Crystalline forms of CFTR modulators

Patent metadata

Field	Value
Publication number	US-12319693-B2
Application number	US-202318493667-A
Country	US
Kind code	B2
Filing date	Oct 24, 2023
Priority date	Aug 14, 2019
Publication date	Jun 3, 2025
Grant date	Jun 3, 2025

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 A

2. A pharmaceutical composition comprising the Compound I calcium salt hydrate Form A 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 the one or more additional CFTR modulating compounds are selected from
(a) Compound II

(b) Compound III

Compound III-d

(c) Compound IV

5. A method of treating cystic fibrosis comprising administering the Compound I calcium salt hydrate Form A according to claim 1 to a subject in need thereof.

6. The method of treating cystic fibrosis according to claim 5 , wherein the Compound I calcium salt hydrate Form A is administered with one or more additional CFTR modulating compounds.

7. The method of treating cystic fibrosis according to claim 6 , wherein the one or more additional CFTR modulating compound are selected from
(a) Compound II

(b) Compound III

Compound III-d

(c) Compound IV

8. A method of preparing the Compound I calcium salt hydrate Form A according to claim 1 , comprising:
(a) charging Compound I Form A and calcium methoxide (Ca(OMe) 2 ) with IPA/H 2 O
(b) heating to 70° C., and
(c) isolating the resulting solids,

to provide substantially crystalline Compound I calcium salt hydrate Form A.

9. Compound I calcium salt hydrate Form A

characterized by an X-ray powder diffractogram (XRPD) having signals at 4.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta.

10. The Compound I calcium salt hydrate Form A according to claim 9 , characterized by an X-ray powder diffractogram (XRPD) having (a) signals at 4.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta; and (b) signals at one or more of 10.5±0.2 degrees two-theta, 10.6±0.2 degrees two-theta, and 17.8±0.2 degrees two-theta.

11. The Compound I calcium salt hydrate Form A according to claim 9 , characterized by an X-ray powder diffractogram (XRPD) having (a) signals at 4.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta; and (b) signals at two or more of 10.5±0.2 degrees two-theta, 10.6±0.2 degrees two-theta, and 17.8±0.2 degrees two-theta.

12. The Compound I calcium salt hydrate Form A according to claim 9 , characterized by an X-ray powder diffractogram (XRPD) having (a) signals at 4.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta; and (b) signals at 10.5±0.2 degrees two-theta, 10.6±0.2 degrees two-theta, and 17.8±0.2 degrees two-theta.

13. The Compound I calcium salt hydrate Form A according to claim 1 , characterized by an X-ray powder diffractogram substantially similar to FIG. 6 .

14. The Compound I calcium salt hydrate Form A according to claim 1 , characterized by a monoclinic crystal system, a C 2 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Cu K α radiation (λ=1.5478 Å) of

a
11.13 ± .01 Å
α
90°

b
13.77 ± .01 Å
β
101.93 ± .01°

c
22.21 ± .01 Å
γ
90°.

15. Compound I calcium salt hydrate Form A

characterized by a 13 C solid state nuclear magnetic resonance ( 13 C ssNMR) spectrum with a peak at 17.0±0.2 ppm.

16. The Compound I calcium salt hydrate Form A according to claim 15 , characterized by a 13 C ssNMR spectrum with a peak at 7.8±0.2 ppm.

17. The Compound I calcium salt hydrate Form A according to claim 15 , characterized by a 13 C ssNMR spectrum with peaks at 17.0±0.2 ppm and 7.8±0.2 ppm.

18. The Compound I calcium salt hydrate Form A according to claim 15 , characterized by a 13 C ssNMR spectrum substantially similar to FIG. 7 .

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

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

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

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61P43/00

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