IP Library › Granted Patent US 12,275,706
Granted Patent B2
US 12,275,706 · App. 18/958,628 · Granted Apr 15, 2025

Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer

Inventors: Adrian St. Clair Brown (Ely, GB); Peter Lamb (Oakland, CA); William P. Gallagher (Princeton, NJ)
Assignee: Exelixis, Inc.
C07D215/22C07D215/233
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Quick Facts
Patent No.
US 12,275,706
App. No.
18/958,628
Granted
Apr 15, 2025
Kind
B2
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.

Claims (6)

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 amorphous, characterized by a powder X-ray diffraction pattern substantially in accordance with the pattern shown in FIG. 22 .

2. 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 , characterized by a solid state 13 C NMR spectrum comprising four or more peaks selected from 12.2, 17.8, 20.3, 21.8, 27.2, 33.8, 41.7, 56.9, 69.9, 99.9, 102.2, 115.6, 122.2, 134.4, 137.8, 142.9, 149.1, 150.9, 157.3, 159.7, 167.0, 171.7, 173.1, 177.4, and 179.5, ±0.2 ppm.

3. 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 , characterized by a solid state 13 C NMR spectrum substantially in accordance with FIG. 23 .

4. 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 , characterized by a solid state 15 N NMR spectrum substantially in accordance with FIG. 24 .

5. 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 , characterized by a solid state 19 F NMR spectrum substantially in accordance with FIG. 25 .

6. 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 , characterized by a DSC thermogram substantially in accordance with FIG. 26 .

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2024
From: PHARMORPHIX
To: EXELIXIS, INC.
Reel/Frame 069472/0508 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2024
From: BRISTOL-MYERS SQUIBB COMPANY
To: EXELIXIS, INC.
Reel/Frame 069472/0662 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2024
From: LAMB, PETER
To: EXELIXIS, INC.
Reel/Frame 069472/0709 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2024
From: GALLAGHER, WILLIAM P.
To: BRISTOL-MYERS SQUIBB COMPANY
Reel/Frame 069472/0741 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 3, 2024
From: BROWN, ADRIAN ST. CLAIR
To: PHARMORPHIX
Reel/Frame 069472/0747 →
Continuity (14)
Continuation 18612538 · Mar 21, 2024
Continuation 18465462 · Sep 12, 2023
Continuation 18157568 · Jan 20, 2023
Continuation 17505275 · Oct 19, 2021
Continuation 17371372 · Jul 9, 2021
Continuation 17171752 · Feb 9, 2021
Continuation 17149365 · Jan 14, 2021
Continuation 17070514 · Oct 14, 2020
Continuation 16796250 · Feb 20, 2020
Continuation 15617725 · Jun 8, 2017
Division 14340871 · Jul 25, 2014
Division 13145054
Provisional Application 61145421 · Jan 16, 2009
Related Publication 20250084037A1 · Mar 13, 2025
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