Granted Patent B2

US 12,319,693 · App. 18/493,667 · Granted Jun 3, 2025

Inventors: Yi Shi (Natick, MA); Kevin J. Gagnon (Acton, MA); Jicong Li (Cambridge, MA); Jennifer Lu (San Diego, CA); Ales Medek (Winchester, MA); Muna Shrestha (Belmont, MA); Michael Waldo (Grafton, MA); Beili Zhang (San Diego, CA); Carl L Zwicker (Wakefield, MA); Corey Don Anderson (Brighton, MA); Jeremy J. Clemens (San Diego, CA); Thomas Cleveland (San Marcos, CA); Timothy Richard Coon (Carlsbard, CA); Bryan Frieman (La Jolla, CA); Peter Grootenhuis (Del Mar, CA); Sara Sabina Hadida Ruah (La Jolla, CA); Jason McCartney (Cardiff by the Sea, CA); Mark Thomas Miller (Rancho Santa Fe, CA); Prasuna Paraselli (San Diego, CA); Fabrice Pierre (La Jolla, CA); Sara E. Swift (San Diego, CA); Jinglan Zhou (San Diego, CA)

Assignee: Vertex Pharmaceuticals Incorporated

C07D471/08C07B2200/13

Abstract

Claims (46)

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.

Assignments (4)

Continuity (4)

References Cited (215)

Cited By (1)

US 12,612,416