Claims for Patent: 10,544,125

Summary for Patent: 10,544,125

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, CA), Yan; Changren (Camarillo, CA)
Assignee:	Advenchen Pharmaceuticals, LLC (Moorpark, CA)
Application Number:	16/125,401
Patent Claims:	1. A crystalline form of a compound, 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quino-lin-7-yloxy)me- thyl)cyclopropanamine, wherein the crystalline form exhibits a XRPD having the following characteristic peaks: TABLE-US-00009 NO. Angle 1 7.640 2 8.642 3 9.361 4 10.091 5 13.740 6 14.479 7 15.186 8 15.766 9 17.206 10 18.569 11 19.271 12 20.041 13 22.211 14 22.814 15 23.398 16 24.455 17 25.524 18 26.703 19 27.337 20 28.061 21 28.801 22 29.845 23 31.331 24 31.621 25 32.840 26 33.714 27 38.348. 2. The compound of claim 1, wherein the characteristic peaks have an intensity greater than about 10%. 3. The compound of claim 1, wherein the peaks have d values of: TABLE-US-00010 NO. d value 1 11.56173 2 10.22328 3 9.43969 4 8.75881 5 6.43957 6 6.11252 7 5.82962 8 5.61643 9 5.14957 10 4.77448 11 4.60215 12 4.42696 13 3.99909 14 3.89483 15 3.79886 16 3.63702 17 3.48708 18 3.33576 19 3.25978 20 3.17732 21 3.09732 22 2.99133 23 2.85271 24 2.82721 25 2.72504 26 2.65632 27 2.34534. 4. The compound of claim 1, wherein the peaks have intensity values as follows: TABLE-US-00011 NO. Intensity (%) 1 19.5 2 20 3 13.3 4 100.0 5 26.4 6 54.7 7 10.1 8 20.3 9 7.4 10 18.6 11 11.0 12 49.5 13 58.4 14 11.2 15 11.6 16 76.6 17 34.6 18 12.7 19 18.4 20 18.5 21 6.3 22 13.8 23 7.1 24 9.5 25 10.5 26 3.8 27 9.6. 5. The compound of claim 1, wherein the 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quino-lin-7-yloxy)me- thyl)cyclopropanamine is a bishydrochloride salt. 6. A method of treating a neoplastic disease, said method comprising: administering to a patient in need thereof a salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)-me- thyl)-cyclopropanamine; and administering a second therapeutic agent to the patient; wherein the 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquino-lin-7-yloxy)-me- thyl)-cyclopropanamine salt is selected from: a bishydrochloride acid salt, a bishydrochloridehydrate acid salt, a bismaleic acid salt and a succinic acid salt; wherein the neoplastic disease comprises solid tumors, selected from lung, renal, colorectal, gastric, melanoma, head/neck, thyroid, pancreatic, liver, prostate, bladder, brain, sarcoma, breast, ovarian, cervical and endometrial cancers; and blood cancers, selected from ALL, CLL, AML, CML and Multiple Myeloma. 7. The method of claim 6, wherein the second therapeutic agent is a chemotherapeutic agent. 8. The method of claim 7, wherein the second therapeutic agent is selected from a platinum-based agent and a taxane-based agents. 9. The method of claim 7, wherein the second therapeutic agent is selected from paclitaxel, cisplatin, and carboplatin. 10. The method of claim 7, further comprising administering a third therapeutic agent to the patient. 11. The method of claim 10, wherein the second therapeutic agent is paclitaxel and the third therapeutic agent is cisplatin or carboplatin. 12. The method of claim 9, further comprising administering a third therapeutic agent to the patient wherein the third therapeutic agent is an immunotherapy agent. 13. The method of claim 12, wherein the immunotherapy agent is selected from nivolumab, pembrolizumab, ipilimumab, blinatumomab, elotuzumab, daratumumab, and a talimogene laherparepvec based agent. 14. The method of claim 6, wherein the second therapeutic agent is an immunotherapy agent. 15. The method of claim 14, wherein the immunotherapy agent is selected from nivolumab, pembrolizumab, ipilimumab, blinatumomab, elotuzumab, daratumumab, and a talimogene laherparepvec based agent. 16. The method of claim 6, wherein the second therapeutic agent is an anti-VEGF antibody or a VEGF trap. 17. A crystalline form of a compound, 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quino-lin-7-yloxy)me- thyl)cyclopropanamine, wherein the crystalline form exhibits a XRPD having the following characteristic peaks: TABLE-US-00012 NO. Angle 1 10.091 2 14.479 3 20.041 4 22.211 5 24.455. 18. The compound of claim 17, wherein the characteristic peaks have an intensity greater than about 10%. 19. A method of treating a neoplastic disease, said method comprising: administering the compound of claim 17 and a second therapeutic agent to a patient in need thereof; and wherein the neoplastic disease comprises solid tumors, selected from lung, renal, colorectal, gastric, melanoma, head/neck, thyroid, pancreatic, liver, prostate, bladder, brain, sarcoma, breast, ovarian, cervical and endometrial cancers; and blood cancers, selected from ALL, CLL, AML, CML and Multiple Myeloma. 20. The method of claim 19, further comprising administering a third therapeutic agent to the patient.

Details for Patent 10,544,125

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	03/25/2011		2035-05-04
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	For Injection	125514	09/04/2014		2035-05-04
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	Injection	125514	01/15/2015		2035-05-04