JP2004175788A - Crystal of 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy) ethyl] purine bis(2, 2, 2-trifluoroethly) ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new crystal of 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2, 2, 2-trifluoroethyl) ester useful as an antiviral agent. <P>SOLUTION: The new crystal of 2-amino-6-(4-methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl]purine bis(2, 2, 2-trifluoroethyl) ester is obtained and a medicinal agent represented by the antiviral agent containing the same as the effective ingredient is provided. <P>COPYRIGHT: (C)2004,JPO

Description

  The present invention relates to a novel crystal of 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester and a novel crystal thereof. It exists in a pharmaceutical composition as an active ingredient.

2-Amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester is effective as an antiviral agent Is known (see Patent Document 1). However, the existence of a crystal form of the compound has not been reported so far, and a method for producing a specific crystal form has not been known. Therefore, it was difficult to produce a specific crystal form.
JP-A-9-255699

  The present invention relates to a novel crystal of 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester and a novel crystal thereof. It is intended to provide a pharmaceutical composition comprising, as an active ingredient.

  The present inventors have conducted intensive studies in view of the above object, and as a result, have found that 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2- The inventors have found novel crystals of (trifluoroethyl) ester, and have completed the present invention.

That is, the gist of the present invention is as follows.
Crystals of 1.2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester.
2. Form A crystals of said compound characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 27.9 ± 0.2 ° in a powder X-ray diffraction (XRD) pattern;
(2) an endothermic peak at about 93 ° C. in differential scanning calorimetry (DSC);
(3) in a solid ³¹ P-NMR (SS-NMR) spectrum, having a peak of a chemical shift of 24.0 ppm; and / or
(4) It has an absorption peak at 3192 ± 2 cm ⁻¹ in an infrared absorption (IR) spectrum.
3. Form A crystals of said compound characterized by any of the following physicochemical properties:
(1) In the XRD pattern, diffraction peaks (2θ) at 4.0, 8.2, 8.9, 10.0, 11.6, 12.0 and / or 13.2 (± 0.2 ° each). Having;
(2) an endothermic peak at about 93 ° C. in DSC;
(3) having a peak of a chemical shift of 24.0 ppm in an SS-NMR spectrum; and / or
(4) In the IR spectrum, it has an absorption peak at 3192 ± 2 cm ⁻¹ .
4. Form A having diffraction peaks (2θ) at 4.0, 8.2, 8.9, 10.0, 11.6, 12.0, and 13.2 (± 0.2 ° each) in an XRD pattern. crystal.
5. In the XRD pattern, 4.0, 8.2, 8.9, 10.0, 11.6, 12.0, 13.2, 15.5, 16.3, 19.1, 20.1, 20. 5. Said Form A crystal having a diffraction peak (2θ) at 5, 20.9, 23.3, 23.8, 27.5 and / or 27.9 (± 0.2 ° each).
6. In the XRD pattern, 4.0, 8.2, 8.9, 10.0, 11.6, 12.0, 13.2, 15.5, 16.3, 19.1, 20.1, 20. 5. The Form A crystal having a diffraction peak (2θ) at 5, 20.9, 23.3, 23.8, 27.5, and 27.9 (each ± 0.2 °).
7. The above-mentioned type A crystal having a characteristic peak in the XRD pattern shown in FIG.
8. The Form A crystal having a characteristic thermal analysis pattern in DSC shown in FIG. 9.
9. The Form A crystal having a characteristic peak of a chemical shift in the SS-NMR spectrum shown in FIG. 20.
10. The form A crystal having no absorption peak at 3402 ± 5 cm ⁻¹ in an IR spectrum.
11. In the IR spectrum, 3312.8, 3192.6, 1630.3, 1437.3, 1376.1, 1258.5, 1026.5, 839.3, 830.6 and / or 821.6 (cm ^-1 respectively) The crystalline form A having an absorption peak at ± 0.5%).
12. In the IR spectrum, 3312.8, 3192.6, 1630.3, 1437.3, 1376.1, 1258.5, 1026.5, 839.3, 830.6, and 821.6 (cm ^-1 , ± The type A crystal having an absorption peak at 0.5%).
13. The form A crystal showing the characteristic peak in the IR spectrum shown in FIG. 49.
14． Form B crystals of said compound characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 14.2 ± 0.1 ° in the XRD pattern;
(2) DSC, having an endothermic peak and an exothermic peak at about 75 ° C. and / or having an endothermic peak at about 93 ° C .;
(3) having a peak of a chemical shift of 22.0 ppm and / or 23.7 ppm in an SS-NMR spectrum; and / or
(4) The IR spectrum has an absorption peak at 3205 ± 2 cm ⁻¹ .
15. In the XRD pattern, 6.6 ± 0.1 °, 7.6 ± 0.1 °, 8.8, 11.1, 11.3, 12.4, 12.8, 13.2 and / or 14. The Form B crystal having a diffraction peak (2θ) at 2 ± 0.1 ° (± 0.2 ° unless otherwise specified).
16. In the XRD pattern, 6.6 ± 0.1 °, 7.6 ± 0.1 °, 8.8, 11.1, 11.3, 12.4, 12.8, 13.2, and 14.2 ±. The above-mentioned Form B crystal having a diffraction peak (2θ) at 0.1 ° (± 0.2 ° unless otherwise specified).
17. In the XRD pattern, 6.6 ± 0.1 °, 7.6 ± 0.1 °, 8.8, 11.1, 11.3, 12.4, 12.8, 13.2, 14.2 ±. 0.1 °, 16.8, 17.2, 17.8, 18.2, 18.6, 19.2, 20.1, 20.4, 21.0, 22.7, 23.0, 23 Said B-form crystal having a diffraction peak (2θ) at 7, 24.8, 27.1 and / or 27.6.
18. In the XRD pattern, 6.6 ± 0.1 °, 7.6 ± 0.1 °, 8.8, 11.1, 11.3, 12.4, 12.8, 13.2, 14.2 ±. 0.1 °, 16.8, 17.2, 17.8, 18.2, 18.6, 19.2, 20.1, 20.4, 21.0, 22.7, 23.0, 23 Said Form B crystal having diffraction peaks (2θ) at 0.7, 24.8, 27.1 and 27.6.
19. The B-type crystal having a characteristic peak in the XRD pattern shown in FIG.
20. The above-mentioned Form B crystal having an endothermic peak and an exothermic peak at about 75 ° C and an endothermic peak at about 93 ° C in DSC.
21. The Form B crystal having a characteristic thermal analysis pattern in DSC shown in FIG.
22. The form B crystal having the peak of the chemical shift of 22.0 ppm and 23.7 ppm in the SS-NMR spectrum.
23. The Form B crystal having a characteristic peak of a chemical shift in the SS-NMR spectrum shown in FIG. 21.
24. The form B crystal having an absorption peak at 3205 ± 5 cm ⁻¹ in an IR spectrum.
25. In the IR spectrum, at 3322.3, 3205.5, 1633.5, 1350.0, 1261.1, 1029.9, 826.8 and / or 660.1 (cm ^-1 , ± 0.5%, respectively). The crystalline form B having an absorption peak.
26. In the IR spectrum, absorption peaks at 3322.3, 3205.5, 1633.5, 1350.0, 1261.1, 1029.9, 826.8, and 660.1 (cm ⁻¹ , ± 0.5%, respectively). The type B crystal having the formula:
27. 51. The B-type crystal showing a characteristic peak in the IR spectrum shown in FIG.
28. Form C crystals of said compound characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 6.4 ± 0.1 ° and / or 13.9 ± 0.1 ° in the XRD pattern;
(2) an endothermic peak at about 93 ° C. in DSC;
(3) having a peak of a chemical shift of 19.3 ppm and / or 22.7 ppm in an SS-NMR spectrum; and / or
(4) In the IR spectrum, it has an absorption peak at 3402 ± 5 cm ⁻¹ .
29. The above-mentioned Form C crystal having diffraction peaks (2θ) at 6.4 ± 0.1 ° and 13.9 ± 0.1 ° in an XRD pattern.
30. In the XRD pattern, 3.2, 6.4 ± 0.1 °, 9.6 ± 0.1 °, 12.3, 12.8, 13.3, 13.9 ± 0.1 ° and / or 14 The above-mentioned Form C crystal having a diffraction peak (2θ) at 8 (± 0.2 ° unless otherwise specified).
31. In the XRD pattern, 3.2, 6.4 ± 0.1 °, 9.6 ± 0.1 °, 12.3, 12.8, 13.3, 13.9 ± 0.1 ° and 14.8. The above-mentioned type C crystal having a diffraction peak (2θ) at (± 0.2 ° unless otherwise specified).
32. In the XRD pattern, 3.2, 6.4 ± 0.1 °, 9.6 ± 0.1 °, 12.3, 12.8, 13.3, 13.9 ± 0.1 °, 14.8 , 16.0, 16.3, 16.8, 17.8, 18.9, 20.5, 21.1, 21.7, 22.4 and / or 23.3 (± 0.2 unless otherwise specified). The crystalline form C having a diffraction peak (2θ) at (°).
33. In the XRD pattern, 3.2, 6.4 ± 0.1 °, 9.6 ± 0.1 °, 12.3, 12.8, 13.3, 13.9 ± 0.1 °, 14.8 , 16.0, 16.3, 16.8, 17.8, 18.9, 20.5, 21.1, 21.7, 22.4 and 23.3 (± 0.2 ° unless otherwise noted) The C-type crystal having a diffraction peak (2θ) at.
34. The C-type crystal having a characteristic peak in the XRD pattern shown in FIG.
35. The C-type crystal having a characteristic thermal analysis pattern in DSC shown in FIG.
36. The Form C crystal having a peak of a chemical shift of 19.3 ppm or 22.7 ppm in an SS-NMR spectrum.
37. The C-type crystal having a characteristic peak of a chemical shift in the SS-NMR spectrum shown in FIG.
38. In IR spectrum, the C-shaped crystal having an absorption peak at 3402 ± ^{5 cm -1} and / or 1438 ± ^{5 cm -1.}
39. In IR spectrum, the C-shaped crystal having an absorption peak at 3402 ± ^{5 cm -1} and 1438 ± ^{5 cm -1.}
40. In the IR spectrum, 3405.5, 3323.5, 3198.7, 1643.1, 1437.9, 1345.7, 1264.4, 1215.4, 1022.8, 839.1, 830.6 and / or The aforementioned Form C crystal having an absorption peak at 660.3 (cm ⁻¹ , ± 0.5%, respectively).
41. In the IR spectrum, 3405.5, 3323.5, 3198.7, 1643.1, 1437.9, 1345.7, 1264.4, 1215.4, 1022.8, 839.1, 830.6 and 660. The C-type crystal having an absorption peak at 3 (cm ⁻¹ , ± 0.5%, respectively).
42. 52. The C-type crystal showing a characteristic peak in the IR spectrum shown in FIG.
43. A C / X crystal of the compound characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 7.5 ± 0.1 ° in the XRD pattern;
(2) an endothermic peak at about 92 ° C. in DSC;
(3) having a peak of a chemical shift of 18.4, 20.8 and / or 23.8 (all in ppm) in an SS-NMR spectrum; and / or
(4) In the IR spectrum, it has an absorption peak at 3402 ± 5 cm ⁻¹ .
44. The C / X-type crystal having a diffraction peak (2θ) at 3.2, 6.4, 9.6, and / or 13.3 (all ± 0.2 °) in an XRD pattern.
45. The C / X type crystal having a diffraction peak (2θ) at 3.2, 6.4, 9.6, and 13.3 (all ± 0.2 °) in an XRD pattern.
46. In the XRD pattern, 3.2, 6.4, 9.6, 12.3, 13.3, 16.8, 17.8, 18.9, 20.5 and / or 24.3 (all ± 0 The C / X type crystal having a diffraction peak (2θ) at 2 °).
47. In the XRD pattern, 3.2, 6.4, 9.6, 12.3, 13.3, 16.8, 17.8, 18.9, 20.5 and 24.3 (all ± 0.2 The above C / X type crystal having a diffraction peak (2θ) at (°).
48. The C / X type crystal having a characteristic peak in the XRD pattern shown in FIG.
49. The C / X type crystal having a characteristic thermal analysis pattern in the DSC shown in FIG.
50. The C / X type crystal having a peak of a chemical shift of 18.4, 20.8, or 23.8 (all in ppm) in an SS-NMR spectrum.
51. The C / X type crystal having a peak of a chemical shift of 18.4, 19.3, 20.8, 22.6 and / or 23.8 (all ppm) in an SS-NMR spectrum.
52. The C / X type crystal having a peak of a chemical shift of 18.4, 19.3, 20.8, 22.6 or 23.8 (all in ppm) in an SS-NMR spectrum.
53. The C / X type crystal having a characteristic peak of a chemical shift in the SS-NMR spectrum shown in FIG.
54. In the IR spectrum, 3405.2, 3324.3, 3198.4, 1643.1, 1437.9, 1345.8, 1263.9, 1215.3, 1022.8, 838.9, 830.4 and / or The C / X-type crystal having an absorption peak at 660.7 (cm ⁻¹ , ± 0.5%, respectively).
55. In the IR spectrum, 3405.2, 3324.3, 3198.4, 1643.1, 1437.9, 1345.8, 1263.9, 1215.3, 1022.8, 838.9, 830.4 and 660. The C / X-type crystal having an absorption peak at 7 (cm ⁻¹ , ± 0.5%, respectively).
56. 52. The C / X-type crystal showing a characteristic peak in the IR spectrum shown in FIG.
57. Form D crystals of said compound characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 4.4, 9.2 and / or 25.5 (all ± 0.1 °) in the XRD pattern;
(2) DSC, having an endothermic peak at about 78 ° C. and / or about 89 ° C .;
(3) having a chemical shift peak of 24.2 and / or 27.2 (all ppm) in an SS-NMR spectrum; and / or
(4) The IR spectrum has an absorption peak at 3489 ± 2 cm ⁻¹ .
58. The D-type crystal having a diffraction peak (2θ) at 4.4, 9.2, and 25.5 (all ± 0.1 °) in an XRD pattern.
59. Diffraction peaks at 4.4 ± 0.1, 8.2, 9.2 ± 0.1, 11.0, 11.7 and / or 13.2 (± 0.2 ° unless otherwise noted) in the XRD pattern. The above-mentioned type D crystal having 2θ).
60. In the XRD pattern, diffraction peaks at 4.4 ± 0.1 °, 8.2, 9.2 ± 0.1 °, 11.0, 11.7 and 13.2 (± 0.2 ° unless otherwise specified) ( The above-mentioned type D crystal having 2θ).
61. 4.4 ± 0.1 °, 8.2, 9.2 ± 0.1 °, 11.0, 11.7, 13.2, 15.2, 15.8, 16.0, 16 in the XRD pattern .8, 17.0, 17.3, 17.6, 18.1, 18.6, 19.1, 19.7, 20.8, 21.6, 22.0, 23.0, 24.0 And / or the Form D crystal having a diffraction peak (2θ) at 24.3 (± 0.2 ° unless otherwise specified).
62. 4.4 ± 0.1 °, 8.2, 9.2 ± 0.1 °, 11.0, 11.7, 13.2, 15.2, 15.8, 16.0, 16 in the XRD pattern .8, 17.0, 17.3, 17.6, 18.1, 18.6, 19.1, 19.7, 20.8, 21.6, 22.0, 23.0, 24.0 And the D-form crystal having a diffraction peak (2θ) at 24.3 (± 0.2 ° unless otherwise specified).
63. The D-type crystal having a characteristic peak in the XRD pattern shown in FIG.
64. The above-mentioned Form D crystal having endothermic peaks at about 78 ° C. and about 89 ° C. in DSC.
65. The D-type crystal having a characteristic thermal analysis pattern in DSC shown in FIG.
66. The above-mentioned Form D crystal having a peak of a chemical shift of 24.2 and 27.2 (all in ppm) in an SS-NMR spectrum.
67. The D-type crystal having a characteristic peak of a chemical shift in the SS-NMR spectrum shown in FIG.
68. In the IR spectrum, 3490.4, 3346.2, 3211.3, 1645.5, 1449.9, 1375.7, 1362.8, 1263.1, 1251.3, 1223.9, 1212.3, 1122. 6, said D-form crystal having an absorption peak at 100, 1002.8, 888.9, 830.1 and / or 821.2 (cm ⁻¹ , ± 0.5%, respectively).
69. In the IR spectrum, 3490.4, 3346.2, 3211.3, 1645.5, 1449.9, 1375.7, 1362.8, 1263.1, 1251.3, 1223.9, 1212.3, 1122. 6, wherein the D-form crystal has an absorption peak at 100, 1002.8, 888.9, 830.1, and 821.2 (cm ⁻¹ , ± 0.5%, respectively).
70. 53. The D-type crystal showing a characteristic peak in the IR spectrum shown in FIG.
71. An E-form crystal of the compound characterized by any of the following physicochemical properties:
(1) show characteristic peaks in the XRD pattern shown in FIG. 6; and / or
(2) DSC shows an endothermic peak at about 93 ° C.
72. The E-form crystal showing a characteristic thermal analysis pattern in the DSC shown in FIG.
73. An α-form crystal of the compound characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 4.9 ± 0.2 ° and / or 7.2 ± 0.1 ° in the XRD pattern;
(2) having an endothermic peak at about 64 ° C. in DSC; and / or
(3) In the SS-NMR spectrum, it has a peak of a chemical shift of 25.6 ppm.
74. The α-form crystal having diffraction peaks (2θ) at 4.9 ± 0.2 ° and 7.2 ± 0.1 ° in an XRD pattern.
75. In the XRD pattern, diffraction peaks (2θ) at 4.9, 7.2 ± 0.1 °, 9.8, 11.1, 11.8 and / or 14.7 (± 0.2 ° unless otherwise specified). The α-form crystal having:
76. XRD pattern has diffraction peaks (2θ) at 4.9, 7.2 ± 0.1 °, 9.8, 11.1, 11.8, and 14.7 (± 0.2 ° unless otherwise specified). The α-form crystal.
77. In the XRD pattern, 4.9, 7.2 ± 0.1 °, 9.8, 11.1, 11.8, 14.7, 18.6, 20.2, 20.3, 21.1, 21 The α-form crystal having a diffraction peak (2θ) at 6.6, 25.0 and / or 29.9 (± 0.2 ° unless otherwise specified).
78. In the XRD pattern, 4.9, 7.2 ± 0.1 °, 9.8, 11.1, 11.8, 14.7, 18.6, 20.2, 20.3, 21.1, 21. The α-form crystal having diffraction peaks (2θ) at 6, 25.0 and 29.9 (± 0.2 ° unless otherwise specified).
79. The α-form crystal having a characteristic peak in the XRD pattern shown in FIG.
80. The α-form crystal having a characteristic thermal analysis pattern in DSC shown in FIG.
81. The α-form crystal having a characteristic peak of a chemical shift in the SS-NMR spectrum shown in FIG.
82.2 Amorphous 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester.
83. Said amorphous characterized by one of the following physicochemical properties:
(1) shows a characteristic peak in the XRD pattern shown in FIG. 8;
(2) does not show a distinct endothermic peak in DSC; and / or
(3) It has a characteristic peak in the SS-NMR spectrum shown in FIG.
84. The amorphous material having a characteristic thermal analysis pattern in the DSC shown in FIG.
85. A pharmaceutical composition comprising the above-mentioned crystal or amorphous as an active ingredient.
86. The aforementioned pharmaceutical composition used as an antiviral agent.
87. The aforementioned pharmaceutical composition, wherein the virus is selected from hepatitis B virus and varicella-zoster virus.
88.2 2-Amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester was prepared from isopropanol and n-heptane solution. A method for producing the C-type crystal, comprising a step of precipitating.
89. A method for producing the C-type crystal using the A-type, B-type, C / X-type, D-type, or α-type crystal or the amorphous.
90. A method for producing the C-type crystal using the α-type crystal.
91. 92. A method for producing the C-form crystal, comprising a step of washing the α-form crystal in an n-heptane solvent. The method for producing the C-form crystal, which comprises a step of suspending the α-form crystal in a mixed solvent of isopropanol and n-heptane.
93. Method for producing said C-type crystal using said C / X-type crystal94. A method for producing the C-type crystal, comprising a step of suspending the C / X-type crystal in a mixed solvent of isopropanol and n-heptane.

  According to the present invention, a novel crystal of 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester And a pharmaceutical composition typified by an antiviral agent comprising the same as an active ingredient.

  Hereinafter, the present invention will be described in detail.

  In the present invention, 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester represented by the following formula: A new crystal of

Particularly, in the present invention, C-type crystals having the following physicochemical characteristics are preferred.
(1) having a characteristic peak in the XRD pattern shown in FIG. 3;
(2) having a characteristic thermal analysis pattern in the DSC shown in FIG. 11;
(3) having a characteristic peak in the SS-NMR spectrum shown in FIG. 22; and
(4) It has a characteristic peak in the IR spectrum shown in FIG.

  Further, in the present invention, respective crystals having the following physicochemical characteristics are also preferred.

Form A crystal characterized by one of the following physicochemical properties:
(1) having a characteristic peak in the XRD pattern shown in FIG. 1;
(2) having a characteristic thermal analysis pattern in the DSC shown in FIG. 9;
(3) having a characteristic peak in the SS-NMR spectrum shown in FIG. 20; and
(4) It has a characteristic peak in the IR spectrum shown in FIG.

Form B crystal characterized by one of the following physicochemical properties:
(1) having a characteristic peak in the XRD pattern shown in FIG. 2;
(2) having a characteristic thermal analysis pattern in the DSC shown in FIG. 10;
(3) having a characteristic peak in the SS-NMR spectrum shown in FIG. 21; and
(4) It has a characteristic peak in the IR spectrum shown in FIG.

A C / X type crystal characterized by one of the following physicochemical properties:
(1) having a characteristic peak in the XRD pattern shown in FIG. 4;
(2) having a characteristic thermal analysis pattern in the DSC shown in FIG. 12;
(3) having a characteristic peak in the SS-NMR spectrum shown in FIG. 23; and
(4) It has a characteristic peak in the IR spectrum shown in FIG.

Form D crystals characterized by one of the following physicochemical properties:
(1) having a characteristic peak in the powder X-ray diffraction pattern shown in FIG. 5;
(2) having a characteristic thermal analysis pattern in the DSC shown in FIG. 13;
(3) having a characteristic peak in the SS-NMR spectrum shown in FIG. 24; and
(4) It has a characteristic peak in the IR spectrum shown in FIG.

Form E crystal characterized by one of the following physicochemical properties:
(1) having a characteristic peak in the XRD pattern shown in FIG. 6; and (2) having a characteristic thermal analysis pattern in the DSC shown in FIG.

Form α crystals characterized by any of the following physicochemical properties:
(1) having a characteristic peak in the XRD pattern shown in FIG. 7;
(2) having a characteristic thermal analysis pattern in the DSC shown in FIG. 15; and
(3) It has a characteristic peak in the SS-NMR spectrum shown in FIG.

In the present invention, 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2) characterized by any of the following physicochemical properties: , 2,2-trifluoroethyl) ester is also preferable.
(1) having a characteristic peak in the XRD pattern shown in FIG. 8;
(2) having a characteristic thermal analysis pattern in XRD shown in FIG. 16; and
(3) It has a characteristic peak in the SS-NMR spectrum shown in FIG.

  The method for producing the crystal of the present invention is not particularly limited. For example, as shown in the following example, a substance obtained by the method described in Example 3 of JP-A-9-255595 is dissolved in isopropanol by heating. A method for obtaining a C-type crystal by adding n-heptane and cooling; heating and dissolving the C-type crystal obtained above in isopropanol, adding n-heptane, cooling, and adding a seed crystal to obtain a A-type crystal. A method for obtaining a B-type crystal by heating and dissolving the C-form crystal obtained above in isopropanol and then adding water to cool the same; heating and dissolving the C-form crystal obtained in isopropanol and then adding water; A method for obtaining a D-form crystal by cooling and adding a seed crystal; a method for obtaining an α-form crystal by heat-treating a C-form crystal in isopropanol or a mixed solvent of isopropanol / n-heptane; A method for obtaining an α-form crystal by heating and dissolving the substance obtained by the method described in Example 1 of the present invention in isopropanol and then adding and cooling n-heptane; a method for obtaining an amorphous form by heating and melting a C-form crystal: α-form A method for obtaining a C / X crystal by heating and drying the crystal; a method for obtaining a C / X crystal by heating and washing the α-form crystal in an n-heptane or isopropanol / n-heptane mixed solution; There is a method of obtaining a C-type crystal by heating and washing in a mixed solution of isopropanol / n-heptane.

  JP-A-9-255699 discloses 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl). There is no description that specific crystals can be obtained for the ester, and no sufficient information is disclosed for producing the crystals of the present invention.

  The crystal of the present invention is useful as an active ingredient of a medicine, and specifically, is useful as an active ingredient of an antiviral agent. It is also expected to have antitumor activity, as found in other ionic phosphonate nucleotide analogs. The virus to which the medicament of the present invention is applied is not particularly limited, and specifically, RNA viruses such as human immunodeficiency virus, influenza virus, hepatitis C virus, herpes simplex virus I, herpes simplex virus II, cytomegalovirus, and the like. DNA viruses such as viruses, varicella-zoster virus, and hepatitis B virus are included, more preferably, hepatitis B virus and varicella-zoster virus, and further preferably, hepatitis B virus.

  When the crystal of the present invention is used as a medicine, it may be administered alone, but it is administered by producing a pharmaceutical composition containing the above compound as an active ingredient using a pharmaceutically acceptable pharmaceutical additive. It is preferred to do so. The composition of a pharmaceutical composition will be determined by the solubility of the compound, the chemical nature, the route of administration, the dosage regimen, and the like. For example, granules, fine granules, powders, tablets, hard syrups, soft capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, suspensions, liposomes, etc. Or intravenously, intramuscularly or subcutaneously as an injection. It can also be prepared as an injection powder and used at the time of use.

  As the pharmaceutically acceptable additive for pharmaceutical preparation, an organic or inorganic solid or liquid carrier suitable for oral, enteral, parenteral or topical administration can be used. The above-mentioned pharmaceutical composition may contain, in addition to the above-mentioned carriers, auxiliary agents such as wetting agents, suspending agents, sweetening agents, fragrances, coloring agents, and preservatives. Liquid preparations may also be used in capsules of absorbable substances such as gelatin. For the preparation of a parenteral preparation, that is, an injection, a solvent or a suspending agent is used.

  Since the crystals of the present invention have high oral absorption as shown in JP-A-9-255699, oral administration is a preferred route of administration of the medicament of the present invention. The preparation of each of the above-mentioned preparations can be performed according to a conventional method. The clinical dose of the medicament of the present invention, when used orally, is generally 0.1 to 500 mg / kg, preferably 1 to 50 mg / kg, per day for an adult, as the compound of the present invention. However, the above dose may be appropriately increased or decreased depending on the age, medical condition, symptom, presence or absence of simultaneous administration, and the like. The daily dose may be administered once a day, or divided into two to several times a day at appropriate intervals, or may be administered intermittently every few days. When used as an injection, the weight of the compound of the present invention is 0.01 to 50 mg / kg, preferably 0.1 to 5 mg / kg, per day for an adult.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist.
Example 1 Production of Form C Crystal 15.05 g of the substance obtained in Example 3 of JP-A-9-255699 was dissolved in 90 ml of isopropanol by heating to 63 ° C with stirring. 150 ml of n-heptane was added to the solution while maintaining the temperature from 53 ° C to 63 ° C. After cooling to room temperature, the mixture was stirred at room temperature for 3 hours. The precipitated crystals were separated by suction filtration and dried under reduced pressure at 57 ° C. for 6 hours. 13.09 g of crystals were obtained.
Example 2 Production of Form A Crystal 11 g of the crystal obtained in Example 1 was dissolved in 57 ml of ethanol by heating to 70 ° C. 46 ml of water was added to this solution, and the mixture was cooled and stirred in ice water. The precipitated crystals were collected by filtration and washed with a small amount of an ethanol / water (4/3) solution to obtain seed crystals.

50 g of the crystals obtained in Example 1 were dissolved in 500 ml of isopropanol by heating to 70 ° C. While gradually returning the solution to room temperature, 800 ml of n-heptane was added in eight portions. About 20 mg of the seed crystal obtained by the above method was added to this solution, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with a small amount of a solution of isopropanol / n-heptane (5/8), and dried under reduced pressure at 25 ° C for 16 hours. 40 g of crystals were obtained.
Example 3 Production of Form B Crystal 20 g of the crystal obtained in Example 1 was dissolved in 200 ml of isopropanol by heating to 80 ° C. 400 ml of water was added to this solution, and the mixture was heated and stirred at 100 ° C. for 15 minutes, and then the solution was cooled in water to room temperature to produce an oil. The solution was stirred in ice water for 2 hours and crystallized. The resulting crystals were collected by filtration, washed with a small amount of a solution of isopropanol / water (1/2), and dried under reduced pressure at 25 ° C. for 16 hours. 16.4 g of crystals were obtained.
Example 4 Production of C / X Form Crystals 8.84 g (in terms of dry product) of the α form crystals obtained in Example 7 described below were dried under reduced pressure at 57 ° C. for 6 hours to obtain the title crystals.
Example 5 Production of Form D Crystal 20 g of the crystal obtained in Example 1 was dissolved in 200 ml of isopropanol by heating to 80 ° C. After 800 ml of water was added to this solution and heated at 100 ° C. for 15 minutes, the solution was cooled in water to room temperature to produce an oil. The supernatant was removed and the oil crystallized on standing at room temperature. To this, 150 ml of an isopropanol / water (1/2) solution was added and stirred. The crystals were collected by filtration and washed with a small amount of a solution of isopropanol / water (1/2) to obtain seed crystals.

20 g of the substance obtained in Example 1 was dissolved in 200 ml of isopropanol by heating to 80 ° C. 400 ml of water was added to this solution, and the solution was heated at 100 ° C. for 15 minutes. After cooling the solution in water to room temperature, an oil was formed. About 20 mg of a seed crystal obtained by the above-mentioned production method was added to this solution, and the mixture was stirred for 1 hour at room temperature to crystallize. The generated crystals were collected by filtration, washed with a small amount of a solution of isopropanol / water (1/2), and dried under reduced pressure at 25 ° C. for 16 hours. 7.4 g of crystals were obtained.
Example 6 Preparation of Form E Crystal The Form C crystal obtained in Example 1 was stored in a desiccator saturated with ethanol at room temperature for 87 to 130 hours to give the title crystal.
Example 7 Production of Form α Crystal After stirring 9.98 g of the crystal obtained in Example 1 in 34 ml of isopropanol at 34 to 35 ° C. for 1 hour, the generated crystal was collected by filtration to obtain the title crystal.
Example 8 Production of Amorphous 3 g of the crystal obtained in Example 1 was heated at 97 ° C. for 30 minutes, and then cooled with ice to obtain an amorphous.
Example 9 XRD Measurement The XRD pattern of each of the crystals and amorphous obtained in the above example was measured under the following measurement conditions.
(Measurement condition)
Apparatus: RINT 2500 type powder X-ray diffractometer (Rigaku Corporation)
X-ray: CuKα
Scanning range: 3-40 ° 2θ
Sample rotation: 60 rpm
FIGS. 1 to 7 show the XRD patterns of the crystals obtained in Examples 1 to 7, respectively, and FIG. 8 shows the XRD patterns of the amorphous material of Example 8.

It can be seen that each crystal shows a different XRD pattern except for the C / X type crystal.
Example 10 Thermal Analysis (DSC)
Approximately 2 mg of each crystal and amorphous obtained in the above example were weighed, packed in an aluminum pan, sealed and measured. The measurement conditions are as follows.
(Measurement condition)
Equipment: DSC6200 (Seiko Instruments)
Measuring range: 40-120 ° C
Heating rate: 5 ° C./min. Atmosphere: N ₂ 40 mL / min. DSC curves of each crystal are shown in FIGS. 9 to 15, and DSC curves of the amorphous are shown in FIG.

  From FIG. 11, it was found that the C-type crystal had an endothermic peak at about 93 ° C.

  From FIG. 9, it was found that Form A crystal also had an endothermic peak at about 93 ° C.

  From FIG. 12, it was found that the C / X type crystal had an endothermic peak at about 92 ° C.

  From FIG. 13, it was found that the D-type crystal showed an endothermic peak at about 78 ° C., and then had an exothermic peak derived from the dislocation from the D-type crystal to the C-type crystal. Furthermore, it was found that it had an endothermic peak at about 89 ° C. Although the second endothermic peak was slightly different from the endothermic peak of the C-form crystal, the transition from D-form to C-form was confirmed from the XRD-DSC data shown in FIG.

  From FIG. 10, it was found that the B-type crystal exhibited an endothermic peak and an exothermic peak at about 75 ° C., and further had an endothermic peak at about 93 ° C.

  FIG. 15 shows that the α-form crystal has an endothermic peak at about 64 ° C., and has an endothermic peak at about 93 ° C. after dislocation to the C / X form.

  From FIG. 18, it was found that the endotherm around 64 ° C. was accompanied by the elimination of isopropanol.

  From FIG. 19, it was found that the α-form was rearranged into the C / X form by heat.

  From FIG. 14, it was found that Form E had an endothermic peak at about 93 ° C.

From FIG. 16, it was found that amorphous does not show a clear endothermic peak.
Example 11 SS-NMR spectrum measurement The SS-NMR spectrum of each crystal and amorphous obtained in the above example was measured under the following measurement conditions.
(Measurement condition)
Apparatus: MSL-300 (Bruker)
Probe: 4mmφ CP / MAS
MAS: 10 kHz
Temperature: room temperature Waiting time: 600 seconds The SS-NMR spectra of each crystal and amorphous are shown in FIGS.

As shown, the SS-NMR spectra of Form A, Form B, Form C, Form C / X, Form D, α and amorphous were found to have peaks with different chemical shifts.
Example 12 IR measurement The IR of each crystal obtained in the above example was measured by the KBr tablet method under the following measurement conditions.
(Measurement condition)
Apparatus: Paragon 1000 (Perkin Elmer)
Measurement range: 4000-400 cm ^-1
Resolution: 4.0 cm ^-1
FIGS. 27 to 31 show IR spectra of the respective crystals.
Example 13 Single crystal structure analysis Single crystal structure analysis of the C-type and α-type crystals obtained in Examples 1 and 7 was performed. The crystallographic parameters are shown below, and the crystal structures are shown in FIGS. From the results, it can be seen that the C-form crystal is an anhydride and the α-form crystal is an isopropanol solvate.
(Single Crystal of Form C Crystallographic Parameters)
Space group: P2 ₁ / c
Lattice constant: a = 28.630 (2) Å
b = 8.5426 (6) Å
c = 20.540 (2) Å
β = 106.356 (1) °
Volume: 4820.2 (6) Å ³
No. of formula units per cell: 8
Calculate density: 1.586 g / cm ³
(Single crystal of α-form crystal, crystallographic parameters)
Space group: Pbca
Lattice constant: a = 16.2907 (14) Å
b = 9.5301 (8) Å
c = 36.141 (3) Å
α = β = γ = 90 °
Volume ： 5611.0 (8) Å ³
No. of formula units per cell: 8
Calculate density: 1.505 mg / m ³
Example 14 Solubility The solubility of each crystal obtained in Examples 1 to 3 and 5 was measured by the rotating disk method under the following conditions. The resulting solubility curve is shown in FIG.
(Disc formation)
Sample: about 80mg
Pressure: 1 ton diameter: 10mmφ
Pressurization time: 1 minute (dissolution test conditions)
Apparatus: NTR-6100A dissolution tester (Toyama Sangyo)
Eluate: 600 ml, pH 1.2 (Japan Pharmacopoeia, one solution of collapse test method)
Disk rotation speed: 250 rpm
Temperature: 25 ° C
The gradient (μg / mL / min) of the dissolution rate in FIG. 34 was 0.22 for the A-type crystal, 0.24 for the B-type crystal, 0.23 for the C-type crystal, and 0.15 for the D-type crystal. . That is, it was found that the dissolution rates of the A-type, B-type and C-type crystals were almost equal, and the dissolution rate of the D-type crystal was lower than that of the A-type, B-type and C-type crystals.
Example 15 Hygroscopicity An appropriate amount of each crystal obtained in Examples 1 to 5 was weighed, and the change in weight was measured by a moisture adsorption device under the following conditions. The results (isothermal moisture absorption curves) are shown in FIGS.
(Measurement condition)
Apparatus: MB300G (VTI)
Measurement range: 5-95% (relative humidity: RH)
Step: 5% (RH)
Temperature: 25 ° C
Form A, Form B, and Form C crystals were found not to exhibit hygroscopicity in the range of 0% to 95% relative humidity. Form D was found to have 0.5 molecule of water in the range of 40% to 95% relative humidity.
Example 16 Physical and Chemical Stability of Each Crystal Form The physical and chemical stability of each crystal form under the following conditions were examined.
(Storage conditions)
80 ° C. 1 week 40 ° C. 1 month, 2 months Light irradiation 1 month, 2 months 40 ° C./75% RH 0.5 month, 1 month, 2 months (1) Physical stability From FIG. It was found that at 1 ° C. for 1 week and at 40 ° C./75% RH for 0.5 month, the crystal rearranged into Form C crystal.

  From FIG. 41, it was found that the B-type crystal rearranged into the C-type crystal at 80 ° C. for one week and at 40 ° C./75% RH for 0.5 month.

  From FIG. 42, it was found that the C-type crystal was stable under any conditions.

  From FIG. 43, it was found that the D-type crystal rearranged into the C-type at 80 ° C. for one week. Furthermore, it was found from FIG. 44 that the D-form crystal was partially transformed into the C-form at 60 ° C. for 5 days.

From these results, it was found that Form A, Form B and Form D crystals rearrange to Form C by heat, but Form C crystals are stable under these conditions.
(2) Chemical Stability From FIG. 45 to FIG. 48, it was found that the amount of the decomposed product of the C-type crystal was slightly larger than that of the A-type, B-type, and D-type crystals at 40 ° C./75% RH for 2 months. However, the amount of the decomposition product was 0.7% or less, and no remarkable change was observed in the stability test (25 ° C./60% RH 36 months and 40 ° C./75% RH 6 months, polyethylene double bag with silica gel). Was. From this, it was considered that the chemical stability of the C-type crystal was not a problem.

  From these results, it was confirmed that the C-form crystal was suitable as the developed form.

Based on the above results, 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester had four polymorphs. It is evident that it has a form (A, B, C, C / X) and three pseudocrystalline polymorphs (D, E, α). The A-type and B-type crystals rearranged into C-type crystals due to heat. The C / X type crystal was found to be a mixture of the C type crystal and other crystal components. Form C crystal was found to be stable to heat, light, and humidity, and had good physical and chemical stability. From this, it can be said that Form C crystal is suitable as a drug substance.
Example 17 Production of Form C Crystal from Form α Crystal 11.03 g (in terms of dry product) of the form α crystal obtained in Example 7 was stirred in 165 ml of n-heptane at 53 ° C. for 8 hours. After cooling from 53 ° C. to room temperature, the mixture was stirred at room temperature for 3 hours. The crystals were collected by filtration and dried under reduced pressure at 57 ° C. for 6 hours. 10.98 g of crystals were obtained. When the obtained crystal was subjected to X-ray measurement, it was found to be C-type.
Example 18 Production of Form C Crystal from Form C / X Crystal 50.53 g of the form C / X crystal obtained in Example 4 was placed in 1100 ml of a solution of isopropanol / n-heptane (1/10) at 53 ° C. and 4.5. Stirred for hours. After cooling from 53 ° C. to room temperature, the mixture was stirred at room temperature for 1 hour. The crystals were collected by filtration and dried under reduced pressure at 57 ° C. for 4 hours. 49.73 g of crystals were obtained. When the obtained crystal was subjected to X-ray measurement, it was found to be C-type.
Example 19 Production of α Form Crystal 10.13 g of the crystal obtained in Example 1 was stirred in a mixed solvent of isopropanol / n-heptane 60 ml / 10 ml at 34-36 ° C. for 30 minutes, and the formed crystal was collected by filtration. Crystals were obtained. When X-ray measurement was performed as it was, it was in the α-form.
Example 20 Production of Form C Crystal from Form α Crystal 9.98 g (in terms of dry product) of the form α crystal obtained in Example 7 was placed in a mixed solvent of n-heptane / isopropanol 149.7 ml / 0.3 ml at 53 ° C. Stir for 8 hours. After cooling from 53 ° C. to room temperature, the mixture was stirred at room temperature for 3 hours. The crystals were collected by filtration and dried under reduced pressure at 57 ° C. for 6 hours. 9.05 g of crystals were obtained. When the obtained crystal was subjected to X-ray measurement, it was found to be C-type.
Example 21 Production of Form α Crystal 42.9 kg of the substance obtained in Example 1 was added to 168.6 kg of isopropanol and dissolved by heating to 64.3 ° C. The mixture was filtered while hot and washed with 33.9 kg of isopropanol. 429 L of n-heptane was added and cooled to room temperature. Stirred at room temperature for 3 hours. The precipitated crystals were separated by a centrifugal filter. 46.8 kg of undried crystals were obtained. When the undried crystals were subjected to X-ray measurement as they were, they were in the α-form.
Example 22 IR measurement The IR of each crystal obtained in the above example was measured by the KBr tablet method under the following measurement conditions.
(Measurement condition)
Equipment: Spectrum One (Perkin Elmer)
Measurement range: 4000-400 cm ^-1
Resolution: 2.0cm ^-1
FIGS. 49 to 53 show IR spectra of the respective crystals.
Reference Example Reproduction of Example 3 described in Japanese Patent Application Laid-Open No. 9-255595. In Example 3 of Japanese Patent Application Laid-Open No. 9-255595, 2-amino-6- (4-methoxyphenylthio) -9- [2- ( There is no specific description on a method for obtaining crystals of phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester. Therefore, crystals were obtained by a method which can be inferred from only the information described in the publication, and the XRD pattern was measured under the same conditions as in Example 9.

  A substance obtained by reproducing Example 3 of JP-A-9-255699 was dissolved in 5% methanol-chloroform, the solvent was distilled off, the residue was washed with diisopropyl ether, and dried under vacuum to obtain crystals. The conditions for dissolving in methanol-chloroform and evaporating the solvent were changed as follows.

得られた各サンプルのＸＲＤパターンを上記実施例で得られた各結晶のＸＲＤパターンと比較したところ、サンプルＡはＣ／Ｘ形のＸＲＤパターンと一致し、その他のサンプルに関してはＣ形のＸＲＤパターンと一致した。即ち、特開平９−２５５６９５号公報に記載の内容から特定の結晶を得ようとしても、当該公報に記載されていない種々の条件により様々な結晶が得られることが判明した。

When the XRD pattern of each sample obtained was compared with the XRD pattern of each crystal obtained in the above example, the sample A matched the XRD pattern of the C / X type, and the XRD pattern of the C type for the other samples. And matched. That is, it was found that even if an attempt was made to obtain a specific crystal from the contents described in JP-A-9-255595, various crystals could be obtained under various conditions not described in the publication.

  From these results, it is clear that it is difficult to separately form a specific crystal only with the information described in JP-A-9-255699.

FIG. 3 is a view showing an XRD pattern of an A-type crystal. FIG. 3 is a view showing an XRD pattern of a B-type crystal. FIG. 3 is a view showing an XRD pattern of a C-type crystal. FIG. 3 is a view showing an XRD pattern of a C / X type crystal. FIG. 3 is a view showing an XRD pattern of a D-type crystal. FIG. 3 is a view showing an XRD pattern of an E-type crystal. FIG. 3 is a view showing an XRD pattern of an α-type crystal. FIG. 3 is a diagram showing an XRD pattern of an amorphous state. FIG. 3 is a view showing a DSC curve of an A-type crystal. FIG. 3 is a view showing a DSC curve of a B-type crystal. FIG. 3 is a view showing a DSC curve of a C-type crystal. FIG. 3 is a view showing a DSC curve of a C / X type crystal. FIG. 3 is a view showing a DSC curve of a D-type crystal. FIG. 3 is a view showing a DSC curve of an E-type crystal. FIG. 3 is a view showing a DSC curve of an α-form crystal. It is a figure which shows the DSC curve of an amorphous. It is a figure which shows the XRD-DSC data of a D-type crystal. FIG. 3 is a view showing TG / DTA data of an α-form crystal. FIG. 3 is a view showing an XRD pattern of an α-type crystal after heating. It is a figure which shows the SS-NMR spectrum of a type A crystal. It is a figure which shows the SS-NMR spectrum of a B-type crystal. It is a figure which shows the SS-NMR spectrum of a C-type crystal. It is a figure which shows the SS-NMR spectrum of a C / X type crystal. It is a figure which shows the SS-NMR spectrum of a D-type crystal. It is a figure which shows the SS-NMR spectrum of a form crystal. It is a figure which shows SS-NMR spectrum of an amorphous. 19 is a diagram showing an IR spectrum of the A-type crystal obtained in Example 12. FIG. 14 is a diagram showing an IR spectrum of a B-type crystal obtained in Example 12. FIG. 14 is a diagram showing an IR spectrum of the C-type crystal obtained in Example 12. FIG. 17 is a diagram showing an IR spectrum of the C / X-type crystal obtained in Example 12. FIG. 14 is a diagram showing an IR spectrum of a D-type crystal obtained in Example 12. FIG. It is a figure which shows the single crystal structure of a C-type crystal. FIG. 3 is a diagram showing a single crystal structure of an α-type crystal. It is a figure which shows the solubility curve of A type crystal, B type crystal, C type crystal, and D type crystal. FIG. 3 is a diagram showing an isothermal moisture absorption curve of an A-type crystal. It is a figure which shows the isothermal moisture absorption curve of a B-type crystal. It is a figure which shows the isothermal moisture absorption curve of a C-type crystal. FIG. 3 is a diagram showing an isothermal moisture absorption curve of a C / X type crystal. It is a figure which shows the isothermal moisture absorption curve of a D-type crystal. FIG. 3 is a view showing physical stability of Form A crystal. FIG. 3 is a view showing physical stability of a B-type crystal. FIG. 3 is a view showing physical stability of a C-type crystal. FIG. 3 is a view showing physical stability of a D-type crystal. FIG. 3 is a view showing an XRD pattern of a D-type crystal after storage at 60 ° C. for 5 days. FIG. 3 is a view showing the chemical stability of Form A crystal. It is a figure which shows the chemical stability of a B-type crystal. FIG. 4 is a view showing the chemical stability of Form C crystal. It is a figure which shows the chemical stability of a D-type crystal. 17 is an IR spectrum of Form A crystal obtained in Example 22. 23 is an IR spectrum of the B-type crystal obtained in Example 22. 15 is an IR spectrum of the C-type crystal obtained in Example 22. 14 is an IR spectrum of the C / X-type crystal obtained in Example 22. 19 is an IR spectrum of the D-type crystal obtained in Example 22.

Claims (94)

Crystals of 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester. The crystal according to claim 1, characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 27.9 ± 0.2 ° in a powder X-ray diffraction pattern;
(2) an endothermic peak at about 93 ° C. in differential scanning calorimetry;
(3) having a peak of a chemical shift of 24.0 ppm in a solid ³¹ P-NMR spectrum; and / or
(4) The infrared absorption spectrum has an absorption peak at 3192 ± 2 cm ⁻¹ . The crystal according to claim 1, characterized by any of the following physicochemical properties:
(1) In the powder X-ray diffraction pattern, diffraction peaks at 4.0, 8.2, 8.9, 10.0, 11.6, 12.0 and / or 13.2 (± 0.2 ° each). (2θ);
(2) an endothermic peak at about 93 ° C. in differential scanning calorimetry;
(3) having a peak of a chemical shift of 24.0 ppm in a solid ³¹ P-NMR spectrum; and / or
(4) The infrared absorption spectrum has an absorption peak at 3192 ± 2 cm ⁻¹ . The powder X-ray diffraction pattern has diffraction peaks (2θ) at 4.0, 8.2, 8.9, 10.0, 11.6, 12.0, and 13.2 (± 0.2 ° each). The crystal according to claim 3. In the powder X-ray diffraction pattern, 4.0, 8.2, 8.9, 10.0, 11.6, 12.0, 13.2, 15.5, 16.3, 19.1, 20.1 5. A diffraction peak (2θ) at 20.5, 20.9, 23.3, 23.8, 27.5 and / or 27.9 (± 0.2 ° each). The crystal according to the above. In the powder X-ray diffraction pattern, 4.0, 8.2, 8.9, 10.0, 11.6, 12.0, 13.2, 15.5, 16.3, 19.1, 20.1 The diffraction peak (2θ) at 20.5, 20.9, 23.3, 23.8, 27.5, and 27.9 (each ± 0.2 °). Crystal. 7. The crystal according to claim 2, which has a characteristic peak in the powder X-ray diffraction pattern shown in FIG. The crystal according to any one of claims 2 to 7, which has a characteristic thermal analysis pattern in differential scanning calorimetry shown in Fig. 9. The crystal according to claim 2, having a characteristic peak of a chemical shift in a solid-state ³¹ P-NMR spectrum shown in FIG. 20. The crystal according to any one of claims 2 to 9, which has no absorption peak at 3402 ± 5 cm ^-1 in an infrared absorption spectrum. In the infrared absorption spectrum, 3312.8, 3192.6, 1630.3, 1437.3, 1376.1, 1258.5, 1026.5, 839.3, 830.6 and / or 821.6 (cm respectively) The crystal according to claim 2, having an absorption peak at ( ⁻¹ , ± 0.5%). In the infrared absorption spectrum, 3312.8, 3192.6, 1630.3, 1437.3, 1376.1, 1258.5, 1026.5, 839.3, 830.6, and 821.6 (cm ^-1 respectively) The crystal according to any one of claims 2 to 11, which has an absorption peak at (± 0.5%). The crystal according to any one of claims 2 to 12, which shows a characteristic peak in an infrared absorption spectrum shown in Fig. 49. The crystal according to claim 1, characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 14.2 ± 0.1 ° in the powder X-ray diffraction pattern;
(2) in differential scanning calorimetry, having an endothermic peak and an exothermic peak at about 75 ° C. and / or having an endothermic peak at about 93 ° C .;
(3) having a peak of a chemical shift of 22.0 ppm and / or 23.7 ppm in a solid ³¹ P-NMR spectrum; and / or
(4) In the infrared absorption spectrum, it has an absorption peak at 3205 ± 2 cm ⁻¹ . In the powder X-ray diffraction pattern, 6.6 ± 0.1 °, 7.6 ± 0.1 °, 8.8, 11.1, 11.3, 12.4, 12.8, 13.2 and / or 15. The crystal according to claim 14, having a diffraction peak (2θ) at 14.2 ± 0.1 ° (± 0.2 ° unless otherwise specified). In the powder X-ray diffraction pattern, 6.6 ± 0.1 °, 7.6 ± 0.1 °, 8.8, 11.1, 11.3, 12.4, 12.8, 13.2 and 14 16. The crystal according to claim 14 or 15, having a diffraction peak (2θ) at 2 ± 0.1 ° (± 0.2 ° unless otherwise specified). In the powder X-ray diffraction pattern, 6.6 ± 0.1 °, 7.6 ± 0.1 °, 8.8, 11.1, 11.3, 12.4, 12.8, 13.2, 14 0.2 ± 0.1 °, 16.8, 17.2, 17.8, 18.2, 18.6, 19.2, 20.1, 20.4, 21.0, 22.7, 23. The crystal according to any one of claims 14 to 16, having a diffraction peak (2θ) at 0, 23.7, 24.8, 27.1, and / or 27.6. In the powder X-ray diffraction pattern, 6.6 ± 0.1 °, 7.6 ± 0.1 °, 8.8, 11.1, 11.3, 12.4, 12.8, 13.2, 14 0.2 ± 0.1 °, 16.8, 17.2, 17.8, 18.2, 18.6, 19.2, 20.1, 20.4, 21.0, 22.7, 23. The crystal according to any one of claims 14 to 17, which has diffraction peaks (2θ) at 0, 23.7, 24.8, 27.1, and 27.6. 19. The crystal according to claim 14, having a characteristic peak in the powder X-ray diffraction pattern shown in FIG. 20. The crystal according to any one of claims 14 to 19, which has an endothermic peak and an exothermic peak at about 75 ° C and an endothermic peak at about 93 ° C in differential scanning calorimetry. 21. The crystal according to claim 14, which has a characteristic thermal analysis pattern in differential scanning calorimetry shown in FIG. The crystal according to any one of claims 14 to 21, which has a peak of a chemical shift of 22.0 ppm and 23.7 ppm in a solid-state ³¹ P-NMR spectrum. The crystal according to any one of claims 14 to 22, which has a characteristic peak of a chemical shift in a solid-state ³¹ P-NMR spectrum shown in Fig. 21. 24. The crystal according to claim 14, which has an absorption peak at 3205 ± 5 cm ^-1 in an infrared absorption spectrum. In the infrared absorption spectrum, 3322.3, 3205.5, 1633.5, 1350.0, 1261.1, 1029.9, 826.8 and / or 660.1 (cm ⁻¹ , ± 0.5%, respectively) 25) The crystal according to any one of claims 14 to 24, which has an absorption peak in (1). In the infrared absorption spectrum, at 3322.3, 3205.5, 1633.5, 1350.0, 1261.1, 1029.9, 826.8, and 660.1 (cm ⁻¹ , ± 0.5%, respectively). 26. The crystal according to claim 14, which has an absorption peak. 27. The crystal according to claim 14, which exhibits a characteristic peak in the infrared absorption spectrum shown in FIG. The crystal according to claim 1, characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 6.4 ± 0.1 ° and / or 13.9 ± 0.1 ° in the powder X-ray diffraction pattern;
(2) an endothermic peak at about 93 ° C. in differential scanning calorimetry;
(3) having a peak of a chemical shift of 19.3 ppm and / or 22.7 ppm in a solid-state ³¹ P-NMR spectrum; and / or
(4) The infrared absorption spectrum has an absorption peak at 3402 ± 5 cm ⁻¹ . 29. The crystal according to claim 28, having a diffraction peak (2θ) at 6.4 ± 0.1 ° and 13.9 ± 0.1 ° in a powder X-ray diffraction pattern. In the powder X-ray diffraction pattern, 3.2, 6.4 ± 0.1 °, 9.6 ± 0.1 °, 12.3, 12.8, 13.3, 13.9 ± 0.1 ° and 30. The crystal according to claim 28 or 29, having a diffraction peak (2θ) at / or 14.8 (± 0.2 ° unless otherwise specified). In the powder X-ray diffraction pattern, 3.2, 6.4 ± 0.1 °, 9.6 ± 0.1 °, 12.3, 12.8, 13.3, 13.9 ± 0.1 ° and 31. The crystal according to claim 28, having a diffraction peak (2θ) at 14.8 (± 0.2 ° unless otherwise specified). In the powder X-ray diffraction pattern, 3.2, 6.4 ± 0.1 °, 9.6 ± 0.1 °, 12.3, 12.8, 13.3, 13.9 ± 0.1 °, 14.8, 16.0, 16.3, 16.8, 17.8, 18.9, 20.5, 21.1, 21.7, 22.4 and / or 23.3 (± unless otherwise specified) 32. The crystal according to claim 28, having a diffraction peak (2θ) at 0.2 °). In the powder X-ray diffraction pattern, 3.2, 6.4 ± 0.1 °, 9.6 ± 0.1 °, 12.3, 12.8, 13.3, 13.9 ± 0.1 °, 14.8, 16.0, 16.3, 16.8, 17.8, 18.9, 20.5, 21.1, 21.7, 22.4 and 23.3 (± 0. 33. The crystal according to claim 28, having a diffraction peak (2θ) at 2 °). The crystal according to any one of claims 28 to 33, having a characteristic peak in the powder X-ray diffraction pattern shown in Fig. 3. 35. The crystal according to claim 28, having a characteristic thermal analysis pattern in differential scanning calorimetry shown in FIG. The crystal according to any one of claims 28 to 35, which has a peak of a chemical shift of 19.3 ppm and 22.7 ppm in a solid-state ³¹ P-NMR spectrum. The crystal according to any one of claims 28 to 36, having a characteristic peak of a chemical shift in a solid-state ³¹ P-NMR spectrum shown in Fig. 22. In the infrared absorption spectrum, crystal according to any of claims 28 37 having an absorption peak at 3402 ± ^{5 cm -1} and / or 1438 ± ^{5 cm -1.} In the infrared absorption spectrum, crystal according to claim 28 having an absorption peak at 3402 ± ^{5 cm -1} and 1438 ± ^{5 cm -1} 38 of. In the infrared absorption spectrum, 3405.5, 3323.5, 3198.7, 1643.1, 1437.9, 1345.7, 1264.4, 1215.4, 1022.8, 839.1, 830.6 and 40. The crystal according to any one of claims 28 to 39, having an absorption peak at / or 660.3 (cm ^-1 , ± 0.5%, respectively). In the infrared absorption spectrum, 3405.5, 3323.5, 3198.7, 1643.1, 1437.9, 1345.7, 1264.4, 1215.4, 1022.8, 839.1, 830.6 and 41. The crystal according to any one of claims 28 to 40, having an absorption peak at 660.3 (cm ^-1 , ± 0.5%, respectively). The crystal according to any one of claims 28 to 41, which exhibits a characteristic peak in the infrared absorption spectrum shown in Fig. 51. The crystal according to claim 1, characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 7.5 ± 0.1 ° in a powder X-ray diffraction pattern;
(2) an endothermic peak at about 92 ° C. in differential scanning calorimetry;
(3) having a peak of a chemical shift of 18.4, 20.8 and / or 23.8 (all in ppm) in a solid ³¹ P-NMR spectrum; and / or
(4) The infrared absorption spectrum has an absorption peak at 3402 ± 5 cm ⁻¹ . The crystal according to claim 43, having a diffraction peak (2θ) at 3.2, 6.4, 9.6, and / or 13.3 (all ± 0.2 °) in the powder X-ray diffraction pattern. The crystal according to claim 42 or 44, having a diffraction peak (2θ) at 3.2, 6.4, 9.6, and 13.3 (all ± 0.2 °) in the powder X-ray diffraction pattern. In the powder X-ray diffraction pattern, 3.2, 6.4, 9.6, 12.3, 13.3, 16.8, 17.8, 18.9, 20.5 and / or 24.3 (any The crystal according to any one of claims 43 to 45, having a diffraction peak (2θ) at ± 0.2 °. In the powder X-ray diffraction pattern, 3.2, 6.4, 9.6, 12.3, 13.3, 16.8, 17.8, 18.9, 20.5 and 24.3 (all ±) The crystal according to any one of claims 43 to 46, having a diffraction peak (2θ) at 0.2 °). 48. The crystal according to claim 43, having a characteristic peak in the powder X-ray diffraction pattern shown in FIG. 49. The crystal according to claim 43, having a characteristic thermal analysis pattern in differential scanning calorimetry shown in FIG. 50. The crystal according to any one of claims 43 to 49, which has a peak of a chemical shift of 18.4, 20.8, and 23.8 (all in ppm) in a solid-state ³¹ P-NMR spectrum. 51. Any of claims 43 to 50 having a chemical shift peak of 18.4, 19.3, 20.8, 22.6 and / or 23.8 (all in ppm) in the solid-state ³¹ P-NMR spectrum. The crystals described. 52. The solid according to any one of claims 43 to 51, having a peak of a chemical shift of 18.4, 19.3, 20.8, 22.6 and 23.8 (all in ppm) in a solid-state ³¹ P-NMR spectrum. crystal. 53. The crystal according to any one of claims 43 to 52, having a characteristic peak of a chemical shift in a solid-state ³¹ P-NMR spectrum shown in Fig. 23. In the infrared absorption spectrum, 3405.2, 3324.3, 3198.4, 1643.1, 1437.9, 1345.8, 1263.9, 1215.3, 1022.8, 838.9, 830.4 and 54. The crystal according to any one of claims 43 to 53 having an absorption peak at / or at 660.7 (cm ^-1 , ± 0.5%, respectively). In the infrared absorption spectrum, 3405.2, 3324.3, 3198.4, 1643.1, 1437.9, 1345.8, 1263.9, 1215.3, 1022.8, 838.9, 830.4 and The crystal according to any one of claims 43 to 54, having an absorption peak at 660.7 (cm ^-1 , ± 0.5%, respectively). The crystal according to any one of claims 43 to 55, which exhibits a characteristic peak in an infrared absorption spectrum shown in Fig. 52. The crystal according to claim 1, characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 4.4, 9.2 and / or 25.5 (all ± 0.1 °) in the powder X-ray diffraction pattern;
(2) having an endothermic peak at about 78 ° C. and / or about 89 ° C. in differential scanning calorimetry;
(3) having a peak of a chemical shift of 24.2 and / or 27.2 (all in ppm) in a solid ³¹ P-NMR spectrum; and / or
(4) In the infrared absorption spectrum, it has an absorption peak at 3489 ± 2 cm ⁻¹ . 58. The crystal according to claim 57, having a diffraction peak (2θ) at 4.4, 9.2, and 25.5 (all ± 0.1 °) in the powder X-ray diffraction pattern. 4.4 ± 0.1, 8.2, 9.2 ± 0.1, 11.0, 11.7 and / or 13.2 (± 0.2 ° unless otherwise specified) in the powder X-ray diffraction pattern The crystal according to claim 57 or 58, having a diffraction peak (2θ). 4.4 ± 0.1 °, 8.2, 9.2 ± 0.1 °, 11.0, 11.7 and 13.2 (± 0.2 ° unless otherwise specified) in the powder X-ray diffraction pattern The crystal according to any one of claims 57 to 59, having a diffraction peak (2θ). 4.4 ± 0.1 °, 8.2, 9.2 ± 0.1 °, 11.0, 11.7, 13.2, 15.2, 15.8, 16. 0, 16.8, 17.0, 17.3, 17.6, 18.1, 18.6, 19.1, 19.7, 20.8, 21.6, 22.0, 23.0, The crystal according to any one of claims 57 to 60, having a diffraction peak (2θ) at 24.0 and / or 24.3 (± 0.2 ° unless otherwise specified). 4.4 ± 0.1 °, 8.2, 9.2 ± 0.1 °, 11.0, 11.7, 13.2, 15.2, 15.8, 16. 0, 16.8, 17.0, 17.3, 17.6, 18.1, 18.6, 19.1, 19.7, 20.8, 21.6, 22.0, 23.0, 62. The crystal according to any one of claims 57 to 61, having a diffraction peak (2θ) at 24.0 and 24.3 (± 0.2 ° unless otherwise specified). 63. The crystal according to claim 57, having a characteristic peak in the powder X-ray diffraction pattern shown in FIG. 64. The crystal according to any one of claims 57 to 63, which has an endothermic peak at about 78 ° C and about 89 ° C in differential scanning calorimetry. 65. The crystal according to any one of claims 57 to 64, having a characteristic thermal analysis pattern in differential scanning calorimetry shown in Fig. 13. The crystal according to any one of claims 57 to 65, having a peak of a chemical shift of 24.2 and 27.2 (all in ppm) in a solid-state ³¹ P-NMR spectrum. The crystal according to any one of claims 57 to 66, having a characteristic peak of a chemical shift in a solid-state ³¹ P-NMR spectrum shown in Fig. 24. In the infrared absorption spectrum, 3490.4, 3346.2, 3211.3, 1645.5, 1449.9, 1375.7, 1362.8, 1263.1, 1251.3, 1223.9, 1212.3, 68. The crystal according to any of claims 57 to 67 having an absorption peak at 1122.6, 1002.8, 888.9, 830.1 and / or 821.2 (cm ^-1 , ± 0.5% respectively). . In the infrared absorption spectrum, 3490.4, 3346.2, 3211.3, 1645.5, 1449.9, 1375.7, 1362.8, 1263.1, 1251.3, 1223.9, 1212.3, 69. The crystal according to any one of claims 57 to 68, having an absorption peak at 1122.6, 1002.8, 888.9, 830.1, and 821.2 (cm ^-1 , ± 0.5%, respectively). The crystal according to any one of claims 57 to 69, which exhibits a characteristic peak in an infrared absorption spectrum shown in Fig. 53. The crystal according to claim 1, characterized by any of the following physicochemical properties:
(1) shows a characteristic peak in the powder X-ray diffraction pattern shown in FIG. 6; and / or
(2) In differential scanning calorimetry, an endothermic peak is observed at about 93 ° C. 73. The crystal according to claim 71, which shows a characteristic thermal analysis pattern in the differential scanning calorimetry shown in Fig. 14. The crystal according to claim 1, characterized by any of the following physicochemical properties:
(1) having a diffraction peak (2θ) at 4.9 ± 0.2 ° and / or 7.2 ± 0.1 ° in the powder X-ray diffraction pattern;
(2) having an endothermic peak at about 64 ° C. in differential scanning calorimetry; and / or
(3) In a solid-state ³¹ P-NMR spectrum, it has a peak of a chemical shift of 25.6 ppm. 74. The crystal according to claim 73, having a diffraction peak (2θ) at 4.9 ± 0.2 ° and 7.2 ± 0.1 ° in the powder X-ray diffraction pattern. In the powder X-ray diffraction pattern, diffraction peaks at 4.9, 7.2 ± 0.1 °, 9.8, 11.1, 11.8, and / or 14.7 (± 0.2 ° unless otherwise specified) 75. The crystal according to claim 73 or 74, having (2θ). In the powder X-ray diffraction pattern, diffraction peaks (2θ) were found at 4.9, 7.2 ± 0.1 °, 9.8, 11.1, 11.8, and 14.7 (± 0.2 ° unless otherwise specified). 77. A crystal according to any of claims 73 to 75 having the formula: In the powder X-ray diffraction pattern, 4.9, 7.2 ± 0.1 °, 9.8, 11.1, 11.8, 14.7, 18.6, 20.2, 20.3, 21. 77. The crystal according to any of claims 73 to 76, having a diffraction peak (2θ) at 1, 21.6, 25.0 and / or 29.9 (± 0.2 ° unless otherwise specified). 4.9, 7.2 ± 0.1 °, 9.8, 11.1, 11.8, 14.7, 18.6, 20.2, 20.3, 21.1 in powder X-ray diffraction pattern 78. The crystal according to any of claims 73 to 77 having diffraction peaks (2θ) at, 21.6, 25.0 and 29.9 (± 0.2 ° unless otherwise specified). The crystal according to any one of claims 73 to 78, having a characteristic peak in the powder X-ray diffraction pattern shown in Fig. 7. The crystal according to any one of claims 73 to 79, having a characteristic thermal analysis pattern in differential scanning calorimetry shown in Fig. 15. The crystal according to any one of claims 73 to 80, having a characteristic peak of a chemical shift in a solid-state ³¹ P-NMR spectrum shown in Fig. 25. Amorphous 2-amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester. 83. The amorphous of claim 82, characterized by any of the following physicochemical properties:
(1) shows a characteristic peak in the powder X-ray diffraction pattern shown in FIG. 8;
(2) does not show a distinct endothermic peak in differential scanning calorimetry; and / or
(3) It has a characteristic peak in the solid-state ³¹ P-NMR spectrum shown in FIG. 83. The amorphous material according to claim 82, having a characteristic thermal analysis pattern in differential scanning calorimetry shown in Fig. 16. A pharmaceutical composition comprising the crystal or amorphous according to any one of claims 1 to 84 as an active ingredient. 86. The pharmaceutical composition according to claim 85 for use as an antiviral agent. 87. The pharmaceutical composition according to claim 86, wherein the virus is selected from hepatitis B virus and varicella-zoster virus. 2-Amino-6- (4-methoxyphenylthio) -9- [2- (phosphonomethoxy) ethyl] purine bis (2,2,2-trifluoroethyl) ester is precipitated from isopropanol and n-heptane solution. 43. The method for producing a crystal according to claim 28, comprising a step. The method for producing a crystal according to any one of claims 2 to 27, 43 to 70 and 73 to 81, and a crystal according to any one of claims 28 to 42 using the amorphous material according to any one of claims 82 to 84. . 90. The method according to claim 89, wherein the crystal according to any one of claims 73 to 81 is used. 90. The production method according to claim 89, further comprising a step of suspending the crystal according to any one of claims 73 to 81 in an n-heptane solvent. 90. The method according to claim 89, further comprising the step of washing the crystals according to any one of claims 73 to 81 in a mixed solvent of isopropanol and n-heptane. The manufacturing method according to claim 89, wherein the crystal according to any one of claims 43 to 56 is used. The production method according to claim 89, further comprising a step of suspending the crystal according to any one of claims 43 to 56 in a mixed solvent of isopropanol and n-heptane.

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