Salts of Antiviral Phosphonate Analogues and Process for Preparation Thereof

US 20200131211A1
Filed: 03/16/2018
Published: 04/30/2020
Est. Priority Date: 03/17/2017
Status: Active Grant

First Claim

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1. An acid salt of the compound of Formula (I):

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Abstract

The present invention relates to certain acid salts of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)(phenoxy) phosphoryloxy)methyl pivalate of Formula (I),

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to processes for their preparation; to pharmaceutical compositions comprising such compounds, and methods of treating a disease which responds to inhibition of nucleotide reverse transcriptase activity.

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58 Claims

1. An acid salt of the compound of Formula (I):
- View Dependent Claims (2, 3, 4, 6, 9, 10, 12, 14, 15, 18, 19, 21, 23, 24, 26, 27, 29, 31, 32, 35, 36, 38, 55, 56, 57)
- - 2. The acid salt according to claim 1 in the form of the (R, R) diastereomer.
  - 3. The acid salt according to claim 2 in monovalent form.
  - 4. The (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate succinic acid salt, or a solvate or hydrate thereof according to claim 1.
  - 6. The acid salt according to claim 4 having an XRD pattern comprising peaks at about 5.07, 19.2, 20.2, 22.40 and 24.8°
    - 2θ
      
      ±
      
      0.2°
      
      2θ and
      
      /or peaks at about 15.83, 26.20, 27.87 and 30.12°
      
      2θ
      
      ±
      
      0.2°
      
      2θ and
      
      /or peaks at about 10.10, 11.67, 15.07, 17.90, 18.31, 21.55 and 23.22°
      
      2θ
      
      ±
      
      0.2°
      
      2θ
      
      .
  - 9. The acid salt according to claim 4 having an XRD pattern substantially as shown in FIG. 7.
  - 10. The acid salt according to claim 4 having an IR spectrum comprising peaks at about 3331 cm⁻
    - 1, 3165 cm^−
      
      1, 2976 cm^−
      
      1, 1751 cm^−
      
      1, 1664 cm^−
      
      1, 1618 cm^−
      
      1, 1488 cm^−
      
      1, 1418 cm^−
      
      1, 1397 cm^−
      
      1, 1316 cm^−
      
      1, 1273 cm^−
      
      1, 1194 cm¹, 1134 cm^−
      
      1, 1097 cm^−
      
      1, 1067 cm^−
      
      1, 1019 cm^−
      
      1, 986 cm^−
      
      1, 931 cm^−
      
      1, 892 cm^−
      
      1, 827 cm^−
      
      1, 796 cm^−
      
      1, 719 cm^−
      
      1and 688 cm^−
      
      1±
      
      2 cm^−
      
      1or having an IR spectrum substantially as shown in FIG. 8.
  - 12. The acid salt according to claim 4 having a DSC spectrum having a peak at about 137.2°
    - C. or substantially as shown in FIG. 9.
  - 14. The (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate phosphoric acid salt, or a solvate or hydrate thereof according to claim 1.
  - 15. The acid salt according to claim 14, having an XRD pattern comprising peaks at about 3.25 and 16.58°
    - 2θ
      
      ±
      
      0.2°
      
      2θ and
      
      /or peaks at about 9.80 and 23.34°
      
      2θ
      
      ±
      
      0.2°
      
      2θ and
      
      /or peaks at about 9.5 13.2, 17.26, 19.09, 24.84 and 29.16°
      
      2θ
      
      ±
      
      0.2°
      
      2θ
      
      .
  - 18. The acid salt according to claim 14 having an XRD pattern substantially as shown in FIG. 1.
  - 19. The acid salt according to claim 14 having an IR spectrum comprising peaks at about 2974 cm⁻
    - 1, 1750 cm^−
      
      1, 1703 cm^−
      
      1, 1612 cm^−
      
      1, 1591 cm^−
      
      1, 1518 cm^−
      
      1, 1489 cm^−
      
      1, 1414 cm^−
      
      1, 1266 cm^−
      
      1, 1236 cm^−
      
      1, 1199 cm^−
      
      1, 1130 cm^−
      
      1, 1079 cm^−
      
      1, 1049 cm^−
      
      1, 1018 cm^−
      
      1, 986 cm^−
      
      1, 928 cm^−
      
      1, 885 cm^−
      
      1, 760 cm^−
      
      1, 717 cm^−
      
      1and 687 cm^−
      
      1±
      
      2 cm^−
      
      1or having an IR spectrum substantially as shown in FIG. 2.
  - 21. The acid salt according to claim 14 having a DSC spectrum having a peak at about 133°
    - C. or substantially as shown in FIG. 3.
  - 23. The (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalic acid salt, or a solvate or hydrate thereof according to claim 1.
  - 24. The acid salt according to claim 23, having an XRD pattern comprising peaks at about 4.16, 21.30 and 25.7°
    - 2θ
      
      ±
      
      0.2°
      
      2θ and
      
      /or peaks at about 15.65, 17.00, 17.70, 19.35, 23.15 and 30.12°
      
      2θ
      
      ±
      
      0.2°
      
      2θ
      
      .
  - 26. The acid salt according to claim 23 having an XRD pattern substantially as shown in FIG. 4.
  - 27. The acid salt according to claim 23 having an IR spectrum comprising peaks at about 3088 cm⁻
    - 1, 3185 cm^−
      
      1, 2979 cm^−
      
      1, 1735 cm^−
      
      1, 1693 cm^−
      
      1, 1596 cm^−
      
      1, 1512 cm^−
      
      1, 1491 cm^−
      
      1, 1455 cm^−
      
      1, 1411 cm^−
      
      1, 1368 cm^−
      
      1, 1350 cm^−
      
      1, 1264 cm^−
      
      1, 1229 cm^−
      
      1, 1202 cm^−
      
      1, 1137 cm^−
      
      1, 1071 cm^−
      
      1, 1024 cm^−
      
      1, 994 cm^−
      
      1, 908 cm^−
      
      1, 885 cm^−
      
      1, 820 cm^−
      
      1, 765 cm^−
      
      1, 748 cm^−
      
      1, 716 cm^−
      
      1, 704 cm^−
      
      1and 689 cm^−
      
      1±
      
      2 cm^−
      
      1or having an IR spectrum substantially as shown in FIG. 5.
  - 29. The acid salt according to claim 23 having a DSC spectrum having a peak at about 164.9°
    - C. or substantially as shown in FIG. 6.
  - 31. The (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate citric acid salt, or a solvate or hydrate thereof according to claim 1.
  - 32. The acid salt according to claim 31, having an XRD pattern comprising peaks at about 5.48, 11.15, 15.4, 16.22, 22.57 and 25.68°
    - 2θ
      
      ±
      
      0.2°
      
      2θ and
      
      /or peaks at about 7.63, 14.45, 20.10, 20.55 and 21.01°
      
      2θ
      
      ±
      
      0.2°
      
      2θ and
      
      /or 12.01, 16.77, 17.50, 18.67, 21.62, 25.21 and 28.52°
      
      2θ
      
      ±
      
      0.2°
      
      2θ
      
      .
  - 35. The acid salt according to claim 31 having an XRD pattern substantially as shown in FIG. 10.
  - 36. The acid salt according to claim 31 having an IR spectrum comprising peaks at about 2977 cm⁻
    - 1, 1741 cm^−
      
      1, 1679 cm^−
      
      1, 1663 cm^−
      
      1, 1622 cm^−
      
      1, 1590 cm^−
      
      1, 1488 cm^−
      
      1, 1458 cm^−
      
      1, 1421 cm^−
      
      1, 1396 cm^−
      
      1, 1252 cm^−
      
      1, 1197 cm^−
      
      1, 1127 cm^−
      
      1, 1023 cm^−
      
      1, 985 cm^−
      
      1, 823 cm^−
      
      1, 793 cm^−
      
      1, 720 cm^−
      
      1and 688 cm^−
      
      1±
      
      2 cm^−
      
      1or having an IR spectrum substantially as shown in FIG. 11.
  - 38. The acid salt according to claim 31 having a DSC spectrum having a peak at about 102.9°
    - C. or substantially as shown in FIG. 12.
  - 55. A process for preparing an acid salt of (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate according to claim 1, comprising the steps of:
    - i) reacting (((l-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate with an acid in the presence of a suitable solvent; and
      
      optionally thereafterii) isolating the acid addition salt so formed.
  - 56. The process according to claim 55, wherein the acid is selected from succinic acid, phosphoric acid, oxalic acid, citric acid, tartaric acid and fumaric acid.
  - 57. The process according to claim 55, wherein the solvent is a polar solvent or mixture thereof.

5. (canceled)

7-8. -8. (canceled)

11. (canceled)

13. (canceled)

16-17. -17. (canceled)

20. (canceled)

22. (canceled)

25. (canceled)

28. (canceled)

30. (canceled)

33-34. -34. (canceled)

37. (canceled)

39. (canceled)

40. (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartaric acid salt, or a solvate or hydrate thereof, having an XRD pattern comprising peaks at about 4.73 and 20.65°
- 2θ
  
  ±
  
  0.2°
  
  2θ
  
  .
- View Dependent Claims (41, 42, 43, 45)
- - 41. The acid salt according to claim 40, having an XRD pattern comprising peaks at about 16.47, 24.33, 25.07 and 29.26°
    - 2θ
      
      ±
      
      0.2°
      
      2θ
      
      .
  - 42. The acid salt according to claim 40, having an XRD pattern substantially as shown in FIG. 13.
  - 43. The acid salt according to claim 40 having an IR spectrum comprising peaks at about 3315 cm⁻
    - 1, 2975 cm^−
      
      1, 1745 cm^−
      
      1, 1726 cm^−
      
      1, 1679 cm^−
      
      1, 1624 cm^−
      
      1, 1591 cm^−
      
      11489 cm^−
      
      1, 1420 cm^−
      
      1, 1389 cm^−
      
      1, 1324 cm^−
      
      1, 1273 cm^−
      
      1, 1199 cm^−
      
      1, 1141 cm^−
      
      1, 1104 cm^−
      
      1, 1068 cm^−
      
      1, 1025 cm^−
      
      1, 984 cm^−
      
      1, 831 cm^−
      
      1, 806 cm^−
      
      1, 764 cm^−
      
      1, 715 cm^−
      
      1and 681 cm^−
      
      1±
      
      2 cm^−
      
      1or having an IR spectrum substantially as shown in FIG. 14.
  - 45. The acid salt according to claim 40 having a DSC spectrum having a peak at about 137.2°
    - C. or substantially as-shown in FIG. 15.

44. (canceled)

46. (canceled)

47. (((1-(6-amino-9H-purin-9-yl)propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate fumaric acid salt, or a solvate or hydrate thereof, having an XRD pattern comprising peaks at about 5.03, 23.59 and 29.02°
- 2θ
  
  ±
  
  0.2°
  
  2θ
  
  .
- View Dependent Claims (48, 50, 51, 53)
- - 48. The acid salt according to claim 47, having an XRD pattern comprising peaks at about 20.80, 21.2 and 26.04°
    - 2θ
      
      ±
      
      0.2°
      
      2θ and
      
      /or peaks at about 11.26, 12.89, 17.42 and 20.02°
      
      2θ
      
      ±
      
      0.2°
      
      2θ
      
      .
  - 50. The acid salt according to claim 47 having an XRD pattern substantially as shown in FIG. 16.
  - 51. The acid salt according to claim 47 having an IR spectrum comprising peaks at about 3182 cm⁻
    - 1, 3049 cm^−
      
      1, 2976 cm^−
      
      1, 1751 cm^−
      
      1, 1618 cm^−
      
      1, 1489 cm^−
      
      1, 1458 cm^−
      
      1, 1419 cm^−
      
      1, 1395 cm^−
      
      1, 1277 cm^−
      
      1, 1184 cm^−
      
      1, 1098 cm^−
      
      1, 1068 cm^−
      
      1, 980 cm^−
      
      1, 931 cm^−
      
      1, 830 cm^−
      
      1, 787 cm^−
      
      1, 762 cm^−
      
      1, 723 cm^−
      
      1and 687 cm^−
      
      1±
      
      2 cm^−
      
      1or having an IP spectrum substantially as shown in FIG. 17.
  - 53. The acid salt according to claim 47 having a DSC spectrum having a peak at about 119.8°
    - C. or substantially as shown in FIG. 18.

49. (canceled)

52. (canceled)

54. (canceled)

58-67. -67. (canceled)

Specification

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Current Assignee
Cipla (EU) Limited
Original Assignee
Cipla (EU) Limited
Inventors
PHULL, Manjinder Singh, SAWANT, Ashwini Amol, RAO, Dharmaraj Ramachandra, MALHOTRA, Geena, GANGRADE, Manish Gopaldas

Granted Patent

US 11,390,637 B2
Time in Patent Office

Days
Field of Search
US Class Current
CPC Class Codes

A61K 31/661   Phosphorus acids or esters ...

A61P 31/18   for HIV

C07F 9/65616   containing the ring system ...

C07F 9/65618   containing the ring system,...

Salts of Antiviral Phosphonate Analogues and Process for Preparation Thereof

First Claim

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Salts of Antiviral Phosphonate Analogues and Process for Preparation Thereof

First Claim

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Abstract

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58 Claims

Specification

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