CO-CRYSTALS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME

• US 20160339024A1
• Filed: 04/15/2016
• Published: 11/24/2016
• Est. Priority Date: 10/17/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Nti-Addae, Kwame Wiredu, Navamal, Mettachit, O'Neil, Simon Adam, Zhang, Yuegang, Waldo, Michael, Mudunuri, Praveen, Song, Bin, Van Alsten, John Gregg, Strohmeier, Mark, Stavropoulos, Kathy, Kadiyala, Irina Nikolaevna
• Granted Patent: US 10,039,761 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 the co-crystal former is adipic acid and the molar ratio of 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.

9. The co-crystal of claim 3, wherein the co-crystal is in polymorphic Form B.

10. The co-crystal of claim 9, wherein the polymorphic Form B is characterized by C¹³ solid state nuclear magnetic resonance spectroscopy peaks at about 117.9, 97.3, 94.0, 26.7, and 15.7 ppm.

38. A method of sensitizing a cell to an agent that induces a DNA lesion comprising contacting the cell with a co-crystal of claim 1, or a pharmaceutical composition thereof.

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

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

41. The method of claim 40 further comprising administering additional anticancer therapy.

42. The method of claim 41, wherein the additional anticancer therapy is an anticancer agent or radiation therapy, or both.

43. The method of claim 42, wherein the anticancer agent is a DNA-damaging agent.

49. The co-crystal of claim 4 having X-ray powder diffraction peaks at about 6.46+/−

0.2, 7.91+/−

0.2, 11.92+/−

0.2, 12.26+/−

0.2, 12.99+/−

0.2, 14.19+/−

0.2, 18.68+/−

0.2, and 19.07+/−

0.2°

2 Theta.

50. The co-crystal of claim 4, wherein the co-crystal is in polymorphic Form B.

5. The co-crystal of claim 3 having X-ray powder diffraction peaks at about 6.46+/−

0.2, 7.91+/−

0.2, 11.92+/−

0.2, 12.26+/−

0.2, 12.99+/−

0.2, 14.19+/−

0.2, 18.68+/−

0.2, and 19.07+/−

0.2°

2 Theta.

5-1. (canceled)

6. (canceled)

6-1. (canceled)

7-8. -8. (canceled)

11-13. -13. (canceled)

14. A pharmaceutical composition comprising a co-crystal, wherein the co-crystal comprises a compound of the formula

15. The pharmaceutical composition of claim 14, 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, the co-crystal former is adipic acid, and the compound and co-crystal former are together in the crystalline form.

16. The pharmaceutical composition of claim 14, 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, the co-crystal former is adipic acid and the compound and co-crystal former are together in the crystalline form.

17. The pharmaceutical composition of claim 15, wherein the molar ratio of the compound of formula I to adipic acid is about 2 to 1.

19. The pharmaceutical composition of claim 16, further comprising additional adipic acid.

20. The pharmaceutical composition of claim 19, wherein the overall weight ratio of the compound of formula I to adipic acid is in a range from about 85 wt %:

15 wt % to about 60 wt %;

about 40 wt %.

53. The pharmaceutical composition of claim 16, wherein the molar ratio of the compound of formula I to adipic acid is about 2 to 1.

54. The pharmaceutical composition of claim 15, further comprising additional adipic acid.

18. (canceled)

21. (canceled)

22. 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 the co-crystal former under crystallization conditions so as to form the co-crystal in solid phase, wherein the co-crystal former is adipic acid, citric acid, fumaric acid, maleic acid, succinic acid, or benzoic acid.

23. A method for modulating a chemical or physical property of interest of a co-crystal comprising:

(a) measuring the chemical or physical property of interest for 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 the co-crystal former,

(b) determining the mole fraction of 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 the co-crystal former that will result in the desired modulation of the chemical or physical property of interest, and

(c) preparing the co-crystal with the molar fraction determined in step (b).

24. A method of making a co-crystal 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; and

the co-crystal to be formed 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.

25-27. -27. (canceled)

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

mixing a compound of formula (I);

29-37. -37. (canceled)

44. A method of treating cancer in a patient comprising administering to said patient a composition comprising a compound of formula (I) in combination with at least one DNA damaging agent,

wherein the compound of formula (I) is (5)-N-methyl-8-(1-((2′

-methyl-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide, (5)-N-methyl-8-(1-((2′

-methyl-4 6′

-dideutero-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide, or a pharmaceutically acceptable salt thereof; and

wherein the DNA damaging agent is etoposide, doxorubicin liposomal, gemcitabine, paclitaxel, cisplatin, carboplatin, fluorouracil (5-FU), etoposide, doxorubicin, daunorubicin, epirubicin, bleomycin, BMN-673, carboplatin, erlotinib, cisplatin, carboplatin, fluorouracil, or cetuximab.

45. The method of claim 44, wherein the compound of formula (I) is (5)-N-methyl-8-(1-((2′

-methyl-[4,5′

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

46. The method of claim 44, wherein the compound of formula (I) is (5)-N-methyl-8-(1-((2′

-methyl-4 6′

-dideutero-[4,5′

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

47. The method of claim 44, the method further comprising co-administration with radiation therapy.

48. A method of treating cancer in a patient comprising administering to said patient a composition comprising a compound of formula (I) in combination with radiation therapy,

wherein the compound of formula (I) is (5)-N-methyl-8-(1-((2′

-methyl-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide, (5)-N-methyl-8-(1-((2′

-methyl-4 6′

-dideutero-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide, or a pharmaceutically acceptable salt thereof.

51. A mixture of polymorphic Form A of (S)—

N-methyl-8-(1-((2′

-methyl-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide and Form B of (S)—

N-methyl-8-(1-((2′

-methyl-[4,5′

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

52. A mixture of polymorphic Form A of (S)—

N-methyl-8-(1-((2′

-methyl-4′

,6′

-dideutero-[4,5′

-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide and Form B of (S)—

N-methyl-8-(1-((2′

-methyl-4′

,6′

-dideutero-[4,5′

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