Chromane and chromene derivatives and uses thereof

Abstract

Compounds of formula I or pharmaceutically acceptable salts thereof are provided: wherein each of R 1 , R 2 , R 3 , R 4 , y, m, n, and Ar are as defined, and described in classes and subclasses herein, which are agonists or partial agonists of the 2C subtype of brain serotonin receptors. The compounds, and compositions containing the compounds, can be used to treat a variety of central nervous system disorders such as schizophrenia.

1 - 20 . (canceled) 
     
     
         21 . A composition comprising a compound of Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 m is 1 or 2; 
 n is 0 or 1; 
    designates a single or double bond; 
 Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more R x  groups; 
 each R x  is independently halogen, -Ph, —CN, —R or —OR; 
 each R is independently hydrogen, C 1-6  aliphatic or halo-substituted C 1-6  aliphatic; 
 y is 0-3; 
 each R 1  is independently —R, —CN, halogen or —OR; 
 R 2  is hydrogen, C 1-3  alkyl, or —O(C 1-3  alkyl); 
 each of R 3  and R 4  is independently hydrogen, C 1-6  aliphatic or fluoro-substituted C 1-6  aliphatic; 
 and one or more pharmaceutically acceptable carriers, diluents, or excipients, further comprising an additional pharmaceutical agent selected from an anti-psychotic agent, an antidepressive agent, an anti-obesity agent, an agent useful in the modulation of bladder activity, an opioid antagonist, an agent for treating ADD or ADHD, a cognitive improvement agent, an agent for treating sexual dysfunction, or a pain relieving agent. 
 
     
     
         22 . A method for treating a condition selected from at least one of psychotic disorder, an anxiety disorder, a bipolar disorder, a depressive disorder, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), an eating disorder, a bladder control disorder, substance abuse or substance dependence, a cognition disorder, ADD or ADHD, an impulsivity disorder, an addictive disorder, male or female sexual dysfunction, pain, a motion or motor disorder, Parkinson's disease epilepsy, migraine, chronic fatigue syndrome, anorexia nervosa, a sleep disorder, mutism, or one or more central nervous system deficiencies in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 m is 1 or 2; 
 n is 0 or 1; 
    designates a single or double bond; 
 Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more R x  groups; 
 each R 1  is independently halogen, -Ph, —CN, —R or —OR; 
 each R is independently hydrogen, C 1-6  aliphatic or halo-substituted C 1-6  aliphatic; 
 y is 0-3; 
 each R 1  is independently —R, —CN, halogen or —OR; 
 R 2  is hydrogen, C 1-3  alkyl, or —O(C 1-3  alkyl); 
 each of R 3  and R 4  is independently hydrogen, C 1-6  aliphatic or fluoro-substituted C 1-6  aliphatic; 
 or a composition comprising a compound of Formula I, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 
 
     
     
         23 . The method of  claim 22  wherein the psychotic disorder is schizophrenia, paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia, undifferentiated type schizophrenia, a schizophreniform disorder, a schizoaffective disorder, a delusional disorder, substance-induced psychotic disorder, a psychotic disorder not otherwise specified; L-DOPA-induced psychosis; psychosis associated with Alzheimer's dementia; psychosis associated with Parkinson's disease; or psychosis associated with Lewy body disease 
     
     
         24 . The method of  claim 22 , wherein the condition is bipolar disorder and is selected from bipolar I disorder, bipolar II disorder, cyclothymic disorder; bipolar mania, dementia, depression with psychotic features, or cycling between bipolar depression and bipolar mania. 
     
     
         25 . The method of  claim 22 , wherein the depressive disorder is major depressive disorder, seasonal affective disorder, dysthymic disorder, substance-induced mood disorder, depressive disorder not otherwise specified, treatment resistant depression, major depressive episode. 
     
     
         26 . The method of  claim 25 , further comprising administering to the patient an antidepressive agent selected from serotonin reuptake inhibitors (SRIs), norepinephrine reuptake inhibitors (NRIs), combined serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), phosphodiesterase-4 (PDE4) inhibitors, corticotropin releasing factor (CRF) antagonists, alpha.-adrenoreceptor antagonists, triple uptake inhibitors, melatonin agonists, super neurotransmitter uptake blockers (SNUBs), noradrenergic and specific serotonergic antidepressants (NaSSAs), or substance P/neurokinin receptor antagonists. 
     
     
         27 . The method of  claim 22 , wherein the cognitive disorder is a learning disorder. 
     
     
         28 . The method of  claim 22 , wherein the patient is treated for obesity. 
     
     
         29 . The method of  claim 22 , wherein the patient is treated for ADD or ADHD. 
     
     
         30 . The method of  claim 22 , wherein the substance abuse substance dependence is of a recreational substance, a pharmacologic agent, a tranquilizer, a stimulant, sedative, or illicit drug. 
     
     
         31 . The method of  claim 22 , further comprising administering to the patient an additional pharmaceutical agent selected from an anti-psychotic agent, an antidepressive agent, an anti-obesity agent, an agent useful in the modulation of bladder activity, an opioid antagonist, an agent for treating ADD or ADHD, a cognitive improvement agent, an agent for treating sexual dysfunction, or a pain relieving agent. 
     
     
         32 . A method for treating schizophrenia in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I. 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 m is 1 or 2; 
 n is 0 or 1; 
    designates a single or double bond; 
 Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more R x  groups; 
 each R x  is independently halogen, -Ph, —CN, —R or —OR; 
 each R is independently hydrogen, C 1-6  aliphatic or halo-substituted C 1-6  aliphatic; 
 y is 0-3; 
 each R 1  is independently —R, —CN, halogen or —OR; 
 R 2  is hydrogen, C 1-3  alkyl, or —O(C 1-3  alkyl); 
 each of R 3  and R 4  is independently hydrogen, C 1-6  aliphatic or fluoro-substituted C 1-6  aliphatic; 
 or a composition comprising a compound of Formula I, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 
 
     
     
         33 . A method for treating obesity in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I. 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 m is 1 or 2; 
 n is 0 or 1; 
    designates a single or double bond; 
 Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more R x  groups; 
 each R x  is independently halogen, -Ph, —CN, —R or —OR; 
 each R is independently hydrogen, C 1-6  aliphatic or halo-substituted C 1-6  aliphatic; 
 y is 0-3; 
 each R 1  is independently —R, —CN, halogen or —OR; 
 R 2  is hydrogen, C 1-3  alkyl, or —O(C 1-3  alkyl); 
 each of R 3  and R 4  is independently hydrogen, C 1-6  aliphatic or fluoro-substituted C 1-6  aliphatic; 
 or a composition comprising a compound of Formula I, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 
 
     
     
         34 . A method for treating bipolar disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 m is 1 or 2; 
 n is 0 or 1; 
    designates a single or double bond; 
 Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more R x  groups; 
 each R x  is independently halogen, -Ph, —CN, —R or —OR; 
 each R is independently hydrogen, C 1-6  aliphatic or halo-substituted C 1-6  aliphatic; 
 y is 0-3; 
 each R 1  is independently —R, —CN, halogen or —OR; 
 R 2  is hydrogen, C 1-3  alkyl, or —O(C 1-3  alkyl); 
 each of R 3  and R 4  is independently hydrogen, C 1-6  aliphatic or fluoro-substituted C 1-6  aliphatic; 
 or a composition comprising a compound of Formula I, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 
 
     
     
         35 . A method for treating depression in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein:
 m is 1 or 2; 
 n is 0 or 1; 
    designates a single or double bond; 
 Ar is thienyl, furyl, pyridyl, or phenyl wherein Ar is optionally substituted with one or more R x  groups; 
 each R x  is independently halogen, -Ph, —CN, —R or —OR; 
 each R is independently hydrogen, C 1-6  aliphatic or halo-substituted C 1-6  aliphatic; 
 y is 0-3; 
 each R 1  is independently —R, —CN, halogen or —OR; 
 R 1  is hydrogen, C 1-3  alkyl, or —O(C 1-3  alkyl); 
 each of R 3  and R 4  is independently hydrogen, C 1-6  aliphatic or fluoro-substituted C 1-6  aliphatic; 
 or a composition comprising a compound of Formula I, and one or more pharmaceutically acceptable carriers, diluents, or excipients.