Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator

• US 9,701,639 B2
• Filed: 10/07/2015
• Issued: 07/11/2017
• Est. Priority Date: 10/07/2014
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Medek, Ales, Zhang, Yuegang, Strohmeier, Mark, Caesar, Jr., John, Connelly, Patrick Raymond, Fawaz, Majed, Luss-Lusis, Eduard, McClain, Brian, Miao, Hai, Nti-Addae, Kwame Wiredu, Yin, Ping
• Primary Examiner(s): Seaman, D M
• Application Number:
  US14/877,914
• Publication Number:
  US 20160096807A1
• Time in Patent Office: 643 Days
• CPC Class Codes: A61K 31/225 Polycarboxylic acids
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 69/18 of trihydroxylic compounds
• CPC Class Codes: C07C 69/30 esterified with trihydroxylic compounds fats, oils C11B, C11C
• CPC Class Codes: C07C 69/34 Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
• CPC Class Codes: C07C 69/58 Esters of straight chain acids with eighteen carbon atoms in the acid moiety
• CPC Class Codes: C07C 69/587 Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4

Abstract

The present disclosure relates to co-crystals comprising N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1) and a co-former and methods for their preparation. The present disclosure further relates to pharmaceutical compositions comprising the co-crystal forms, as well as methods of treatment therewith and kits.

Claims

1. A pharmaceutical composition comprising a co-crystal of Compound 1 and only one triglyceride, wherein the triglyceride is chosen from the following structural formula:

2. The pharmaceutical composition of claim 1, wherein the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±

0.2 degrees at the following positions;

3.5, 6.9, and 10.9.

3. The pharmaceutical composition of claim 1, wherein the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±

0.2 degrees at the following positions;

3.5, 6.9, 9.2, 10.9, 16.9, 18.0, and 23.8.

4. The pharmaceutical composition of claim 1, wherein the co-crystal is characterized as having a ¹³C ssNMR spectrum with characteristic peaks expressed in ppm±

0.1 at the following positions;

178.6, 155.0, and 119.4.

5. The pharmaceutical composition of claim 1, wherein the co-crystal is characterized as having a ¹³C ssNMR spectrum with characteristic peaks expressed in ppm±

0.1 at the following positions;

178.6, 155.0, 130.5, and 119.4.

6. The pharmaceutical composition of claim 1, wherein the stoichiometry of Compound 1 to the triglyceride in the co-crystal is 3 to 1.

7. The pharmaceutical composition of claim 1, wherein the stoichiometry of Compound 1 to the triglyceride in the co-crystal is 6 to 1.

8. The pharmaceutical composition of claim 1, wherein Compound 1 forms a hexamer in the co-crystal and further wherein R₁, R₂, and R₃ are independently C_7-29 aliphatic.

9. The pharmaceutical composition of claim 1, wherein the co-crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is maintained for at least 10 hours.

10. The pharmaceutical composition of claim 1, wherein the triglyceride is chosen from:

glyceryl trioleate, glyceryl tristearate, glycerol tridecanoate, glycerol trihexanoate, glyceryl tritridecanoate, glycerol trioctanoate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tributyrate, glyceryl trilinoleate, glyceryl tridodecanoate, glyceryl decanoate, glyceryl tripalmitoleate, glycerol trierucate, glyceryl tripropionate, palmitodiolein, triarachidonin, glyceryl trilinolenate, trierucin, glycerol triarachidate, glyceryl tri(cis-13-docosenoate), glyceryl tripetroselinate, glyceryl tribehenate, glyceryl trielaidate, and triacetin.

15. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, COPD, or dry-eye disease, the method comprising the step of administering to the patient a therapeutic effective amount of the co-crystal of claim 1.

16. The method according to claim 15, wherein the disease is cystic fibrosis.

17. The method according to claim 15, further comprising co-administering one or more additional therapeutic agents to the subject.

18. The method according to claim 17, wherein the additional therapeutic agent is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid or (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.

19. The method according to claim 18, wherein the additional therapeutic agent is administered concurrently with, prior to, or subsequent to the co-crystal.

21. The pharmaceutical composition according to claim 1 or 11,

wherein the solid formulated for oral administration is a capsule, a tablet, a pill, a powder, or a granule.

11. A pharmaceutical composition comprising a therapeutically effective amount of Compound 1 and a pharmaceutically acceptable carrier or excipient, wherein Compound 1 is represented by the following structural formula:

12. The pharmaceutical composition according to claim 11, further comprising an additional therapeutic agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1, or a nutritional agent, or combinations thereof.

13. The pharmaceutical composition according to claim 12, wherein the additional therapeutic agent is a CFTR modulator other than Compound 1.

14. The pharmaceutical composition according to claim 13, wherein the CFTR modulator is (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid or (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.

20. A method of preparing a co-crystal comprising Compound 1 and a triglyceride,

wherein Compound 1 is represented by the following structural formula: