Compounds, compositions and methods
The disclosed subject matter provides certain polymorphic forms of Compound (I) as well as pharmaceutical compositions comprising Compound (I) or such polymorphic forms, and methods of using or making such compounds and pharmaceutical compositions. It has now been discovered that Compound (I) can exist in multiple crystalline forms (polymorphs). One particular crystalline form, Form II, has been found to be more thermodynamically stable and, thus, likely more suitable for bulk preparation and handling than other polymorphic forms. Efficient and economic methods have been developed to prepare Compound (I) and Form II in high purity on a large scale. In animal studies, Form II has demonstrated safety and efficacy in treating depressive disorders and, when micronized, improved absorption compared to non-micronized Form II.
1. Crystalline Form II of compound (I), which is at least about 90% pure,
exhibiting
an X-ray powder diffraction pattern, obtained using copper Kα radiation, comprising a peak of 2-theta angle of about 5.9 degree.
2. Crystalline Form II of claim 1 , wherein the X-ray powder diffraction pattern comprises peaks of 2-theta angles of about 5.9 and 8.8 degrees.
3. Crystalline Form II of claim 1 , wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 1A .
4. Crystalline Form II of claim 1 , which further exhibits at least one of:
an ultraviolet absorbance spectrum, obtained using methanol as diluent, substantially as shown in FIG. 2 ;
an infrared spectrum substantially as shown in FIG. 3 ;
a thermogravimetric analysis curve substantially as shown in FIG. 6 ; and
a differential scanning calorimetry thermogram substantially as shown in FIG. 7 .
5. Crystalline Form II of claim 4 , wherein the differential scanning calorimetry thermogram of the compound is substantially as shown in FIG. 7 .
6. Crystalline Form II of claim 1 , which is at least about 95% pure crystalline Form II of the Compound (I).
7. Crystalline Form II of claim 1 , which is at least about 98% pure crystalline Form II of the Compound (I).
8. A pharmaceutical composition comprising an effective amount of Crystalline Form II of claim 1 .
9. The pharmaceutical composition of claim 8 , further comprising an adjunct selected from (1) non-steroidal anti-inflammatory agents; (2) COX-2 inhibitors; (3) bradykinin B1 receptor antagonists; (4) sodium channel blockers and antagonists; (5) nitric oxide synthase (NOS) inhibitors; (6) glycine site antagonists; (7) potassium channel openers; (8) AMPA/kainate receptor antagonists; (9) calcium channel antagonists; (10) GABA-A receptor modulators; (11) matrix metalloprotease (MMP) inhibitors; (12) thrombolytic agents; (13) opioids; morphine; (14) neutrophil inhibitory factor (NIF); (15) L-Dopa; (16) carbidopa; (17) levodopa/carbidopa; (18) dopamine agonists; (19) anticholinergics; (20) amantadine; (21) carbidopa; (22) catechol O-methyltransferase (COMT) inhibitors; entacapone and tolcapone; (23) Monoamine oxidase B (MAO-B) inhibitors; (24) opiate agonists or antagonists; (25) 5HT receptor agonists or antagonists; (26) NMDA receptor agonists or antagonists; (27) NK1 antagonists; (28) selective serotonin reuptake inhibitors (S SRI) and selective serotonin and norepinephrine reuptake inhibitors (SSNRI); (29) tricyclic antidepressant drugs, (30) norepinephrine modulators; (31) lithium; (32) valproate; (33) D-serine; (34) neurontin (gabapentin); (35) antitussives; (36) antihistamines; (37) decongestants; (38) expectorants; (39) mucolytics; (40) antipyretics; and (41) analgesics.
10. A method of treating a condition responsive to an NR2B antagonist, comprising administering to a patient in need thereof an effective amount of Crystalline Form II of claim 1 .
11. The method of claim 10 , wherein the condition is a depressive disorder.
12. The method of claim 10 , wherein the condition is major depressive disorder.
13. The method of claim 10 , wherein Crystalline Form II is administered as an adjunct to a serotonin reuptake inhibitor or a serotonin and norepinephrine reuptake inhibitor.
14. The method of claim 10 , further comprising administering an anti-hypertensive agent to the patient.
15. The method of claim 14 , wherein the active ingredient of said anti-hypertensive agent consists essentially of an α 1 -adrenoreceptor antagonist.
16. A method of targeting N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) expressed on a cell comprising administering to a patient in need thereof an effective amount of Crystalline Form II of claim 1 .
17. The method of claim 16 , wherein the patient is suffering from a condition selected from Parkinson's disease, neuropathic pain, bone and joint pain, repetitive motion pain, dental pain, cancer pain, myofascial pain, perioperative pain, chronic pain, dysmennorhea, pain associated with angina, inflammatory pain, headache, migraine, cluster headache, schizophrenia, stroke, traumatic brain injury, Alzheimer's disease, cerebral ischemia, amyotrophic lateral sclerosis, Huntington's disease, sensorineural hearing loss, tinnitus, glaucoma, neurological damage caused by epileptic seizures or by neurotoxin poisoning or by impairment of glucose and/or oxygen to the brain, vision loss caused by neurodegeneration of the visual pathway, Restless Leg Syndrome, multi-system atrophy, non-vascular headache, chronic, subchronic or acute cough, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, pain caused by central sensitization, dyskinesias, depressive disorders, trauma- and stressor-related disorders, bipolar disorders with depressive features, anxiety disorders, and obsessive-compulsive and related disorders.
18. The method of claim 16 , wherein the patient is suffering from major depressive disorder.
19. The method of claim 16 , wherein the patient is suffering from treatment-resistant major depressive disorder.
20. The method of claim 16 , further comprising administering an anti-hypertensive agent comprising an active ingredient consisting essentially of an ai-adrenoreceptor antagonist to the patient.
21. A method of treating suicidal ideation, comprising administering an effective amount of Compound (I)
to a patient who has, is suspected of having, or has been diagnosed with having suicidal ideation.
22. The method of claim 21 , wherein the patient has been further diagnosed with having a depressive disorder.
23. The method of claim 21 , wherein the Compound (I) is in crystalline Form II as characterized by:
an X-ray powder diffraction pattern, obtained using copper Kα radiation, comprising a peak of 2-theta angle of about 5.9 degree
e.
24. The method of claim 23 , wherein the crystalline Form II of Compound (I) is further characterized by at least one of:
an ultraviolet absorbance spectrum, obtained using methanol as diluent, substantially as shown in FIG. 2 ;
an infrared spectrum substantially as shown in FIG. 3 ;
a thermogravimetric analysis curve substantially as shown in FIG. 6 ; and
a differential scanning calorimetry thermogram substantially as shown in FIG. 7 .
25. The method of claim 21 , further comprising administering an anti-hypertensive agent comprising an active ingredient consisting essentially of an α 1 -adrenoreceptor antagonist to the patient.