Multicyclic compounds and methods of use thereof
Provided herein are multicyclic compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.
1. A compound of formula:
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. A compound of formula:
or a pharmaceutically acceptable salt or stereoisomer thereof.
3. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.
4. A method of treating, or managing a neurological disorder, comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
5. The method of claim 4 , wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, sensitization accompanying neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effect of medications, insomnia, substance abuse or dependency, addiction, eating disorder, sexual dysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria.
6. The method of claim 5 , wherein the disorder is psychosis or schizophrenia.
7. The method of claim 5 , wherein the disorder is Parkinson's psychosis.
8. The method of claim 4 , wherein the disorder is bipolar disorder, Alzheimer's disease agitation, attention deficit disorder or attention deficit hyperactivity disorder.
9. A pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient or carrier.
10. A method of treating, or managing a neurological disorder, comprising administering to a subject a therapeutically or prophylactically effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof.
11. The method of claim 10 , wherein the neurological disorder is schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis, psychoaffective disorder, aggression, delirium, Parkinson's psychosis, excitative psychosis, Tourette's syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavior disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesias, Huntington's disease, dementia, mood disorder, anxiety, affective disorder, depression, major depressive disorder, dysthymia, bipolar disorder, manic disorder; seasonal affective disorder; attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, vertigo, epilepsy, pain, neuropathic pain, sensitization accompanying neuropathic pain, inflammatory pain, fibromyalgia, migraine, cognitive impairment, movement disorder, restless leg syndrome, multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effect of medications, insomnia, substance abuse or dependency, addiction, eating disorder, sexual dysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, or premenstrual dysphoria.
12. The method of claim 11 , wherein the disorder is psychosis or schizophrenia.
13. The method of claim 11 , wherein the disorder is Parkinson's psychosis.
14. The method of claim 10 , wherein the disorder is bipolar disorder, Alzheimer's disease agitation, attention deficit disorder or attention deficit hyperactivity disorder.
15. A method of producing N-methyl-1-(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine:
or a pharmaceutically acceptable salt or stereoisomer thereof, by treating (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine with ethyl chloroformate to produce ethyl ((5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methyl)carbamate, and reducing said ethyl ((5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methyl)carbamate to form N-methyl-1-(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine.
16. The method of claim 15 , further comprising treating said N-methyl-1-(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine with HCl to form:
17. The method of claim 15 , further comprising reducing 4,5-dihydro-4-(nitromethyl)cyclopenta[b]thiophen-6-one to form (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine.
18. A compound:
or a pharmaceutically acceptable salt thereof.
19. A compound of formula
or a pharmaceutically acceptable salt thereof, prepared by the method of claim 15 .
20. The compound of claim 19 , a pharmaceutically acceptable salt thereof, wherein said method further comprises treating said N-methyl-1-(5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine with HCl to form:
21. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein said method further comprises reducing 4,5-dihydro-4-(nitromethyl)cyclopenta[b]thiophen-6-one to form (5,6-dihydro-4H-cyclopenta[b]thiophen-4-yl)methanamine.