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Last Updated: October 23, 2020

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Claims for Patent: 10,420,749

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Summary for Patent: 10,420,749
Title:Crystalline form of lorlatinib free base
Abstract: This invention relates to a crystalline form of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H- -8,4-(metheno)pyrazolo[4,3-h] [2,5,11]benzoxadiazacyclo-tetradecine-3-carbonitrile (lorlatinib) free base (Form 7). This invention also relates to pharmaceutical compositions comprising Form 7, and to methods of using Form 7 and such compositions in the treatment of abnormal cell growth, such as cancer, in a mammal.
Inventor(s): Pencheva; Klimentina Dimitrova (Sandwich, GB), Birch; Melissa J. (Sandwich, GB)
Assignee: Pfizer Inc. (New York, NY)
Application Number:15/743,894
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, having a powder X-ray diffraction (PXRD) pattern comprising peaks at 2.theta. values of: 9.6, 10.1 and 16.2 .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: 17.3 .degree.2.theta..+-.0.2 .degree.2.theta..

3. The crystalline form of claim 2, having a PXRD pattern further comprising a peak at the 2.theta. value of: 14.3 .degree.2.theta..+-.0.2 .degree.2.theta..

4. The crystalline form of claim 1, having a Raman spectrum comprising wavenumber (cm.sup.-1) values of: 2229 and 2240 cm.sup.-1.+-.2 cm.sup.-1.

5. The crystalline form of claim 1, having a .sup.13C solid state NMR spectrum comprising resonance (ppm) values of: 39.1 and 142.1 ppm.+-.0.2 ppm.

6. The crystalline form of claim 1, having a .sup.19F solid state NMR spectrum comprising resonance (ppm) values of: -108.2 and -115.2 ppm.+-.0.2 ppm.

7. A crystalline form of lorlatinib free base, having a Raman spectrum comprising wavenumber (cm.sup.-1) values of: 2229 and 2240 cm.sup.-1.+-.2 cm.sup.-1.

8. The crystalline form of claim 7, having a Raman spectrum further comprising the wavenumber (cm.sup.-1) value of: 1619 cm.sup.-1.+-.2 cm.sup.-1.

9. The crystalline form of claim 8, having a Raman spectrum further comprising the wavenumber (cm.sup.-1) value of: 1553 cm.sup.-1.+-.2 cm.sup.-1.

10. The crystalline form of claim 9, having a Raman spectrum further comprising the wavenumber (cm.sup.-1) value of: 774 cm.sup.-1.+-.2 cm.sup.-1.

11. The crystalline form of claim 7, having a .sup.13C solid state NMR spectrum comprising resonance (ppm) values of: 39.1 and 142.1 ppm.+-.0.2 ppm.

12. The crystalline form of claim 7, having a .sup.19F solid state NMR spectrum comprising resonance (ppm) values of: -108.2 and -115.2 ppm.+-.0.2 ppm.

13. A crystalline form of lorlatinib free base, having a .sup.13C solid state NMR spectrum comprising two or more resonance (ppm) values of: 39.1 and 142.1 ppm.+-.0.2 ppm.

14. The crystalline form of claim 13, having a .sup.13C solid state NMR spectrum further comprising the resonance (ppm) value of: 112.3 ppm.+-.0.2 ppm.

15. The crystalline form of claim 14, having a .sup.13C solid state NMR spectrum further comprising the resonance (ppm) value of: 25.8 ppm.+-.0.2 ppm.

16. The crystalline form of claim 15, having a .sup.13C solid state NMR spectrum further comprising the resonance (ppm) value of: 117.7 ppm.+-.0.2 ppm.

17. A crystalline form of lorlatinib free base, having a .sup.19F solid state NMR spectrum comprising a resonance (ppm) value selected from the group consisting of: -108.2 and -115.2 ppm.+-.0.2 ppm.

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

19. A method of treating abnormal cell growth in a mammal comprising administering to the mammal a therapeutically effective amount of the crystalline form of lorlatinib free base according to claim 1, wherein the abnormal cell growth is cancer mediated by anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 receptor tyrosine kinase (ROS1).

20. The method of claim 19, wherein the cancer is non-small cell lung cancer (NSCLC).

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