# US 10,501,418 B2 · 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

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- Number: US 10,501,418 B2
- Document ID: US10501418B2
- Status: Granted
- Kind: B2
- Application number: 15/118,738
- Filed: 2015-02-16
- Published: 2017-02-16
- Granted: 2019-12-10
- Earliest claimed: 2014-02-14
- Assignees: Exelixis, Inc.
- Applicants: Exelixis, Inc.
- Inventors: Dana T. Aftab; Nathan Guz; Stephen Lau; Noel Hamill; Tracy Walker; Jana Galbraith; Simon Yau; Khalid Shah
- Web page: https://patentgrep.com/patent/US10501418B2

## CPC

- C07D 215/233: only one oxygen atom which is attached in position 4
- A61P 35/00: Antineoplastic agents
- C07D 215/22: attached in position 2 or 4
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## 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.

## Claims

### Claim 1

A crystalline solid form of Compound 1:
wherein said crystalline solid form is in Form III and said Form III is characterized by an x-ray powder diffraction pattern (CuKα) comprising peaks at 7.0, 7.8, 11.1, and 14.1 (°2θ±0.2 °2θ), or at 9.4, 12.6, 22.3, and 24.3 (°2θ±0.2°2θ), or at 7.0, 7.8, 9.4, 11.1, 12.6, 14.1, 22.3, and 24.3 (°2θ±0.2 °2θ), wherein measurement is at room temperature.

### Claim 2 (depends on 1)

The crystalline solid form of Compound 1 designated as Compound 1 Form III as recited in claim 1 wherein said Form III is characterized by an x-ray powder diffraction pattern (CuKα) comprising peaks at 7.0, 7.8, 11.1, and 14.1 (°2 θ±0.2°2θ), wherein measurement is at room temperature.

### Claim 3 (depends on 1)

The crystalline solid form of Compound 1 designated as Compound 1 Form III as recited in claim 1 wherein said Form III is characterized by an x-ray powder diffraction pattern (CuKα) comprising peaks at 9.4, 12.6, 22.3, and 24.3 (°2 θ±0.2°2θ), wherein measurement is at room temperature.

### Claim 4 (depends on 1)

The crystalline solid form of Compound 1 designated as Compound 1 Form III as recited in claim 1 wherein said Form III is characterized by an x-ray powder diffraction pattern (CuKα) comprising peaks at 7.0, 7.8, 9.4, 11.1, 12.6, 14.1, 22.3, and 24.3 (°2 θ±0.2°2θ), wherein measurement is at room temperature.

### Claim 5 (depends on 4)

The crystalline solid form of Compound 1 designated as Compound 1 Form III as recited in claim 4 wherein said Form III is characterized by an x-ray powder diffraction pattern (CuKα) further comprising peaks at 15.5 and 17.3 (°2 θ±0.2°2θ) wherein measurement is at room temperature.

### Claim 6 (depends on 1)

The crystalline solid form of Compound 1 designated as Compound 1 Form III as recited in claim 1 wherein said Form III is characterized by an x-ray powder diffraction pattern (CuKα) substantially in accordance with the pattern shown in FIG. 11.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective dose of a substantially pure crystalline solid form of Compound 1 designated as Compound 1 Form III as recited in claim 1 and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 1)

A pharmaceutical formulation comprising:
Ingredient
(% w/w)
Compound 1 Solid Form III as
31.68
recited in claim 1
Microcrystalline Cellulose
38.85
Lactose anhydrous
19.42
Hydroxypropyl Cellulose
3.00
Croscarmellose Sodium
3.00
Total Intra-granular
95.95
Silicon dioxide, Colloidal
0.30
Croscarmellose Sodium
3.00
Magnesium Stearate
0.75
Total
100.00.

### Claim 9 (depends on 1)

A pharmaceutical formulation comprising:
Ingredient
(% w/w)
Compound 1 Solid Form III as recited
25.0-33.3
in claim 1
Microcrystalline Cellulose
q.s
Hydroxypropyl Cellulose
3
Poloxamer
0-3
Croscarmellose Sodium
6.0
Colloidal Silicon Dioxide
0.5
Magnesium Stearate
0.5-1.0
Total
100.

### Claim 10 (depends on 1)

A pharmaceutical formulation comprising:
Ingredient
Theoretical Quantity (mg/unit dose)
Compound 1 Solid Form III as
100.0
recited in claim 1
Microcrystalline Cellulose PH-102
155.4
Lactose Anhydrous 60M
77.7
Hydroxypropyl Cellulose, EXF
12.0
Croscarmellose Sodium
24
Colloidal Silicon Dioxide
1.2
Magnesium Stearate (Non-Bovine)
3.0
Opadry Yellow
16.0
Total
416.

### Claim 11 (depends on 1)

A pharmaceutical formulation comprising:
Ingredient
% w/w
Compound 1 Solid Form III as recited in claim 1
31.7
Microcrystalline Cellulose (Avicel PH-102)
38.9
Lactose Anhydrous (60M)
19.4
Hydroxypropyl Cellulose (EXF)
3.0
Croscarmellose Sodium (Ac-Di-Sol)
6.0
Colloidal Silicon Dioxide
0.3
Magnesium Stearate
0.75
Opadry Yellow Film Coating which includes:
4.00
HPMC 2910/Hypromellose 6 cp
Titanium dioxide
Triacetin
Iron Oxide Yellow.