Claims for Patent: 10,100,034

Summary for Patent: 10,100,034

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 A13818 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:	15/659,510
Patent Claims:	1. A process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)met- hyl)cyclopropanamine (AL3818) by condensing intermediate (X1) with (Y1) in a solvent at the presence of KI or NaI, or intermediate (X2) with (Y2) to form intermediate (Z) which is deprotected to give the final compound (AL3818) in Scheme I ##STR00009## Wherein R is selected from H and C.sub.1-C.sub.6alkoxy; R is further selected from H and --OMe. 2. The process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)meth- yl)cyclopropanamine (AL3818) according to claim 1 where AL3818 can be prepared according to Process A2 when R is 4-OMe by deprotecting intermediate (Z-2) with TFA in DCM at 0.degree. C.-30.degree. C. for 1-24 hours (Z-2) can be prepared by reacting intermediate (X1) with (Y1-2) 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 ##STR00010## 3. The process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)meth- yl)cyclopropanamine (AL3818) according to claim 2 where (Z-1) is prepared according to Process B1 by reacting intermediate (X2-1) with (Y2) in pyridine or lutidine at a temperature of 60.degree. C.-160.degree. C. for 1-12 hours ##STR00011## 4. The process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)meth- yl)cyclopropanamine (AL3818) according to claim 3 where (Z-2) is prepared according to Process B2 by reacting intermediate (X2-2) with (Y2) in pyridine or lutidine at a temperature of 60.degree. C.-160.degree. C. for 1-12 hours ##STR00012## 5. The process to prepare intermediate (Z) according to claim 1, wherein R is H or --OMe, KI is used according to first step of Process A1 and A2 with DMF at 80.degree. C. and wherein Lutidine is used according to first step of Process B1 and B2 at 135.degree. C. 6. The process to synthesize 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)meth- yl)cyclopropanamine (AL3818) according to claim 1, wherein R is H, HCOONH4/Pd/C is used for the deprotection step at 45.degree. C.; wherein R is --OMe, DCM/TFA (10/1) is used for the deprotection step at 25.degree. C. 7. A salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)-met- hyl)-cyclopropanamine, wherein the salt is selected from: a bishydrochloride acid salt, a bishydrochloridehydrate acid salt, a bismaleic acid salt and a succinic acid salt. 8. A crystalline form of the bishydrochloride salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)met- hyl)cyclopropanamine according claim 7 wherein the crystalline form exhibits a XRPD having 21 of the following characteristic peaks with intensity % greater than 10% expressed in d values and angles as follows: TABLE-US-00009 NO. Angle d value Intensity (%) 1 7.640 11.56173 19.5 2 8.642 10.22328 20 3 9.361 9.43969 13.3 4 10.091 8.75881 100.0 5 13.740 6.43957 26.4 6 14.479 6.11252 54.7 7 15.186 5.82962 10.1 8 15.766 5.61643 20.3 9 17.206 5.14957 7.4 10 18.569 4.77448 18.6 11 19.271 4.60215 11.0 12 20.041 4.42696 49.5 13 22.211 3.99909 58.4 14 22.814 3.89483 11.2 15 23.398 3.79886 11.6 16 24.455 3.63702 76.6 17 25.524 3.48708 34.6 18 26.703 3.33576 21.7 19 27.337 3.25978 18.4 20 28.061 3.17732 18.5 21 28.801 3.09732 6.3 22 29.845 2.99133 13.8 23 31.331 2.85271 7.1 24 31.621 2.82721 9.5 25 32.840 2.72504 10.5 26 33.714 2.65632 3.8 27 38.348 2.34534 9.6. 9. A crystalline form of the bishydrochloridehydrate acid salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)met- hyl)cyclopropanamine according claim 7 wherein the crystalline form exhibits a XRPD having 9 of the following characteristic peaks with intensity % greater than 10% expressed in d values and angles as follows: TABLE-US-00010 NO. Angle d value Intensity (%) 1 5.506 16.03679 28.0 2 6.817 12.95694 100 3 8.087 10.92445 29.9 4 9.766 9.04936 20.6 5 13.318 6.64283 22.3 6 14.332 6.17523 7.0 7 16.159 5.48067 15.7 8 19.474 4.55451 8.8 9 20.920 4.24296 6.5 10 20.920 3.87231 28.2 11 25.087 3.54678 20.2 12 25.874 3.44064 22.7. 10. A crystalline form of the bismaleic acid salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)met- hyl)cyclopropanamine according claim 7 wherein the crystalline form exhibits a XRPD having pattern comprising 22 of the following characteristic peaks with intensity % greater than 10% expressed in d values and angles as follows: TABLE-US-00011 NO. Angle d value Intensity (%) 1 6.716 13.14986 29.7 2 8.816 10.02189 34.3 3 9.743 9.07069 15.3 4 10.033 8.80923 21.4 5 11.777 7.50803 21.2 6 13.418 6.59342 6.2 7 14.816 5.97445 11.0 8 16.089 5.50434 9.5 9 16.801 5.27279 24.5 10 17.360 5.10409 87.9 11 17.179 5.15755 70.7 12 18.190 4.87308 20.2 13 18.704 4.74028 16.7 14 19.296 4.59623 5.0 15 19.920 4.45371 12.6 16 20.824 4.26227 65.5 17 21.457 4.13785 100.0 18 22.411 3.96393 4.5 19 22.876 3.88434 5.8 20 23.204 3.83021 19.0 21 23.622 3.76332 78.4 22 24.418 3.64247 6.3 23 26.140 3.40621 87.0 24 26.958 3.30469 26.5 25 27.383 3.25443 61.3 26 28.154 3.16697 41.5 27 29.554 3.02013 6.8 28 30.611 2.91815 23.7 29 31.373 2.84906 14.3 30 33.457 2.67620 6.7 31 34.541 2.59465 2.8 32 35.137 2.55199 3.8 33 35.734 2.51067 2.5 34 37.129 2.41949 8.6 35 39.704 2.26833 3.9. 11. A crystalline form of the succinic acid salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)met- hyl)cyclopropanamine according claim 7 wherein the crystalline form exhibits a XRPD having 7 of the following characteristic peaks with intensity % greater than 10% expressed in d values and angles as follows: TABLE-US-00012 NO. Angle d value Intensity (%) 1 5.765 15.31849 12.9 2 8.038 10.98994 7.4 3 11.639 7.59700 27.7 4 12.9506 6.83065 100 5 16.1415 5.48683 18.0 6 17.4835 5.06846 18.7 7 18.385 4.82175 17.8 8 19.394 4.57325 1.1 9 20.756 4.27609 13.4 10 22.034 4.03092 2.8 11 23.167 3.83630 1.8 12 24.085 3.69200 16.9 13 24.485 3.63268 14.6 14 25.737 3.45874 13.7 15 28.621 3.11637 6.4 16 29.255 3.05025 22.1 17 31.357 2.85048 0.9 18 31.967 2.79743 2.1 19 35.630 2.51780 2.4. 12. A salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)meth- yl)-cyclopropanamine according to claim 7 with DSC and TGA having following characteristics: bishydrochloride acid salt with DSC Melting Range (Exo): 249-280 with Peak Temp=268.degree. C. TGA demonstrating as an unsolvated material with weight loss at about 230.degree. C. (between 225-235.degree. C.), shown in FIG. 4, FIG. 5; bishydrochloridehydrate acid salt with DSC Melting Range (Exo): 207-260.degree. C. with Peak Temp=226.degree. C. TGA demonstrating 2.68% (.about.3%, 1 water) weight loss till 120.degree. C. (between 115-125.degree. C.) and further weight loss at about 170.degree. C. (between 165-175.degree. C.), shown in FIG. 7, FIG. 8; bismaleic acid salt with DSC Melting Range (Endo): 165-202.degree. C. with Peak Temp=183.degree. C. TGA demonstrating as an unsolvated material with weight loss at about 160.degree. C. (between 155-165.degree. C.), shown in FIG. 10, FIG. 11; or succinic acid salt with DSC Melting Range: Melting Range (Endo): 176-202.degree. C. with Peak Temp=198.degree. C. TGA demonstrating as an unsolvated material with weight loss at about 180.degree. C. (between 175-185.degree. C.), shown in FIG. 13, FIG. 14. 13. A pharmaceutical composition comprising: a bishydrochloride acid, bishydrochloridehydrate acid, bismaleic acid or succinic acid salt of 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)meth- yl)cyclopropanamine; and a pharmaceutically acceptable carrier. 14. A method of treating a neoplastic disease, said method comprising administering a compound as defined in claim 7 to a subject in need thereof. 15. A method of treating as claimed in claim 14, wherein the neoplastic disease is 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. 16. A method of treating as claimed in claim 14, wherein the combing chemotherapy agents are selected from platinum based or taxane based agents. 17. A method of treating as claimed in claim 14, wherein the combing chemotherapy agent selected from the group consisting of cisplatin, carboplatin, paclitaxel or cisplatin/paclitaxel or carboplatin/paclitaxel. 18. A method of treating as claimed in claim 14, wherein the combining immunotherapy agents are selected from nivolumab, pembrolizumab, ipilimumab, blinatumomab, elotuzumab, daratumumab, talimogene laherparepvec based agents. 19. A method of treating an optometric disease, said method comprising administering a compound as defined in claim 7. 20. A method of treating as claimed in claim 19, wherein an optometric disease is AMD and the combing anti-VEGF antibody is ranibizumab, or the VEGF trap is aflibercep. 21. A method of treating a neoplastic disease, said method comprising administering a pharmaceutical composition comprising the compound as defined claim 7 and a pharmaceutically acceptable excipient to a subject in need thereof. 22. A method of treating a neoplastic disease, said method comprising administering a pharmaceutical composition comprising the compound as defined claim 7 with chemotherapy agents or immunotherapy agents to a subject in need thereof. 23. A method of treating an optometric disease, said method comprising administering a pharmaceutical composition comprising the compound as defined claim 7 and a pharmaceutically acceptable excipient to a subject in need thereof. 24. A method of treating an optometric disease, said method comprising administering a pharmaceutical composition comprising the compound as defined claim 7 with an anti-VEGF antibody or VEGF trap to a subject in need thereof.

Details for Patent 10,100,034

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	June 30, 2006		2035-05-04
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	August 10, 2012		2035-05-04
Genentech, Inc.	LUCENTIS	ranibizumab	Injection	125156	October 13, 2016		2035-05-04