US2018002289A1PendingUtilityA1

Malate salt of N-(4-phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer

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Assignee: EXELIXIS INCPriority: Jan 16, 2009Filed: Jun 8, 2017Published: Jan 4, 2018
Est. expiryJan 16, 2029(~2.5 yrs left)· nominal 20-yr term from priority
Inventors:Adrian St. Clair BrownPeter LambWilliam P. Gallagher
A61P 5/14A61P 43/00A61P 35/00A61P 25/00C07D 215/22C07D 215/233C07B 2200/13A61K 31/47
67
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Claims

Abstract

Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, including a (L)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous forms of the malate salts. Also disclosed are pharmaceutical compositions comprising at least one malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide; and methods of treating cancer comprising administering at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide.

Claims

exact text as granted — not AI-modified
1 - 15 . (canceled) 
     
     
         16 . N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt, wherein said salt is crystalline. 
     
     
         17 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (DL)-malate salt. 
     
     
         18 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to  claim 16 , wherein said salt is the (L)-malate salt or (D)-malate salt. 
     
     
         19 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to  claim 18 , wherein said salt is the (L)-malate salt. 
     
     
         20 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to  claim 18 , wherein said salt is the (D)-malate salt. 
     
     
         21 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to  claim 18 , wherein said salt is in crystalline Form N-1 and said Form N-1 is characterized by at least one of the following:
 (i) a solid state  13 C NMR spectrum with four or more peaks selected from 18.1, 42.9, 44.5, 70.4, 123.2, 156.2, 170.8, 175.7, and 182.1, ±0.2 ppm; 
 (ii) an x-ray powder diffraction (XRPD) pattern (CuKα λ=1.5418 Å) comprising four or more 2θ values selected from: 12.8±0.2°2θ, 13.5±0.2°2θ, 16.9±0.2°2θ, 19.4±0.2°2θ, 21.5±0.2°2θ, 22.8±0.2°2θ, 25.1±0.2°2θ, 27.6±0.2°2θ, wherein measurement of the crystalline form is at room temperature; and/or 
 (iii) an x-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in  FIG. 1 . 
 
     
     
         22 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to  claim 21 , wherein said salt is at least 90 weight % Form N-1, based on weight of said salt. 
     
     
         23 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to  claim 18 , wherein said salt is in crystalline Form N-2 and said Form N-2 is characterized by at least one of the following:
 (i) a solid state  13 C NMR spectrum with four or more peaks selected from 23.0, 25.9, 38.0, 41.7, 69.7, 102.0, 122.5, 177.3, 179.3, 180.0, and 180.3, ±0.2 ppm; 
 (ii) an x-ray powder diffraction (XRPD) pattern (CuKα λ=1.5418 Å) comprising 2θ values at 20.9±0.2°2θ and 21.9±0.2°2θ, and two or more 2θ values selected from: 6.4±0.2°29, 9.1±0.2°2θ, 12.0±0.2°2θ, 12.8±0.2°2θ, 13.7±0.2°2θ, 17.1±0.2°2θ, 22.6±0.2°2θ, 23.7±0.2°2θ, wherein measurement of the crystalline form is at room temperature; and/or 
 (iii) an x-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in  FIG. 8 . 
 
     
     
         24 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to  claim 23 , wherein said salt is at least 90 weight % Form N-2, based on weight of said salt. 
     
     
         25 . A pharmaceutical composition comprising the N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to  claim 16 ; and a pharmaceutically acceptable excipient. 
     
     
         26 . A method of treating cancer in a subject, comprising administering to the subject in need thereof N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide malate salt, wherein said salt is crystalline. 
     
     
         27 . The method of  claim 26 , wherein the cancer is selected from the group consisting of stomach cancer, esophageal carcinoma, kidney cancer, liver cancer, ovarian carcinoma, cervical carcinoma, large bowel cancer, small bowel cancer, brain cancer, lung cancer, bone cancer, prostate carcinoma, pancreatic carcinoma, skin cancer, bone cancer, lymphoma, solid tumors, Hodgkin's disease, non-Hodgkin's lymphoma and thyroid cancer. 
     
     
         28 . The method of  claim 27 , wherein the cancer is thyroid cancer. 
     
     
         29 . The method of  claim 27 , wherein the cancer is kidney cancer. 
     
     
         30 . The method of  claim 27 , wherein the cancer is liver cancer.

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