Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-
View Patent ↗Novel [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinolines are described in the present invention. These compounds and crystalline forms SA1 and N-2 are used in the treatment of various neurological and physiological disorders. Methods of making these compounds and crystalline forms SA-1 and N-2 are also described in the present invention.
1. Crystalline Form SA-1 of
wherein:
the carbon atom designated * is in the S configuration; characterized by the following unit cell parameters:
Cell dimensions:
a=11.0668(9) Å
b=7.3750(6) Å
c=15.3927(14) Å
alpha=90°
beta=100.594(7)°
gamma=90°
Space group: Monoclinic, P2 1
Volume: 1234.90(18) Å 3
Z, Calculated Density: 2, 1.363 Mg/m 3 ,
wherein measurement of said crystalline form is at a temperature of between about 20° C. to about 25° C.;
or characterized by fractional atomic coordinates within the unit cell as listed in Table 6; or
with characteristic peaks in a powder X-ray diffraction pattern at values of 2 theta of 5.8±0.1, 8.1±0.1, 9.1±0.1, 10.8±0.1, 11.7±0.1, 13.0±0.1, 13.3±0.1, 14.5±0.1, 15.1±0.1, 15.4±0.1, 16.2±0.1, and 16.8±0.1, at a temperature between about 20° C. and about 25° C.;
or characterized by a melt with decomposition endotherm with onset of about 85° C.;
or a pharmaceutically acceptable salt thereof.
2. Substantially pure crystalline Form SA-1 of
having a purity of at least about 95 wt %
wherein:
the carbon atom designated * is in the S configuration and characterized by the following unit cell parameters:
Cell dimensions:
a=11.0668(9) Å
b=7.3750(6) Å
c=15.3927(14) Å
alpha=90°
beta=100.594(7)°
gamma=90°
Space group: Monoclinic, P2 1
Volume: 1234.90(18) Å 3
Z, Calculated Density: 2, 1.363 Mg/m 3 ,
wherein measurement of said crystalline form is at a temperature of between about 20° C. to about 25° C.,
or characterized by fractional atomic coordinates within the unit cell as listed in Table 6; or with characteristic peaks in a powder X-ray diffraction pattern at values of 2 theta of 5.8±0.1, 8.1±0.1, 9.1±0.1, 10.8±0.1, 11.7±0.1, 13.0±0.1, 13.3±0.1, 14.5±0.1, 15.1±0.1, 15.4±0.1, 16.2±0.1, and 16.8±0.1, at a temperature between about 20° C. and about 25° C.;
or characterized by a melt with decomposition endotherm with onset of about 85° C.
3. The crystalline form of claim 2 , wherein said Form SA-1 has a purity of at least 98 wt %.
4. The crystalline form of claim 2 , wherein said Form SA-1 has a purity of at least 99 wt %.
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the crystalline form according to claim 1 .
6. A method of treating a disorder which is created by or is dependent upon decreased availability of norepinephrine, dopamine, or serotonin, wherein the disorder is selected from the group consisting of attention deficit hyperactivity disorder (ADHD), cognition impairment, anxiety disorders, generalized anxiety disorder (GAD), panic disorder, bipolar disorder or manic depression or manic-depressive disorder, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, social phobia, simple phobias, pre-menstrual dysphoric disorder (PMDD), social anxiety disorder (SAD), major depressive disorder (MDD), postnatal depression, dysthymia, depression associated with Alzheimer's disease, Parkinson's disease, or psychosis, supranuclear palsy, eating disorders, obesity, anorexia nervosa, bulimia nervosa, binge eating disorder, diabetes, ischemic diseases, pain, substance abuse disorders, chemical dependencies, nicotine addiction, cocaine addiction, amphetamine addiction, alcohol addiction, Lesch-Nyhan syndrome, neurodegenerative diseases, Parkinson's disease, late luteal phase syndrome or narcolepsy, psychiatric symptoms, anger, rejection sensitivity, movement disorders, extrapyramidal syndrome, Tic disorders, restless leg syndrome (RLS), tardive dyskinesia, sleep related eating disorder (SRED), night eating syndrome (NES), stress urinary incontinence (SUI), migraine, neuropatheic pain, diabetic neuropathy, lower back pain, fibromyalgia syndrome (FS), osteoarthritis pain, arthritis pain, chronic fatigue syndrome (CFS), sexual dysfunction, premature ejaculation, male impotence, thermoregulatory disorders, and irritable bowel synddrome (IBS),
said method comprising: administering to a patient in need of such treatment a therapeutically effective amount of cyrstalline form according to claim 1 or a pharmaceutically acceptable salt thereof.
7. The method according to claim 6 further comprising:
administering a therapeutically effective amount of a serotonin 1A receptor antagonist or a pharmaceutically acceptable salt thereof.
8. The method according to claim 7 , wherein the serotonin 1A receptor antagonist is selected from the group consisting of WAY 100135 and spiperone.
9. The method according to claim 6 further comprising:
administering a therapeutically effective amount of a selective neurokinin-1 receptor antagonist or a pharmaceutically acceptable salt thereof.
10. The method according to claim 6 further comprising:
administering a therapeutically effective amount of a norepinephrine precursor or a pharmaceutically acceptable salt thereof.
11. The method according to claim 10 , wherein the norepinephrine precursor is selected from the group consisting of L-tyrosine and L-phenylalanine.
12. A method of inhibiting synaptic norepinephrine uptake in a patient comprising: administering to the patient a therapeutically effective inhibitory amount of a crystalline form according to claim 1 or a pharmaceutically acceptable salt thereof.
13. A method of inhibiting synaptic serotonin uptake in a patient comprising: administering to the patient a therapeutically effective inhibitory amount of a crystalline form according to claim 1 or a pharmaceutically acceptable salt thereof.
14. A method of inhibiting synaptic dopamine uptake in a patient comprising: administering to the patient a therapeutically effective inhibitory amount of a crystalline form according to claim 1 or a pharmaceutically acceptable salt thereof.
15. A method of suppressing the desire of humans to smoke comprising: administering to a human in need of such suppression an effective amount, to relieve the desire to smoke, of a crystalline form according to claim 1 or a pharmaceutically acceptable salt thereof.
16. A method of suppressing the desire of humans to consume alcohol comprising: administering to a human in need of such suppression an effective amount, to relieve the desire to consume alcohol, of a crystalline form according to claim 1 or a pharmaceutically acceptable salt thereof.