Crystalline forms of 1-(4-{[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-4-fluoro-piperidin-1-yl)-propenone, salt forms thereof, and processes to obtain

Patent metadata

Field	Value
Publication number	US-11878967-B2
Application number	US-201917252804-A
Country	US
Kind code	B2
Filing date	Jun 17, 2019
Priority date	Jun 19, 2018
Publication date	Jan 23, 2024
Grant date	Jan 23, 2024

Abstract

A solid form of 1-(4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methy}-4-fluoro-piperidin-1-yl)-propenone, or pharmaceutically acceptable salts thereof, is useful as a BTK inhibitor.

First claim

We claim:

1. A substantially crystalline solid form of compound 1,

wherein the solid form is a crystalline anhydrous form.

2. A substantially crystalline solid form of compound 1,

wherein the solid form is a crystalline anhydrous form A2,
wherein form A2 is characterized by four or more 2θ XRPD peaks at 7.5±0.2°, 10.8±0.2°, 17.0±0.2°, 17.5±0.2°, 18.7±0.2°, 20.5±0.2°, 21.7±0.2°, 22.3±0.2°, 23.6±0.2°, and 24.0±0.2° degrees.

3. A substantially crystalline solid form of compound 1,

wherein the solid form is a crystalline form A2, having has a space group P-1 with the lattice parameters a=9.5±0.1 Å, b=10.7±0.1 Å, c=12.8±0.1 Å, and α=71.0±0.1°, β=68.99±0.1°, γ=71.9±0.1°.

4. A substantially crystalline solid form of compound 1,

wherein the solid form is A1, having a space group P21/n with the lattice parameters a=12.8±0.1 Å, b=12.9±0.1 Å, c=28.6±0.1 Å, and β=98.0±0.1° with α=γ=90°.

5. A substantially crystalline solid form of compound 1,

wherein the solid form is a crystalline form A2, wherein form A2 is characterized by a 2θ XRPD spectrum, comprising peaks at 17.0±0.2°, 18.7±0.2°, and 21.7±0.2° degrees.

6. A pharmaceutical composition comprising the solid form of compound 1 of claim 5 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

7. A method for treating a BTK-mediated disorder in a patient in need thereof, the method comprising:
administering to said patient the solid form of compound 1 of claim 5 .

8. A method for producing a medicament for the prophylactic or therapeutic treatment of a BTK-mediated disorder, the method comprising:
formulating the solid form of compound 1 of claim 5 , or physiologically acceptable salts thereof.

9. A substantially crystalline solid form of compound 1,

wherein the solid form is A1,
wherein form A1 is characterized by four or more 2θ XRPD peaks at 17.1±0.2°, 17.4±0.2°, 18.8±0.2°, 20.0±0.2°, and 21.1±0.2° degrees.

10. A pharmaceutical composition comprising the solid form of compound 1 of claim 9 , a pharmaceutically acceptable adjuvant, carrier, or vehicle.

11. A method for treating a BTK-mediated disorder in a patient in need thereof, the method comprising:
administering to said patient the solid form of compound 1 of claim 9 .

12. A method for producing a medicament for the prophylactic or therapeutic treatment of a BTK-mediated disorder, the method comprising: formulating the solid form of compound 1 of claim 9 .

13. A pharmaceutically acceptable salt of a substantially crystalline solid form of compound 1,

which is selected from the group consisting of HCl salt HCl-NF1 of compound 1, HCl salt HCl-NF2 of compound 1, HCl salt HCl-NF3 of compound 1, HBr salt HBr-NF1 of compound 1, HBr salt HBr-NF2 of compound 1, oxalate salt form oxalate-NF1 of compound 1, maleate salt form maleate-NF1 of compound 1, maleate salt form maleate-NF2 of compound 1, fumarate salt form fumarate-NF1 of compound 1, fumarate salt form fumarate-NF2 of compound 1, fumarate salt form fumarate-NF3 of compound 1, fumarate salt form fumarate-NF4 of compound 1, fumarate salt form fumarate-NF5 of compound 1, and mesylate salt form mesylate-NF1 of compound 1.

14. The pharmaceutically acceptable salt of claim 13 , which is HCl-NF1 salt and is characterized by two or more 2θ XRPD peaks at 15.7±0.2°, 19.1±0.2°, 20.3±0.2°, and 20.8±0.2° degrees.

15. The pharmaceutically acceptable salt of claim 13 , which is HCl-NF2 salt and is characterized by two or more 2θ XRPD peaks at 7.8±0.2°, 13.0±0.2°, and 15.6±0.2° degrees.

16. The pharmaceutically acceptable salt of claim 13 , which is HCl-NF3 salt and is characterized by two or more 2θ XRPD peaks at 14.8±0.2°, 16.8±0.2°, 20.1±0.2°, and 20.4±0.2° degrees.

17. The pharmaceutically acceptable salt of claim 13 , which is HBr-NF1 salt and is characterized by two or more 2θ XRPD peaks at 6.9±0.2°, 19.1±0.2°, 20.4±0.2°, 20.8±0.2°, and 21.9±0.2° degrees.

18. The pharmaceutically acceptable salt of claim 13 , which is HBr-NF2 salt and is characterized by two or more 2θ XRPD peaks at 4.9±0.2°, 13.2±0.2°, and 20.0±0.2° degrees.

19. The pharmaceutically acceptable salt of claim 13 , which is oxalate-NF1 salt and is characterized by two or more 2θ XRPD peaks at 16.2±0.2°, 17.7±0.2°, 18.6±0.2°, 21.1±0.2°, and 21.3±0.2° degrees.

20. The pharmaceutically acceptable salt maleate of claim 13 , which is maleate-NF1 salt and is characterized by two or more 2θ XRPD peaks at 18.1±0.2°, 19.1±0.2°, 20.8±0.2°, and 24.8±0.2° degrees.

21. The pharmaceutically acceptable salt of claim 13 , which is maleate-NF2 salt and is characterized by two or more 2θ XRPD peaks at 10.8±0.2°, 17.1±0.2°, 19.2±0.2°, and 20.7±0.2° degrees.

22. The pharmaceutically acceptable salt of claim 13 , is fumarate-NF1 salt and is characterized by two or more 2θ XRPD peaks at 9.0±0.2°, 17.0±0.2°, 18.4±0.2°, and 22.1±0.2° degrees.

23. The pharmaceutically acceptable salt of claim 13 , which is mesylate-NF1 salt and is characterized by two or more 2θ XRPD peaks at 18.7±0.2°, 19.5±0.2°, and 21.1±0.2° degrees.

Assignees

• Merck Patent Gmbh

Inventors

• Lange Michael
• Kuehn Clemens
• Schlueter Tobias
• Mederski Werner
• Maillard David
• Burini Edoardo

Classifications

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title