoms selected from N, S and O;
- where a is an integer from 0-2;
- R27 and R28 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, —COOR31, —CONR31R32, —CN and —CF3;
- and R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, —NO2, —NR31R32, —NR31COR32, —OR31, —OCOR31, —COOR31, —CONR31R32, —CN, —CF3, —SO2NR31R32 and C1-6alkyl-OR31;
- where R31 and R32 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl;
- or a pharmaceutically acceptable salt or an optical isomer thereof.
37 more elements
A compound having the formula:
- wherein:
- R1 and R2 are independently selected from the group consisting of H, C1-6alkyl, C3-8cycloalkyl, C1-3alkylaryl, C1-3alkyl-C3-8cycloalkyl and aryl;
- q is an integer from 0-1;
- r is an integer from 0-4;
- t is an integer from 0-4;
- A is selected from the group consisting of R8, —NR8R9,
- where R8, R9, R10 and R11 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R12 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R10 or R11 to form a 5-6 membered ring;
- and R13 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R11 to form a 5-6 membered ring;
- D is selected from the group consisting of a direct link, C3-8cycloalkyl, C1-6alkenyl, C1-4alkenylaryl, aryl and 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, —CO—, —SO2—, —O—CO—, —NR14—SO2— and —NR14—CO—, where R14 is selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylary;
- G 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;
- J is selected from the group consisting of R15, —NR15R16,
- where R15, R16, R17 and R18 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R19 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R17 or R18 to form a 5-6 membered ring;
- and R20 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R18 to form a 5-6 membered ring;
- with the proviso that when J is R15, then G must contain at least one N atom;
- L is selected from the group consisting of R33, —NR33R34,
- where R33, R34, R35 and R36 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R37 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R35 or R36 to form a 5-6 membered ring;
- and R38 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R36 to form a 5-6 membered ring;
- M is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C1-6alkenyl, C1-6alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- T is selected from the group consisting of H, —COOR23, —CONR23R24, —CF3, —CF2CF3 and a group having the formula:
- where:
- R23 and R24 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl;
- U′ and U″ are independently selected from the group consisting of —O—, —S—, —N— and —NH—;
- with the proviso that at least one of U′ or U″ is —N— or —NH—;
- R25 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo, C2-6alkenylheterocyclo, —CF3 and —CF2CF3;
- V is selected from the group consisting of —S—, —SO—, —SO2—, —O— and —NR26—, where R26 is selected from the group consisting of H, C1-6alkyl and benzyl;
- and W is selected from the group consisting of:
- a C6-10 heterocyclic ring system substituted by R29 and R30 and containing 1-4 heteroatoms selected from N, S and O;
- where a is an integer from 0-2;
- R27 and R28 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, —COOR31, —CONR31R32, —CN and —CF3;
- and R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, —NO2, —NR31R32, —NR31COR32, —OR31, —OCOR31, —COOR31, —CONR31R32, —CN, —CF3, —SO2NR31R32 and C1-6alkyl-OR31;
- where R31 and R32 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl;
- or a pharmaceutically acceptable salt or an optical isomer thereof.
33 more elements
A compound having the formula:
- wherein:
- q is an integer from 0-1;
- t is an integer from 0-4;
- A is selected from the group consisting of R8, —NR8R9,
- where R8, R9, R10 and R11 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R12 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R10 or R11 to form a 5-6 membered ring;
- and R13 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R11 to form a 5-6 membered ring;
- D is selected from the group consisting of a direct link, C3-8cycloalkyl, C1-6alkenyl, C1-4alkenylaryl, aryl and 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, —CO—, —SO2—, —O—CO—, —NR14—SO2— and —NR14—CO—, where R14 is selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- L is selected from the group consisting of R33, —NR33R34,
- where R33, R34, R35 and R36 are independently selected from the group consisting of H, —OH, C1-6alkyl, aryl and C1-4alkylaryl;
- R37 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R35 or R36 to form a 5-6 membered ring;
- and R38 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R36 to form a 5-6 membered ring;
- M is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C1-6alkenyl, C1-6alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
- T is selected from the group consisting of H, —COOR23, —CONR23R24, —CF3, —CF2CF3 and a group having the formula:
- where:
- R23 and R24 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl;
- U′ and U″ are independently selected from the group consisting of —O—, —S—, —N— and —NH—;
- with the proviso that at least one of U′ or U″ is —N— or —NH—;
- R25 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo, C2-6alkenylheterocyclo, —CF3 and —CF2CF3;
- V is selected from the group consisting of —S—, —SO—, —SO2—, —O— and —NR26—, where R26 is selected from the group consisting of H, C1-6alkyl and benzyl;
- and W is selected from the group consisting of:
- a C6-10 heterocyclic ring system substituted by R29 and R30 and containing 1-4 heteroatoms selected from N, S and O;
- where a is an integer from 0-2;
- R27 and R28 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, —COOR31, —CONR31R32, —CN and —CF3;
- and R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, —NO2, —NR31R32, —NR31COR32, —OR31, —OCOR31, —COOR31, —CONR31R32, —CN, —CF3, —SO2NR31R32 and C1-6alkyl-OR31;
- where R31 and R32 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl;
- or a pharmaceutically acceptable salt or an optical isomer thereof.
25 more elements
Dependencies are inferred from the claim text.