Co-crystals and pharmaceutical compositions comprising the same

Patent metadata

Field	Value
Publication number	US-10039761-B2
Application number	US-201615130266-A
Country	US
Kind code	B2
Filing date	Apr 15, 2016
Priority date	Oct 17, 2013
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

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

wherein each of R 1 and R 2 is H or 2 H 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.

First claim

What is claimed is:

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

and
a co-crystal former, wherein the co-crystal former is adipic acid, wherein each of R 1 and R 2 is hydrogen or deuterium.

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.

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.

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.

Assignees

• Vertex Pharma

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

Classifications

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K38/14

  Peptides containing saccharide radicals; Derivatives thereof {, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin} · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/555

  containing heavy metals, e.g. hemin, hematin, melarsoprol · CPC title