Details for Patent: 9,809,549

Title:	Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'(4-fluorophenyl)cycl- opropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
Abstract:	Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cy- clopropane-1,1-dicarboxamide, including a (L)-malate salt, a (D)-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)-cy- clopropane-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)cyc- lopropane-1,1-dicarboxamide.
Inventor(s):	Brown; Adrian St. Clair (Ely, GB), Lamb; Peter (Oakland, CA), Gallagher; William P. (Princeton, NJ)
Assignee:	Exelixis, Inc. (South San Francisco, CA)
Filing Date:	Jul 25, 2014
Application Number:	14/340,871
Claims:	1. N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (L) malate salt, 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 .sup.13C 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) a powder x-ray diffraction pattern (CuK.alpha. .lamda.=1.5418 .ANG.) comprising four or more 2.theta. values selected from: 12.8.+-.0.2.degree. 2.theta., 13.5.+-.0.2.degree. 2.theta., 16.9.+-.0.2.degree. 2.theta., 19.4.+-.0.2.degree. 2.theta., 21.5.+-.0.2.degree. 2.theta., 22.8.+-.0.2.degree. 2.theta., 25.1.+-.0.2.degree. 2.theta., 27.6.+-.0.2.degree. 2.theta., 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. 2. A pharmaceutical composition comprising the N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (L) malate salt according to claim 1; and a pharmaceutically acceptable excipient. 3. A method of treating thyroid cancer in a subject comprising administration of the N-1 form of crystalline N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (L) malate salt according to claim 1. 4. A method of treating glioblastoma in a subject comprising administration of the N-1 form of crystalline N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyc- lopropane-1,1-dicarboxamide (L) malate salt according to claim 1. 5. The method of claim 3, wherein the thyroid cancer is medullary thyroid cancer.