Co-crystals and pharmaceutical compositions comprising the same

• US 10,039,761 B2
• Filed: 04/15/2016
• Issued: 08/07/2018
• Est. Priority Date: 10/17/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Nti-Addae, Kwame Wiredu, O'Neil, Simon Adam, Zhang, Yuegang, Waldo, Michael, Mudunuri, Praveen, Song, Bin, Van Alsten, John Gregg, Strohmeier, Mark, Stavropoulos, Kathy, Kadiyala, Irina Nikolaevna, Navamal, Mettachit
• Primary Examiner(s): TRAN, MY CHAU T
• Application Number:
  US15/130,266
• Publication Number:
  US 20160339024A1
• Time in Patent Office: 844 Days
• Field of Search: 514183, 5142305, 514256, 514257
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 38/14 Peptides containing saccharide radicals; Derivatives thereof , e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 2005/1098 Enhancing the effect of the particle by an injected agent or implanted device
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• CPC Class Codes: C07C 55/10 Succinic acid
• CPC Class Codes: C07C 55/14 Adipic acid
• CPC Class Codes: C07C 57/145 Maleic acid
• CPC Class Codes: C07C 57/15 : Fumaric acid
• CPC Class Codes: C07C 59/265 : Citric acid
• CPC Class Codes: C07C 63/08 : Salts thereof
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Abstract

The present invention relates to compositions and co-crystals each comprising a compound of formula I having the structure:

wherein each of R¹ and R² is H or ²H and a co-crystal former selected from adipic acid, citric acid, fumaric acid, maleic acid, succinic acid, or benzoic acid. Also within the scope of this invention are methods of making and using the same.

Claims

1. A co-crystal comprising a compound of the formula

2. The co-crystal of claim 1, wherein a molar ratio of the adipic acid to the compound of formula I is about 1 to 2.

3. The co-crystal of claim 2, wherein the compound of formula I is (S)-N-methyl-8-(1-((2′

-methyl-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide.

4. The co-crystal of claim 2, wherein the compound of formula I is (S)-N-methyl-8-(1-((2′

-methyl-4′

,6′

-dideutero-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide.

5. The co-crystal of claim 3, having X-ray powder diffraction peaks at about 6.46, 7.91, 11.92, 12.26, 12.99, 14.19, 18.68, and 19.07°

2-Theta.

6. The co-crystal of claim 3, having a DSC peak in its DSC thermogram at about 195°

C. and about 245°

C.

7. A pharmaceutical composition comprising the co-crystal according to claim 1.

8. The pharmaceutical composition of claim 7 wherein the compound of formula I is (S)-N-methyl-8-(1-((2′

-methyl-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide.

9. The pharmaceutical composition of claim 7 wherein the compound of formula I is (S)-N-methyl-8-(1-((2′

-methyl-4′

,6′

-dideutero-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide.

10. The pharmaceutical composition of claim 7, wherein a molar ratio of the compound of formula I to adipic acid is about 2 to 1.

11. The pharmaceutical composition of claim 7, further comprising a diluent, solvent, excipient, carrier, or solubilizing agent.

14. A method of potentiating a therapeutic regimen for the treatment of cancer in a patient comprising administering to said patient an effective amount of the co-crystal of claim 1, or the pharmaceutical composition of claim 7.

15. A method of treating cancer in a patient comprising administering to said patient an effective amount of the co-crystal of claim 1, or the pharmaceutical composition of claim 7.

16. The method of claim 14, wherein the therapeutic regimen includes radiation therapy.

17. The method of claim 14, wherein the therapeutic regimen includes chemotherapy.

18. The method of claim 14, wherein the therapeutic regimen includes both radiation therapy and chemotherapy.

19. The method of claim 14, wherein the co-crystal is administered with etoposide, doxorubicin, daunorubicin, epirubicin or bleomycin.

20. The co-crystal of claim 4, having a DSC peak in its DSC thermogram at about 195°

C. and about 245°

C.

21. The co-crystal of claim 4, having X-ray powder diffraction peaks at about 6.46, 7.91, 11.92, 12.26, 12.99, 14.19, 18.68, and 19.07°

2-Theta.

12. A method of making a co-crystal comprising:

grinding, heating, co-subliming, co-melting, or contacting either (S)-N-methyl-8-(1-((2′

-methyl-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide or (S)-N-methyl-8-(1-((2′

-methyl-4′

,6′

-dideutero-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide with a co-crystal former under crystallization conditions so as to form the co-crystal in solid phase, wherein the co-crystal former is adipic acid.

13. A method of making a co-crystal, wherein the co-crystal comprises (i) either (S)-N-methyl-8-(1-((2′

-methyl-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide or (S)-N-methyl-8-(1((2′

-methyl-4′

,6′

-dideutero-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide; and

(ii) adipic acid;

the method comprising providing a pre-existing co-crystal as a seed to prepare the co-crystal, wherein the pre-existing co-crystal comprises;

(i) either (S)-N-methyl-8-(1-((2′

-methyl-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide or (S)-N-methyl-8-(1-((2′

-methyl-4′

,6′

-dideutero-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide; and

(ii) adipic acid.