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. 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 Compound (I)
exhibiting at least one of:
(a) an X-ray powder diffraction pattern, obtained using copper Kα radiation, comprising a peak of 2-theta angle of about 5.9 degree;
(b) an infrared spectrum substantially as shown in FIG. 3 ;
(c) a thermogravimetric analysis curve substantially as shown in FIG. 6 ; and
(d) a differential scanning calorimetry thermogram substantially as shown in FIG. 7 .
2. The method 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. The method of claim 1 , wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 1A .
4. The method of claim 1 , wherein the differential scanning calorimetry thermogram of the compound is substantially as shown in FIG. 7 .
5. The method of claim 1 , wherein the crystalline Form II of compound I has a purity of at least 95%.
6. The method of claim 1 , wherein the condition is 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, as well as pain associated with angina, and inflammatory pain of varied origins, headache, migraine and 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, or other 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.
7. The method of claim 1 , wherein the condition is major depressive disorder.
8. The method of claim 1 , wherein the condition is treatment-resistant major depressive disorder.
9. The method of claim 8 , wherein the compound is administered as an adjunct to a serotonin reuptake inhibitor or a serotonin and norepinephrine reuptake inhibitor.
10. The method of claim 7 , wherein the compound is administered as an adjunct to a serotonin reuptake inhibitor or a serotonin and norepinephrine reuptake inhibitor.
11. The method of claim 6 , wherein the compound is administered as an adjunct to a therapeutic agent selected from the group consisting of: (1) a non-steroidal anti-inflammatory agent; (2) a COX-2 inhibitor; (3) a bradykinin B1 receptor antagonist; (4) a sodium channel blocker and antagonist; (5) a nitric oxide synthase (NOS) inhibitor; (6) a glycine site antagonist; (7) a potassium channel opener; (8) an AMPA/kainate receptor antagonist; (9) a calcium channel antagonist; (10) a GABA-A receptor modulator; (11) a matrix metalloprotease (MMP) inhibitor; (12) a thrombolytic agent; (13) an opioid; (14) a neutrophil inhibitory factor (NIF); (15) L-Dopa; (16) carbidopa; (17) levodopa/carbidopa; (18) a dopamine agonist; (19) an anticholinergic; (20) amantadine; (21) a catechol O-methyltransferase (COMT) inhibitor; (22) a monoamine oxidase B (MAO-B) inhibitor; (23) an opiate agonist or antagonist; (24) a 5HT receptor agonist or antagonist; (25) an NMDA receptor agonist or antagonist; (26) a NK1 antagonist; (27) a selective serotonin reuptake inhibitor (SSRI) and a selective serotonin and norepinephrine reuptake inhibitor (SSNRI); (28) a tricyclic antidepressant, (29) a norepinephrine modulator; (30) lithium; (31) valproate; (32) D-serine; (33) neurontin; (34) an antitussive; (35) an antihistamine; (36) a decongestant; (37) an expectorant; (38) a mucolytic; (39) an antipyretic; and (40) an analgesic.
12. The method of claim 1 , wherein the compound is administered as an adjunct to a therapeutic agent selected from the group consisting of: (1) a non-steroidal anti-inflammatory agent; (2) a COX-2 inhibitor; (3) a bradykinin B1 receptor antagonist; (4) a sodium channel blocker and antagonist; (5) a nitric oxide synthase (NOS) inhibitor; (6) a glycine site antagonist; (7) a potassium channel opener; (8) an AMPA/kainate receptor antagonist; (9) a calcium channel antagonist; (10) a GABA-A receptor modulator; (11) a matrix metalloprotease (MMP) inhibitor; (12) a thrombolytic agent; (13) an opioid; (14) a neutrophil inhibitory factor (NIF); (15) L-Dopa; (16) carbidopa; (17) levodopa/carbidopa; (18) a dopamine agonist; (19) an anticholinergic; (20) amantadine; (21) a catechol O-methyltransferase (COMT) inhibitor; (22) a monoamine oxidase B (MAO-B) inhibitor; (23) an opiate agonist or antagonist; (24) a 5HT receptor agonist or antagonist; (25) an NMDA receptor agonist or antagonist; (26) a NK1 antagonist; (27) a selective serotonin reuptake inhibitor (SSRI) and a selective serotonin and norepinephrine reuptake inhibitor (SSNRI); (28) a tricyclic antidepressant, (29) a norepinephrine modulator; (30) lithium; (31) valproate; (32) D-serine; (33) neurontin; (34) an antitussive; (35) an antihistamine; (36) a decongestant; (37) an expectorant; (38) a mucolytic; (39) an antipyretic; and (40) an analgesic.