Organic compounds

Abstract

The invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving the 5-HT 2A receptor, the serotonin transporter (SERT), pathways involving the dopamine D 1 and D 2 receptor signaling system, and/or the μ-opioid receptor.

1 . A method for the treatment or prophylaxis of a central nervous system disorder, comprising administering to a patient in need thereof a compound of a Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         X is —NH— or —N(CH 3 )—; 
         L is selected from O, NH, NR a , and S; 
         Z is —CH(O—R 1 )—, —O— or —C(O)—; 
         R 1  is H, —C(O)—C 1-21  alkyl, optionally saturated or unsaturated and optionally substituted with one or more hydroxy or C 1-22  alkoxy groups; 
         R a  is:
 halogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, or C 3-6  cycloalkyl, each of which can be independently substituted with up to three independently selected R b  groups, for example C- 1-3 haloalkyl or C 1-3 hydroxyalkyl; or 
 aryl optionally substituted with up to five independently selected R b ; and 
 
         each R b  is independently selected from H, halogen, NH 2 , NO 2 , OH, C(O)OH, CN, SO 3 , and C 1-4  alkyl; 
         in free or salt form; 
         optionally in an isolated or purified free or salt form; 
         wherein the disease or disorder is selected from a pain disorder, a drug dependency disorder, obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), general anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, pathological grooming disorder, kleptomania, pyromania, attention deficit-hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorder, and related disorders, neuropathic pain, idiopathic pain, chronic pain, fibromyalgia, opiate dependency, cocaine dependency, amphetamine dependency, alcohol dependency, opiate overdose, and combinations thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein L is O. 
     
     
         3 . The method according to  claim 1 , wherein Z is —CH(O—R 1 )—. 
     
     
         4 . The method according to  claim 1 , wherein Z is —C(═O)—. 
     
     
         5 . The method according to  claim 1 , wherein Z is —O—. 
     
     
         6 . The method according to  claim 1 , wherein X is —NH—. 
     
     
         7 . The method according to  claim 1 , wherein X is —N(CH 3 )—. 
     
     
         8 . The method according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The method according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method according to  claim 1  wherein the compound is in the form of a salt. 
     
     
         11 . The method according to  claim 1 , wherein the compound is administered to the patient in the form of a pharmaceutically acceptable composition comprising the compound in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable diluent or carrier. 
     
     
         12 . The method of  claim 11 , wherein the pharmaceutically acceptable diluent or carrier comprises a polymeric matrix. 
     
     
         13 . The method according to  claim 12 , wherein the polymeric matrix is a biodegradable poly(d,l-lactide-co-glycolide) microsphere. 
     
     
         14 . The method according to  claim 1  wherein the central nervous system disorder is selected from idiopathic pain, neuropathic pain, chronic pain, fibromyalgia, dental pain, and traumatic pain, obsessive-compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), general anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, compulsive gambling disorder, compulsive eating disorder, body dysmorphic disorder, hypochondriasis, pathological grooming disorder, kleptomania, pyromania, attention deficit-hyperactivity disorder (ADHD), attention deficit disorder (ADD), impulse control disorder, and related disorders. 
     
     
         15 . The method according to  claim 14 , wherein the central nervous system disorder is neuropathic pain or traumatic pain, obsessive-compulsive disorder (OCD) or obsessive-compulsive personality disorder (OCPD). 
     
     
         16 . The method according to  claim 14 , wherein said patient is not responsive to or cannot tolerate the side effects from, treatment with selective serotonin reuptake inhibitors (SSRIs), treatment with serotonin-norepinephrine reuptake inhibitors (SNRIs), treatment with antipsychotic agents, and/or non-narcotic analgesics and/or opioid drugs, or wherein the use of opioid drugs are contraindicated in said patient. 
     
     
         17 . The method according to  claim 1 , wherein said patient is not responsive to or cannot tolerate the side effects from opioid drugs, or wherein the use of opioid drugs are contraindicated in said patient, and said opioid drugs are selected from morphine, codeine, thebaine, oripavine, morphine dipropionate, morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil, remifentanil, octfentanil, sufentanil, carfentanyl, meperidine, prodine, promedol, propoxyphene, dextropropoxyphene, methadone, diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and anileridine, or any combinations thereof, or wherein the patient is not response to or cannot tolerate the side effects from treatment with SSRIs selected from citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, or (SNRIs) selected from venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran, or antipsychotic agents selected from clomipramine, risperidone, quetiapine and olanzapine. 
     
     
         18 . The method according to  claim 14 , wherein said patient also suffers from opioid use disorder. 
     
     
         19 . The method according to  claim 14 , wherein the method further comprises administration of an additional therapeutic agent selected from an agonist or partial agonist, or inverse agonist or antagonist, of the mu-opiate, kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors. 
     
     
         20 . (canceled) 
     
     
         21 . The method according to  claim 19 , wherein said additional therapeutic agent is selected from buprenorphine, methadone, naloxone, and naltrexone.