TRICYCLIC INHIBITORS OF POLY(ADP-RIBOSE) POLYMERASES

• Main Authors: TIKHE, JAYASHREE, WEBBER, STEPHEN, EVAN, THORENSEN, LARS, HENRIK, CANAN-KOCH, STACIE, S
• Format: Patent
• Language: English; Russian
• Published: 28.10.2004
• Edition: 7
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

1. A compound of general formula (I) capable to inhibit poly (ADP-ribose) polymerase (PARP): wherein: R is halogen; cyano group; an optionally substituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl having 3-18 atoms, comprising from 1 to 5 N, O or S atoms, (C4-C18) aryl or heteroaryl group with an aromatic ring having 4-18 atoms comprising from 1 to 5 N, O or S atoms, (C4-18)aryl or heteroaryl group with an aromatic ring of 4-18 atoms, containing from 1 to 5 N, O or S atoms; or -C(O)-R where R is H; an optionally substituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, (C3-C18) heterocycloalkyl group containing from 1 to 5 N, O or S atoms, (C4-C18)aryl or heteroaryl group with an aromatic ring of 4-18 atoms, containing from 1 to 5 N, O or S atoms, wherein said substituted groups are substituted by hydroxy, halo, oxo, aryl, acyl, sulfonyl, mercapto, nitro, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, amino, carbamoyl, aryloxy, heteroaryloxy, arylthio, or heteroarylthio; or OR , where R and R are each independently H or an optionally substituted (C1-C10) alkyl, (C2-C10)alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms containing from 1 to 5 N, O or S atoms, an aryl group with an aromatic ring of 4-18 carbon atoms or a heteroaryl group with an aromatic ring of 4-18 atoms containing from 1 to 5 N, O or S atoms, wherein said substituted groups are substituted by hydroxy, halo, oxo, aryl, acyl, sulfonyl, mercapto, nitro, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, amino, carbamoyl, aryloxy, heteroaryloxy, arylthio, or heteroarylthio; R is H or (C1-C10) alkyl; R is H or (C1-C10) alkyl; R is H, halogen, or (C1-C10) alkyl; X is O or S; Y is (CR R ) (CR R )n or N=C(R ), where n is 0 or 1; R and R are each independently H or an optionally substituted (C1-C10) alkyl, (C2-C10)alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms containing from 1 to 5 N, O or S atoms, or -C(O)-R , where R is H; an optionally substituted (C1-C10) alkyl, (C2-C10)alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms containing from 1 to 5 N, O or S atoms, (C4-18)aryl or heteroaryl group with an aromatic ring of 4-18 atoms, containing from 1 to 5 N, O or S atoms, wherein said substituted groups are substituted by hydroxy, halo, oxo, aryl, acyl, sulfonyl, mercapto, nitro, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl aryl, heteroaryl, carboxy, amino, carbamoyl, aryloxy, heteroaryloxy, arylthio, or heteroarylthio; and R and R are each independently H or an optionally substituted (C1-C10) alkyl, (C2-C10)alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms containing from 1 to 5 N, O or S atoms, or -C(O)-R , where R is H; an optionally substituted (C1-C10) alkyl, (C2-C10)alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms containing from 1 to 5 N, O or S atoms, (C4-18)aryl or heteroaryl group with an aromatic ring of 4-18 atoms, containing from 1 to 5 N, O or S atoms, wherein said substituted groups are substituted by hydroxy, halo, oxo, aryl, acyl, sulfonyl, mercapto, nitro, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl aryl, heteroaryl, carboxy, amino, carbamoyl, aryloxy, heteroaryloxy, arylthio, or heteroarylthio; wherein, when R , R , R and R are each H, R is not unsubstituted phenyl; or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate of this compound. 2. A compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof. 3. A compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof. 4. A compound according to claims 1-3 or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof, having an inhibition constant (Ki) PARP of 100 mkM or less in an enzyme inhibition assay. 5. A compound according to claims 1-3 or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof, having a cytotoxicity potentiation activity corresponding to a PF50 of at least 1 in a cytotoxicity potentiation assay. 6. A pharmaceutical composition comprising: (a) an effective amount of a PARP-inhibiting agent that is a compound according to any of claims 1-3 or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof; and (b) a pharmaceutically acceptable carrier for said PARP-inhibiting agent. 7. A method of inhibiting PARP activity, comprising contacting the enzyme with an effective amount of a compound, a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof according to any of claims 1-3 or of a composition according to claim 6. 8. A method according to claim 7, wherein the enzyme is poly(ADP-ribose)polymerase or tankyrase. 9. A method of inhibiting PARP activity in a mammalian tissue by administering to a mammalian a therapeutically effective amount of a compound, pharmaceutically acceptable salt, prodrug, active metabolite, active metabolite or solvate thereof according to any of claims 1-3 or of a composition according to claim 6. 10. A compound of formula (II) having a PARP-inhibiting capacity: wherein: P is 2; R is H or (C1-C10) alkyl; R is halogen or an optionally substituted (C4-18)aryl, (C1-C10)alkyl, (C2-C10) alkenyl, (C2-10) alkynyl, or acyl group-C(O)-R , where R is H; an optionally substituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms, containing from 1 to 5 N, O or S atoms, (C4-C18)aryl or heteroaryl group with an aromatic ring of 4-18 atoms, or OR or, where R and R are each independently H or an optionally substituted (C1-C10) alkyl, (C2-C10)alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms containing from 1 to 5 N, O or S atoms, an aryl group with an aromatic ring of 4-18 carbon atoms or a heteroaryl group with an aromatic ring of 4-18 atoms containing from 1 to 5 N, O or S atoms, wherein said substituted groups are substituted by hydroxy, halo, oxo, aryl, acyl, sulfonyl, mercapto, nitro, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy, amino, carbamoyl, aryloxy, heteroaryloxy, arylthio, or heteroarylthio; R is H or (C1-C10) alkyl; and R is H or halogen; or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate of this compound. 11. A pharmaceutical composition comprising: (a) an effective amount of a PARP-inhibiting agent that is a compound according to claim 10 or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof; and (b) a pharmaceutically acceptable carrier for said inhibiting agent. 12. A method of inhibiting PARP activity, comprising contacting the enzyme with an effective amount of a compound, a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof according to claim 10 or of a composition according to claim 11. 13. A method according to claim 12, wherein PARP is poly(ADP-ribose)polymerase or tankyrase. 14. A method of inhibiting PARP activity in a mammalian tissue by administering to a mammalian a therapeutically effective amount of a compound, pharmaceutically acceptable salt, prodrug, active metabolite, active metabolite or solvate thereof according to claim 10 or of a composition according to claim 11. 15. A compound of formula (III) having a PARP-inhibiting capacity: wherein: R is H, halogen or (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms, containing from 1 to 5 N, O or S atoms, (C4-C18)aryl or heteroaryl group unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, nitro, amino and (C1-C10) alkyl or (C4-C18)aryl groups, substituted or unsubstituted by one or more substituents selected from halogen, hydroxy, nitro and amino groups; R is halogen; cyano; or (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C3-C18) cycloalkyl, heterocycloalkyl group of 3-18 atoms, containing from 1 to 5 N, O or S atoms, (C4-C18)aryl or heteroaryl group with an aromatic ring of 4-18 atoms containing from 1 to 5 N, O or S atoms, unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, nitro, amino and (C1-C10) alkyl or (C4-C18)aryl groups, substituted or unsubstituted by one or more substituents selected from halogen, hydroxy, nitro and amino groups; R is H or (C1-C10) alkyl; and R is H, halogen or (C1-C10) alkyl; where R , R and R are not all H. 16. A pharmaceutical composition comprising: (a) an effective amount of a PARP-inhibiting agent that is a compound according to claim 15 or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof; and (b) a pharmaceutically acceptable carrier for said inhibiting agent. 17. A method of inhibiting PARP activity, comprising contacting the enzyme with an effective amount of a compound, a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof according to claim 15 or of a composition according to claim 16. 18. A method according to claim 17, wherein PARP is poly(ADP-ribose)polymerase or tankyrase. 19. A method of inhibiting PARP activity in a mammalian tissue by administering to a mammalian a therapeutically effective amount of a compound, pharmaceutically acceptable salt, prodrug, active metabolite, active metabolite or solvate thereof according to claim 15 or of a composition according to claim 16. Соединения приведенной ниже формулы (I) являются ингибиторами активности поли(ADP-рибозил)трансферазы (ПАРП) и полезны в качестве терапевтических средств при лечении раковых заболеваний и для облегчения последствий удара, травмы головы и нейр