TECHNICAL FIELD OF THE INVENTION

The invention relates to novel crystalline solid forms of salts of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and solvates thereof, including hydrates, that are useful for the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly renal cell carcinoma (RCC) and medullary thyroid cancer (MTC).

BACKGROUND OF THE INVENTION

Commonly assigned PCT Patent Publication No. WO 2005/030140, incorporated by reference herein in its entirety, discloses novel inhibitors of multiple receptor tyrosine kinases (RTKs) implicated in tumor growth and angiogenesis, pathologic bone remodeling, and metastatic progression of cancer. In particular, the compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is specifically described in WO 2005/030140 as an RTK inhibitor. N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-M-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is also known in the art as cabozantinib. The chemical structure of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (cabozantinib) is represented by Compound 1.



Compound 1 was found to have an enzyme Ret IC50value of about 5.2 nM (dihydrate) and an enzyme c-Met IC50value of about 1.3 nM (dihydrate). The assay that was used to measure this c-Met activity is described in paragraph [0458] in WO2005/030140.

During initial development experiments, Compound 1 (a free base) was found to be a BCS class II compound having low solubility and high permeability. Because Compound 1 was observed to have low solubility in water, it was initially considered unsuitable for solid oral dosage development, and hence the pharmaceutical development focused on finding a salt with suitable hygroscopicity, thermal stability, chemical stability, physical stability, and solubility.

The malate salt of Compound 1, as described in WO 2010/083414, the entire contents of which is incorporated by reference, was subsequently identified as providing an acceptable combination of crystallinity, solubility, and stability as compared to Compound 1 free base. On Nov. 29, 2012, the S-malate salt of N-{4-[(6,7-dimethoxyquinolin-4-yfloxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (also known as cabozantinib or COMETRIQ®) was approved by the United States Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC). In December 2013, the European Committee for Medicinal Products for Human Use (CHMP), issued a positive opinion on the Marketing Authorization Application (MAA), submitted to the European Medicines Agency, or EMA, for COMETRIQ® for the proposed indication of progressive, unresectable, locally advanced, or metastatic MTC. More recently, in 2015, cabozantinib as the S-malate salt was approved as CABOMETYX® for the treatment of advance renal cell carcinoma.

Besides therapeutic efficacy, the Applicant continues to endeavor to provide suitable form(s) of Compound 1 that have favorable properties related to processing, manufacturing, storage stability, and/or usefulness as a drug. Accordingly, the discovery of new crystalline solid forms of Compound 1 that possesses some or all of these desired properties remains vital to drug development. Thus, disclosed herein are novel crystalline solid forms of Compound 1 that may be used in pharmaceutical compositions for the treatment of proliferative diseases such as cancer.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention, which is directed to novel crystalline solid forms of salts of Compound 1, as well as pharmaceutical compositions containing, methods for using, and processes for making such crystalline solid forms. The crystalline solid forms include solvated solid forms, including hydrates. Among other uses, crystalline solid forms of Compound 1 are useful for preparing pharmaceutical compositions expected to have utility in treating cancer. Accordingly, one aspect of the invention pertains to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a solid form of Compound 1.

As indicated previously, Compound 1 inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth and angiogenesis, pathologic bone remodeling, and metastatic progression of cancer. Accordingly, crystalline solid forms of the Compound 1 are useful for treating cancer. Thus, another aspect of the invention pertains to a method for treating cancer comprising administering to a subject a therapeutically effective amount of a solid form of Compound 1 as disclosed herein. The invention is also directed to processes for preparing crystalline solid forms of Compound 1.

The solid forms are summarized in Table 1.

TABLE 1Novel crystalline solid forms of salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamideFormComment1Compound 1•citrate, monohydrate, 1:12Compound 1•malonate, 3.6 mol eq water, 1:13Compound 1•oxalate, anhydrous, 1:14Compound 1•ethane disulfonate, deliquescent, 1:15Compound 1•sulphate, 3.7 mol eq water, 1:16Compound 1•besylate, anhydrous, 1:17Compound 1•esylate, anhydrous, 1:18Novel form related to Compound 1 free base9Compound 1•mesylate, anhydrous, 1:110Compound 1•tosylate, anhydrous, 1:111Compound 1•sulfate, 2.4 mol eq water, 1:112Compound 1•ethane disulfonate, anhydrous, 2:1 API:acid13Compound 1•oxalate, anhydrous, 1:114Compound 1•pyruvate, anhydrous, 1:115Compound 1•besylate, 1.4 mol. eq. THF, 1:116Compound 1•mesylate, dihydrate, 1:117Compound 1•succinate, 0.4 mol eq acetonitrile and 0.86 moleq water, 1:0.7 API:acid18Compound 1•esylate, 0.4 mol eq acetonitrile, 1:119Compound 1•isethionate, monohydrate, 1:120Compound 1•glutarate, 0.59 mol eq water, 1:121Compound 1•sulfate, monohydrate, 1:122Compound 1•tosylate, 0.8 mol eq water, 1:123Compound 1•succinate, TGA weight loss equates to ~0.8mol eq of water24Compound 1•malonate, anhydrous, 1:125Compound 1•mesylate, 0.3 mol eq acetonitrile, 1:126Compound 1•gluconate, 2.6 moles water, 1:127Compound 1•isethionate, monohydrate, 1:1

A total of 27 forms were observed during the screen. One of the patterns (Form 8) was free base related. The remaining 26 solids were assessed according to their crystallinity, solvation state, stoichiometry, ease of manufacture, deliquescence, stability to desolvation, molecular weight, and acceptability/toleration with respect to oral dosing. Aqueous solubility and optical microscopy were also determined.

In a particular aspect, the invention is directed to crystalline solid salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), wherein the salts are selected from the group consisting of: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) ⋅ pyruvate; N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) ⋅ glutarate; and N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) ⋅ isethionate monohydrate.

Forms 14, 19, and 20 (pyruvate, glutarate, and isethionate) were prepared on a 250-1000 mg scale and confirmed as the same forms that were observed in the initial screen. The three salts were also fully characterized by XRPD, DSC, TG/DTA, DVS, and1H NMR microscopy. An investigation into their crystal habit was also performed. Compound 1 pyruvate and glutarate were irregular particles with low aspect ratio, whereas Compound 1 isethionate showed a crystal habit of needle morphology.

The salt forms described herein possess a number of advantageous properties. Examples of such advantageous properties include a lower molecular weight giving a higher activity per weight ratio, higher solubility, improved filterability and flow properties due to particle morphology/aspect ratio, and lower hygroscopicity. Further, many of the salts described herein are natural human metabolites and are therefore well-tolerated in vivo.

