# US 11,299,500 B2 · Crystalline form of lorlatinib free base hydrate

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- Number: US 11,299,500 B2
- Document ID: US11299500B2
- Status: Granted
- Kind: B2
- Application number: 16/650,505
- Filed: 2018-10-04
- Published: 2020-10-01
- Granted: 2022-04-12
- Earliest claimed: 2017-10-10
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Paul Bowles; Peter Robert Rose
- Web page: https://patentgrep.com/patent/US11299500B2

## CPC

- C07D 498/18: Bridged systems
- A61P 35/00: Antineoplastic agents
- 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

This invention relates to a crystalline form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclo-tetradecine-3-carbonitrile (lorlatinib) free base hydrate (Form 24). This invention also relates to pharmaceutical compositions comprising Form 24, and to methods of using Form 24 and such compositions in the treatment of abnormal cell growth, such as cancer, in a mammal.

## Claims

### Claim 1

A crystalline form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (lorlatinib) free base hydrate, having a powder X-ray diffraction (PXRD) pattern comprising peaks at 2θ values of: 8.8, 9.7, 17.6 and 18.8 °2θ±0.2 °2θ.

### Claim 2 (depends on 1)

The crystalline form of claim 1, having a PXRD pattern further comprising a peak at the 2θ value of: 10.9 °20±0.2 °2θ.

### Claim 3 (depends on 1)

The crystalline form of claim 1, having a 13C solid state NMR spectrum comprising resonance (ppm) values of: 40.2, 41.2 and 136.2 ppm±0.2 ppm.

### Claim 4 (depends on 1)

The crystalline form of claim 1, having a 19F solid state NMR spectrum comprising a resonance (ppm) value of: −104.0 ppm±0.2 ppm.

### Claim 5 (depends on 1)

The crystalline form of lorlatinib free base hydrate of claim 1, for use as a medicament for treating cancer in a mammal, wherein the cancer is selected from the group consisting of ALK-positive non-small cell lung cancer (NSCLC) mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1), ALK-positive anaplastic large cell lymphoma (ALCL), and ALK-positive neuroblastoma.

### Claim 6 (depends on 1)

The crystalline form of lorlatinib free base hydrate of claim 1, for use in the treatment of cancer in a mammal, wherein the cancer is selected from the group consisting of ALK-positive non-small cell lung cancer (NSCLC) mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1), ALK-positive anaplastic large cell lymphoma (ALCL), and ALK-positive neuroblastoma.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising the crystalline form of lorlatinib free base hydrate of claim 1, and a pharmaceutically acceptable carrier or excipient.

### Claim 8 (depends on 1)

A method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of the crystalline form of lorlatinib free base hydrate of claim 1, wherein the cancer is selected from the group consisting of ALK-positive non-small cell lung cancer (NSCLC) mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1), ALK-positive anaplastic large cell lymphoma (ALCL), and ALK-positive neuroblastoma.

### Claim 9

A crystalline form of lorlatinib free base hydrate, having a 13C solid state NMR spectrum comprising two or more resonance (ppm) values of: 40.2, 41.2 and 136.2 ppm±0.2 ppm.

### Claim 10 (depends on 9)

The crystalline form of claim 9, having a 13C solid state NMR spectrum further comprising the resonance (ppm) value of: 128.1 ppm±0.2 ppm.

### Claim 11 (depends on 9)

The crystalline form of claim 9, having a 13C solid state NMR spectrum further comprising the resonance (ppm) value of: 145.3 ppm±0.2 ppm.

### Claim 12 (depends on 9)

The crystalline form of claim 9, having a 19F solid state NMR spectrum comprising a resonance (ppm) value of: −104.0 ppm±0.2 ppm.

### Claim 13

A crystalline form of lorlatinib free base hydrate, having a 19F solid state NMR spectrum comprising a resonance (ppm) value of: −104.0 ppm±0.2 ppm.