Claims for Patent: 9,751,859

Summary for Patent: 9,751,859

Title:	Process for preparing an anti-cancer agent, 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)meth- yl)cyclopropanamine, its crystalline form and its salts
Abstract:	The present invention relates a new process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)meth- yl)cyclopropanamine (AL3818). A stable crystalline form of Al3818 has been prepared. Salts and their crystalline forms of AL3818 have been also prepared. Anti-cancer and optometric activities of AL3818 and its salts have been further tested. New process has been outlined in Scheme I. ##STR00001##
Inventor(s):	Chen; Guoqing Paul (Westlake Village, CA), Yan; Changren (Camarillo, CA)
Assignee:	Advenchen Pharmaceuticals, LLC (Moorpark, CA)
Application Number:	15/143,630
Patent Claims:	1. A crystalline form of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)met- hyl)cyclopropanamine of AL3818 exhibiting at least one of following characters: a melting point at 208.degree. C.-210.degree. C.; a DSC Melting Range (Endo): 207-220.degree. C. with Peak Temp=216.degree. C., pattern shown in FIG. 1; a TGA thermogram that doesn't exhibit significant weight loss until at 205-215.degree. C., pattern shown in FIG. 2. 2. A crystalline form of 1-((4-(4-Fluoro-1-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)met- hyl)cyclopropanamine according claim 1 exhibiting a XRPD having pattern shown in FIG. 3 comprising 10 characteristic peaks with intensity % greater than 10% expressed in d values and angles as follows: TABLE-US-00009 Angle d value 13.344 6.62986 15.858 5.58405 16.799 5.27326 17.640 5.02377 18.770 4.72373 20.650 4.29771 21.633 4.10463 23.087 3.84934 25.128 3.54112 26.607 3.34755. 3. A crystalline form of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)met- hyl)cyclopropanamine according claim 1 exhibiting a XRPD having pattern shown in FIG. 3 comprising 26 characteristic peaks with all intensity % expressed in d values and angles as follows: TABLE-US-00010 d Intensity NO. Angle value (%) 1 10.892 8.11623 2.1 2 11.589 7.62991 6.1 3 12.195 7.25174 5.9 4 13.344 6.62986 36.2 5 15.858 5.58405 31.5 6 16.799 5.27326 77.9 7 17.640 5.02377 18.8 8 18.770 4.72373 11.9 9 19.987 4.43884 7.2 10 20.650 4.29771 42.0 11 21.633 4.10463 15.3 12 23.087 3.84934 100.0 13 24.356 3.65157 3.5 14 25.128 3.54112 14.6 15 25.669 3.46768 3.8 16 26.607 3.34755 18.0 17 26.607 3.34755 3.1 18 29.050 3.07132 5.7 19 29.797 2.99602 1.5 20 30.681 2.91167 4.3 21 31.853 2.80718 1.2 22 33.524 2.67095 2.8 23 34.789 2.57667 2.6 24 35.873 2.50131 2.2 25 37.391 2.40313 3.9 26 38.637 2.32846 1.4. 4. A pharmaceutical composition that comprises as an active ingredient a compound as defined in claim 1 of the compound and a pharmaceutically acceptable carrier. 5. A method of treating an optometric disease, said method comprising administering a compound as defined in claim 1. 6. A method of treating as claimed in claim 5, wherein an optometric disease is AMD and the combing anti-VEGF antibody is ranibizumab, or the VEGF trap is aflibercep. 7. A method of treating an optometric disease, said method comprising administering a pharmaceutical composition comprising a compound as defined in claim 1 and pharmaceutically acceptable excipients to a subject in need thereof. 8. A method of treating an optometric disease, said method comprising administering a pharmaceutical composition comprising the compound as defined claim 1 with an anti-VEGF antibody or VEGF trap to a subject in need thereof. 9. A process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yl-oxy)me- thyl)cyclopropanamine (AL3818) according to claim 1 where AL3818 can be prepared according to Process A1 when R is H by deprotecting intermediate (Z-1) with HCOONH4 (ammonium formate) and Pd/C in an alcoholic solvent at 25.degree. C.-80.degree. C. for 0.1-4 hours (Z-1) can be prepared by reacting intermediate (X1) with (Y1-1) at the presence of KI or NaI with K.sub.2CO.sub.3 in acetone or DMF at a temperature of 60.degree. C.-160.degree. C. for 2-24 hours. ##STR00009##

Details for Patent 9,751,859

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	06/30/2006		2035-05-04
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	08/10/2012		2035-05-04
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	10/13/2016		2035-05-04
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	03/20/2018		2035-05-04