Crystalline forms of CFTR modulators

Patent metadata

Field	Value
Publication number	US-11873300-B2
Application number	US-202016992441-A
Country	US
Kind code	B2
Filing date	Aug 13, 2020
Priority date	Aug 14, 2019
Publication date	Jan 16, 2024
Grant date	Jan 16, 2024

Abstract

Crystalline forms of Compound I:

pharmaceutically acceptable salts thereof, and solvates and hydrates thereof are disclosed. Pharmaceutical compositions comprising the same, methods of treating cystic fibrosis using the same, and methods for making the same are also disclosed.

First claim

The invention claimed is:

1. Compound I calcium salt hydrate Form D

2. A pharmaceutical composition comprising the compound according to claim 1 .

3. The pharmaceutical composition according to claim 2 , further comprising one or more additional CFTR modulating compounds.

4. The pharmaceutical composition according to claim 3 , wherein at least one additional CFTR modulating compound is a CFTR potentiator.

5. The pharmaceutical composition according to claim 3 , wherein at least one additional CFTR modulating compound is a CFTR corrector.

6. The pharmaceutical composition according to claim 3 , wherein the one or more additional CFTR modulating compounds are selected from:
(a) Compound II:

7. A method of treating cystic fibrosis comprising administering the Compound I calcium salt hydrate Form D

to a subject in need thereof.

8. The method of treating cystic fibrosis according to claim 7 , wherein the Compound I calcium salt hydrate Form D is administered with one or more additional CFTR modulating compounds.

9. The method of treating cystic fibrosis according to claim 8 , wherein the one or more additional CFTR modulating compound are selected from:

10. A method of preparing Compound I calcium salt hydrate Form D according to claim 1 , comprising
(a) charging Compound I calcium salt hydrate Form A with EtOH/water.
(b) heating to 65° C., and
(c) isolating the resulting solids,

to provide Compound I calcium salt hydrate Form D.

11. The Compound I calcium salt hydrate Form D

characterized by an X-ray powder diffractogram (XRPD) having signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta.

12. The Compound I calcium salt hydrate Form D of claim 11 , characterized by an XRPD having (a) signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta; and (b) one or more signals selected from 5.5±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 19.7±0.2 degrees two-theta, 21.5±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.0±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta.

13. Compound I calcium salt hydrate Form D of claim 11 , characterized by an XRPD having signals at 6.1±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, and 22.8±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta.

14. The Compound I calcium salt hydrate Form D of claim 11 , characterized by an XRPD having signals at 6.1±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, 19.7±0.2 degrees two-theta, 22.8±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta.

15. The Compound I calcium salt hydrate Form D of claim 1 , characterized by an X-ray powder diffractogram substantially similar to FIG. 13 .

16. The Compound I calcium salt hydrate Form D

characterized by a triclinic crystal system, a P1 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Cμ Kα radiation (λ=1.5478 Å) of

a
12.78 ± .01 Å
α
64.93 ± .02º

b
16.64 ± .01 Å
β
75.10 ± .02º

c
18.19 ± .01 Å
γ
 68.22 ± .02º.

17. The Compound I calcium salt hydrate Form D

characterized by a 13 C solid state nuclear magnetic resonance ( 13 C ss NMR) spectrum with one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm.

18. The substantially crystalline Compound I calcium salt hydrate Form D of claim 17 , characterized by a 13 C ssNMR spectrum with one or more peaks selected from 179.8±0.2 ppm, 130.2±0.2 ppm, 125.6±0.2 ppm, 120.9±0.2 ppm, 55.2±0.2 ppm, 44.3±0.2 ppm, 35.0±0.2 ppm, and 1.6±0.2 ppm.

19. The Compound I calcium salt hydrate Form D of claim 17 , characterized by a 13 C ssNMR spectrum with (a) one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm; and (b) one or more peaks selected from 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and 98.6±0.2 ppm.

20. The Compound I calcium salt hydrate Form D of claim 1 , characterized by a 13 C ssNMR spectrum substantially similar to FIG. 14 .

21. The pharmaceutical composition according to claim 2 , wherein at least 85% of the Compound I is Compound I calcium salt hydrate Form D.

22. The pharmaceutical composition according to claim 2 , wherein at least 95% of the Compound I is Compound I calcium salt hydrate Form D.

23. A pharmaceutical composition comprising Compound I and a pharmaceutically acceptable carrier, wherein the Compound I comprises Compound I calcium salt hydrate Form D

24. The composition according to claim 23 , wherein at least 85% of the Compound I is Compound I calcium salt hydrate Form D.

25. The composition according to claim 23 , wherein at least 95% of the Compound I is Compound I calcium salt hydrate Form D.

Assignees

• Vertex Pharma

Inventors

• Shi Yi
• Gagnon Kevin J
• Li Jicong
• Lu Jennifer
• Medek Ales
• Shrestha Muna
• Waldo Michael
• Zhang Beili
• Zwicker Carl L
• Anderson Corey Don
• Clemens Jeremy J
• Cleveland Thomas
• Coon Timothy Richard
• Frieman Bryan
• Grootenhuis Peter
• Hadida Ruah Sara Sabina
• Mccartney Jason
• Miller Mark Thomas
• Paraselli Prasuna
• Pierre Fabrice
• Swift Sara E
• Zhou Jinglan

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D471/08 Primary

  Bridged systems · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D513/22 Primary

  in which the condensed system contains four or more hetero rings · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title