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Last Updated: March 29, 2024

Claims for Patent: 9,861,638


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Summary for Patent: 9,861,638
Title:Salts and polymorphs of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one
Abstract: The present invention relates to novel polymorphic forms of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one, and to processes for their preparation. Such polymorphic forms may be a component of a pharmaceutical composition and may be used to treat a mammalian disease condition mediated by poly(ADP-ribose) polymerase activity including the disease condition such as cancer.
Inventor(s): Basford; Patricia Ann (Sandwich, GB), Campeta; Anthony Michael (Ledyard, CT), Gillmore; Adam (Sandwich, GB), Jones; Matthew Cameron (Sandwich, GB), Kougoulos; Eleftherios (Morrisville, NC), Luthra; Suman (Groton, CT), Walton; Robert (Sandwich, GB)
Assignee: PFIZER INC. (New York, NY)
Application Number:14/698,463
Patent Claims: 1. A method of inhibiting poly(ADP-ribose) polymerase (PARP) activity in a mammal having a BRCA1 and/or BRCA2 mutation, wherein the mammal has ovarian cancer, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a salt selected from the group consisting of a camsylate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one and a maleate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one and a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein the pharmaceutical composition comprising a salt is administered with a therapeutically effective amount of a compound selected from the group consisting of an anti-tumor agent, an anti-angiogenesis agent, a signal transduction inhibitor, an anti-proliferative agent, a mitotic inhibitor, an alkylating agent, an anti-metabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic, an anti-hormone and an anti-androgen.

3. The method of claim 2, wherein said anti-tumor agent is selected from the group consisting of temozolomide, irinotecan, topotecan, cisplatin and doxorubicin hydrochloride.

4. The method of claim 1, wherein said pharmaceutical composition comprising a salt comprises a camsylate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one wherein said camsylate salt is S-camsylate polymorph Form A, wherein the polymorph has a powder X-ray diffraction pattern comprising one or more or two or more or three peaks at diffraction angles (2.theta.) selected from the group consisting of 12.2 .+-.0.2, 14.8 .+-.0.2 and 22.5 .+-.0.2, wherein said powder X-ray diffraction pattern is obtained using copper K-alpha.sub.1 X-rays at a wavelength of 1.5406 .ANG.ngstroms.

5. The method of claim 1, wherein said pharmaceutical composition comprising a salt comprises a maleate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one wherein said maleate salt is selected from the group consisting of maleate polymorph Form A, wherein the polymorph has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2.theta.) of 6.0 .+-.0.2, 20.3 .+-.0.2, and 21.7 .+-.0.2, wherein said powder X-ray diffraction pattern is obtained using copper K-alpha.sub.1 X-rays at a wavelength of 1.5406 .ANG.ngstroms and maleate polymorph Form B, wherein the polymorph has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2.theta.) of 7.5 .+-.0.2, 11.3 .+-.0.2, and 24.3 .+-.0.2, wherein said powder X-ray diffraction pattern is obtained using copper K-alpha.sub.1 X-rays at a wavelength of 1.5406 .ANG.ngstroms.

6. The method of claim 1, wherein said pharmaceutical composition comprising a salt is administered in a solid dosage form.

7. The method of claim 6, wherein said solid dosage form is selected from the group consisting of a tablet, a powder, a pellet, a troche and a lozenge.

8. The method of claim 1, wherein said pharmaceutical composition comprising a salt is administered in an amount wherein the dose of the salt is from about 0.001 to about 1000 mg/kg of body weight of the mammal.

9. The method of claim 1, wherein said pharmaceutical composition comprising a salt is administered in an amount wherein the dose of the salt is from about 0.001 to about 50 mg/kg of body weight of the mammal.

10. A method of treating cancer in a mammal having a BRCA1 and/or BRCA2 mutation, wherein the mammal has ovarian cancer, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a salt selected from the group consisting of a camsylate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one and a maleate salt of 8-fluoro-2-{4-[(methylamino)methyl]pheny}-1,3,4,5-tetrahydro-6H-azepino[5- ,4,3-cd]indol-6-one and a pharmaceutically acceptable carrier.

11. The method of claim 10, wherein the pharmaceutical composition comprising a salt is administered with a therapeutically effective amount of a compound selected from the group consisting of an anti-tumor agent, an anti-angiogenesis agent, a signal transduction inhibitor, an anti-proliferative agent, a mitotic inhibitor, an alkylating agent, an anti-metabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic, an anti-hormone and an anti-androgen.

12. The method of claim 11, wherein said anti-tumor agent is selected from the group consisting of temozolomide, irinotecan, topotecan, cisplatin and doxorubicin hydrochloride.

13. The method of claim 10, wherein said pharmaceutical composition comprising a salt comprises a camsylate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one wherein said camsylate salt is S-camsylate polymorph Form A, wherein the polymorph has a powder X-ray diffraction pattern comprising one or more or two or more or three peaks at diffraction angles (2.theta.) selected from the group consisting of 12.2 .+-.0.2, 14.8 .+-.0.2 and 22.5 .+-.0.2, wherein said powder X-ray diffraction pattern is obtained using copper K-alpha.sub.1 X-rays at a wavelength of 1.5406 .ANG.ngstroms.

14. The method of claim 10, wherein said pharmaceutical composition comprising a salt comprises a maleate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[- 5,4,3-cd]indol-6-one wherein said maleate salt is selected from the group consisting of maleate polymorph Form A, wherein the polymorph has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2.theta.) of 6.0 .+-.0.2, 20.3 .+-.0.2, and 21.7 .+-.0.2, wherein said powder X-ray diffraction pattern is obtained using copper K-alpha.sub.1 X-rays at a wavelength of 1.5406 .ANG.ngstroms and maleate polymorph Form B, wherein the polymorph has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2.theta.) of 7.5 .+-.0.2, 11.3 .+-.0.2, and 24.3 .+-.0.2, wherein said powder X-ray diffraction pattern is obtained using copper K-alpha.sub.1 X-rays at a wavelength of 1.5406 .ANG.ngstroms.

15. The method of claim 10, wherein said pharmaceutical composition comprising a salt is administered in a solid dosage form.

16. The method of claim 15, wherein said solid dosage form is selected from the group consisting of a tablet, a powder, a pellet, a troche and a lozenge.

17. The method of claim 10, wherein said pharmaceutical composition comprising a salt is administered in an amount wherein the dose of the salt is from about 0.001 to about 1000 mg/kg of body weight of the mammal.

18. The method of claim 10, wherein said pharmaceutical composition comprising a salt is administered in an amount wherein the dose of the salt is from about 0.001 to about 50 mg/kg of body weight of the mammal.

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