Co-crystal forms of a novobiocin analog and proline
Disclosed are co-crystal forms of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide and L-proline or D-proline, their pharmaceutical compositions, processes of manufacture, and methods of use for treating neurodegenerative disorders such as diabetic peripheral neuropathy.
1. A co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide and L-proline (1:2), characterized by an X-ray powder diffractogram comprising the following peaks: 14.76, 16.86, 19.00, and 21.05 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å.
2. The co-crystal according to claim 1 , wherein the X-ray powder diffractogram further comprises peaks at 12.14, 17.51, 18.89, and 19.41 °2θ±0.20 °2θ.
3. The co-crystal according to claim 1 , wherein the X-ray powder diffractogram is substantially as shown in FIG. 1 .
4. The co-crystal according to claim 1 , characterized by a differential scanning calorimetry (DSC) thermogram comprising an exotherm at about 211° C.
5. The co-crystal according to claim 4 , wherein the DSC thermogram is substantially as shown in FIG. 2 .
6. A co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide and L-proline (1:2), characterized by an X-ray powder diffractogram comprising the following peaks: 9.20, 16.19, 18.45, and 24.51 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å.
7. The co-crystal according to claim 6 , wherein the X-ray powder diffractogram further comprises peaks at 11.83, 17.16, 20.15, and 25.34 °2θ±0.2 °2θ.
8. The co-crystal according to claim 6 , wherein the X-ray powder diffractogram is substantially as shown in FIG. 14 .
9. The co-crystal according to claim 6 , characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm having an onset temperature of about 211.2° C.
10. The co-crystal according to claim 9 , wherein the DSC thermogram is substantially as shown in FIG. 15 .
11. A co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide and L-proline acetone solvate (1:1:1), characterized by an X-ray powder diffractogram comprising the following peaks: 14.64, 17.53, 18.91, and 21.33 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å.
12. The co-crystal according to claim 11 , wherein the X-ray powder diffractogram further comprises peaks at 12.10, 15.14, 18.26, and 19.56 °2θ±0.2 °2θ.
13. The co-crystal according to claim 11 , wherein the X-ray powder diffractogram is substantially as shown in FIG. 10 .
14. The co-crystal according to claim 11 , characterized by a thermogravimetric analysis (TGA) thermogram comprising weight loss steps that conclude at about 150° C. and about 220° C.
15. The co-crystal according to claim 14 , wherein the TGA thermogram is substantially as shown in FIG. 11 .
16. A co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide, L-proline, methyl ethyl ketone, and pyrazine in a molar ratio of about 1:12:0.6:0.1, characterized by an X-ray powder diffractogram comprising the following peaks: 10.42, 14.62, 19.28, and 21.14 °2θ±0.20 °2θ as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54178 Å.
17. The co-crystal according to claim 16 , wherein the X-ray powder diffractogram further comprises peaks at 11.85, 14.93, 17.40, and 19.28 °2θ±0.2 °2θ.
18. The co-crystal according to claim 16 , wherein the X-ray powder diffractogram is substantially as shown in FIG. 17 .
19. The co-crystal according to claim 16 , characterized by unit cell dimensions as follows: a=10.975 Å, b=10.310 Å, c=15.704 Å, α=90°, β=108.56°, and γ=90°.
20. A co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide and D-proline (1:1), characterized by an X-ray powder diffractogram comprising the following peaks: 11.77, 14.52, 19.54, and 21.23 °2θ±0.20 °2θ as determined on a diffractometer using Cu-K α1 radiation at a wavelength of 1.5405929 Å.
21. The co-crystal according to claim 20 , wherein the X-ray powder diffractogram further comprises peaks at 8.45, 13.18, 16.95, and 19.12 °2θ±0.2 °2θ.
22. The co-crystal according to claim 20 , wherein the X-ray powder diffractogram is substantially as shown in FIG. 18 .
23. The co-crystal according to claim 20 , characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm at about 130° C.
24. The co-crystal according to claim 23 , wherein the DSC thermogram is substantially as shown in FIG. 19 .
25. A co-crystal of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide and L-proline (1:1), characterized by an X-ray powder diffractogram comprising the following peaks: 8.52, 16.33, 19.50, and 21.22 °2θ±0.20 °2θ as determined on a diffractometer using Cu-K α1 radiation at a wavelength of 1.5405929 Å.
26. The co-crystal according to claim 25 , wherein the X-ray powder diffractogram further comprises peaks at 9.19, 13.22, 14.75, and 17.57 °2θ±0.2 °2θ.
27. The co-crystal according to claim 25 , wherein the X-ray powder diffractogram is substantially as shown in FIG. 23 .
28. The co-crystal according to claim 25 , characterized by unit cell dimensions as follows: a=10.126 Å, b=11.021 Å, c=30.259 Å, α=90°, β=90°, and γ=90°.
29. The co-crystal according to claim 25 , characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm at about 145° C.
30. The co-crystal according to claim 29 , wherein the DSC thermogram is substantially as shown in FIG. 24 .
31. A pharmaceutical composition comprising a co-crystal according to any one of claims 1 , 6 , 11 , 16 , 20 , and 25 and a pharmaceutically acceptable solid carrier.
32. A method for inhibiting heat shock protein 90 (Hsp90) in a subject, comprising administering to the subject a therapeutically effective amount of a co-crystal according to any one of claims 1 , 6 , 11 , 16 , 20 , and 25 .
33. A method for treating or preventing a neurodegenerative disorder in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a co-crystal according to any one of claims 1 , 6 , 11 , 16 , 20 , and 25 .
34. The method according to claim 33 , wherein the neurodegenerative disorder is diabetic peripheral neuropathy.
35. A method for preventing or reducing the likelihood of diabetic peripheral neuropathy from developing in a subject, comprising administering to the subject a therapeutically effective amount of a co-crystal according to any one of claims 1 , 6 , 11 , 16 , 20 , and 25 , wherein the subject suffers from Type 1 or Type 2 diabetes.
36. A method of increasing the concentration of N-(2-(5-(((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide (4a) relative to N-(2-(5-(((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetra-hydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)-acetamide (4b) in a starting composition comprising 4a and 4b, comprising contacting the starting composition with proline in a solvent, and subjecting the starting composition, proline, and solvent to crystallization conditions, whereby a co-crystal of 4a and proline is produced, wherein the bulk co-crystal exhibits a concentration of 4a that is higher than in the starting composition comprising 4a and 4b.
37. The method according to claim 36 , wherein the proline is L-proline.
38. The method according to claim 36 , wherein the proline is D-proline.
39. The method according to claim 36 , wherein the method further comprises heating the starting composition, proline, and solvent.
40. The method according to claim 36 , wherein the concentration of 4a is determined by HPLC.
41. The method according to claim 36 , wherein the concentration of 4a in the bulk co-crystal of 4a and proline is about 3 to about 20% (w/w) higher than in the starting composition.
42. The method according to claim 36 , wherein the concentration of 4a in the bulk co-crystal of 4a and proline is about 5 to about 15% (w/w) higher than in the starting composition.
43. The method according to claim 36 , wherein the concentration of 4a in the bulk co-crystal of 4a and proline increases by about 5%, about 10%, or about 15% (w/w).