Granted Patent B2

US 12,227,481 · App. 18/344,267 · Granted Feb 18, 2025

Inventor: Khalid Shah (Half Moon Bay, CA)

Assignee: Exelixis, Inc.

C07D215/22C07B2200/13

Abstract

Claims (117)

1. Crystalline solid salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1), wherein the crystalline solid 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) citrate monohydrate Form 1;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) malonate Form 2;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) oxalate Form 3;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) sulfate Form 5;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) esylate Form 7;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) mesylate Form 9;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) tosylate Form 10;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) sulfate Form 11;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) oxalate Form 13;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) besylate Form 15;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) mesylate dihydrate Form 16;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) succinate Form 17;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) esylate Form 18;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) sulfate monohydrate Form 21;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) tosylate Form 22;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) succinate Form 23;

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) malonate Form 24; and

N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1) mesylate Form 25.

2. The crystalline solid salts of claim 1 , wherein

Compound 1 ⋅citrate monohydrate Form 1 comprises Compound 1 and citrate in a 1:1 molar ratio;

Compound 1 ⋅malonate Form 2 comprises Compound 1 and malonate in a 1:1 molar ratio;

Compound 1 ⋅oxalate Form 3 comprises Compound 1 and oxalate in a 1:1 molar ratio;

Compound 1 ⋅sulfate Form 5 comprises Compound 1 and sulfate in a 1:1 molar ratio;

Compound 1 ⋅esylate Form 7 comprises Compound 1 and esylate in a 1:1 molar ratio;

Compound 1 ⋅mesylate Form 9 comprises Compound 1 and mesylate in a 1:1 molar ratio;

Compound 1 ⋅tosylate Form 10 comprises Compound 1 and tosylate in a 1:1 molar ratio;

Compound 1 ⋅sulfate Form 11 comprises Compound 1 and sulfate in a 1:1molar ratio;

Compound 1 ⋅oxalate Form 13 comprises Compound 1 and oxalate in a 1:1 molar ratio;

Compound 1 ⋅besylate Form 15 comprises Compound 1 and besylate in a 1:1 molar ratio;

Compound 1 ⋅mesylate dihydrate Form 16 comprises Compound 1 and mesylate in a 1:1 molar ratio;

Compound 1 ⋅succinate Form 17 comprises Compound 1 and succinate in a 1:0.7 molar ratio;

Compound 1 ⋅esylate Form 18 comprises Compound 1 and esylate in a 1:1 molar ratio;

Compound 1 ⋅sulfate monohydrate Form 21 comprises Compound 1 and sulfate in a 1:1 molar ratio;

Compound 1 ⋅tosylate Form 22 comprises Compound 1 and tosylate in a 1:1 molar ratio;

Compound 1 ⋅succinate Form 23 comprises Compound 1 and succinate in a 1:0.6 molar ratio;

Compound 1 ⋅malonate Form 24 comprises Compound 1 and malonate in a 1:0.6 molar ratio; and

Compound 1 ⋅mesylate Form 25 comprises Compound 1 and mesylate in a 1:1 molar ratio.

3. The crystalline solid salts of claim 1 , wherein

Compound 1 ⋅citrate monohydrate Form 1 is characterized by an XRPD pattern comprising one or more peaks selected from 4.02, 9.61, 13.35, 13.50, 15.52, 16.45, 18.49, 20.94, 21.29, 21.50, 21.59, 23.85, 26.83, and 27.12 degrees 2θ;

Compound 1 ⋅malonate Form 2 is characterized by an XRPD pattern comprising one or more peaks selected from 6.36, 7.97, 11.99, 12.09, 12.75, 13.64, 17.52, 19.58, 20.57, 21.82, 23.43, 24.73, 24.79, 25.01, 26.09, 26.93, 27.36, 27.42, and 27.61 degrees 2θ;

Compound 1 ⋅oxalate Form 3 is characterized by an XRPD pattern comprising one or more peaks selected from 7.40, 9.44, 9.78, 10.36, 12.67, 12.97, 13.60, 14.42, 15.87, 18.65, 19.06, 21.21, 22.05, 22.76, 23.07, 24.89, and 25.69 degrees 2 θ;

Compound 1 ⋅sulfate Form 5 is characterized by an XRPD pattern comprising one or more peaks selected from 9.56, 10.08, 13.29, 13.86, 14.17, 22.27, 22.60, 22.93, 25.16, and 27.70 degrees 2θ;

Compound 1 ⋅esylate Form 7 is characterized by an XRPD pattern comprising one or more peaks selected from 5.18, 11.63, 14.09, 14.79, 16.89, 19.92, 21.05, and 26.46 degrees 2θ;

Compound 1 ⋅mesylate Form 9 is characterized by an XRPD pattern comprising one or more peaks selected from 5.75, 11.33, 15.57, 16.19, 16.34, 16.76, 17.36, 17.90, 20.87, 22.69, and 23.08 degrees 2θ;

Compound 1 ⋅tosylate Form 10 is characterized by an XRPD pattern comprising one or more peaks selected from 4.77, 9.58, 14.17, 14.26, 15.55, 15.61, 18.20, 18.29, 19.30, 20.12, 26.13, 26.20, 27.11, and 28.99 degrees 2θ;

Compound 1 ⋅sulfate Form 11 is characterized by an XRPD pattern comprising one or more peaks selected from 6.75, 9.64, 11.06, 12.70, 13.70, 13.92, 14.76, 21.13, 23.58, 24.46, 24.52, 26.66, 27.62, and 29.81 degrees 2θ;

Compound 1 ⋅oxalate Form 13 is characterized by an XRPD pattern comprising one or more peaks selected from 12.67, 12.86, 13.63, 20.83, 21.28, 22.65, 23.59, 25.89, 26.55, and 26.60degrees 2θ;

Compound 1 ⋅besylate Form 15 is characterized by an XRPD pattern comprising one or more peaks selected from 5.75, 10.42, 13.04, 15.59, 16.47, 17.95, 18.17, 18.85, 19.41, 20.90, 22.50, 23.24, and 24.36 degrees 2θ;

Compound 1 ⋅mesylate dihydrate Form 16 is characterized by an XRPD pattern comprising one or more peaks selected from 6.71, 9.70, 10.76, 13.35, 13.47, 15.67, 16.20, 18.65, 19.09, 19.33, 21.77, 21.87, 23.00, 23.98, 25.25, 26.86, and 27.19 degrees 2θ;

Compound 1 ⋅succinate Form 17 is characterized by an XRPD pattern comprising one or more peaks selected from 5.96, 6.74, 11.88, 12.15, 13.69, 13.74, 16.47, 20.43, 20.70, 22.85, 24.69, 24.76, and 26.59 degrees 2θ;

Compound 1 ⋅esylate Form 18 is characterized by an XRPD pattern comprising one or more peaks selected from 9.45, 9.86, 15.31, 16.85, 20.83, 21.72, 22.82, and 24.60 degrees 2θ;

Compound 1 ⋅sulfate monohydrate Form 21 is characterized by an XRPD pattern comprising one or more peaks selected from 6.61, 13.26, 13.60, 14.67, 16.40, 17.66, 19.96, 20.37, 20.76, 21.09, 21.25, and 23.30 degrees 2θ;

Compound 1 ⋅tosylate Form 22 is characterized by an XRPD pattern comprising one or more peaks selected from 13.75, 14.20, 14.77, 18.05, 19.28, 19.88, 20.51, 22.63, 25.41, 25.48, and 27.29 degrees 2θ;

Compound 1 ⋅succinate Form 23 is characterized by an XRPD pattern comprising one or more peaks selected from 6.35, 11.82, 12.20, 12.47, 13.76, 17.86, 18.04, 20.96, 21.96, 22.96, 23.79, 24.10, 24.96, and 25.59 degrees 2θ;

Compound 1 ⋅malonate Form 24 is characterized by an XRPD pattern comprising one or more peaks selected from 6.77, 12.36, 12.86, 21.02, 22.85, 23.61, 25.12, 26.31, 28.01, and 30.36 degrees 2θ; and

Compound 1 ⋅mesylate Form 25 is characterized by an XRPD pattern comprising one or more peaks selected from 9 .42, 9.75, 10.72, 11.98, 15.52, 17.71, 19.51, 19.66, 21.65, 21.96, 22.54, 23.35, 24.55, and 25.92 degrees 2θ.

4. The crystalline solid salts of claim 1 , wherein

Compound 1 ⋅citrate monohydrate Form 1 is characterized by an XRPD pattern comprising one or more peaks selected from 9.61, 13.35, 13.50, 21.50, 23.85, 26.83, and 27.12 degrees 2θ;

Compound 1 ⋅malonate Form 2 is characterized by an XRPD pattern comprising one or more peaks selected from 6.36, 7.97, 12.75, 19.58, 20.57, 23.43, 25.01, 26.93, 27.36, and 27.42 degrees 2θ;

Compound 1 ⋅oxalate Form 3 is characterized by an XRPD pattern comprising one or more peaks selected from 9.78, 10.36, 12.97, 13.60, 23.07, and 25.69 degrees 2θ;

Compound 1 ⋅sulfate Form 5 is characterized by an XRPD pattern comprising one or more peaks selected from 9.56, 10.08, 13.29, 13.86, 22.60, and 25.16 degrees 2θ;

Compound 1 ⋅esylate Form 7 is characterized by an XRPD pattern comprising one or more peaks selected from 14.79 and 19.92 degrees 2θ;

Compound 1 ⋅mesylate Form 9 is characterized by an XRPD pattern comprising one or more peaks selected from 5.75, 15.57, 16.19, 17.90, 20.87, 22.69, and 23.08 degrees 2θ;

Compound 1 ⋅tosylate Form 10 is characterized by an XRPD pattern comprising one or more peaks selected from 15.55, 18.29, 19.30, 20.12, 26.13, and 26.20 degrees 2θ;

Compound 1 ⋅sulfate Form 11 is characterized by an XRPD pattern comprising one or more peaks selected from 12.70, 13.92, 23.58, 24.46, 24.52, and 26.66 degrees 2θ;

Compound 1 ⋅oxalate Form 13 is characterized by an XRPD pattern comprising one or more peaks selected from 12.67, 13.63, 20.83, 22.65, 23.59, and 26.55 degrees 2θ;

Compound 1 ⋅besylate Form 15 is characterized by an XRPD pattern comprising one or more peaks selected from 5.75, 10.42, 15.59, 16.47, and 24.36 degrees 2θ;

Compound 1 ⋅mesylate dihydrate Form 16 is characterized by an XRPD pattern comprising one or more peaks selected from 9.70, 13.47, 21.77, 21.87, 23.98, and 26.86 degrees 2θ;

Compound 1 ⋅succinate Form 17 is characterized by an XRPD pattern comprising one or more peaks selected from 5.96, 6.74, 11.88, 13.74, 20.70, and 24.76 degrees 2θ;

Compound 1 ⋅esylate Form 18 is characterized by an XRPD pattern comprising one or more peaks selected from 9.45, 9.86, 20.83, and 21.72 degrees 2θ;

Compound 1 ⋅sulfate monohydrate Form 21 is characterized by an XRPD pattern comprising one or more peaks selected from 6.61, 13.60, 20.37, 20.76, 21.09, and 23.30 degrees 2θ;

Compound 1 ⋅tosylate Form 22 is characterized by an XRPD pattern comprising one or more peaks selected from 13.75, 14.77, 18.05, 19.88, 22.63, and 25.41 degrees 2θ;

Compound 1 ⋅succinate Form 23 is characterized by an XRPD pattern comprising one or more peaks selected from 11.82, 12.47, 22.96, and 24.96 degrees 2θ;

Compound 1 ⋅malonate Form 24 is characterized by an XRPD pattern comprising one or more peaks selected from 12.36, 12.86, 21.02, 22.85, 23.61, and 25.12 degrees 2θ; and

Compound 1 ⋅mesylate Form 25 is characterized by an XRPD pattern comprising one or more peaks selected from 9.42, 9.75, 19.66, 21.65, 22.54, 23.35, and 24.55 degrees 2θ.

5. The crystalline solid salts of claim 1 , wherein

Compound 1 ⋅citrate monohydrate Form 1 is characterized by an XRPD pattern comprising peaks at 9.61, 13.35, 13.50, 21.50, 23.85, 26.83, and 27.12 degrees 2θ;

Compound 1 ⋅malonate Form 2 is characterized by an XRPD pattern comprising peaks at 6.36, 7.97, 12.75, 19.58, 20.57, 23.43, 25.01, 26.93, 27.36, and 27.42 degrees 2θ;

Compound 1⋅oxalate Form 3 is characterized by an XRPD pattern comprising peaks at 9.78, 10.36, 12.97, 13.60, 23.07, and 25.69 degrees 2θ;

Compound 1 ⋅sulfate Form 5 is characterized by an XRPD pattern comprising peaks at 9.56, 10.08, 13.29, 13.86, 22.60, and 25.16 degrees 2θ;

Compound 1 ⋅esylate Form 7 is characterized by an XRPD pattern comprising peaks at 14.79 and 19.92 degrees 2θ;

Compound 1 ⋅mesylate Form 9 is characterized by an XRPD pattern comprising peaks at 5.75, 15.57, 16.19, 17.90, 20.87, 22.69, and 23.08 degrees 2θ;

Compound 1 ⋅tosylate Form 10 is characterized by an XRPD pattern comprising peaks at 15.55, 18.29, 19.30, 20.12, 26.13, and 26.20 degrees 2θ;

Compound 1 ⋅sulfate Form 11 is characterized by an XRPD pattern comprising peaks at 12.70, 13.92, 23.58, 24.46, 24.52, and 26.66 degrees 2θ;

Compound 1 ⋅oxalate Form 13 is characterized by an XRPD pattern comprising peaks at 12.67, 13.63, 22.65, 23.59, and 26.55 degrees 2θ;

Compound 1 ⋅besylate Form 15 is characterized by an XRPD pattern comprising peaks at 5.75, 10.42, 15.59, 16.47, and 24.36 degrees 2θ;

Compound 1 ⋅mesylate dihydrate Form 16 is characterized by an XRPD pattern comprising peaks at 9.70, 13.47, 21.77, 21.87, 23.98, and 26.86 degrees 2θ;

Compound 1 ⋅succinate Form 17 is characterized by an XRPD pattern comprising peaks at 5.96, 6.74, 11.88, 13.74, 20.70, and 24.76 degrees 2θ;

Compound 1 ⋅esylate Form 18 is characterized by an XRPD pattern comprising peaks at 9.45, 9.86, 20.83, and 21.72 degrees 2θ;

Compound 1 ⋅sulfate monohydrate Form 21 is characterized by an XRPD pattern comprising peaks at 13.60, 20.37, 20.76, 21.09, and 23.30 degrees 2θ;

Compound 1 ⋅tosylate Form 22 is characterized by an XRPD pattern comprising peaks at 13.75, 14.77, 18.05, 19.88, 22.63, and 25.41 degrees 2θ;

Compound 1 ⋅succinate Form 23 is characterized by an XRPD pattern comprising peaks at 11.82, 12.47, 22.96, and 24.96 degrees 2θ;

Compound 1 ⋅malonate Form 24 is characterized by an XRPD pattern comprising peaks at 12.36, 12.86, 21.02, 22.85, 23.61, and 25.12 degrees 2θ; and

Compound 1 ⋅mesylate Form 25 is characterized by an XRPD pattern comprising peaks at 9.42, 9.75, 19.66, 21.65, 22.54, 23.35, and 24.55 degrees 2θ.

6. The crystalline solid salts of claim 1 , wherein

Compound 1 ⋅citrate monohydrate Form 1 is characterized by an XRPD pattern according to FIG. 1 ;

Compound 1 ⋅malonate Form 2 is characterized by an XRPD pattern according to FIG. 1 ;

Compound 1 ⋅oxalate Form 3 is characterized by an XRPD pattern according to FIG. 1 ;

Compound 1 ⋅sulfate Form 5 is characterized by an XRPD pattern according to FIG. 2 ;

Compound 1 ⋅esylate Form 7 is characterized by an XRPD pattern according to FIG. 3 ;

Compound 1 ⋅mesylate Form 9 is characterized by an XRPD pattern according to FIG. 3 ;

Compound 1 ⋅tosylate Form 10 is characterized by an XRPD pattern according to FIG. 4 ;

Compound 1 ⋅sulfate Form 11 is characterized by an XRPD pattern according to FIG. 4 ;

Compound 1 ⋅oxalate Form 13 is characterized by an XRPD pattern according to FIG. 5 ;

Compound 1 ⋅besylate Form 15 is characterized by an XRPD pattern according to FIG. 5 ;

Compound 1 ⋅mesylate dihydrate Form 16 is characterized by an XRPD pattern according to FIG. 6 ;

Compound 1 ⋅succinate Form 17 is characterized by an XRPD pattern according to FIG. 6 ;

Compound 1 ⋅esylate Form 18 is characterized by an XRPD pattern according to FIG. 6 ;

Compound 1 ⋅sulfate monohydrate Form 21 is characterized by an XRPD pattern according to FIG. 7 ;

Compound 1 ⋅tosylate Form 22 is characterized by an XRPD pattern according to FIG. 8 ;

Compound 1 ⋅succinate Form 23 is characterized by an XRPD pattern according to FIG. 8 ;

Compound 1 ⋅malonate Form 24 is characterized by an XRPD pattern according to FIG. 8 ; and

Compound 1 ⋅mesylate Form 25 is characterized by an XRPD pattern according to FIG. 9 .

7. A pharmaceutical composition comprising a therapeutically effective amount of a substantially pure crystalline solid salt of Compound 1 as recited in claim 1 and a pharmaceutically acceptable carrier.

8. A method of treating cancer comprising administering to a subject a therapeutically effective amount of a substantially pure crystalline solid salt of Compound 1 as recited in claim 1 .

9. The method of claim 8 , wherein the cancer is selected from the group consisting of thyroid cancer, stomach cancer, esophageal carcinoma, kidney cancer, liver cancer, ovarian carcinoma, cervical carcinoma, bladder cancer, large bowel cancer, small bowel cancer, brain cancer, lung cancer, bone cancer, prostate carcinoma, pancreatic carcinoma, skin cancer, bone cancer, lymphoma, solid tumors, Hodgkin's disease, and non-Hodgkin's lymphoma.

Assignments (1)

Continuity (4)

References Cited (30)