Patent EA-005318-B1 (EA)
Title: Stable polymorph of n-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride, methods of production, and pharmaceutical uses thereof
Inventor: CONNELL RICHARD D
IPC: C07D239/94
Filed: 2000-11-09
Abstract: 1. A substantially homogeneous crystalline polymorph of the hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine designated the B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.26, 12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and 26.91. 2. The polymorph of claim 1, characterized by the X-ray powder diffraction pattern shown in Figure 3. 3. A crystalline polymorph of the hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine designated the B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.26, 12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and, 26.91, which is substantially free of the A polymorph. 4. The polymorph of claim 3, characterized by the X-ray powder diffraction pattern shown in Figure 3. 5. The polymorph of claim 3, for use in the treatment of anomalous cell growth expressing epidermal growth factor receptors (EGFR) in a mammal. 6. A composition comprising a crystalline polymorph of the hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine designated the B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.26, 12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and, 26.91 and a carrier, wherein the composition is free of the A polymorph. 7. The composition of claim 6, wherein the hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)-4-quinazolinamine exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately: 8. The composition of claim 6, wherein the N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride in the polymorph B form is characterized by the X-ray powder diffraction pattern shown in Figure 3. 9. A composition comprising a substantially homogeneous crystalline polymorph of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride in the form of polymorph B, which is characterized by the following peaks: or and at least one carrier. 10. A pharmaceutical composition which comprises a therapeutically effective amount of the polymorph of claim 1 and a pharmaceutically acceptable carrier, wherein the composition is free of the A polymorph. 11. The pharmaceutical composition of claim 10, wherein said composition is adapted for oral administration. 12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is in the form of a tablet. 13. The pharmaceutical composition of claim 10, wherein the therapeutically effective amount is from about 1 to about 7000 mg/day. 14. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount is from about 5 to about 2500 mg/day. 15. The pharmaceutical composition of claim 14, wherein the therapeutically effective amount is from about 100 to about 1600 mg/day. 16. The pharmaceutical composition of claim 14, wherein the therapeutically effective amount is from about 5 to about 200 mg/day. 17. The pharmaceutical composition of claim 16, wherein the therapeutically effective amount is from about 25 to about 200 mg/day. 18. A pharmaceutical composition comprising crystalline polymorph of claim 3 and any chemotherapeutic agent and an immunotherapeutic agent for use in the treatment of NSCLC (non small cell lung cancer), pediatric malignancies, cervical and other tumors caused or promoted by human papilloma virus (HPV), endometrium cancer, glioma, melanoma, Barrett's esophagus (pre-malignant syndrome), adrenal and skin cancers and auto immune, neoplastic cutaneous diseases and atherosclerosis in a mammal. 19. A pharmaceutical composition comprising crystalline polymorph of claim 3 and an antitumor agent selected from the group consisting of 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 anti-hormone, and an anti-androgen for use in the treatment of treatment of anomalous cell growth expressing epidermal growth factor receptors (EGFR) in a mammal. 20. A pharmaceutical composition comprising N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine or one of pharmaceutically acceptable salts thereof in anhydrous and hydrate forms, and either or both anti-EGFR and anti EGF antibodies, or a member of the group consisting of inhibitors of MMP (matrix metallo-proteinase), VEGFR (vascular endothelial growth factor receptor), farnesyl transferase, CTLA4, (cytotoxic T lymphocyte antigen 4) and erbB2, MAb toVEGFr, rhuMAb-VEGF, erbB2 MAb and avb3 Mab for use in the treatment of NSCLC (non small cell lung cancer), pediatric malignancies, cervical and other tumors caused or promoted by human papilloma virus (HPV), endometrium cancer, glioma, melanoma, Barrett's esophagus (pre-malignant syndrome), adrenal and skin cancers and auto immune, neoplastic cutaneous diseases and atherosclerosis in a mammal. 21. Use a polymorph of claim 3 for manufacturing a medicament useful in the treatment of anomalous cell growth expressing epidermal growth factor receptors (EGFR) in a mammal. 22. Use of claim 21 wherein anomalous cell growth is brain, squamous cell, bladder, gastric, pancreatic, lever, multiform gliobastoma, breast, head, neck, oesophageal, prostate, colorectal, lung, renal, kidney, ovarian, gynecological and thyroid cancer. 23. Use of claim 21 wherein anomalous cell growth is from non-small cell lung cancer (NSCLC), refractory ovarian cancer, head and neck cancer. 24. Use of claim 21 wherein the medicament comprises from about 1 to about 7000 mg/day of polymorph. 25. Use of claim 24 wherein the medicament comprises from about 5 to about 2500 mg/day of polymorph. 26. Use of claim 25 wherein the medicament comprises from about 100 to about 1600 mg/day of polymorph. 27. Use of claim 25 wherein the medicament comprises from about 5 to about 200 mg/day of polymorph. 28. Use of claim 27 wherein the medicament comprises from about 25 to about 200 mg/day of polymorph. 29. Use of claim 22 wherein the anomalous cell growth is pancreatic cancer. 30. Use of claim 22 wherein the anomalous cell growth is colorectal cancer. 31. Use of claim 22 wherein the anomalous cell growth is prostrate cancer. 32. Use of claim 22 wherein the anomalous cell growth is breast cancer. 33. Use of claim 22 wherein the anomalous cell growth is gastric cancer. 34. Use of claim 22 wherein the anomalous cell growth is ovarian cancer. 35. Use of claim 22 wherein the anomalous cell growth is multiform glioblastoma. 36. Use of claim 22 wherein the anomalous cell growth is lever cancer. 37. Use of claim 22 wherein the anomalous cell growth is kidney cancer. 38. Use of claim 22 wherein the anomalous cell growth is stomach cancer. 39. Use of claim 22 wherein the anomalous cell growth is bladder cancer. 40. Use of claim 23 wherein the anomalous cell growth is non-small cell lung cancer (NSCLC). 41. Use of claim 23 wherein the anomalous cell growth is head and neck cancer. 42. Use a compound of claim 3 or a composition of claim 6 for manufacturing a medicament useful in the treatment of tumor by inducing differentiation of tumor cells, expressing epidermal growth factor receptors (EGFR) in a tumor. 43. Use a pharmaceutical composition comprising N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine or one of pharmaceutically acceptable salts thereof in anhydrous and hydrate forms for manufacturing a medicament useful for treating is non-small cell lung cancer (NSCLC), pediatric malignancies, cervical and other tumors caused or promoted by human papilloma virus (HPV), Barrett's esophagus (pre-malignant syndrome), adrenal and skin cancers in a mammal. 44. Use a pharmaceutical composition of claim 3 and a pharmaceutically carrier for manufacturing a medicament useful in the treatment of NSCLC (non small cell lung cancer), pediatric malignancies, cervical and other tumors caused or promoted by human papilloma virus (HPV), endometrium cancer, glioma, melanoma, Barrett's esophagus (pre-malignant syndrome), adrenal and skin cancers and auto immune, neoplastic cutaneous diseases and atherosclerosis in a mammal. 45. Use of claim 43 or 44 for the treatment of is non-small cell lung cancer (NSCLC). 46. Use of claim 43 or 44 for the treatment of endometrium cancer. 47. Use of claim 44 for the treatment of glioma. 48. Use of claim 44 for the treatment of melanoma. 49. Use a pharmaceutical composition comprising N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine or one of pharmaceutically acceptable salts thereof in anhydrous and hydrate forms for manufacturing a medicament useful for treating of basal or squamous cell carcinoma of the skin in areas exposed to the sun or in persons of high risk to said carcinoma. 50. A method of preparing a crystalline polymorph of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride designated the B polymorph, which is free of the A polymorph, comprising the step of recrystallizing N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride in a solvent comprising alcohol. 51. The method of claim 50 wherein the solvent further comprises water. 52. The method of claim 50, wherein N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride is prepared by coupling a compound of formula 6 with a compound of formula 4 53. The method of claim 52, wherein said compound of formula 6 is prepared by reacting a compound of formula 5 in a suspension of metal alkali and solvent and with heating. 54. The method of claim 52, wherein said compound of formula 4 is prepared by chlorinating a compound of formula 3 55. A method for the production