4-(heteroaryl-methyl and substituted heteroaryl-methyl)-imidazole-2-thiones acting as alpha2 adrenergic agonists

Abstract

Compounds of Formula 1 where the variables have the meaning defined in the specification are agonists of alpha 2 adrenergic receptors. Several compounds of the disclosure are specific or selective to alpha 2B and/or alpha 2C adrenergic receptors in preference over alpha 2A adrenergic receptors. Additionally some of the claimed compounds have no or only minimal cardiovascular and/or sedatory activity. The compounds of Formula 1 are useful as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of alpha 2 adrenergic receptors. Compounds of Formula 1 which have no significant cardiovascular and/or sedatory activity are useful for treating pain and other conditions with minimal side effects.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       Where m, n and q are integers selected from zero 0, 1, 2, 3 and 4 with the proviso that the sum of m, n and q is 1, 2, 3 or 4;
 W, X and Y represent a carbon or a heteroatom independently selected from N, O and S with the proviso that at least one of said W, X and Y groups represents a heteroatom; 
 the dashed lines represent a bond or absence of a bond with the proviso that there are no more than 3 dashed lines present in the ring and with the further proviso that no dashed line representing a bond is connected to an oxygen or sulfur heteroatom; 
 R 1  is independently H, alkyl of 1 to 4 carbons, fluoro substituted alkyl of 1 to 4 carbons, (CH 2 ) s CN, (CH 2 ) s —OR 2 , (CH 2 ) s —NR 4 R 5 ; 
 s is an integer selected from 1, 2 and 3; 
 R 2  is independently H, alkyl of 1 to 4 carbons, C(O)R 8 , carbocyclic aryl or heterocyclic aryl having 1 to 3 heteroatoms independently selected from N, O and S; 
 p is an integer selected from 0, 1, 2, 3, 4 and 5; 
 R 3  is independently selected from the groups consisting of alkyl of 1 to 4 carbons, fluoro substituted alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, F, Cl, Br, I, N 3 , NO 2 , (CH 2 ) t —OR 2 , (CH 2 ) t —NR 5 R 6 , (CH 2 ) t —CN, C(O)R 4 , C(O)OR 4 , (CH 2 ) t —SO 2 R 4 , carbocyclic aryl or heterocyclic aryl having 1 to 3 heteroatoms independently selected from N, O and S; 
 
       t is an integer selected from 0, 1, 2 and 3; 
       R 4  and R 5  independently are H or alkyl of 1 to 4 carbons 
       R 6  is independently H, alkyl of 1 to 4 carbons, carbocyclic aryl or heterocyclic aryl having 1 to 3 heteroatoms independently selected from N, O and S; 
       Optionally R 7  and R 8  together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; 
       said carbocyclic or heterocyclic ring jointly formed by R 7  and R 8  being optionally substituted with 1 to 7 R 9  groups; 
       R 9  is independently selected from the groups consisting of alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons, CH 2 OR 2 , CH 2 N(R 2 ) 2 , CH 2 CN, C(O)R 2 , C(O)OR 6 , SO 3 R 6 , SO 2 N(R 2 ) 2 , CH 2 SR 2 , F, Cl, Br, I, fluoro substituted alkyl of 1 to 4 carbons, CN, N 3 , NO 2 , N(R 2 ) 2 , OR 2 , SR 2  or R 8  is O or S double bonded to one carbon of said carbocyclic or heterocyclic ring, with the proviso that the ring 
       
         
           
           
               
               
           
         
       
       does not represent an imidazole, substituted imidazole, a 2-furanone or substituted 2-furanone. 
     
     
         2 . A compound in accordance with  claim 1  having the formula 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound in accordance with  claim 1  having the formula 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound in accordance with  claim 1  having the formula 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound in accordance with  claim 1  having the formula 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound in accordance with  claim 1  having the formula 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound in accordance with  claim 1  having the formula 
       
         
           
           
               
               
           
         
       
       wherein w is 1, 2, 3 or 4 and p is 0, 1 or 2. 
     
     
         8 . A compound in accordance with  claim 7  wherein R 9  is selected from the group consisting of F, Cl, Br and methyl and w is 1 or 2. 
     
     
         9 . A compound in accordance with  claim 7  where one R 1  groups is H the other is alkyl of 1 to 4 carbons. 
     
     
         10 . A compound in accordance with  claim 9  having the formula 
       
         
           
           
               
               
           
         
       
     
     
         11 . A method comprising administering to a mammal a pharmaceutical composition containing a therapeutically effective dose of a compound in accordance with  claim 1  for the treatment of chronic pain, visceral pain, neuropathic pain, corneal pain, glaucoma, elevated intraocular pressure, ischemic neuropathies, neurodegenerative diseases, diarrhea, nasal congestion, muscle spasticity, diuresis, withdrawal syndromes, neurodegenerative diseases, optic neuropathy, spinal ischemia, stroke, memory and cognition deficits, attention deficit disorder, psychoses, manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia, arthritis, spondylitis, gouty arthritis, osteoarthritis, juvenile arthritis, autoimmune diseases, lupus erythematosus, chronic gastrointestinal inflammations, Crohn's disease, gastritis, irritable bowel syndrome (IBS), functional dyspepsia, ulcerative colitis, or a combination thereof. 
     
     
         12 . A method in accordance with  claim 15  where the pharmaceutical composition is administered to the mammal to treat pain. 
     
     
         13 . A method in accordance with  claim 17  where the pharmaceutical composition is administered to the mammal to treat neuropathic pain. 
     
     
         14 . A method in accordance with  claim 18  where the pharmaceutical composition is administered to the mammal to visceral pain. 
     
     
         15 . A method in accordance with  claim 16  where the pharmaceutical composition is administered orally. 
     
     
         16 . A compound of the structure 
       
         
           
           
               
               
           
         
       
       wherein A is H or methyl, and 
       B is monocyclic or bicyclic heteroaryl having 0, 1, or 2 substituents, 
       wherein each substituent is independently Cl, Br, F, or methyl. 
     
     
         17 . The compound of  claim 16  of the structure 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 17  of the structure 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 16  wherein B is indolyl having a single substituent. 
     
     
         20 . The compound of  claim 16  wherein B is pyridinyl having a single substituent.