Aminotetralins as 5-HT1Dalpha agonists

Abstract

A class of novel aminotetralins is disclosed useful as 5-HT 1Dα agonists.

We claim:  
     
         1 . A compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  and R 2  are each individually hydroen or —(C 1 -C 6 )alkyl;  
 R 3  is —(C 2 -C 8 )alkenyl, —(CH 2 ) q (C 3 -C 8 )cycloalkyl, —(CH 2 ) n O(CH 2 ) p R 5 ,  
                     
 substituted with one substituent selected from the group consisting of —(C 1 -C 6 )alkyl and —(C 3 -C 8 )cycloalkyl;  
 where A-B is >C═CH— or >CR 4 CH 2 —;  
 D is —CH 2 — or oxygen;  
 R 4  is hydrogen or —OH;  
 R5 is —(C 3 -C 8 )cycloalkyl, or phenyl substituted with one substituent selected from the group consisting of halo, —(C 1 -C 6 )alkyl and (C 1 -C 6 alkoxy;  
 m is an integer from 1 to 5 both inclusive;  
 n is an integer from 0 to 4 both inclusive;  
 p is an integer from 1 to 7 both inclusive; and  
 q is an integer from 0 to 4 both inclusive;  
 or a pharmaceutically acceptable salt or optical isomer thereof;  
 provided that when D is oxygen, >A-B is not >CH═CH—; and when R 4  is —OH, D is oxygen.  
 
     
     
         2 . A compound of formula I as claimed in  claim 1  wherein R 1  and R 2  are each individually hydrogen or —(C 1 -C 6 )alkyl; 
 R 3  is  
                     
 and  
 m is 2 or 3.  
 
     
     
         3 . A compound of formula I as claimed in  claim 2  wherein A-B- are >C═CH—or >CR 4 CH 2 —.  
     
     
         4 . A compound of formula I as claimed in  claim 3  wherein A-B- is CR 4 CH 2 — and D is —CH 2 —.  
     
     
         5 . A compound of  claim 4  which is (R)-2-N,N-dimethylamino-8-(2-methlcyclopent-1-yl)tetralin hydrochloride.  
     
     
         6 . A pharmaceutical formulation comprising a compound of formula I as claimed in  claim 1  together with a pharmaceutically acceptable carrier or diluent therefor.  
     
     
         7 . A method of activating the 5-HT 1Dα  receptor which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula II  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  and R 2  are each individually hydrogen or —(C 1 -C 6 )alkyl;  
         R 3′  is —(C 1 -C 8 )alkyl, —(CH 2 ) q (C 3 -C 8 )cycloalkyl, —(C 2 -C 8 )alkenyl, —(C 1 -C 8 )alkan-1-ol-1-yl, —(CH 2 ) n O(CH 2 ) p R 5′ ,  
         
           
             
             
                 
                 
             
           
         
         substituted with one substituent selected from the group consisting of —(C 1 -C 6 )alkyl and —(C 3 -C 8 )cycloalkyl;  
         where A-B is >C═CH— or >CR 4 CH 2 —;  
         D is —CH 2 — or oxygen;  
         R 4  is hydrogen or —OH;  
         R 5′  is —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )alkoxy, phenyl or phenyl substituted with one substituent selected from the group consisting of halo, —(C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy;  
         m is an integer from 1 to 5 both inclusive;  
         n is an integer from 0 to 4 both inclusive;  
         p is an integer from 1 to 7 both inclusive; and  
         q is an integer from 0 to 4 both inclusive;  
         or a pharmaceutically acceptable salt or optical isomer thereof;  
         provided that when D is oxygen, >A-B is not >C═CH—.  
       
     
     
         8 . A method of alleviating the pathological effects of 5-HT 1Dα  receptor-activated diseases in a mammal in need of such treatment comprising administering to said mammal a pharmaceutically effective amount of a compound of formula II.  
     
     
         9 . A method of  claim 8  in which the receptor-activated diseases are useful in the treatment of dementia, migraine, sexual dysfunction, irritative bladder symptms of benign prostatic hyperplasia, urge incontinence and excessive bladder activity, caused by baceterial cystitis, interstitial cystitis, radiation/chemotherapy-induced cystitis, outlet obstruction, neurogenic bladder, spinal cord injury, stroke, and nocturnal enurisis.  
     
     
         10 . A method of  claim 7  in which the compound is (R)-2-N,N-dimethylamino-8-(2-methylcyclopent-1-yl)tetralin hydrochloride.  
     
     
         11 . A method of  claim 8  in which the compound is (R)-2-N,N-dimethylamino-8-(2-methylcyclopent-1-yl)tetralin hydrochloride.  
     
     
         12 . A method of  claim 9  in which the compound is (R)-2-N,N-dimethylamino-8-(2-methylcyclopent-1-yl)tetralin hydrochloride.  
     
     
         13 . A method of  claim 7  wherein the mammal is a human.  
     
     
         14 . A method of  claim 8  wherein the mammal is a human.  
     
     
         15 . A method of  claim 9  wherein the mammal is a human.  
     
     
         16 . A compound according to  claim 1  for use as a pharmaceutically active compound.  
     
     
         17 . A compound according to  claim 1  for use in alleviating the pathological effects of 5-HT 1Dα  receptor-activated diseases in a mammal.  
     
     
         18 . A compound according to  claim 1  for use in the treatment of dementia, Parkinson's Disease, appetite modulation, anxiety, migraine, sexual dysfunction, irritative bladder symptoms of benign prostatic hyperplasia, urge incontinence and excessive bladder activity, caused by baceterial cystitis, interstitial cystitis, radiation/chemotherapy-induced cystitis, outlet obstruction, neurogenic bladder, spinal cord injury, stroke, and nocturnal enurisis.  
     
     
         19 . Use of a compound of formula II  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  and R 2  are each individually hydrogen or —(C 1 -C 6 )alkyl;  
         R 3′  is —(C 1 -C 8 )alkyl, —(CH 2 ) q (C 3 -C 8 )cycloalkyl, —(C 2 -C 8 )alkenyl, —(C 1 -C 8 )alkan-1-ol-1-yl, —(CH 2 ) n O(CH 2 ) p R 5′ ,  
         
           
             
             
                 
                 
             
           
         
         substituted with one substituent selected from the group consisting of —(C 1 -C 6 )alkyl and —(C 3 -C 8 )cycloalkyl;  
         where A-B is >C═CH— or >CR 4 CH 2 —;  
         D is —CH 2 — or oxygen;  
         R 4  is hydrogen or —OH;  
         R 5′  is —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )alkoxy, phenyl or phenyl substituted with one substituent selected from the group consisting of halo, —(C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy;  
         m is an integer from 1 to 5 both inclusive;  
         n is an integer from 0 to 4 both inclusive;  
         p is an integer from 1 to 7 both inclusive; and  
         q is an integer from 0 to 4 both inclusive;  
         or a pharmaceutically acceptable salt or optical isomer thereof;  
         provided that when D is oxygen, >A-B is not >C═CH—; optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for alleviating the pathological effects of 5-HT 1Dα  receptor-activated diseases.