Antiviral phosphonate analog salts and methods of making the same
阅读说明：本技术 抗病毒的膦酸酯类似物的盐及其制备方法 (Antiviral phosphonate analog salts and methods of making the same ) 是由 M·S·富尔 A·A·萨万特 D·R·拉奥 G·马尔霍特拉 M·G·甘格拉德 于 2018-03-16 设计创作，主要内容包括：本发明涉及式(I)的(((1-(6-氨基-9H-嘌呤-9-基)丙-2-基氧基)甲基)(苯氧基)磷酰氧基)甲基新戊酸酯的某些酸式盐、其制备方法；包含这些化合物的药物组合物以及用于治疗疾病的方法,所述疾病对抑制核苷酸逆转录酶的活性产生响应。<Image he="325" wi="700" file="DDA0002204353820000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(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), methods of preparing the same; pharmaceutical compositions comprising these compounds and methods for treating diseases that respond to inhibition of nucleotide reverse transcriptase activity.)
1. An acid salt of a compound of formula (I):
The acid salt is selected from: (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate succinate;
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate phosphate;
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalate;
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate citrate;
Or a solvate or hydrate thereof.
2. The acid salt of claim 1 in the form of an (R, R) diastereomer.
3. The acid salt of claim 1 or 2 in a monovalent form.
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate succinate, or a solvate or hydrate thereof.
5. The compound of claim 4, in substantially crystalline form.
6. the compound of claim 4 or 5, having an XRD pattern comprising peaks at about 5.07, 19.2, 20.2, 22.40 and 24.8 ° 2 theta ± 0.2 ° 2 theta.
7. The compound of any one of claims 4 to 6, having an XRD pattern comprising peaks at about 15.83, 26.20, 27.87 and 30.12 ° 2 θ ± 0.2 ° 2 θ.
8. the compound of any one of claims 4 to 7, having an XRD pattern comprising peaks at about 10.10, 11.67, 15.07, 17.90, 18.31, 21.55 and 23.22 ° 2 θ ± 0.2 ° 2 θ.
9. A compound according to any one of claims 4 to 8 having an XRD pattern substantially as shown in figure 7.
10. The compound according to any one of claims 4 to 9, having an IR spectrum comprised at about 3331cm-1、3165cm-1、2976cm-1、1751cm-1、1664cm-1、1618cm-1、1488cm-1、1418cm-1、1397cm-1、1316cm-1、1273cm-1、1194cm-1、1134cm-1、1097cm-1、1067cm-1，1019cm-1、986cm-1、931cm-1、892cm-1、827cm-1、796cm-1、719cm-1And 688cm-1±2cm-1the peak at (c).
11. The compound of any one of claims 4 to 10, having an IR spectrum substantially as shown in figure 8.
12. The compound according to any one of claims 4 to 11, having a DSC profile with a peak at about 137.2 ℃.
13. A compound according to any one of claims 4 to 12 having a DSC profile substantially as shown in figure 9.
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate phosphate, or a solvate or hydrate thereof.
15. The compound of claim 14, having an XRD pattern comprising peaks at about 3.25 and 16.58 ° 2 Θ ± 0.2 ° 2 Θ.
16. The compound of claim 14 or 15, having an XRD pattern comprising peaks at about 9.80 and 23.34 ° 2 Θ ± 0.2 ° 2 Θ.
17. A compound according to any one of claims 14 to 16, having an XRD pattern comprising peaks at about 9.5, 13.2, 17.26, 19.09, 24.84 and 29.16 ° 2 Θ ± 0.2 ° 2 Θ.
18. A compound according to any one of claims 14 to 17 having an XRD pattern substantially as shown in figure 1.
19. The compound of any one of claims 14 to 18, having an IR spectrum comprising at about 2974cm-1、1750cm-1、1703cm-1、1612cm-1、1591cm-1、1518cm-1、1489cm-1、1414cm-1、1266cm-1、1236cm-1、1199cm-1、1130cm-1、1079cm-1、1049cm-1、1018cm-1、986cm-1、928cm-1、885cm-1、760cm-1、717cm-1And 687cm-1±2cm-1The peak at (c).
20. The compound of any one of claims 14 to 19, having an IR spectrum substantially as shown in figure 2.
21. The compound of any one of claims 14 to 20, having a DSC profile with a peak at about 133 ℃.
22. A compound according to any one of claims 14 to 21 having a DSC profile substantially as shown in figure 3.
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalate, or a solvate or hydrate thereof.
24. The compound of claim 23, having an XRD pattern comprising peaks at about 4.16, 21.30 and 25.7 ° 2 Θ ± 0.2 ° 2 Θ.
25. The compound of claim 23 or 24, having an XRD pattern comprising peaks at about 15.65, 17.00, 17.70, 19.35, 23.15 and 30.12 ° 2 Θ ± 0.2 ° 2 Θ.
26. A compound according to any one of claims 23 to 25 having an XRD pattern substantially as shown in figure 4.
27. The compound of any one of claims 23 to 26, having an IR spectrum comprising about 3088cm-1、3185cm-1、2979cm-1、1735cm-1、1693cm-1，1596cm-1、1512cm-1、1491cm-1、1455cm-1、1411cm-1、1368cm-1、1350cm-1、1264cm-1、1229cm-1、1202cm-1、1137cm-1、1071cm-1、1024cm-1、994cm-1、908cm-1、885cm-1、820cm-1、765cm-1、748cm-1、716cm-1、704cm-1And 689cm-1±2cm-1The peak at (c).
28. The compound of any one of claims 23 to 27, having an IR spectrum substantially as shown in figure 5.
29. The compound of any one of claims 23 to 28, having a DSC profile with a peak at about 164.9 ℃.
30. A compound according to any one of claims 23 to 29 having a DSC profile substantially as shown in figure 6.
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate citrate, or a solvate or hydrate thereof.
32. The compound of claim 31, having an XRD pattern comprising peaks at about 5.48, 11.15, 15.4, 16.22, 22.57 and 25.68 ° 2 Θ ± 0.2 ° 2 Θ.
33. The compound of claim 31 or 32, having an XRD pattern comprising peaks at about 7.63, 14.45, 20.10, 20.55 and 21.01 ° 2 Θ ± 0.2 ° 2 Θ.
34. the compound of any one of claims 31 to 33, having an XRD pattern further comprising peaks at about 12.01, 16.77, 17.50, 18.67, 21.62, 25.21 and 28.52 ° 2 Θ ± 0.2 ° 2 Θ.
35. A compound according to any one of claims 31 to 34 having an XRD pattern substantially as shown in figure 10.
36. The compound of any one of claims 31 to 35, having an IR spectrum comprising at about 2977cm-1、1741cm-1、1679cm-1、1663cm-1、1622cm-1、1590cm-1、1488cm-1、1458cm-1、1421cm-1、1396cm-1、1252cm-1、1197cm-1、1127cm-1、1023cm-1、985cm-1、823cm-1、793cm-1、720cm-1And 688cm-1±2cm-1The peak at (c).
37. The compound of any one of claims 31 to 36, having an IR spectrum substantially as shown in figure 11.
38. The compound of any one of claims 31 to 37, having a DSC profile with a peak at about 102.9 ℃.
39. a compound according to any one of claims 31 to 38 having a DSC profile substantially as shown in figure 12.
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartrate, or a solvate or hydrate thereof, having an XRD pattern comprising peaks at about 4.73 and 20.65 ° 2 θ ± 0.2 ° 2 θ.
41. The compound of claim 40, having an XRD pattern comprising peaks at about 16.47, 24.33, 25.07 and 29.26 ° 2 θ ± 0.2 ° 2 θ.
42. A compound according to claim 40 or 41 having an XRD pattern substantially as shown in figure 13.
43. The compound of any one of claims 40 to 42, having an IR spectrum comprising at about 3315cm-1、2975cm-1、1745cm-1、1726cm-1、1679cm-1、1624cm-1、1591cm-1、1489cm-1、1420cm-1、1389cm-1、1324cm-1、1273cm-1、1199cm-1、1141cm-1、1104cm-1、1068cm-1、1025cm-1、984cm-1、831cm-1、806cm-1、764cm-1、715cm-1And 681cm-1±2cm-1The peak at (c).
44. The compound of any one of claims 40 to 43, having an IR spectrum substantially as shown in figure 14.
45. The compound of any one of claims 40 to 44, having a DSC profile with a peak at about 137.2 ℃.
46. A compound according to any one of claims 40 to 45 having a DSC profile substantially as shown in figure 15.
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate fumarate, or a solvate or hydrate thereof, having an XRD pattern comprising peaks at about 5.03, 23.59, and 29.02 ° 2 θ ± 0.2 ° 2 θ.
48. The compound of claim 47, having an XRD pattern comprising peaks at about 20.80, 21.2 and 26.04 ° 2 θ ± 0.2 ° 2 θ.
49. The compound of claim 47 or 48, having an XRD pattern comprising peaks at about 11.26, 12.89, 17.42 and 20.02 ° 2 θ ± 0.2 ° 2 θ.
50. A compound according to any one of claims 47 to 49 having an XRD pattern substantially as shown in figure 16.
51. The compound of any one of claims 47 to 50, having an IR spectrum comprising at about 3182cm-1、3049cm-1、2976cm-1、1751cm-1、1618cm-1、1489cm-1、1458cm-1、1419cm-1、1395cm-1、1277cm-1、1184cm-1、1098cm-1、1068cm-1，980cm-1、931cm-1、830cm-1、787cm-1、762cm-1、723cm-1And 687cm-1±2cm-1the peak at (c).
52. The compound of any one of claims 47 to 51, having an IR spectrum substantially as shown in figure 17.
53. The compound of any one of claims 47 to 52, having a DSC profile with a peak at about 119.8 ℃.
54. A compound according to any one of claims 47 to 53 having a DSC profile substantially as shown in figure 18.
55. A process for preparing the acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of claim 1, comprising the steps of:
i) Reacting (((1- (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 then optionally
ii) isolating the acid addition salt thus formed.
56. The method of claim 55, wherein the acid is selected from the group consisting of succinic acid, phosphoric acid, oxalic acid, citric acid, tartaric acid, and fumaric acid.
57. The method of claim 55 or 56, wherein the solvent is a polar solvent or a mixture thereof.
58. The method of claim 57, wherein the polar solvent is an alcohol, ether, ketone, ester, chlorinated solvent, nitrile, or hydrocarbon, or any combination thereof.
59. The method of claim 57 or 58, wherein the polar solvent is selected from the group consisting of methanol, ethanol, isopropanol, butanol, 1, 2-dimethoxyethanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, tetrahydrofuran, diethyl ether, 1, 4-bis-ethanolAn alkane, diisopropyl ether, methyl tert-butyl ether, acetone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, chloroform, dichloromethane, acetonitrile, benzene, toluene, and xylene, or any combination thereof.
60. A process according to any one of claims 55 to 59, wherein the acid salt is isolated by crystallization and/or precipitation and/or evaporation.
61. A pharmaceutical composition comprising an acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of any one of claims 1-54, and one or more pharmaceutically acceptable excipients.
62. The acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate according to any one of claims 1-54, for use in the treatment or prevention of a disease that is responsive to inhibition of nucleotide reverse transcriptase activity.
63. The acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate according to any one of claims 1-54, for use in the treatment or prevention of HIV and/or AIDS.
64. A method for treating a disease responsive to inhibition of nucleotide reverse transcriptase activity, comprising administering to a patient in need thereof a therapeutically effective amount of the acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate according to any one of claims 1-54.
65. The method of claim 63, wherein the disease is HIV and/or AIDS.
66. Use of the acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate according to any one of claims 1-54, in the manufacture of a medicament for the treatment or prevention of a disease that is responsive to inhibition of nucleotide reverse transcriptase activity.
67. The use according to claim 65, wherein the disease is HIV and/or AIDS.
Technical Field
The present invention relates to acid salts of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate, methods of preparation thereof, pharmaceutical compositions containing the same, and methods of treatment using the same.
Related background art:
In WO 2014/068265, compounds of formula (I) (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate are disclosed.
Valuable pharmacological properties are attributed to this compound. For example, it is useful as a nucleotide reverse transcriptase inhibitor for the treatment of diseases which respond to inhibition of the activity of protein kinases.
There is a continuing need for new or improved forms of existing nucleotide reverse transcriptase inhibitors to develop new, improved and more effective pharmaceutical formulations for the treatment of cancer and other diseases. The salt forms and methods of making the same described herein address these needs and other objectives.
The invention content is as follows:
The invention relates in particular to acid salts of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
In one aspect, the present invention provides an acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate selected from:
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate phosphate (phosphate);
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalate (oxalate);
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate succinate (succinate);
(((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate citrate (citrate);
or a solvate or hydrate thereof.
In certain aspects, the acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of the present invention may be in a solvated form. Examples of solvated forms include, but are not limited to, solvates with ethanol, tetrahydrofuran, diethyl ether, acetone, and/or water (i.e., hydrates). Thus, in the context of the present invention, the term "solvate" includes hydrates.
In another aspect, the present invention provides (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartrate (tartrate), or a solvate or hydrate thereof, having an XRD pattern comprising peaks at about 4.73 and 20.65 ° 2 Θ ± 0.2 ° 2 Θ.
In yet another aspect, the present invention provides (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate fumarate (fumarate), or a solvate or hydrate thereof, having an XRD pattern comprising peaks at about 5.03, 23.59, and 29.02 ° 2 Θ ± 0.2 ° 2 Θ.
In certain aspects, the acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of the present invention may be substantially crystalline or amorphous. The number of solvent molecules in the crystalline or amorphous structure of the salt is not limited and can be, for example, from about 0.1 to about 7 moles of solvent per mole of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
In another aspect of the invention, the acid salt of ((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate may be in a desolvated form.
The invention also provides one or more polymorphic forms of an acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
The present invention also relates to a process for preparing various crystalline acid salts of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate esters, comprising the steps of: reacting (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate free base with an acid selected from fumaric acid, tartaric acid, phosphoric acid, oxalic acid, succinic acid or citric acid in a suitable solvent and then optionally isolating the acid addition salt so formed.
The present invention also relates to a pharmaceutical composition comprising:
(a) An acid salt of ((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate, which may be present in crystalline or amorphous form, or a solvate or hydrate thereof; and
(b) At least one pharmaceutically acceptable excipient.
The present invention also relates to a method of treating a disease that responds to inhibition of nucleotide reverse transcriptase activity, such as HIV and/or AIDS, comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of an acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate, or a solvate or hydrate thereof.
Brief description of the drawings:
Figure 1 shows an X-ray powder diffraction pattern (XRD) of form I of the phosphate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 2 shows an Infrared (IR) absorption spectrum of crystalline form I of the phosphate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 3 shows a Differential Scanning Calorimetry (DSC) plot of form I of the phosphate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
figure 4 shows an X-ray powder diffraction pattern (XRD) of form II of the oxalate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 5 shows an Infrared (IR) absorption spectrum of crystalline form II of the oxalate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 6 shows a Differential Scanning Calorimetry (DSC) profile of crystalline form II of the oxalate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 7 shows an X-ray powder diffraction pattern (XRD) of form III of the succinate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 8 shows an Infrared (IR) absorption spectrum of crystalline form III of the succinate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 9 shows a Differential Scanning Calorimetry (DSC) profile of form III of the succinate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 10 shows an X-ray powder diffraction pattern (XRD) of form IV of the citrate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 11 shows an Infrared (IR) absorption spectrum of form IV of the citrate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 12 shows a Differential Scanning Calorimetry (DSC) profile of form IV of the citrate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 13 shows an X-ray powder diffraction pattern (XRD) of form V of the tartrate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 14 shows an Infrared (IR) absorption spectrum of form V of the tartrate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 15 shows a Differential Scanning Calorimetry (DSC) profile of form V of the tartrate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
figure 16 shows an X-ray powder diffraction pattern (XRD) of form VI of the fumarate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 17 shows an Infrared (IR) absorption spectrum of crystalline form VI of the fumarate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 18 shows a Differential Scanning Calorimetry (DSC) profile of crystalline form VI of the fumarate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Figure 19 shows a comparison of intrinsic dissolution data for the Fumarate salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate with Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide Fumarate (TAF).
Figure 20 shows intrinsic dissolution data for various acid salts of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate.
Detailed Description
The present invention provides, inter alia, an acid salt of the nucleotide reverse transcriptase inhibitor (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate, or a solvate or hydrate thereof, selected from the group consisting of phosphate, oxalate, succinate and citrate.
These salts modulate the activity of one or more nucleotide reverse transcriptases and are useful, for example, in the treatment of diseases associated with nucleotide reverse transcriptase expression or activity, such as Acquired Immune Deficiency Syndrome (AIDS) and/or HIV infection.
The salts of the present invention have a number of advantageous properties relative to the free base form. In particular, these salts are highly crystalline, which will facilitate the preparation of pharmaceutical formulations and improve the general handling, handling and storage of the active ingredients. The salts of the present invention also have excellent water solubility, dissolution rate, chemical stability (with longer shelf life), compatibility with excipients, and reproducibility compared to the free base form.
The compound of formula (I) ((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate may exist as diastereomers having the (R, R), (S, S), (R, S) or (S, R) configuration. Preferably, the compound of formula (I) or acid salt thereof is in the form of the (R, R) diastereoisomer. Thus, the salts of the present invention also include all diastereomers present in the salts.
The salts of the present invention also include all isotopes of atoms present in the salts. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
The acid salts of the present invention may be prepared by: the free base compound of (I) and the acid containing the anion in the desired salt form are combined in solution, and then the solid salt product is optionally isolated from the reaction solution by known methods including, but not limited to, crystallization and/or precipitation and/or evaporation, and the like. Other salt formation techniques are known in the art and may be used as an alternative.
It has been found that the use of certain solvents in the above process produces different polymorphic forms of the acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I), which may exhibit one or more of the advantageous properties described above. Methods of preparing the polymorphs described herein, as well as characterization of these polymorphs, are described in more detail below.
Since polymorphic forms are reliably characterized by the position of the peaks in the X-ray diffraction pattern, the polymorphic forms of the present invention have been characterized by powder X-ray diffraction spectroscopy, which produces a fingerprint of a particular crystalline form.
In one aspect, a pharmaceutically acceptable acid addition salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) is a phosphate salt of formula (Ia):
The phosphate salt according to the invention is the 1:1 salt of phosphoric acid with (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate. Thus, the phosphate is a monophosphate salt of formula (Ia).
In another aspect, the present invention relates to a process for the preparation of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate phosphate of formula (Ia) comprising reacting the free base of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I):
The phosphates according to the invention are characterized by good crystallinity and low amorphization (amorphization) during grinding and pressing. Furthermore, it is not hygroscopic and is readily soluble in physiologically acceptable solvents.
In another aspect, the present invention provides a crystalline polymorphic form of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate phosphate of formula (Ia), hereinafter referred to as form I.
in one aspect, form I is characterized by an X-ray powder diffraction pattern comprising 2 θ values measured on a Rigaku, MiniFlex 2 bench-top X-ray powder diffractometer using CuK α radiation.
In one aspect, form I is characterized by an XRD pattern comprising peaks at 3.25 and 16.58 ° 2 Θ ± 0.2 ° 2 Θ. The XRD pattern may include other peaks at 9.80 and 23.34 ° 2 θ ± 0.2 ° 2 θ. The XRD pattern may further include other peaks at 9.5, 13.2, 17.26, 19.09, 24.84, and 29.16 ° 2 θ ± 0.2 ° 2 θ.
In one aspect, form I has an XRD pattern substantially as shown in figure 1.
In one aspect, the XRD pattern of form I has peaks at the 2 theta values as shown in table 1.
TABLE 1
Diffraction Angle (2 theta value)
Strength (%)
3.25
100.0
9.50
14.79
9.80
20.23
13.2
13.03
16.58
57.63
17.26
11.94
19.09
10.19
23.34
22.63
24.84
19.12
29.16
11.66
Form I can also be characterized by an IR spectrum comprising an IR spectrum at about 2974cm-1、1750cm-1、1703cm-1、1612cm-1、1591cm-1、1518cm-1、1489cm-1、1414cm-1、1266cm-1、1236cm-1、1199cm-1、1130cm-1、1079cm-1、1049cm-1、1018cm-1、986cm-1、928cm-1、885cm-1、760cm-1、717cm-1And 687cm-1±2cm-1Characteristic peak of (c).
In one aspect, form I has an IR spectrum substantially as shown in figure 2.
Form I can also be characterized by a DSC profile that exhibits a significant (exothermic) peak between about 133 ℃ and about 136 ℃, preferably a peak at about 133 ℃.
In another aspect, form I has a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 3.
Those skilled in the art will recognize that form I can be further characterized by other known analytical and/or spectroscopic methods, including but not limited to thermogravimetric analysis (TGA), Dynamic Vapor Sorption (DVS), solid state NMR, and raman spectroscopy.
in another aspect, a pharmaceutically acceptable acid addition salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) is an oxalate salt of formula (Ib):
The oxalate salt according to the invention is the 1:1 salt of oxalic acid with (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate. Thus, the oxalate salt is the mono-oxalate salt of formula (Ib).
In another aspect, the present invention relates to a process for the preparation of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalate of formula (Ib), which comprises reacting the free base of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) with oxalic acid.
The oxalate according to the invention is characterized by good crystallinity and low amorphization during grinding and pressing. Furthermore, it is not hygroscopic and is readily soluble in physiologically acceptable solvents.
In another aspect, the present invention provides a crystalline polymorphic form of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalate of formula (Ib), hereinafter referred to as form II.
In one aspect, form II is characterized by an X-ray powder diffraction pattern comprising 2 θ values measured on a Rigaku, MiniFlex 2 bench-top X-ray powder diffractometer using CuK α radiation.
In one aspect, form II is characterized by an XRD pattern comprising peaks at 4.16, 21.30, and 25.7 ° 2 Θ ± 0.2 ° 2 Θ. The XRD pattern may include other peaks at 15.65, 17.00, 17.70, 19.35, 23.15 and 30.12 ° 2 θ ± 0.2 ° 2 θ.
In one aspect, form II has an XRD pattern substantially as shown in figure 4.
In one aspect, the XRD pattern of form II has peaks at 2 theta values as shown in table 2.
TABLE 2
Diffraction Angle (2 theta value)
Strength (%)
4.16
100.0
15.65
12.43
17.00
18.10
17.70
14.63
19.35
12.76
23.15
11.04
25.7
32.84
30.12
17.37
Form II may also be characterized by IR spectroscopy, which includesAt about 3088cm-1、3185cm-1、2979cm-1、1735cm-1、1693cm-1，1596cm-1、1512cm-1、1491cm-1、1455cm-1、1411cm-1、1368cm-1、1350cm-1、1264cm-1、1229cm-1、1202cm-1、1137cm-1、1071cm-1、1024cm-1、994cm-1、908cm-1、885cm-1、820cm-1、765cm-1、748cm-1、716cm-1、704cm-1And 689cm-1±2cm-1characteristic IR spectral peaks at (a).
In one aspect, form II has an IR spectral pattern substantially as shown in figure 5.
Form II may also be characterized by a DSC profile that exhibits a significant (exothermic) peak between about 164 ℃ and about 168 ℃, preferably a peak at about 164.9 ℃.
In another aspect, form II has a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 6.
Those skilled in the art will recognize that crystalline form II can be further characterized by other known analytical and/or spectroscopic methods, including but not limited to thermogravimetric analysis (TGA), Dynamic Vapor Sorption (DVS), solid state NMR, and raman spectroscopy.
in another aspect, a pharmaceutically acceptable acid addition salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) is a succinate salt of formula (Ic):
The succinate salt according to the invention is the 1:1 salt of succinic acid with (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate. Thus, the succinate salt is a monosuccinate salt of formula (Ic).
In another aspect, the invention relates to a process for the preparation of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate succinate of formula (Ic), comprising reacting the free base of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) with succinic acid.
The succinate salt according to the invention is characterized by good crystallinity and low amorphization during milling and pressing. Furthermore, it is not hygroscopic and is readily soluble in physiologically acceptable solvents.
In another aspect, the present invention provides a crystalline polymorphic form of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate succinate of formula (Ic), hereinafter referred to as form III.
Form III may be characterized by an X-ray powder diffraction pattern comprising 2 θ values measured on a Rigaku, MiniFlex 2 bench top X-ray powder diffractometer using CuK α radiation.
Form III is characterized by an XRD pattern including peaks at 5.07, 19.2, 20.2, 22.40, and 24.8 ° 2 Θ ± 0.2 ° 2 Θ. The XRD pattern may include other peaks at 15.83, 26.20, 27.87, and 30.12 ° 2 θ ± 0.2 ° 2 θ. The XRD pattern may further include other peaks at 10.10, 11.67, 15.07, 17.90, 18.31, 21.55, and 23.22 ° 2 θ ± 0.2 ° 2 θ.
In one aspect, form III has an XRD pattern substantially as shown in figure 7.
In one aspect, the XRD pattern of form III has peaks at 2 theta values as shown in table 3.
TABLE 3
Form III may also be characterized by an IR spectrum comprising about 3331cm-1、3165cm-1、2976cm-1、1751cm-1、1664cm-1、1618cm-1、1488cm-1、1418cm-1、1397cm-1、1316cm-1、1273cm-1、1194cm-1、1134cm-1、1097cm-1、1067cm-1，1019cm-1、986cm-1、931cm-1、892cm-1、827cm-1、796cm-1、719cm-1And 688cm-1±2cm-1Characteristic IR spectral peaks at (a).
In one aspect, form III can have an IR spectral pattern substantially as shown in figure 8.
Form III may also be characterized by a DSC profile that exhibits a significant (exothermic) peak between about 137 ℃ and about 143 ℃, preferably a peak at about 137.2 ℃.
In another aspect, form III can have a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 9.
those skilled in the art will recognize that form III may be further characterized by other known analytical and/or spectroscopic methods, including but not limited to thermogravimetric analysis (TGA), Dynamic Vapor Sorption (DVS), solid state NMR, and raman spectroscopy.
In another aspect, a pharmaceutically acceptable acid addition salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) is a citrate salt of formula (Id):
The citrate salt according to the invention is the 1:1 salt of citric acid with (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate. Thus, the citrate salt is a mono-citrate salt of formula (Id).
In another aspect, the invention relates to a process for the preparation of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate citrate of formula (Id), comprising reacting the free base of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) with citric acid.
The citrate salt according to the invention is characterized by good crystallinity and low amorphization during milling and pressing. Furthermore, it is not hygroscopic and is readily soluble in physiologically acceptable solvents.
In another aspect, the present invention provides a crystalline polymorphic form of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate citrate of formula (Id), hereinafter referred to as form IV.
in one aspect, form IV is characterized by an X-ray powder diffraction pattern comprising 2 θ values measured on a Rigaku, MiniFlex 2 bench-top X-ray powder diffractometer using CuK α radiation.
Form IV may be characterized by an XRD pattern including peaks at 5.48, 11.15, 15.4, 16.22, 22.57, and 25.68 ° 2 Θ ± 0.2 ° 2 Θ. The XRD pattern may include other peaks at 7.63, 14.45, 20.10, 20.55 and 21.01 ° 2 θ ± 0.2 ° 2 θ. The XRD pattern also included other peaks at 12.01, 16.77, 17.50, 18.67, 21.62, 25.21 and 28.52 ° 2 θ ± 0.2 ° 2 θ.
In one aspect, form IV has an XRD pattern substantially as shown in figure 10.
In one aspect, the XRD pattern of form IV has peaks at 2 theta values as shown in table 4.
TABLE 4
Diffraction Angle (2 theta value)
Strength (%)
5.48
70.22
7.63
23.87
11.15
70.20
12.01
132.43
14.45
24.28
15.4
59.63
16.22
52.79
16.77
11.88
17.50
19.20
18.67
15.37
20.10
43.86
20.55
23.07
21.01
26.68
21.62
16.67
22.57
100.0
25.21
19.41
25.68
61.92
28.52
16.48
Form IV may also be characterized by an IR spectrum comprising about 2977cm-1、1741cm-1、1679cm-1、1663cm-1、1622cm-1、1590cm-1、1488cm-1、1458cm-1、1421cm-1、1396cm-1、1252cm-1、1197cm-1、1127cm-1、1023cm-1、985cm-1、823cm-1、793cm-1、720cm-1And 688cm-1±2cm-1Characteristic IR spectral peaks at (a).
In one aspect, form IV can have an IR spectral pattern substantially as shown in figure 11.
Form IV can also be characterized by a DSC profile that exhibits a significant (exotherm) peak between about 102 ℃ and 108 ℃, preferably a peak at about 102.9 ℃.
In another aspect, form IV can have a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 12.
Those skilled in the art will recognize that form IV may be further characterized by other known analytical and/or spectroscopic methods, including but not limited to thermogravimetric analysis (TGA), Dynamic Vapor Sorption (DVS), solid state NMR, and raman spectroscopy.
In another aspect, the present invention provides a crystalline polymorph of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartrate of formula (Id), hereinafter referred to as form V.
In one aspect, form V is characterized by an X-ray powder diffraction pattern comprising 2 θ values measured on a Rigaku, MiniFlex 2 bench-top X-ray powder diffractometer using CuK α radiation.
In one aspect, form V is characterized by an XRD pattern comprising peaks at 4.73 and 20.65 ° 2 Θ ± 0.2 ° 2 Θ. The XRD pattern may include other peaks at 16.47, 24.33, 25.07, and 29.26 ° 2 θ ± 0.2 ° 2 θ.
Form V has an X-ray powder diffraction (XRD) pattern substantially as shown in figure 13.
The XRD pattern of crystalline polymorphic form V may have peaks at 2 theta values as shown in table 5.
TABLE 5
Diffraction Angle (2 theta value)
Strength (%)
4.73
100.0
16.47
20.39
20.65
55.90
24.33
20.10
25.07
22.85
29.26
28.48
Form V may also be characterized by an IR spectrum comprising at least about 3315cm-1、2975cm-1、1745cm-1、1726cm-1、1679cm-1、1624cm-1、1591cm-1、1489cm-1、1420cm-1、1389cm-1、1324cm-1、1273cm-1、1199cm-1、1141cm-1、1104cm-1、1068cm-1、1025cm-1、984cm-1、831cm-1、806cm-1、764cm-1、715cm-1And 681cm-1±2cm-1Characteristic IR spectral peaks at (a).
In one aspect, form V can have an IR spectral pattern substantially as shown in figure 14.
Form V may also be characterized by a DSC profile that exhibits a significant (exothermic) peak between about 137 ℃ and about 143 ℃, preferably a peak at about 137.2 ℃.
In another aspect, form V can have a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 15.
Those skilled in the art will recognize that form V may be further characterized by other known analytical and/or spectroscopic methods, including but not limited to thermogravimetric analysis (TGA), Dynamic Vapor Sorption (DVS), solid state NMR, and raman spectroscopy.
In another aspect, the present invention relates to a process for preparing form V of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartrate of formula (Ie), comprising reacting the free base of ((((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) with tartaric acid.
In another aspect, the present invention provides a crystalline polymorphic form of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate fumarate of formula (If), hereinafter referred to as form VI.
in one aspect, form VI is characterized by an X-ray powder diffraction pattern comprising 2 θ values measured on a Rigaku, MiniFlex 2 bench-top X-ray powder diffractometer using CuK α radiation.
Form VI, on the other hand, is characterized by an XRD pattern comprising peaks at 5.03, 23.59, and 29.02 ° 2 Θ ± 0.2 ° 2 Θ. The XRD pattern may include other peaks at 20.80, 21.2 and 26.04 ° 2 θ ± 0.2 ° 2 θ. The XRD pattern also included other peaks at 11.26, 12.89, 17.42 and 20.02 ° 2 θ ± 0.2 ° 2 θ.
In one aspect, form VI has an XRD pattern substantially as shown in figure 16.
In one aspect, the XRD pattern of form VI has peaks at 2 theta values as shown in table 6.
TABLE 6
Diffraction Angle (2 theta value)
Strength (%)
5.03
72.78
11.26
18.00
12.89
10.52
17.42
12.14
20.02
13.44
20.80
21.50
21.20
28.14
23.59
100.0
26.04
34.30
29.02
31.13
Form VI may also be characterized by an IR spectrum comprising about 3182cm-1、3049cm-1、2976cm-1、1751cm-1、1618cm-1、1489cm-1、1458cm-1、1419cm-1、1395cm-1、1277cm-1、1184cm-1、1098cm-1、1068cm-1，980cm-1、931cm-1、830cm-1、787cm-1、762cm-1、723cm-1And 687cm-1±2cm-1characteristic IR spectral peaks at (a).
In one aspect, form VI can have an IR spectral pattern substantially as shown in figure 17.
Form VI may also be characterized by a DSC profile that exhibits a significant (exothermic) peak between about 119.8 ℃ and about 123 ℃, preferably a peak at about 119.8 ℃.
In another aspect, form VI can have a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 18.
Those skilled in the art will recognize that form VI may be further characterized by other known analytical and/or spectroscopic methods, including but not limited to thermogravimetric analysis (TGA), dynamic vapor sorption (DVIS), solid state NMR, and raman spectroscopy.
In another aspect, the present invention relates to a process for preparing form VI of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartrate of formula (Ie), comprising reacting the free base of ((((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) with fumaric acid.
In one aspect, the (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) is prepared by reacting the compound 9- [2- (phosphonomethoxy) propyl ] adenine of formula (II) with chloromethyl pivalate of formula (III) in the presence of an auxiliary base. The auxiliary base may be an inorganic or organic base, and is preferably an organic base. In one aspect, the auxiliary base is preferably a tertiary amine, particularly a trialkylamine. The reaction is suitably carried out in the presence of a solvent selected from polar aprotic solvents or mixtures thereof.
The compound of formula (I) (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate can be converted to an acid addition salt by first isolating the free base or without isolating the free base. In one aspect (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) is not isolated, i.e., the free base is converted in situ to the acid salt.
In one aspect (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) is dissolved in a suitable solvent to facilitate formation of the acid salt. Suitable solvents include, but are not limited to, polar solvents and mixtures thereof. Examples of suitable solvents include, but are not limited to, alcohols such as methanol, ethanol, isopropanol, butanol, 1, 2-dimethoxyethanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, analogs or mixtures thereof; ethers, e.g. tetrahydrofuran, diethyl ether, 1, 4-bisAlkanes, DIPE, MTBE and analogs thereof; ketones, such as acetone, MIBK; aprotic polar solvents such as DMF, dimethylacetamide, dimethylsulfoxide or mixtures thereof; esters, such as ethyl acetate and isopropyl acetate; chlorinated solvents, such as chloroform, dichloromethane; nitriles, such as acetonitrile; hydrocarbons such as benzene, toluene, xylene or the like or mixtures thereof. Preferably, the solvent is one or more solvents selected from the group consisting of aprotic solvents, hydrocarbons, ethers, alcohols and ketones. More preferably, the solvent is selected from Isopropanol (IPA), methanol and acetone, or any combination thereof.
A solution containing (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) is treated with phosphoric acid, oxalic acid, succinate, citric acid, fumaric acid, or tartaric acid. The acid may be in the form of a solution or a solid. The resulting acid addition salt may be isolated as a solid by any known technique including, but not limited to, cooling, quenching, complete or partial distillation of the solvent, and/or filtration.
Alternatively, the acid addition salts of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I) according to the present invention may be prepared by salt interconversion methods. The process comprises reacting an acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate with a suitable base to form the free base of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate of formula (I), and then converting the free base so formed (by addition of acid) to an acid salt form.
In certain aspects, the acid salts and polymorphic forms described herein can potentially exhibit improved properties. For example, in certain aspects, the acid salts and polymorphic forms described herein can potentially exhibit improved stability. This improved stability may have potentially beneficial effects on the preparation of compounds of formula (I), for example providing the ability to store process intermediates for extended periods of time. Improved stability may also benefit compositions or pharmaceutical compositions of compounds of formula (I). In other aspects, the salts and polymorphic forms described herein can also potentially lead to increased yields of the compound of formula (I), or potentially to improved quality of the compound of formula (I). In certain aspects, the salts and polymorphs described herein may also exhibit improved pharmacokinetic properties and/or potentially improved bioavailability.
The acid salts and polymorphic forms of the invention may be administered by any route suitable for the condition to be treated. Suitable routes of administration include, but are not limited to, oral, rectal, nasal, pulmonary, topical, vaginal and parenteral routes.
The pharmaceutical compositions of the present invention comprise a compound of formula (I) of the type disclosed herein, or a pharmaceutically acceptable acid addition salt thereof, together with one or more pharmaceutically acceptable excipients, and optionally one or more other active pharmaceutical ingredients.
In one aspect, the pharmaceutical compositions of the present invention are formulated so that the active pharmaceutical ingredient present therein is released immediately. In another aspect, the pharmaceutical compositions of the present invention are formulated to provide controlled release of the active pharmaceutical ingredient present therein. Controlled release includes delayed, sustained and pulsed release of the active pharmaceutical ingredient.
Suitable pharmaceutical excipients are known in the art and include, but are not limited to, carriers, diluents and/or vehicles (vehicles). An excipient must be "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not injurious to the patient. The excipients may be selected to provide a desired release profile of the active pharmaceutical ingredient present.
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. Suitable doses include, but are not limited to, 25mg, 50mg, 100mg, 150mg, 200mg, 250mg, and 300 mg.
In one aspect of the invention, there is provided an acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate having an intrinsic dissolution profile as shown in figure 20.
In one aspect of the present invention, there is provided an acid salt of (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate having an intrinsic dissolution profile as shown in table 8.
in one aspect of the invention, (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate fumarate exhibits dissolution of at least about 10% in about 30 minutes, and/or about 20% in about 60 minutes, and/or about 40% in about 120 minutes, and/or about 60% in about 180 minutes, and/or about 80% in about 240 minutes.
In another aspect of the invention, ((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate oxalate exhibits dissolution of at least about 5% in about 30 minutes, and/or about 10% in about 60 minutes, and/or about 30% in about 120 minutes, and/or about 40% in about 180 minutes, and/or about 60% in about 240 minutes.
In another aspect of the invention, (((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate phosphate exhibits at least about 90% dissolution in about 30 minutes.
In another aspect of the invention, ((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate citrate exhibits dissolution of at least about 20% in about 30 minutes, and/or about 40% in about 60 minutes, and/or about 70% in about 120 minutes.
In another aspect of the invention, ((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate succinate exhibits dissolution of at least about 10% in 30 minutes, and/or about 30% in about 60 minutes, and/or about 80% in about 180 minutes, and/or about 90% in about 240 minutes.
In another aspect of the invention, ((1- (6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) (phenoxy) phosphoryloxy) methyl pivalate tartrate exhibits dissolution of at least about 10% in about 30 minutes, and/or about 20% in about 60 minutes, and/or about 40% in about 120 minutes, and/or about 70% in about 180 minutes, and/or about 80% in about 240 minutes.
The following examples include preferred aspects for illustrating the practice of the invention, it being understood that the details shown are by way of example and are for illustrative discussion of the preferred aspects of the invention.
Examples
XRD
The powder X-ray diffraction pattern was measured using a commercially available Rigaku, Minflex 2 bench top diffractometer using a copper-K-alpha radiation source. The 2 theta values were measured to an accuracy of + -0.2 degrees.
DSC
Differential Scanning Calorimetry (DSC) data were obtained using the following commercial apparatus and experimental conditions:
Instrument make and model: TA Waters and Discovery DSC
Temperature range: 30 to 200 DEG C
Heating rate: 10 ℃ per minute
N2Flow rate: 50ml of
Sample disc type: tzero seal disc
IR
IR spectra were recorded on a commercially available Bruker Alpha IR spectrometer. Samples were prepared by known methods using KBr dispersions (sample concentration 1%).