Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

• US 10,537,565 B2
• Filed: 02/20/2018
• Issued: 01/21/2020
• Est. Priority Date: 12/28/2005
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Hurter, Patricia, Rowe, William, Young, Christopher R., Costache, Adriana, Connelly, Patrick R., Krawiec, Mariusz, Gong, Yuchuan, Feng, Yushi, Trudeau, Martin
• Primary Examiner(s): Seaman, D Margaret M
• Application Number:
  US15/900,147
• Publication Number:
  US 20190070162A1
• Time in Patent Office: 700 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: C07B 2200/13 : Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 215/56 : with oxygen atoms in position 4
• CPC Class Codes: Y10T 428/2982 : Particulate matter [e.g., sphere, flake, etc.]

Abstract

The present invention relates to solid state forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1), pharmaceutical compositions thereof and methods therewith.

Claims

1. A crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, having at least one peak within a 2θ

value range selected from 6.0 to 6.4, 10.8 to 11.2, 16.9 to 17.3, 19.2 to 19.6, 20.9 to 21.3, 22.4 to 22.8, 26.5 to 26.9 and 27.3 to 27.7 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.

2. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 8.2 to 8.6 degrees.

3. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a peak within a 2θ

value range of 10.8 to 11.2 degrees.

4. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 14.6 to 15.0 degrees.

5. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 15.9 to 16.3 degrees.

6. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a peak within a 2θ

value range of 16.9 to 17.3 degrees.

7. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 18.4 to 18.8 degrees.

8. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a peak within a 2θ

value range of 19.2 to 19.6 degrees.

9. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a peak within a 2θ

value range of 20.9 to 21.3 degrees.

10. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a peak within a 2θ

value range of 22.4 to 22.8 degrees.

11. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 23.2 to 23.6 degrees.

12. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 23.7 to 24.1 degrees.

13. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 24.7 to 25.1 degrees.

14. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 25.3 to 25.7 degrees.

15. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a peak within a 2θ

value range of 26.5 to 26.9 degrees.

16. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a peak within a 2θ

value range of 27.3 to 27.7 degrees.

17. A pharmaceutical composition comprising the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to claim 1, and a pharmaceutically acceptable adjuvant or carrier.

18. A process for preparing the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to claim 1, wherein said process comprises the steps of alternatively heating and cooling a slurry of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide and acetonitrile.

20. A method of treating a CFTR mediated disease in a patient comprising the step of administering to said patient a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide or a pharmaceutical composition comprising a crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide according to claim 1 or 19.

21. The method according to claim 20, wherein said disease is cystic fibrosis.

22. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide has a peak within a 2θ

value range of 6.0 to 6.4 degrees.

23. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 7.4 to 7.8 degrees.

24. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 12.1 to 12.5 degrees.

25. The crystal form of claim 1, wherein the crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide further has a peak within a 2θ

value range of 17.8 to 18.2 degrees.

19. A crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, having a monoclinic crystal system, a P2₁ space grouping, and the following unit cell dimensions:

a=11.8011(7) Å

α

=90°

b=5.9819(3) Å

β

=105.110(4)°

c=14.7974(8) Å

γ

=90°

.

26. A crystal form of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, having an X-ray powder diffraction pattern, obtained using Cu K alpha radiation, substantially similar to FIG. 7.