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1. (WO2015100144) CRYSTALLINE FORMS OF A MACROCYCLIC HCV NS3 INHIBITING TRIPEPTIDE
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

WHAT IS CLAIMED IS:

1. A crystalline form of compound I:


wherein, the crystalline form is an ethanol solvate (Compound I Form I), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.6, 11.1, and 15.5 °2Θ as determined on a diffractometer using Cu-Κα radiation.

2. Compound I Form I according to claim 1 , further comprising:

i) a peak at 12.9 °2Θ ± 0.2°;

ii) the diffractogram substantially as shown in Figure 1 ;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 2;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 3;

v) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 4; or

vi) a nuclear magnetic resonance spectrum (1H NMR) substantially as shown in Figure 5.

3. Compound I Form I according to claim 1 comprising about 1.7 mole equivalents of ethanol.

4. A crystalline form of compound I:


wherein, the crystalline form is an ethyl acetate solvate (Compound I Form II) characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.7, 13.0, and 17.4 °2Θ, as determined on a diffractometer using Cu-Κα radiation.

5. Compound I Form II according to claim 4, further comprising:

i) a peak at 15.4 °2Θ ± 0.2°;

ii) a diffractogram substantially as shown in Figure 6;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 7;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 8;

v) a nuclear magnetic resonance spectrum (1H NMR) substantially as shown in Figure 9; or

vi) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 10.

6. Compound I Form II according to claim 4 comprising about 1 mole equivalents of ethyl acetate.

7. A crystalline form of compound I:


wherein, the crystalline form is an isopropanol solvate (Compound I Form III), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 11.1 , 12.8, and 19.7 °2Θ as determined on a diffractometer using Cu-Κα radiation.

8. Compound I Form III according to claim 7, further comprising:

i) a peak at l5.5 °20 ± O.2°;

ii) a diffractogram substantially as shown in Figure 12;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 13;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 14;

v) a nuclear magnetic resonance spectrum (1H NMR) substantially as shown in Figure 15; or

vi) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 16.

9. Compound I Form III according to claim 7 comprising about 0.6 mole equivalents of isopropanol.

10. A crystalline form of compound I:


wherein, the crystalline form is a dihydrate (Compound I Form IV), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.7, 8.9, and 16.0 °2Θ as determined on a diffractometer using Cu-Κα radiation.

11. Compound I Form IV according to claim 10, further comprising:

i) a peak at 13.0 °2Θ ± 0.20°;

ii) a diffractogram substantially as shown in Figure 17;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 18;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure

19;

v) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 20; or

vi) a nuclear magnetic resonance spectrum ( H NMR) substantially as shown in Figure 21.

12. A crystalline form of compound I:


wherein, the crystalline form is a methanol solvate (Compound I Form V), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.2, 12.4, and 19.6 °2Θ as determined on a diffractometer using Cu-Κα radiation.

13. Compound I Form V according to claim 12, further comprising:

i) a peak at 13.7 °2Θ ± 0.20°;

ii) a diffractogram substantially as shown in Figure 22;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 23; or

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 24.

14. Compound I Form V according to claim 12 comprising about >1 to about 2.5 mole equivalent of methanol.

15. A crystalline form of compound I:


wherein, the crystalline form is anhydrous (Compound I Form VI), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 14.6, 15.4, and 20.0 °2Θ as determined on a diffractometer using Cu-Κα radiation.

16. Compound I Form VI according to claim 15, further comprising:

i) a peak at 18.1 °2Θ ± 0.2°;

ii) a diffractogram is substantially as shown in Figure 27;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 28; or

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 29.

17. Compound I Form VI according to claim 15, characterized by a dynamic vapor sorption (DVS) curve substantially as shown in Figure 30.

18. A crystalline form of compound I:


wherein, the crystalline form is anhydrous (Compound I Form VII), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.5, 8.5, and 18.7 °2Θ as determined on a diffractometer using Cu-Κα radiation.

19. Compound I Form VII according to claim 18, further comprising:

i) a peak at l7.5 °20 ± O.2°.

ii) a diffractogram substantially as shown in Figure 31 ;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 32;

iv) a nuclear magnetic resonance spectrum (1H NMR) substantially as shown in Figure 33;

v) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 34; or

vi) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 35.

20. A crystalline form of compound I:


wherein, the crystalline form is anhydrous (Compound I Form VIII), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.8, 8.2, and 20.2 °2Θ as determined on a diffractometer using Cu-Κα radiation.

21. Compound I Form VIII according to claim 20, further comprising:

i) a peak at l6.5 °20 ± O.2°;

ii) a diffractogram substantially as shown in Figure 36;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 37;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 38; or

v) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 39.

22. A crystalline form of compound I:


wherein, the crystalline form is anhydrous (Compound I Form IX), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.1, 9.5, and 19.4 °2Θ as determined on a diffractometer using Cu-Κα radiation.

23. Compound I Form IX according to claim 22, further comprising:

i) a peak at 2O.8 °20 ± O.2°;

ii) a diffractogram substantially as shown in Figure 40;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 41;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 42; or

v) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 43.

24. A crystalline form of compound I:


wherein, the crystalline form is a hemihydrate (Compound I Form X), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.0, 19.0, and 20.4 °2Θ as determined on a diffractometer using Cu-Κα radiation.

25. Compound I Form X according to claim 24, further comprising:

i) a peak at 13.9 °2Θ ± 0.2°;

ii) a diffractogram substantially as shown in Figure 44;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 45;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 46; or

v) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 47.

26. Compound I Form X according to claim 24 comprising about 0.58 mole equivalent of water.

27. A crystalline form of compound I:


wherein, the crystalline form is a dihydrate (Compound I Form XI), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 11.0, 13.9, and 20.9 °2Θ as determined on a diffractometer using Cu-Κα radiation.

28. Compound I Form XI according to claim 27, further comprising:

i) a peak at 15.2 °2Θ ± 0.2°;

ii) a diffractogram substantially as shown in Figure 48.

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 49;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 50; or

v) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 51.

29. Compound I Form XI according to claim 27 comprising about 2.3 mole equivalents of water.

30. A crystalline form of compound I:


wherein, the crystalline form is a tetrahydrate (Compound I Form XII), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 12.4, 14.6, and 19.3 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation.

31. Compound I Form XII according to claim 30, further comprising:

i) a peak at 15.4 °2Θ ± 0.2 °2Θ;

ii) a diffractogram is substantially as shown in Figure 52;

iii) a differential scanning calorimetry (DSC) curve substantially as shown in Figure 53;

iv) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in Figure 54; or

v) a dynamic vapor sorption (DVS) curve substantially as shown in Figure 55.

32. Compound I Form XII according to claim 30 comprising about 3.7 mole equivalents of water.

33. A pharmaceutical composition comprising a compound selected from the group consisting of Compound I Form I according to claim 1 , Compound I Form II according to claim 4, Compound I Form III according to claim 7, Compound I Form IV according to claim 10, Compound I Form V according to claim 12, Compound I Form VI according to claim 15, Compound I Form VII according to claim 18, Compound I Form VIII according to claim 20, Compound I Form IX according to claim 22, Compound I Form X according to claim 24,

Compound I Form XI according to claim 27, and Compound I Form XII according to claim 30, and a pharmaceutically acceptable excipient.

34. A method for treating a subject suffering from hepatitis C virus (HCV), comprising administering to the subject a therapeutically effective amount of Compound I Form I according to claim 1, Compound I Form II according to claim 4, Compound I Form III according to claim 7, Compound I Form IV according to claim 10, Compound I Form V according to claim 12, Compound I Form VI according to claim 15, Compound I Form VII according to claim 18, Compound I Form VIII according to claim 20, Compound I Form IX according to claim 22, Compound I Form X according to claim 24, Compound I Form XI according to claim 27, or Compound I Form XII according to claim 30, and a pharmaceutically acceptable excipient.

35. The method according to claim 34, comprising further administering to the subject at least one anti-HCV agent.

36. A process for making a crystalline form of compound I:


wherein, the crystalline form is an ethanol solvate (Compound I Form I), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 8.6, 11.1, and 15.5 °2Θ as determined on a diffractometer using Cu-Κα radiation, comprising the step of

( 1 ) contacting (laR,5S,8S,9S, 10R,22aR)-5-tert-butyl-N-[( li?,2i?)-2-(difluoromethyl)- 1 - {[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14- methoxy-3 ,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12- ¾]quinoxaline-8-carboxamide with ethanol,

whereby Compound I Form I is formed.

37. A process for making a crystalline form of compound I:


wherein, the crystalline form is an ethyl acetate solvate (Compound I Form II), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 8.7, 13.0, and 17.4 0 as determined on a diffractometer using Cu-Κα radiation, comprising the step of

( 1 ) contacting (1 aR,55,85,9S, 10R,22aR)-5-tert-butyl-N-[( lR,2R)-2-(difluoramethyl)- 1 - {[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14- methoxy-3 ,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecmo [11,12- ¾]quinoxaline-8-carboxamide with ethyl acetate,

whereby Compound I Form II is formed.

38. A process for making a crystalline form of compound I:

wherein, the crystalline form is an isopropanol solvate (Compound I Form III), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 11.1, 12.8, and 19.7 °2Θ as determined on a diffractometer using Cu-Κα radiation, comprising the step of

( 1 ) contacting (1 aR,55,85,9S, 10R,22aR)-5-tert-butyl-N-[( lR,2R)-2-(difluoramethyl)- 1 - {[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14- methoxy-3 ,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12- ¾]quinoxaline-8-carboxamide with isopropanol,

whereby Compound I Form III is formed.

39. A process for making a crystalline form of compound I:


wherein, the crystalline form is a dihydrate (Compound I Form IV), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 8.7, 8.9, and 16.0 °2Θ, as determined on a diffractometer using Cu-Κα radiation, comprising the step of

( 1 ) placing (laR,5S,SS,9S, 10i?,22ai?)-5-tert-butyl-N-[(li?,2i?)-2-(difluoromethyl)- 1 - { [( 1 - methylcyclopropyl)sulfonyl]carbamoyl} cyclopropyl]-9-ethyl- 18,18-difluoro- 14- methoxy-3 ,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12- ¾]quinoxaline-8-carboxamide ethanol solvate (Compound I Form I) characterized by an X-ray powder diffractogram comprising peaks at 8.7, 13.0, and 17.4 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation, at about 40 °C and about 75% relative humidity (R.H.),

whereby Compound I Form IV is formed.

40. A process for making a crystalline form of compound I:


wherein, the crystalline form is a methanol solvate (Compound I Form V), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 6.2, 12.4, and 19.6 °2Θ as determined on a diffractometer using Cu-Κα radiation, comprising the step of

( 1 ) contacting (1 aR,55,85,9S, 10R,22aR)-5-tert-butyl-N-[( lR,2R)-2-(difluoramethyl)- 1 - {[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14- methoxy-3 ,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecmo [11,12- ¾]quinoxaline-8-carboxamide with methanol,

whereby Compound I Form V is formed.

41. A process for making a crystalline form of compound I:

wherein, the crystalline form is anhydrous (Compound I Form VI), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 14.6, 15.4, and 20.0 °2Θ as determined on a diffractometer using Cu-Κα radiation, comprising the step of

(1) heating crystalline (laR,55,8S,9S,10R,22a/¾)-5-ieri-butyl-N-[(lR,2R)-2- (difluoromethyl)- 1 - { [( 1 -methylcyclopropyl)sulfonyl]carbamoyl} cyclopropyl]-9- ethyl-18,18-difiuoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a- tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12- ¾]quinoxaline-8-carboxamide methanol solvate (Compound I Form V) to about 70 °C,

whereby Compound I Form VI is formed.

42. A process for making a crystalline form of compound I:


wherein, the crystalline form is anhydrous (Compound I Form VII), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 6.5, 8.5, and 18.7 °2Θ, as determined on a diffractometer using Cu-Κα radiation, comprising the step of

(1) heating crystalline (laR,55,8S,9S,10R,22a/¾)-5-ieri-butyl-N-[(lR,2R)-2- (difluoromethyl)- 1 - { [( 1 -methylcyclopropyl)sulfonyl]carbamoyl} cyclopropyl]-9- ethyl-18,18-difiuoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a- tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12- ¾]quinoxaline-8-carboxamide ethanol solvate (Compound I Form I) to about 240 °C, whereby Compound I Form VII is formed.

43. A process for making a crystalline form of compound I:


wherein, the crystalline form is anhydrous (Compound I Form VIII), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 7.8, 8.2, and 20.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation, comprising the steps of

(1) contacting crystalline (laR,55,8S,9S,10R,22a/¾)-5-ieri-butyl-N-[(lR,2R)-2- (difluoromethyl)- 1 - { [( 1 -methylcyclopropyl)sulfonyl]carbamoyl} cyclopropyl]-9- ethyl-18,18-difiuoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a- tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12- ¾]quinoxaline-8-carboxamide (anhydrous, Compound I Form VI) with water and heating at about 85 °C in a container; and

(2) adding crystalline (laR,55, 85,95, 10R,22aR)-5-tert-butyl-N-[(lR,2R)-2- (difluoromethyl)- 1 - { [( 1 -methylcyclopropyl)sulfonyl]carbamoyl} cyclopropyl]-9- ethyl-18,18-difiuoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a- tetradecahydro-8H-7, 10- methanocyclopropa[ 18 , 19] [ 1 , 10,3 ,6] dioxadiazacyclononadecino [11,12- ¾]quinoxaline-8-carboxamide methanol solvate (Compound I Form V) in a mixture of acetone and water (1 :4 by volume) to the container of step (1) and heating at about 85 °C,

whereby Compound I Form VIII is formed.

A process for making a crystalline form of compound I


wherein, the crystalline form is anhydrous (Compound I Form IX), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 6.1, 9.5, and 19.4 °2Θ as determined on a diffractometer using Cu-Κα radiation, comprising the steps of contacting

(lai?,5lS,8lS,9lS,10i?,22ai?)-5-fert-butyl-N-[(li?,2i?)-2-(difluoromethyl)-l-{[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18, 19] [ 1 , 10,3,6]dioxadiazacyclononadecino[ 11 , 12-£]quinoxaline-8-carboxamide with 1 : 1 heptane/toluene at about 60 °C, whereby Compound I Form IX is formed.

45. A process for making a crystalline form of compound I:


wherein, the crystalline form is a hemihydrate (Compound I Form X), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 8.0, 19.0, and 20.4 °2Θ as determined on a diffractometer using Cu-Κα radiation, comprising the steps of contacting

(1 ai?,5S,8S,9S, 10 ?,22a ?)-5-te^bu^

methylcyclopropyl)sulfonyl]carbamoyl}cyclopro^

dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18, 19] [ 1 , 10,3,6]dioxadiazacyclononadecino[ 11 , 12-£]quinoxaline-8-carboxamide with water and heating to about 80 °C, whereby Compound I Form X is formed.

46. A process for making a crystalline form of compound I:


wherein, the crystalline form is a dihydrate (Compound I Form XI), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 11.0, 13.9, and 20.9 °2Θ as determined on a diffractometer using Cu-Κα radiation, comprising the steps of contacting

(lai?,5lS,8lS,9lS,10i?,22ai?)-5-fert-butyl-N-[(li?,2i?)-2-(difluoromethyl)-l-{[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18, 19] [ 1 , 10,3,6]dioxadiazacyclononadecino[ 11 , 12-£]quinoxaline-8-carboxamide EtOH:water in a ratio of 1 : 1 , 6:4, or 7:3 (v/v), whereby Compound I Form XI is formed.

A process for making a crystalline form of compound I


wherein, the crystalline form is a tetrahydrate (Compound I Form XII), characterized by an X-ray powder diffractogram comprising peaks (± 0.2°) at 12.4, 14.6, and 19.3 °2Θ as determined on a diffractometer using Cu-Κα radiation, comprising the steps of contacting

(lai?,5lS,8lS,9lS,10i?,22ai?)-5-fert-butyl-N-[(li?,2i?)-2-(difluoromethyl)-l-{[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo- 1 , 1 a,3 ,4,5 ,6,9, 10, 18, 19,20,21 ,22,22a-tetradecahydro-8H-7, 10-methanocyclopropa[ 18, 19] [ 1 , 10,3,6]dioxadiazacyclononadecino[ 11 , 12-£]quinoxaline-8-carboxamide with EtOH:water in a ratio of 4:6 or 1 : 1 (v/v), or acetonitrile: water in a ratio of 2:8, 3:7 or 4:6, or 2:8, 3:7, or acetone:water in a ratio of 4:6 or 1 : 1 (v/v), whereby Compound I Form XII is formed.