Crystalline pyrimidinyl-3,8-diazabicyclo[3.2.1]octanylmethanone compound and use thereof

Patent metadata

Field	Value
Publication number	US-12312358-B2
Application number	US-202017430373-A
Country	US
Kind code	B2
Filing date	Feb 12, 2020
Priority date	Feb 15, 2019
Publication date	May 27, 2025
Grant date	May 27, 2025

Abstract

The present invention discloses a novel crystalline form of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone free base, pharmaceutical composition containing the same, preparations thereof and uses thereof.

First claim

We claim:

1. A crystalline form of ((S)-2,2-difluorocyclopropyl) ((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 5.0, 9.9, and 15.3° 2θ±0.2°2θ.

2. The crystalline form of claim 1 , further characterized by a powder X-ray diffraction pattern peak, in terms of 2θ, at 19.7° 2θ±0.2° 2θ.

3. The crystalline form of claim 1 , further characterized by a powder X-ray diffraction pattern comprising peaks, in terms of 20, at 16.8 and 19.7° 2θ±0.2° 2θ.

4. The crystalline form of claim 1 , where said form is non-hygroscopic and anhydrous.

5. The crystalline form of claim 1 , characterized by at least one solid state 13C nuclear magnetic resonance chemical shift selected from the group consisting of 54.6, 129.8, and 124.9 ppm±0.2 ppm.

6. The crystalline form of claim 1 , characterized by a set of Raman bands at 1578, 1605, and 1566 cm −1 ±2 cm −1 .

7. The crystalline form of claim 1 , further characterized by a Raman band at 1578 cm −1 ±2 cm −1 .

8. The crystalline form of claim 1 , further characterized by a Raman band at 1578 cm −1 ±2 cm −1 and at least one solid state 13C nuclear magnetic resonance chemical shift selected from the group consisting of 54.6 and 129 ppm±0.2 ppm.

9. A pharmaceutical composition comprising the crystalline form of claim 1 or a pharmaceutically acceptable salt thereof; and, a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9 , comprising a topical formulation selected from a cream, transdermal patch, ointment, ophthalmic drops, lotion and gel.

11. The pharmaceutical composition of claim 10 wherein the topical formulation contains about 0.1% to about 5.0% (w/v) crystalline ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone or a pharmaceutically acceptable salt thereof.

12. A method of treating a disease in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a crystalline form of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's Disease, vitiligo, alopecia, psoriasis, psoriatic arthritis, and atopic dermatitis.

13. A method of topically treating a disease in a mammal, comprising administering by a topical mode of administration to a mammal in need thereof a therapeutically effective amount of a crystalline form of claim 1 or a pharmaceutically acceptable salt thereof wherein the disease is selected from the group consisting of vitiligo, alopecia, psoriasis and atopic dermatitis.

14. The crystalline form of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.

15. The crystalline form of claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder selected from the group consisting of lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's Disease, vitiligo, alopecia, psoriasis, psoriatic arthritis, and atopic dermatitis.

16. A crystalline form of ((S)-2,2-difluorocyclopropyl) ((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone, or a pharmaceutically acceptable salt thereof, prepared by re-crystallizing ((2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone) from a suitable solvent, wherein the crystalline form is characterized by a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 5.0, 9.9, and 15.3° 2θ±0.2° 2θ.

17. A topical formulation of comprising a crystalline form of ((S)-2,2-difluorocyclopropyl) ((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, or a pharmaceutically acceptable salt thereof, prepared by combining the crystalline form or the pharmaceutically acceptable salt thereof with excipients suitable for transdermal administration, wherein the crystalline form is characterized by a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 5.0, 9.9, and 15.3° 2θ±0.2° 2θ.

Assignees

• Pfizer

Inventors

• Yang Xiaojing
• Samuel Amanda Patrice Surajhie

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title