Fused Tetracyclic mGluR1 Antagonists as Therapeutic Agents

Abstract

In its many embodiments, the present invention provides tetracyclic compounds of formula I or formula II (wherein the various moieties are as defined herein) useful as metabotropic glutamate receptor (mGluR) antagonists, particularly as selective metabotropic glutamate receptor 1 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases associated with metabotropic glutamate receptor (e.g., mGluR1) such as, for example, pain, migraine, anxiety, urinary incontinence and neurodegenerative diseases such Alzheimer's disease.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein:
 W is S, O, or N(R 10 ); 
 X is N or CR 3 ; 
 Y is N or CR 2 ; 
 J 1  and J 2  are each independently C(R 4 ) or N; 
 R 1  is selected from the group consisting of —H, —NR 5 R 6 , OR 5 , SR 9 , —CN, —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —S(O 2 )NR 6 R 7 —N(R 6 )S(O 2 )R 9 , —N(R 6 )C(O)NR 6 R 7 ; and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; 
 R 2  and R 3  are each independently selected from the group consisting of H, halo, —CN, —NO 2 , —OR 5 , —SR 9 , —NR 5 R 6 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —OS(O 2 )R 9 , —S(O 2 )R 9 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 9 , and —N(R 6 )C(O)NR 6 R 7 ; and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; 
 R 4  is independently selected from the group consisting of H, halo, —CN, —NHC(O)R 6 , —NHSO 2 R 9 , —NR 5 R 6 , —OR 5 , —C(O)R 6 , —C(O 2 )R 6 , —C(O)NR 6 R 7 ; and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 : 
 R 5  is selected from the group consisting of H, —C(O)OR 6 , —SO 2 R 9 , —C(O)NR 6 R 7 , and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; 
 R 6  and R 7  are independently selected from the group consisting of H and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; or 
 R 5  and R 6  or R 6  and R 7 , when attached to the same nitrogen atom, optionally taken together with the nitrogen atom form a 3-8 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to said nitrogen atom; 
 R 8  is selected from the group consisting of H, halo, —OR 5 , —NO 2 , —CN, —NR 6 C(O)R 7 , —NR 6 SO 2 R 9 , —NR 5 R 6 , —C(O)R 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —S(O 2 )NR 6 R 7 , and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one of halo, —CN, —NO 2 , —OR 5 , —SR 9 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —OS(O 2 )R 9 , —S(O 2 )R 9 , —S(O 2 )NR 6 R 7 , —N(R 6 )C(O)NR 6 R 7 , and —NR 6 SO 2 R 9 ; 
 R 9  is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; 
 R 10  is selected from the group consisting of H, —C(O)R 6 , —C(O)OR 6 , —SO 2 R 9 , —C(O)NR 6 R 7 , and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 , 
 A is selected from the group consisting of CHR 4 , CR 4 , O, S, N, NR 4 , C═O, and C═S; 
 B is selected from the group consisting of N, NR 4 , CHR 4 , CR 4 , O, S, C═O, C═S, and C—S—R 9 ; 
 D is selected from the group consisting of CHR 4 , O, S, and NR 4 ; and 
 m is 1-3+ 
 
   
   
       2 . The compound of  claim 1 , wherein 
     
       
         
         
             
             
         
       
     
     is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       3 . The compound of  claim 1 , wherein W is S and Z and X are N. 
   
   
       4 . The compound of  claim 1 , wherein W is S, J 1  is CR 4 , J 2  is N. 
   
   
       5 . The compound of  claim 1 , wherein W is S, J 1  is CR 4 , J 2  is N, Z and X are N. 
   
   
       6 . The compound of  claim 1 , wherein A and B are selected from the group consisting of CHR 4  and CR 4  and D is NR 4 . 
   
   
       7 . The compound of  claim 1 , wherein A is CHR 4  or CR 4 , B is N or NR 4 ; and D is NR 4 . 
   
   
       8 . The compound of  claim 1 , wherein A is N or NR 4 , D is NR 4 , and B is CHR 4  or CR 4 . 
   
   
       9 . The compound of  claim 1 , wherein A and B are selected from the group consisting of CHR 4  and CR 4 , and D is O. 
   
   
       10 . The compound of  claim 1 , wherein A and B are selected from the group consisting of CHR 4  and CR 4 , and D is S. 
   
   
       11 . The compound of  claim 1 , wherein A and B are selected from the group consisting of CHR 4  and CR 4  and D is CR 4 . 
   
   
       12 . The compound of  claim 1 , wherein A is N or NR 4 , B is CHR 4  or CR 4 , and D is NR 4 . 
   
   
       13 . The compound of  claim 1 , wherein A is O, B is CHR 4  or CR 4 , and D is NR 4 . 
   
   
       14 . The compound of  claim 1 , wherein A is S, B is selected from the group consisting of C═O, C═S, and C—S—R 9 , and D is NR 4 . 
   
   
       15 . The compound of  claim 1 , wherein W is S and R 1  is cyclohexyl. 
   
   
       16 . The compound of  claim 1 , wherein W is S and R 1  is p-methylphenyl. 
   
   
       17 . The compound of  claim 1 , wherein W is S and R 1  is p-methoxyphenyl. 
   
   
       18 . The compound of  claim 1 , wherein W is S and R 1  is p-halophenyl. 
   
   
       19 . The compound of  claim 17  wherein the compound is selected from the group consisting of those set forth below or a pharmaceutically acceptable salt or solvate thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       20 . A compound of formula II: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or solvate thereof, wherein:
 W is S, O, or N(R 10 ); 
 X is N or CR 3 ; 
 Y is N or OR 2 ; 
 J 1  and J 2  are each independently C(R 4 ) or N; 
 R 1  is selected from the group consisting of —H, —NR 5 R 6 , —OR 5 , —SR 9 , —CN, —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —S(O 2 )NR 6 R 7 —N(R 6 )S(O 2 )R 9 , —N(R 6 )C(O)NR 6 R 7 ; and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; 
 R 2  and R 3  are each independently selected from the group consisting of H, halo, —CN, —NO 2 , —OR 5 , —SR 9 , —NR 5 R 6 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —OS(O 2 )R 9 , —S(O 2 )R 9 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 9 , and —N(R 6 )C(O)NR 6 R 7 ; and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; 
 R 5  is selected from the group consisting of H, —C(O)OR 6 , —SO 2 R 9 , —C(O)NR 6 R 7 , and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 , 
 R 6  and R 7  are independently selected from the group consisting of H and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; or 
 R 5  and R 6  or R 6  and R 7 , when attached to the same nitrogen atom, optionally taken together with the nitrogen atom form a 3-8 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to said nitrogen atom; 
 R 8  is selected from the group consisting of H, halo, —OR 5 , —NO 2 , —CN, —NR 6 C(O)R 7 , —NR 6 SO 2 R 9 , —NR 5 R 6 , —C(O)R 6 , C(O)OR 6 , —C(O)NR 6 R 7 , —S(O 2 )NR 6 R 7 , and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one of halo, —CN, —NO 2 , —OR 5 , —SR 9 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —OS(O 2 )R 9 , —S(O 2 )R 9 , —S(O 2 )NR 6 R 7 , —N(R 6 )C(O)NR 6 R 7 , and NR 6 SO 2 R 9 ; 
 R 9  is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; 
 R 19  is selected from the group consisting of H, —C(O)R 6 , —C(O)OR 6 , —SO 2 R 9 , —C(O)NR 6 R 7 , and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups optionally substituted with at least one R 8 ; 
 R 11  is halo; 
 R 12  is —NR 13 R 14 ; 
 R 13  is H or alkyl; and 
 R 14  is alkyl substituted with a hydroxy substituent. 
 
   
   
       21 . The compound of  claim 20 , wherein W is S and Z and X are N. 
   
   
       22 . The compound of  claim 20 , wherein W is S, J 1  is CR 4 , J 2  is N. 
   
   
       23 . The compound of  claim 20 , wherein W is S, J 1  is CR 4 , J 2  is N, Z and X are N. 
   
   
       24 . The compound of  claim 20 , wherein W is S and R 1  is p-methylphenyl. 
   
   
       25 . The compound of  claim 20 , wherein W is S and R 1  is p-halophenyl. 
   
   
       26 . The compound of  claim 20 , wherein R 11  is bromo. 
   
   
       27 . The compound of  claim 20 , wherein the compound is selected from the group consisting of those set forth below or a pharmaceutically acceptable salt or solvate thereof: 
     
       
         
         
             
             
         
       
     
   
   
       28 . A pharmaceutical composition comprising at least one compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle. 
   
   
       29 . A pharmaceutical composition comprising at least one compound of  claim 19 , or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle. 
   
   
       30 . The pharmaceutical composition of  claim 28 , further comprising one or more additional therapeutic agents. 
   
   
       31 . The pharmaceutical composition of  claim 29 , further comprising one or more additional therapeutic agents. 
   
   
       32 . The pharmaceutical composition of  claim 30 , wherein said additional therapeutic agents are selected from the group consisting of therapeutic agents suitable for pain management, anti-anxiety agents, anti-migraine agents, and therapeutic agents suitable for treating urinary incontinence. 
   
   
       33 . The pharmaceutical composition of  claim 31 , wherein said additional therapeutic agents are selected from the group consisting of therapeutic agents suitable for pain management, anti-anxiety agents, anti-migraine agents, and therapeutic agents suitable for treating urinary incontinence. 
   
   
       34 . A method of selectively antagonizing metabotropic glutamate receptor 1 (mGluR1) activity in a cell in need thereof, comprising contacting said cell with a therapeutically effective amount of at least one compound of  claim 1  or a pharmaceutically acceptable salt, solvate or ester thereof. 
   
   
       35 . A method of treating a disease or condition associated with metabotropic glutamate receptor 1 (mGluR1) function in a mammal in need of such treatment, comprising administering a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt, solvate or ester thereof. 
   
   
       36 . The method of  claim 35 , wherein said disease or condition is pain. 
   
   
       37 . The method of  claim 35 , wherein said disease or condition is neuropathic pain. 
   
   
       38 . The method of  claim 35 , wherein said disease or condition is allodynia. 
   
   
       39 . The method of  claim 35 , wherein said disease or condition is hyperalgesia. 
   
   
       40 . The method of  claim 35 , wherein said disease or condition is pain associated with inflammation or an inflammatory disease. 
   
   
       41 . The method of  claim 36 , further comprising administering one or more additional therapeutic agent(s) suitable for pain management. 
   
   
       42 . The method of  claim 41 , wherein said additional therapeutic agent is an opioid analgesic. 
   
   
       43 . The method of  claim 41 , wherein said additional therapeutic agent is a non-opioid analgesic. 
   
   
       44 . The method of  claim 35 , wherein said disease or condition is selected from the group consisting of muscle spasms, convulsions, spasticity, migraine, psychoses urinary incontinence, anxiety and related disorders, emesis, brain edema, tardive dyskinesia, depression, drug tolerance and withdrawal, and smoking cessation. 
   
   
       45 . The method of  claim 44 , wherein said disease or condition is anxiety. 
   
   
       46 . The method of claim  55 , further comprising administering one or more additional anti-anxiety agent(s). 
   
   
       47 . The method of  claim 44 , wherein said disease or condition is migraine. 
   
   
       48 . The method of  claim 47 , further comprising administering one or more additional anti-migraine agent(s). 
   
   
       49 . The method of  claim 44 , wherein said disease or condition is urinary incontinence 
   
   
       50 . The method of  claim 49 , further comprising administering one or more additional therapeutic agent(s) suitable for treating urinary incontinence. 
   
   
       51 . The method of  claim 35 , wherein said disease or condition is selected from the group consisting of cerebral deficits subsequent to cardiac bypass surgery or grafting, cerebral ischemia, stroke, spinal cord injuries, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis (ALS), AIDS-induced dementia, inherited ataxias, ocular damage and retinopathy, cognitive disorders, and idiopathic or drug-induced Parkinson's. 
   
   
       52 . The method of  claim 51 , further comprising administering one or more additional therapeutic agent(s). 
   
   
       53 . A compound of  claim 1 , in isolated and purified form.