Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-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)cyclopropane-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)-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-ffuorophenyl)cyclopropane-1,1-dicarboxamide.

What is claimed is: 
     
         1 . N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt. 
     
     
         2 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to  claim 1 , wherein said salt is the (DL)-malate salt. 
     
     
         3 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to  claim 1 , wherein said salt is a (L)-malate salt or (D)-malate salt. 
     
     
         4 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to  claim 3 , wherein said salt is the (L)-malate salt. 
     
     
         5 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to  claim 3 , wherein said salt is the (D)-malate salt. 
     
     
         6 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to any one of  claims 3  to  5 , wherein said salt is crystalline. 
     
     
         7 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to  claim 6 , 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) a powder x-ray diffraction 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 . 
 
     
     
         8 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to  claim 7 , wherein said salt is least 90 weight % Form N-1, based on weight of said salt. 
     
     
         9 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to  claim 6 , 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) a powder x-ray diffraction 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 °2θ, 9.1±0.2 °2θ, 12.0±0.2 °2θ, 12.8±0.2, 13.7±0.2, 17.1±0.2, 22.6±0.2, 23.7±0.2, 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 . 
 
     
     
         10 . The N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to  claim 9 , wherein said salt is least 90 weight % Form N-2, based on weight of said salt. 
     
     
         11 . 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 any one of  claim 4 - 10 ; and a pharmaceutically acceptable excipient. 
     
     
         12 . Use of the N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to any one of  claims 3 - 10 , for the manufacture of a medicament for the treatment of cancer. 
     
     
         13 . N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt according to any one of  claims 3 - 10 , for use in therapy in treating cancer. 
     
     
         14 . The crystalline form of the (L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide according to any one of  claims 6 - 10 , for use as a medicament for treating thyroid cancer in a subject. 
     
     
         15 . The crystalline form of the (L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide according to any one of  claims 6 - 10 , for use as a medicament for treating glioblastoma in a subject.