Claims for Patent: 10,898,482

Summary for Patent: 10,898,482

Title:	Pharmaceutical compositions comprising N-(3,5-dimethoxyphenyl)-N'-1 methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-di- amine
Abstract:	The invention relates to pharmaceutical compositions comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine, or a pharmaceutically acceptable salt thereof or a solvate thereof; to processes for the preparation of said compositions and to the use of said compositions for the manufacture of a medicament for the prophylaxis of or the treatment, in particular the treatment, of diseases, e.g. cancer.
Inventor(s):	Broggini; Diego Fernando Domenico (Schaffhausen, CH)
Assignee:	ASTEX THERAPEUTICS LTD (Cambridge, GB)
Application Number:	15/549,881
Patent Claims:	1. A pharmaceutical composition comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof; a formaldehyde scavenger; and a pharmaceutically acceptable carrier, wherein the formaldehyde scavenger is meglumine base. 2. A pharmaceutical composition according to claim 1 comprising from about 0.1 to about 3% w/w of the formaldehyde scavenger. 3. A pharmaceutical composition according to claim 1, wherein the composition is a tablet or a capsule. 4. A pharmaceutical composition according to claim 1, wherein the composition comprises from 0-2% w/w of 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin- -6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, a pharmaceutically acceptable salt thereof or a solvate thereof. 5. A pharmaceutical composition according to claim 4, wherein the composition comprises from 0-0.05 w/w of 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin- -6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, a pharmaceutically acceptable salt thereof or a solvate thereof. 6. A pharmaceutical composition according to claim 1 comprising from 2 mg to 6 mg base equivalent of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof. 7. A pharmaceutical composition according to claim 1, wherein the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 8. A pharmaceutical composition according to claim 2 comprising 3 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 9. A pharmaceutical composition according to claim 2 comprising 4 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 10. A pharmaceutical composition according to claim 2 comprising 5 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 11. A pharmaceutical composition according to claim 5 comprising 3 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 12. A pharmaceutical composition according to claim 5 comprising 4 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 13. A pharmaceutical composition according to claim 5 comprising 5 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 14. A pharmaceutical composition according to claim 6, wherein the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 15. A pharmaceutical composition according to claim 7 comprising 3 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 16. A pharmaceutical composition according to claim 7 comprising 4 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 17. A pharmaceutical composition according to claim 7 comprising 5 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 18. A method of treating cancer, comprising administering to a patient in need thereof a pharmaceutical composition according to claim 1 daily for 3 weeks (3 weeks on), followed by 1 week wherein the composition is not administered (1 week off), and repeating this cycle of 3 weeks on, 1 week off. 19. A method of treating cancer, comprising administering to a patient in need thereof a pharmaceutical composition according to claim 1 daily for 1 week (1 week on), followed by 1 week wherein the composition is not administered (1 week off), and repeating this cycle of 1 week on, 1 week off. 20. A method of treating cancer, comprising administering to a patient in need thereof a pharmaceutical composition according to claim 1 daily. 21. A method of treating cancer, comprising administering to a patient in need thereof a pharmaceutical composition according to claim 1 once daily. 22. A method of treating cancer according to claim 20 wherein the daily dose ranges from 6 mg to 9 mg base equivalent. 23. A method of treating cancer according to claim 20 wherein the daily dose is 6 mg base equivalent. 24. A method of treating cancer according to claim 20 wherein the daily dose is 8 mg base equivalent. 25. A method of treating cancer according to claim 20 wherein the daily dose is 9 mg base equivalent. 26. A method according to claim 20 wherein the cancer is bladder cancer, urothelial cancer, metastatic urothelial cancer, surgically unresectable urothelial cancer, cholangiocarcinoma, or non-muscle-invasive bladder cancer. 27. A method according to claim 20 wherein the cancer is bladder cancer. 28. A method according to claim 20 wherein the cancer is urothelial cancer. 29. A method according to claim 20 wherein the cancer is metastatic urothelial cancer. 30. A method according to claim 20 wherein the cancer is surgically unresectable urothelial cancer. 31. A method according to claim 20 wherein the cancer is cholangiocarcinoma. 32. A method according to claim 20 wherein the cancer is non-muscle-invasive bladder cancer. 33. A method according to claim 26 wherein the cancer is a cancer with FGFR genomic alterations. 34. A method according to claim 33 wherein the FGFR genomic alterations are translocations, fusions and/or mutations. 35. A method according to claim 34 wherein the alteration is a FGFR3-TACC3 translocation. 36. A method according to claim 34 wherein the alteration is a mutation. 37. A method according to claim 36 wherein the mutation is R248C. 38. A method according to claim 36 wherein the mutation is S249C. 39. A method according to claim 20 wherein the cancer is advanced or refractory non small cell lung cancer (NSCLC), breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, oesophageal cancer, gastric cancer or cholangiocarcinoma. 40. A method according to claim 20 wherein the cancer is multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder cancer, lung cancer, ovarian cancer, breast cancer, gastric cancer, colorectal cancer, or oral squamous cell carcinoma. 41. A method according to claim 20 wherein the cancer is endometrial, ovarian, gastric, hepatocellular, uterine, cervix or colorectal cancer. 42. A method according to claim 20 wherein the cancer is advanced or refractory non small cell lung cancer (NSCLC), breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, oesophageal cancer, gastric cancer, cholangiocarcinoma, multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder cancer, lung cancer, colorectal cancer, oral squamous cell carcinoma, hepatocellular cancer, uterine cancer, or cervix cancer, and wherein the cancer is a cancer with FGFR genomic alterations. 43. A method according to claim 42 wherein the cancer is a cancer with FGFR genomic alterations. 44. A method according to claim 24 wherein the cancer is urothelial cancer. 45. A method according to claim 25 wherein the cancer is urothelial cancer. 46. A method according to claim 24 wherein the cancer is metastatic urothelial cancer. 47. A method according to claim 25 wherein the cancer is metastatic urothelial cancer. 48. A method according to claim 24 wherein the cancer is surgically unresectable urothelial cancer. 49. A method according to claim 25 wherein the cancer is surgically unresectable urothelial cancer. 50. A method according to claim 24 wherein the cancer is cholangiocarcinoma. 51. A method according to claim 25 wherein the cancer is cholangiocarcinoma. 52. A method according to claim 26 wherein the cancer is bladder cancer, urothelial cancer, metastatic urothelial cancer, surgically unresectable urothelial cancer, or cholangiocarcinoma and wherein the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-py- razol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base and the formaldehyde scavenger is meglumine base. 53. A method according to claim 43 wherein the FGFR genomic alterations are translocations, fusions and/or mutations. 54. A method according to claim 32 wherein the cancer is a cancer with FGFR genomic alterations. 55. A method according to claim 54 wherein the FGFR genomic alterations are translocations, fusions and/or mutations. 56. A method according to claim 55 wherein the alteration is a FGFR3-TACC3 translocation. 57. A method according to claim 55 wherein the alteration is a mutation. 58. A method according to claim 57 wherein the mutation is R248C. 59. A method according to claim 57 wherein the mutation is S249C. 60. A method according to claim 32 wherein the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine base. 61. A method according to claim 24 wherein the cancer is non-muscle-invasive bladder cancer. 62. A method according to claim 25 wherein the cancer is non-muscle-invasive bladder cancer. 63. A method of increasing the chemical stability of a pharmaceutical composition comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, said method comprising providing a composition comprising a formaldehyde scavenger and N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the formaldehyde scavenger is meglumine base. 64. A method of preventing, postponing, slowing down or diminishing the transformation of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl- )quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, contained in a pharmaceutical composition, into 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quino- xalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, a pharmaceutically acceptable salt thereof or a solvate thereof, comprising adding a formaldehyde scavenger to said composition, wherein the formaldehyde scavenger is meglumine base. 65. The method according to claim 64, wherein the pharmaceutical composition is a tablet or a capsule. 66. The method according to claim 64, wherein the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methyl ethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base.