Crystalline forms and processes for the preparation of cannabinoid receptor modulators

1. A process for preparing an anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide comprising the steps of:

1) crystallizing (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide from a crystallizing mixture to obtain a crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide in said crystallizing mixture, wherein said crystallizing mixture comprises acetonitrile and water; and

2) isolating said crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide from said crystallizing mixture to obtain said anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.

2. The process according to claim 1 , wherein said crystallizing is conducted at a temperature of about −5° C. to about 5° C.

3. The process according to claim 1 , wherein said crystallizing mixture is prepared by the steps of:

1) dissolving (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide in acetonitrile and a first amount of water to form a first mixture; and

2) adding a second amount of water to said first mixture to obtain said crystallizing mixture.

4. The process according to claim 3 , wherein said dissolving is conducted at a temperature of about 58° C. to about 62° C.

5. The process according to claim 3 , wherein the molar ratio present in said first mixture between (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide, acetonitrile, and first amount water is about 1.0:9.2:37.0 to about 1.0:10.2:41.7.

6. The process according to claim 3 , wherein said adding of said second amount of water to said first mixture is conducted at a rate that the temperature of the mixture of said second amount of water together with said first mixture is at about 25° C. to about 80° C.

7. The process according to claim 3 , wherein the molar ratio present in said crystallizing mixture between (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide, acetonitrile, and water in said crystallizing mixture is about 1.0:9.2:414.7 to about 1.0:10.2:458.3.

8. The process according to claim 3 , wherein (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide prior to said dissolving step is selected from the group consisting of:

1) a dichloromethane solvate of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;

2) an acetone solvate of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;

3) a non-selective solvate of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide; and

4) an ethyl acetate solvate of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide; and

mixtures thereof.

9. The process according to claim 1 , wherein said isolating comprises filtering said crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide from said crystallizing mixture.

10. The process according to claim 1 , wherein said isolating comprises removing said crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide from said crystallizing mixture.

11. The process according to claim 1 , further comprises the step of drying said crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide to obtain said anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.

12. The process according to claim 11 , wherein said drying is conducted at a temperature of about 15° C. to about 80° C.

13. The process according to claim 11 , wherein said drying is conducted at a pressure of less than 760 mm Hg and a temperature of about 55° C. to about 65° C.

14. The process according to claim 1 , wherein after said isolating, said anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide has a chemical purity of about 98% or greater.

15. The process according to claim 1 , wherein after said isolating, said anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide has an enantiomeric excess of about 98% or greater.

16. The process according to claim 1 , wherein after said isolating, said anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide has a chemical purity of about 99% or greater and an enantiomeric excess of about 99% or greater.

17. A process for preparing a pharmaceutical composition comprising the steps of:

1) preparing an anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide according to claim 1 ; and

2) admixing said anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide with a pharmaceutically acceptable carrier.

18. A process for preparing a dosage form comprising the steps of:

1) preparing an anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide according to claim 1 ; and

2) admixing said anhydrous crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide with a pharmaceutically acceptable carrier.

19. An anhydrous non-solvated crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.

20. The anhydrous non-solvated crystalline form according to claim 19 , wherein said anhydrous crystalline form has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.5°±0.2°, and 10.7°±0.2°.

21. The anhydrous non-solvated crystalline form according to claim 19 , wherein said anhydrous crystalline form has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.5°±0.2°, 10.7°±0.2°, and 16.9°±0.2°.

22. The anhydrous non-solvated crystalline form according to claim 19 , wherein said anhydrous crystalline form has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.5°±0.2°, 10.7°±0.2°, 16.9°±0.2°, 25.4°±0.2°, and 11.1°±0.2°.

23. The anhydrous non-solvated crystalline form according to claim 19 , wherein said anhydrous crystalline form has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.5°±0.2°, 10.7°±0.2°, 16.9°±0.2°, 25.4°±0.2°, 11.1°±0.2°, 9.8°±0.2°, and 17.4°±0.2°.

24. The anhydrous non-solvated crystalline form according to claim 19 , wherein said anhydrous crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 159.6° C. and about 169.6° C.

25. The anhydrous non-solvated crystalline form according to claim 19 , wherein said anhydrous crystalline form has a thermogravimetric analysis profile showing about 0.5% weight loss below about 135° C.

26. The anhydrous non-solvated crystalline form according to claim 19 , wherein said anhydrous crystalline form has:

1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.5°±0.2°, and 10.7°±0.2°;

2) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 159.6° C. and about 169.6° C.; and/or

3) a thermogravimetric analysis profile showing about 0.5% weight loss below about 135° C.

27. A composition comprising an anhydrous non-solvated crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide according to claim 19 .

28. A pharmaceutical composition comprising an anhydrous non-solvated crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide according to claim 19 , and a pharmaceutically acceptable carrier.

29. A unit dosage form comprising an anhydrous non-solvated crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide according to claim 19 , and a pharmaceutically acceptable carrier.

30. A process of making a pharmaceutical composition comprising admixing an anhydrous non-solvated crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide according to claim 19 with a pharmaceutically acceptable carrier.

31. A process of making a unit dosage form comprising admixing an anhydrous non-solvated crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide according to claim 19 with a pharmaceutically acceptable carrier; and subdividing the admixture into unit dosage forms, each of which comprises a therapeutically effective amount of the anhydrous non-solvated crystalline form of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide.

32. A method for the treatment of pain in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of an anhydrous non-solvated crystalline form according to claim 19 .

33. A method for the treatment of pain in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of an anhydrous non-solvated crystalline form according to claim 19 ; wherein said pain is associated with one or more disorders selected from the group consisting of: bone pain, joint pain, muscle pain, dental pain, migraine pain, headache pain, inflammatory pain, neuropathic pain, pain that occurs as an adverse effect of a therapeutic, osteoarthritis pain, cancer pain, multiple sclerosis pain, allergic reactions, nephritic syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, HIV related-neuropathy, sciatica, and an autoimmune condition.

34. A method for the treatment of osteoporosis in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of an anhydrous non-solvated crystalline form according to claim 19 .