Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy

Abstract

The present invention relates to aminotetraline and aminoindane derivatives of the formula (I) or a physiologically tolerated salt thereof. The invention relates to pharmaceutical compositions comprising such aminotetraline and aminoindane derivatives, and the use of such aminotetraline and aminoindane derivatives for therapeutic purposes. The aminotetraline and aminoindane derivatives are GlyT1 inhibitors.

We claim: 
     
         1 . Compounds of the formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         A is a 5- or 6-membered ring; 
         R 1  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 6 -alkyl, tri(C 1 -C 4 -alkyl)-silyl-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted M 3 -M 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxy carbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, amino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylcarbonylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxycarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkoxy, (halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylsulfonylamino-C 1 -C 4 -alkoxy, (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, M 3 -M 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, M 3 -M 12 -heterocyclyl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, M 3 -M 12 -heterocyclyloxy, C 1 -C 6 -alkylthio, halogenated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 6 -alkyl)carbonylamino, C 6 -C 12 -arylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 6 -alkyl)sulfonylamino, C 6 -C 12 -arylsulfonylamino or optionally substituted M 3 -M 12 -heterocyclyl; 
         W is —NR 7 — or a bond; 
         A 1  is optionally substituted C 1 -C 4 -alkylene or a bond; 
         Q is —S(O) 2 — or —C(O)—; 
         Y is —NR 8 — or a bond; 
         n1 is 0, 1, 2, or 3; 
         n2 is 0, 1, 2, or 3; 
         X 1  is >N— or >CH—; 
         R 6  is hydrogen, halogen, C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, —CN, hydroxy, C 1 -C 6 -alkoxy or halogenated C 1 -C 6 -alkoxy, or two radicals R 6  together with the carbon atom to which they are attached form a carbonyl group; 
         R 2  is hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, —CN, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 2 -C 6 -alkenyloxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, amino, C 1 -C 6 -alkylamino, C 2 -C 6 -alkenylamino, nitro or optionally substituted M 3 -M 12 -heterocyclyl, or two radicals R 2  together with the ring atoms of A to which they are bound form a 5- or 6 membered ring; 
         m is 0 or 1; 
         R 3  is hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or two radicals R 3  together with the carbon atom to which they are attached form a carbonyl group; 
         Y 1  is a bond or optionally substituted C 1 -C 4 -alkylene; 
         R 4a  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, —CH 2 CN, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, C 6 -C 12 -arylsulfonyl, amino, —NO or optionally substituted M 3 -M 12 -heterocyclyl; or 
         R 4a  is optionally substituted C 1 -C 4 -alkylene that is bound to a carbon atom in Y 1 ; 
         R 4b  is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, —CH 2 CN, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, C 6 -C 12 -arylsulfonyl, amino, —NO or M 3 -M 12 -heterocyclyl; or 
         R 4a , R 4b  together are optionally substituted C 2 -C 6 -alkylene, wherein one —CH 2 — of C 2 -C 6 -alkylene may be replaced by an oxygen atom or —NR 10 ; 
         X 2  is —O—, —NR 11a —, —S—, >CR 12a R 12b  or a bond; 
         X 3  is —O—, —NR 11b —, —S—, >CR 13a R 13b  or a bond; 
         R 5  is optionally substituted C 6 -C 12 -aryl, optionally substituted C 3 -C 12 -cycloalkyl or optionally substituted M 3 -M 12 -heterocyclyl; 
         R 7  is hydrogen or C 1 -C 6 -alkyl; 
         R 8  is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl, amino-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl or M 3 -M 12 -heterocyclyl; or 
         R 8 , R 1  together are C 1 -C 4 -alkylene: 
         R 10  is hydrogen or C 1 -C 6 -alkyl; 
         R 11a  is hydrogen or C 1 -C 6 -alkyl; 
         R 11b  is hydrogen or C 1 -C 6 -alkyl; 
         R 12a  is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, M 3 -M  2 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy; 
         R 12b  is hydrogen or C 1 -C 6 -alkyl, or 
         R 12 , R 12b  together with the carbon atom to which they arc attached form a carbonyl or are optionally substituted C 2 -C 4 -alkylene, wherein one —CH 2 — of C 2 -C 4 -alkylene may be replaced by an oxygen atom or —NR 14 —: 
         R 13a  is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, M 3 -M 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy; 
         R 13b  is hydrogen or C 1 -C 6 -alkyl, or together with the carbon atom to which they are attached form a carbonyl or are optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 15 —; 
         R 14  is hydrogen or C 1 -C 6 -alkyl; and 
         R 15  is hydrogen or C 1 -C 6 -alkyl, 
         or a physiologically tolerated salt thereof. 
       
     
     
         2 . Compound as claimed in  claim 1 , wherein A is a benzene ring or a ring selected from the group consisting of the following 5- or 6-membered heterocyclic rings: 
       
         
           
           
               
               
           
         
       
     
     
         3 . Compound as claimed in  claim 1 , wherein R 1  is C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, or C 3 -C 12 -cycloalkyl. 
     
     
         4 . Compound as claimed in  claim 1 , wherein W is a bond and A 1  is a bond. 
     
     
         5 . Compound as claimed in  claim 1 , wherein Q is —S(O) 2 — and Y is —NR 8 —. 
     
     
         6 . Compound as claimed in  claim 1 , wherein at least one of n1 and n2 is 1,2, or 3 and the sum of n1+n2 is 2,3, or 4. 
     
     
         7 . Compound as claimed in  claim 1 , wherein X 1  is >N—, n1 is 1, and n2 is 1; or X 1  is >CH—, n1 is 1, and n2 is 1. 
     
     
         8 . Compound as claimed in  claim 1 , wherein R 6  is hydrogen, C 1 -C 4 -alkyl, or two radicals R 6  together with the carbon atom to which they are attached form a carbonyl group. 
     
     
         9 . Compound as claimed in  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         wherein R 1 , W, A 1 , Q, Y, n1, n2, X 1 , R 6 , R 2 , m, R 3 , Y 1 , R 4a , R 4b , X 2 , X 3 , R 5  are as defined in  claim 1 . 
       
     
     
         10 . Compound as claimed in  claim 1 , wherein R 2  is hydrogen or halogen. 
     
     
         11 . Compound as claimed in  claim 1 , wherein R 3  is hydrogen or C 1 -C 6 -alkyl. 
     
     
         12 . Compound as claimed in  claim 1 , wherein Y 1  is a bond. 
     
     
         13 . Compound as claimed in  claim 1 , wherein R 4a  is hydrogen, C 1 -C 6 -alkyl, optionally substituted C 3 -C 12 -cycloalkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, or M 3 -M 12 -heterocyclyl and R 4b  is hydrogen or C 1 -C 6 -alkyl; or wherein R 4a , R 46  together are optionally substituted C 2 -C 6 -alkylene, wherein one —CH 2 — of C 2 -C 6 -alkylene may be replaced by an oxygen atom. 
     
     
         14 . Compound as claimed in  claim 1 , wherein X 2  is >CR 12a R 12b , X 3  is a bond, and R 12e  is hydrogen or C 1 -C 6 -alkyl and R 12b  is hydrogen or C 1 -C 6 -alkyl. 
     
     
         15 . Compound as claimed in  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         wherein A, R 1 , W, A 1 , Q, Y, n1, n2, X 1 , R 6 , R 2 , m, R 3 , Y 1 , R 4a , R 4b , X 2 , X 3  are as defined in  claim 1 ; and 
         R 16a , R 16b , R 16c , R 16d , R 16e  independently are hydrogen, halogen, or halogenated C 1 -C 6 -alkyl. 
       
     
     
         16 . Compound as claimed in  claim 1 , wherein m is 1. 
     
     
         17 . Compound as claimed in  claim 1 , wherein
 A is a benzene ring;   R 1  is C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, or optionally substituted M 3 -M 12  heterocyclyl;   W is a bond;   A 1  is a bond;   Q is —S(O) 2 —;   Y is —NR 8 —;   n1 is 1 or 2;   n2 is 1 or 2;   R 6  is hydrogen, C 1 -C 6 -alkyl, or two radicals R 6  together with the carbon atom to which they are attached form a carbonyl group;   X 1  is —>N— or >CH—;   R 2  is hydrogen;   m is 1;   R 3  is hydrogen;   Y 1  is a bond;   R 4a , R 4b  together are optionally substituted C 2 -C 6 -alkylene;   X 2  is >CR 12a R 12b ;   X 3  is a bond;   R 5  is optionally substituted phenyl;   R 8  is hydrogen;   R 12a  is hydrogen; and   R 12b  is hydrogen.   
     
     
         18 . The compound as claimed in  claim 1  which is:
 N-(1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)azetidin-3-yl)-1-methyl-1H-imidazole-4-sulfonamide; 
 N-(1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)azetidin-3-yl)methanesulfonamide; 
 N-(1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)azetidin-3-yl)ethanesulfonamide; 
 N-(1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)azetidin-3-yl)propane-1-sulfonamide; 
 N-(1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)azetidin-3-yl)-2,2-difluorobenzo[d][1,3]dioxole-5-sulfonamide; 
 N-(1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-methylazetidin-3-yl)-1-methyl-1H-imidazole-4-sulfonamide; 
 N-(1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-methylazetidin-3-yl)ethanesulfonamide; 
 N—((R)-1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin-3-yl)-1-methyl-1H-imidazole-4-sulfonamide; 
 N—((S)-1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin-3-yl)-1-methyl-1H-imidazole-4-sulfonamide; 
 N-(1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)piperidin-4-yl)-1-methyl-1H-imidazole-4-sulfonamide; 
 N-((1R,3r)-3-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclobutyl)-1-methyl-1H-imidazole-4-sulfonamide; 
 N-((1S,3s)-3-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclobutyl)-1-methyl-1H-imidazole-4-sulfonamide; 
 N—((S)-1-((7S,8R)-7-(azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxopyrrolidin-3-yl)propane-1-sulfonamide; 
 N-(1-((7S,8R)-8-benzyl-7-(3-azabicyclo[3.1.0]hexan-3-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)azetidin-3-yl)-1-methyl-1H-imidazole-4-sulfonamide: 
 N-(1-((7S,8R)-8-benzyl-7-(3-azabicyclo[3.1.0]hexan-3-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)azetidin-3-yl)-1-methyl-1H-1,2,3-triazole-4-sulfonamide; 
 N-(1-((7S,8R)-8-benzyl-7-(3-azabicyclo[3.1.0]hexan-3-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)azetidin-3-yl)propane-1-sulfonamide; 
 or a physiologically tolerated salt thereof. 
 
     
     
         19 . Pharmaceutical composition which comprises a carrier and a compound of  claim 1 . 
     
     
         20 . A method for treating a neurologic or psychiatric disorder or pain in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of  claim 1 .