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Msg  30459 of 30680  at  12/1/2023 6:33:21 PM  by

JBWIN


Building IP: EXEL Patent Appl "CRYSTALLINE SOLID FORMS OF N-{4-[(6,7-DIMETHOXYQUIN...

 

CRYSTALLINE SOLID FORMS OF N-{4-[(6,7-DIMETHOXYQUINOLIN-4-YL)OXY]PHENYL}-N'-(4-FLUOROPHENYL) CYCLOPROPANE-1,1-DICARBOXAMIDE, PROCESSES FOR MAKING, AND METHODS OF USE

DOCUMENT ID

US 20230382867 A1

DATE PUBLISHED

2023-11-30

INVENTOR INFORMATION

NAME

CITY

STATE

ZIP CODE

COUNTRY

Aftab; Dana T.
San Rafael
CA
N/A
US
Guz; Nathan
Half Moon Bay
CA
N/A
US
Lau; Stephen
South San Francisco
CA
N/A
US
Hamill; Noel
Belfast
N/A
N/A
GB
Walker; Tracy
Lurgan
N/A
N/A
GB
Galbraith; Jana
Kinallen
N/A
N/A
GB
Yau; Simon
Sunnyvale
CA
N/A
US
Shah; Khalid
Half Moon Bay
CA
N/A
US

APPLICANT INFORMATION

NAME
Exelixis, Inc.
CITY
Alameda
STATE
CA
ZIP CODE
N/A
COUNTRY
US
AUTHORITY
N/A
TYPE
assignee

APPLICATION NO

18/363994

DATE FILED

2023-08-02

DOMESTIC PRIORITY (CONTINUITY DATA)

parent US continuation 17212851 20210325 parent-grant-document US 11760726 child US 18363994

parent US continuation 17084312 20201029 parent-grant-document US 11724986 child US 17212851

parent US division 16671834 20191101 parent-grant-document US 10851061 child US 17084312

parent US division 15118738 20160812 parent-grant-document US 10501418 WO division PCT/US2015/016052 20150216 child US 16671834

us-provisional-application US 61939985 20140214

US CLASS CURRENT:

1/1

CPC CURRENT

TYPE

CPC

DATE

CPCI
2013-01-01
CPCI
2013-01-01
CPCA
2013-01-01

Abstract

The invention relates to novel crystalline solid forms of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), 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 thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma. The crystalline solid forms can be used to make the L-malate salt of cabozantinib.

Background/Summary

PRIORITY CLAIM [0001] This application claims priority to U.S. Application Ser. No. 61/939,985, filed Feb. 14, 2014. The entire contents of the aforementioned application are incorporated herein by referenced.

FIELD OF THE INVENTION

[0002] The invention relates to novel crystalline solid forms 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 thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma.

BACKGROUND OF THE INVENTION

[0003] 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}-M-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide is specifically described in WO 2005/030140 as an RTK inhibitor. The chemical structure of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide is represented by Compound 1.

##STR00001##

[0004] Compound 1 was found to have an enzyme Ret IC.sub.50 value of about 5.2 nM (dihydrate) and an enzyme c-Met IC.sub.50 value 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.

[0005] 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.

[0006] The malate salt of the 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 cabozantinib free base. On Nov. 29, 2012, the S-malate salt of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]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. Cabozantinib is being evaluated in a broad development program, including ongoing phase 3 pivotal trials in metastatic renal cell cancer (RCC), and advanced hepatocellular cancer (HCC).

[0007] 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

[0008] These and other needs are met by the present invention, which is directed to novel crystalline solid forms 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 free base crystalline solid forms, as well as solvate, including hydrate, crystalline solid forms. 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.

[0009] 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.

[0010] As a further aspect, any of the crystalline solid forms disclosed herein can be used to make pharmaceutically acceptable salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, including its S-malate salt, which is sold as cabozantinib.



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30460 Re: Building IP: EXEL Patent Appl "CRYSTALLINE SOLID FORMS OF N-{4-[(6,7-DIMETHOXYQUIN... JoeFlow 2 12/1/2023 8:44:30 PM




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