Crystalline forms and processes for the preparation of cannabinoid receptor modulators
The present invention relates to crystalline forms 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 (Compound 1) and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB 2 receptor and are therefore useful in the treatment of CB 2 receptor-mediated disorders, for example, osteoarthritis; pain; hyperalgesia; allodynia; inflammatory hyperalgesia; neuropathic hyperalgesia; acute nociception; osteoporosis; multiple sclerosis-associated spasticity; autoimmune disorders; allergic reactions; CNS inflammation for example; atherosclerosis; undesired immune cell activity, and inflammation associated with a disorder selected from: osteoarthritis, anaphylaxis, Behcet's disease, graft rejection, vasculitis, gout, spondylitis, viral disease, bacterial disease, lupus, inflammatory bowel disease, autoimmune hepatitis, and type 1 diabetes mellitus; age-related macular degeneration; cough; leukemia; lymphoma; CNS tumors; prostate cancer; Alzheimer's disease; stroke-induced damage; dementia; amyotrophic lateral sclerosis; and Parkinson's disease.
1. An acetone solvate 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, wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.3°±0.2°, and 25.0°±0.2°.
2. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a powder X-ray diffraction pattern further comprising peaks, in terms of 2θ, at 8.3°±0.2°, 25.0°±0.2°, and 16.6°±0.2°.
3. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a powder X-ray diffraction pattern further comprising peaks, in terms of 2θ, at 8.3°±0.2°, 25.0°±0.2°, 16.6°±0.2°, 17.3°±0.2°, and 11.0°±0.2°.
4. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a powder X-ray diffraction pattern further comprising peaks, in terms of 2θ, at 8.3°±0.2°, 25.0°±0.2°, 16.6°±0.2°, 17.3°±0.2°, 11.0°±0.2°, 10.1°±0.2°, and 26.0°±0.2°.
5. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a powder X-ray diffraction pattern further comprising peaks, in terms of 2θ, at 8.3°±0.2°, 25.0°±0.2°, 16.6°±0.2°, 17.3°±0.2°, 11.0°±0.2°, 10.1°±0.2°, 26.0°±0.2°, 7.1°±0.2°, and 22.7°±0.2°.
6. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a powder X-ray diffraction pattern further comprising peaks, in terms of 2θ, at 8.3°±0.2°, 25.0°±0.2°, 16.6°±0.2°, 17.3°±0.2°, 11.0°±0.2°, 10.1°±0.2°, 26.0°±0.2°, 7.1°±0.2°, 22.7°±0.2°, 13.7°±0.2°, 16.1°±0.2°, and 25.6°±0.2°.
7. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 158.0° C. and about 168.0° C.
8. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 159.0° C. and about 167.0° C.
9. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a thermogravimetric analysis profile showing about 6.0% weight loss below about 150° C.
10. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has a thermogravimetric analysis profile showing about 5.75% weight loss below about 150° C.
11. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has:
1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.3°±0.2° and 25.0°±0.2°;
2) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 158.0° C. and about 168.0° C.; and/or
3) a thermogravimetric analysis profile showing about 6.0% weight loss below about 150° C.
12. The acetone solvate crystalline form according to claim 1 , wherein said crystalline form has:
1) a powder X-ray diffraction pattern substantially as shown in FIG. 8 ;
2) a differential scanning calorimetry thermogram substantially as shown in FIG. 9 ; and/or
3) a thermogravimetric analysis profile substantially as shown in FIG. 9 .
13. A composition comprising an acetone solvate 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 12 .
14. A pharmaceutical composition comprising an acetone solvate 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 12 , and a pharmaceutically acceptable carrier.
15. A unit dosage form comprising an acetone solvate 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 12 , and a pharmaceutically acceptable carrier.
16. A process of making a pharmaceutical composition comprising admixing an acetone solvate 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 12 with a pharmaceutically acceptable carrier.
17. A process of making a unit dosage form comprising admixing an acetone solvate 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 12 with a pharmaceutically acceptable carrier; and subdividing the admixture into unit dosage forms, each of which comprises a therapeutically effective amount of the acetone solvate 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.
18. A method for the treatment of pain in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of an acetone solvate crystalline form according to claim 12 .
19. A method for the treatment of pain in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of an acetone solvate crystalline form according to claim 12 ; 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.
20. A method for the treatment of osteoporosis in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of an acetone solvate crystalline form according to claim 12 .