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

Patent metadata

Field	Value
Publication number	US-9861638-B2
Application number	US-201514698463-A
Country	US
Kind code	B2
Filing date	Apr 28, 2015
Priority date	Feb 12, 2010
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

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.

First claim

We claim:

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 (2θ) 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 1 X-rays at a wavelength of 1.5406 Ångstroms.

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 (2θ) 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 1 X-rays at a wavelength of 1.5406 Ångstroms and maleate polymorph Form B, wherein the polymorph has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2θ) 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 1 X-rays at a wavelength of 1.5406 Ångstroms.

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 (2θ) 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 1 X-rays at a wavelength of 1.5406 Ångstroms.

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 (2θ) 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 1 X-rays at a wavelength of 1.5406 Ångstroms and maleate polymorph Form B, wherein the polymorph has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2θ) 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 1 X-rays at a wavelength of 1.5406 Ångstroms.

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.

Assignees

• Pfizer

Inventors

• Basford Patricia Ann
• Campeta Anthony Michael
• Gillmore Adam
• Jones Matthew Cameron
• Kougoulos Eleftherios
• Luthra Suman
• Walton Robert

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/06

  of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title