Claims for Patent: 11,299,500

Summary for Patent: 11,299,500

Title:	Crystalline form of lorlatinib free base hydrate
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-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclo-tetradecine-3-carb- onitrile (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.
Inventor(s):	Bowles; Paul (Ledyard, CT), Rose; Peter Robert (Uncasville, CT)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	16/650,505
Patent Claims:	1. A crystalline form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2- H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbo- nitrile (lorlatinib) free base hydrate, having a powder X-ray diffraction (PXRD) pattern comprising peaks at 2.theta. values of: 8.8, 9.7, 17.6 and 18.8 .degree.2.theta..+-.0.2 .degree.2.theta.. 2. The crystalline form of claim 1, having a PXRD pattern further comprising a peak at the 2.theta. value of: 10.9 .degree.20.+-.0.2 .degree.2.theta.. 3. The crystalline form of claim 1, having a .sup.13C solid state NMR spectrum comprising resonance (ppm) values of: 40.2, 41.2 and 136.2 ppm.+-.0.2 ppm. 4. The crystalline form of claim 1, having a .sup.19F solid state NMR spectrum comprising a resonance (ppm) value of: -104.0 ppm.+-.0.2 ppm. 5. 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. 6. 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. 7. A pharmaceutical composition comprising the crystalline form of lorlatinib free base hydrate of claim 1, and a pharmaceutically acceptable carrier or excipient. 8. 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. 9. A crystalline form of lorlatinib free base hydrate, having a .sup.13C solid state NMR spectrum comprising two or more resonance (ppm) values of: 40.2, 41.2 and 136.2 ppm.+-.0.2 ppm. 10. The crystalline form of claim 9, having a .sup.13C solid state NMR spectrum further comprising the resonance (ppm) value of: 128.1 ppm.+-.0.2 ppm. 11. The crystalline form of claim 9, having a .sup.13C solid state NMR spectrum further comprising the resonance (ppm) value of: 145.3 ppm.+-.0.2 ppm. 12. The crystalline form of claim 9, having a .sup.19F solid state NMR spectrum comprising a resonance (ppm) value of: -104.0 ppm.+-.0.2 ppm. 13. A crystalline form of lorlatinib free base hydrate, having a .sup.19F solid state NMR spectrum comprising a resonance (ppm) value of: -104.0 ppm.+-.0.2 ppm.