US-12624036-B2 - Method of treating post-traumatic stress disorder

Abstract

Use of particular substituted heterocycle fused gamma-carboline compounds as pharmaceuticals for the treatment of agitation, aggressive behaviors, posttraumatic stress disorder or impulse control disorders.

Inventors

• Sharon Mates
• Robert Davis
• Kimberly Vanover

Assignees

• INTRA-CELLULAR THERAPIES, INC.

Dates

Publication Date

20260512

Application Date

20200710

Claims (20)

1. 1 . A method for the treatment of posttraumatic stress disorder, comprising administering to a patient in need thereof an effective amount of a compound of Formula I: wherein X is O, —NH or —N(CH 3 ); and Y is —O—, —C(H)(OH)—or —C(O)—, in free or pharmaceutically acceptable salt form.
2. 2 . The method according to claim 1 , wherein the compound of Formula I is selected from a group consisting of compounds of formula I wherein: X is —O— and Y is —C(H)(OH)—, X is —NH— and Y is —C(H)(OH)—, X is —N(CH 3 )— and Y is —C(H)(OH)—, X is —O— and Y is —C(O)—, X is —O— and Y is —O—, X is —N(CH 3 )— and Y is —C(O)—, X is —N(CH 3 )— and Y is —O—, X is —NH— and Y is —C(O)—, and X is —NH— and Y is —O—.
3. 3 . The method of claim 1 , wherein X is —N(CH 3 )— and Y is —C(O)—.
4. 4 . The method of claim 1 , wherein the administration of the compound of Formula I is an adjunct to the administration of one or more additional antidepressants.
5. 5 . The method of claim 4 , wherein the administration of one of more additional antidepressants is an adjunct to administration of the compound of Formula I.
6. 6 . The method of claim 4 , wherein the antidepressant is selected from one or more of amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine, in free or pharmaceutically acceptable salt form.
7. 7 . The method of claim 4 , wherein the antidepressant is one or more antidepressants selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants.
8. 8 . The method of claim 7 , wherein the antidepressant is a SSRI.
9. 9 . The method of claim 1 , wherein the compound of Formula I is administered orally as a composition comprising a pharmaceutically acceptable diluent or carrier as an oral unit dose form that is a tablet or capsule.
10. 10 . The method of claim 1 , wherein the effective amount of the compound of Formula I is a daily dose of about 10 mg to about 50 mg.
11. 11 . The method of claim 1 , wherein the effective amount of the compound of Formula I is a daily dose of about 20 mg to about 40 mg.
12. 12 . The method of claim 1 , wherein the effective amount of the compound of Formula I is a daily dose of about 1 mg to about 10 mg.
13. 13 . The method of claim 1 , further comprising administering one or more additional therapeutic agents selected from compounds that modulate GABA activity, a 5-HT modulator, a melatonin agonist, an ion channel modulator, a serotonin-2 antagonist/reuptake inhibitor, an orexin receptor antagonist, an H3 agonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1 drug, and an antipsychotic agent, in free or pharmaceutically acceptable salt form.
14. 14 . The method of claim 1 , further comprising administering one or more additional therapeutic agents selected from a group consisting of modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin, tiagabine, estazolam, ketanserin, risperidone, eplivanserin, volinanserin, pruvanserin, repinotan, sarizotan, eptapirone, buspirone, melatonin, ramelteon agomelatine, lamotrigine, gabapentin, pregabalin, orexin, ritanserin, nefazodone, serzone, trazodone, Casopitant, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trimipramine, venlafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, and paliperidone, in free or pharmaceutically acceptable salt form.
15. 15 . The method of claim 1 , wherein the patient has not responded adequately to treatment with another antidepressant or combination of antidepressants.
16. 16 . The method of claim 14 , wherein the patient has not responded to treatment with one or more antidepressants selected from selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants.
17. 17 . The method of claim 16 , wherein the patient has not responded to treatment with a SSRI.
18. 18 . The method of claim 16 , wherein the selective serotonin reuptake inhibitors are selected from the group consisting of citalopram, escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, and dapoxetine.
19. 19 . The method of claim 16 , wherein the serotonin-norepinephrine reuptake inhibitors are selected from venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, and sibutramine.
20. 20 . The method of claim 17 , wherein the selective serotonin reuptake inhibitors are selected from the group consisting of citalopram, fluoxetine, paroxetine, and sertraline.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a U.S. continuation application of U.S. application Ser. No. 14/394,469, filed on Oct. 14, 2014, which is a national phase application filed under 35 U.S.C. § 371 of International Application No. PCT/US2013/036512, filed on Apr. 14, 2013, which claims priority from U.S. Provisional Application Nos. 61/624,293, 61/624,292 and 61/624,291, all filed on Apr. 14, 2012; and U.S. Provisional Application Nos. 61/671,723 and 61/671,713, both filed on Jul. 14, 2012, the contents of each of which are incorporated by reference in their entireties. TECHNICAL FIELD The present invention relates to use of particular substituted heterocycle fused gamma-carbolines as described herein, in free or pharmaceutically acceptable salt forms, as pharmaceuticals and pharmaceutical compositions as primary or adjunct therapy in the treatment of agitation, aggressive behaviors, posttraumatic stress disorder (PTSD) and/or impulse control disorder (ICD) such as intermittent explosive disorder (IED). The compounds disclosed herein can be used in combination with antidepressant compounds, e.g., selective serotonin reuptake inhibitors (SSRI's). BACKGROUND OF THE INVENTION Posttraumatic Stress Disorder (PTSD) follows exposure to a traumatic experience involving actual or threatened death or injury or threat to the physical integrity of oneself or others. PTSD includes characteristic symptoms of re-experience, avoidance of stimuli associated with the trauma, and numbing of general responsiveness or hyper-arousal (sleep difficulty, anger, difficulty concentrating, hyper-vigilance or exaggerated startle response) with clinically significant distress or impairment. Lifetime prevalence of PTSD is estimated to be 6.8% among adult Americans, with a prevalence among women more than twice than that among men (Kessler, et al., 2005, Archives of General Psychiatry, 62:593-602). Among combat veterans, at particular risk to develop PTSD, prevalence rates are higher, estimated to be over 25% of Vietnam veterans (Kulka et al., 1990, Trauma and the Vietnam War generation: Report of findings from the National Vietnam Veterans Readjustment Study. New York: Brunner/Mazel), approximately 10% among Gulf War veterans (Kang et al., 2003, American Journal of Epidemiology, 157:141-148), and approximately 14% of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans (Tanielian and Jaycox, 2008, Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery. Santa Monica, CA: RAND Corporation). In addition to the re-experiencing, avoidance, and hyper-arousal cluster of symptoms, PTSD is often associated with dysthymia, sleep disorders, depression, anxiety, substance abuse, bipolar disorder and schizophrenia (Mohamed and Rosenbeck, 2008, J Clin Psychiatry 69:959-965). PTSD is a chronic, costly illness associated with significant long-term disability. Moreover, no successful dramatic treatment of PTSD has been discovered for the severe, chronic cases of this crippling disorder. A number of articles describing developments in PTSD appear in Psychiatric Annals 28:424-468, (1998). Impulse control disorder (ICD) is characterized by a pathological failure to resist an impulse, drive, or temptation to perform an act that is harmful to the person or to others. One type of ICD is Intermittent Explosive Disorder (IED) which involves violence or rage. There is a loss of control grossly out of proportion to any precipitating psychosocial stresses. Disabling outbursts of rage and violent behavior can be related to chronic brain syndrome associated with irreversible CNS (central nervous system) lesions. Yudofsky et al., Am. J. Psychiatry 138:218-220, 1981. Disorders characterized by severe episodic dyscontrol can result from brain dysfunction, e.g., resulting from a failure of modulation of electrical disturbances in the limbic system (amygdala, hippocampus, hypothalamus), temporal lobe epilepsy (TLE), brain lesions or injuries which can have neurological side effects. Other brain dysfunction disorders include motor, personality, or behavior patterns arising from, e.g., neurological impairment in the brain, TLE, viral infections, neurotransmitter disorders, amino acid imbalance, brain tumors, chromosomal abnormalities, metabolic disorders including endocrine disorders, diabetes, and genetic disorders such as disease which involves several genes, and chromosomal disorders. In addition to the traditional ICDs present in the DSM-IV—pathological gambling, trichotillomania, kleptomania, pyromania and intermittent explosive disorder—ICDs may include compulsive—impulsive Internet usage disorder, compulsive—impulsive sexual behaviors, compulsive—impulsive skin picking and compulsive—impulsive shopping. Poor impulse control, agitation, and aggressive behaviors may be further linked to or co-existent with isolation, depression, and anxiety. It may in be seen in patien