US2015158842A1PendingUtilityA1

Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy

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Assignee: ABBVIE DEUTSCHLANDPriority: Aug 13, 2010Filed: Feb 9, 2015Published: Jun 11, 2015
Est. expiryAug 13, 2030(~4 yrs left)· nominal 20-yr term from priority
Inventors:Frauke PohlkiUdo LangeWilhelm AmbergMichael OchseBerthold BehlCharles W. HutchinsWilfried HornbergerMario Mezler
A61P 43/00A61K 31/538A61P 25/24A61P 25/18C07D 217/22A61P 25/04C07D 217/26A61P 25/22C07D 217/08A61K 31/357A61K 31/4725A61P 25/28A61K 31/472C07D 401/12C07D 217/02A61P 25/00
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Claims

Abstract

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

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . Phenalkylamine derivatives of the formula (I) or (II) 
       
         
           
           
               
               
           
         
       
       wherein
 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 C 3 -C 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 -aryloxycarbonyl, 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, C 3 -C 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 3 -C 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 C 3 -C 12 -heterocyclyl; 
 W is —NR 8 — 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 —NW— or a bond; 
 A 2  is optionally substituted C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-CO—, —CO—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-O—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-NR 10 -C 1 -C 4 -alkylene, optionally substituted C 2 -C 4 -alkenylen, optionally substituted C 2 -C 4 -alkynylene, optionally substituted C 6 -C 12 -arylene, optionally substituted C 6 -C 12 -heteroarylene or a bond; 
 X 1  is —O—, —NR 11 —, —S—, or >CH 2 ; 
 X 4  is —O—, —NR 19 —, —S—, or >CH 2 ; 
 n is 0, 1, or 2; 
 m is 0, 1, or 2; 
 R 6  is hydrogen, halogen, C 1 -C 6 -alkyl or 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, hydroxy-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 C 3 -C 12 -heterocyclyl, or two radicals R 2  together with the ring atoms to which they are bound form a 5- or 6 membered ring; 
 R 3  is hydrogen or C 1 -C 6 -alkyl; 
 X 2  is —O—, —NR 7 —, —S—, >CR 12a R 12b  or a bond; 
 X 3  is —O—, —NR 7 —, —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 C 3 -C 12 -heterocyclyl; 
 Y 1  is >CR 14a R 14b  or a bond; 
 Y 2  is >CR 15a R 15b ; 
 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, 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 C 3 -C 12 -heterocyclyl; or 
 R 4a , R 3  
 together are optionally substituted C 1 -C 6 -alkylene; or 
 
 R 4a , R 14a  
 together are optionally substituted C 1 -C 6 -alkylene; 
 
 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 C 3 -C 12 -heterocyclyl; or 
 R 4a , R 4b  
 together are optionally substituted C 1 -C 6 -alkylene, wherein one —CH 2 — of C 1 -C 6 -alkylene may be replaced by an oxygen atom or —NR 16 ; or 
 
 R 7  is hydrogen or C 1 -C 6 -alkyl; 
 R 8  is hydrogen or C 1 -C 6 -alkyl; 
 R 9  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 C 3 -C 12 -heterocyclyl; or 
 R 9 , R 1  
 together are C 1 -C 4 -alkylene; or 
 
 R 9  is C 1 -C 4 -alkylene that is bound to a carbon atom in A 2  and A 2  is C 1 -C 4 -alkylene; 
 R 10  is hydrogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkylsulfonyl; 
 R 11  is hydrogen or C 1 -C 6 -alkyl, or 
 R 9 , R 11  
 together are C 1 -C 4 -alkylene, 
 
 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, C 3 -C 12 -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 12a , R 12b  
 together are carbonyl or 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 17 —; 
 
 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, C 3 -C 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 
 R 13a , R 13b  
 together are carbonyl or 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 18 —; 
 
 R 14 a 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, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy; 
 R 14b  is hydrogen or C 1 -C 6 -alkyl, or 
 R 14a , R 14b  
 together are carbonyl or optionally substituted C 1 -C 4 -alkylene, wherein one or two —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 20 ; 
 
 R 15a  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, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy; 
 R 15b  is hydrogen or C 1 -C 6 -alkyl, or 
 R15a R 15b  
 together are carbonyl or optionally substituted C 1 -C 4 -alkylene, wherein one or two —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 20 ; 
 
 R 16  is hydrogen or C 1 -C 6 -alkyl; 
 R 17  is hydrogen or C 1 -C 6 -alkyl; 
 R 18  is hydrogen or C 1 -C 6 -alkyl, 
 R 19  is hydrogen or C 1 -C 6 -alkyl, and 
 R 20  is hydrogen or C 1 -C 6 -alkyl, 
 or a physiologically tolerated salt thereof. 
 
     
     
         2 . Compound as claimed in  claim 1 , wherein —Y-A 2 - comprises at least 1 or 2 atoms in the main chain. 
     
     
         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, halogenated C 1 -C 6 -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 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 2 -C 6 -alkenyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino or optionally substituted C 3 -C 12 -heterocyclyl. 
     
     
         4 . Compound as claimed in  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , W, A 1 , Q Y, A 2 , X 1 , X 4 , n, R 6 , R 2 , R 3 , X 2 , X 3 , R 5 , Y 1 , Y 2 , R 4a , R 4b  are as defined in any one of  claims 1  to  3 . 
     
     
         5 . Compound as claimed in  claim 1 , wherein R 1 —W-A 1 -Q-Y-A 2  is R 1 —S(O) 2 —NH-A 2 , R 1 —NH—S(O) 2 -A 2 , R 1 —C(O)—NH-A 2 - or R 1 —NH—C(O)-A 2 -. 
     
     
         6 . Compound as claimed in  claim 1 , wherein n is 1. 
     
     
         7 . Compound as claimed in  claim 1 , wherein X 4  is —O— or —NR 19 —. 
     
     
         8 . Compound as claimed in  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , W, A 1 , Q, m, R 6 , R 2 , R 3 , X 2 , X 3 , R 5 , Y 1 , Y 2 , R 4a , R 4b  are as defined in any one of  claims 1  to  6 . 
     
     
         9 . Compound as claimed in  claim 1 , wherein R 1 —W-A 1 -Q- is R 1 —S(O) 2 —NH—, R 1 —NH—S(O) 2 —, R 1 —C(O)—NH— or R 1 —NH—C(O)—. 
     
     
         10 . Compound as claimed in  claim 1 , wherein m is 1 or 2. 
     
     
         11 . Compound as claimed in  claim 1 , wherein X 2  is CR 12a R 12b , and X 3  is a bond. 
     
     
         12 . Compound as claimed in  claim 1 , wherein R 12a  is hydrogen or C 1 -C 6 -alkyl and R 12b  is hydrogen or C 1 -C 6 -alkyl, or R 12a , R 12b  together are optionally substituted C 1 -C 4 -alkylene. 
     
     
         13 . Compound as claimed in  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1 , W, A 1 , Q, Y, A 2 , X 1 , X 4 , n, m, R 6 , R 2 , R 3 , X 2 , X 3 , Y 1 , Y 2 , R 4a , R 4b  are as defined in any one of  claims 1  to  12 ; and R 21a , R 21b , R 21c , R 21d , R 21a  independently are hydrogen, halogen, optionally substituted C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, CN, hydroxy, C 1 -C 6 -alkoxy, amino, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino or C 3 -C 12 -heterocyclyl. 
     
     
         14 . Compound as claimed in  claim 1 , wherein Y 1  is a bond and Y 2  is >CR 15a R 15b , 
     
     
         15 . Compound as claimed in  claim 1 , wherein R 4 a is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, CH 2 CN, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 3 -C 12 -cycloalkyl, C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, amino, —NO or C 3 -C 12 -heterocyclyl, or R 4a , R 3  together are optionally substituted C 1 -C 4 -alkylene, or R 4a , R 14a  together are optionally substituted C 1 -C 4 -alkylene. 
     
     
         16 . Compound as claimed in  claim 1 , wherein R 4a , R 4b  are optionally substituted C 1 -C 6 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom. 
     
     
         17 . Compound as claimed in  claim 1 , which is a compound of formula (I) wherein R 1  is C 1 -C 6 -alkyl or optionally substituted C 3 -C 12 -heterocyclyl;
 W is a bond;   A l  is a bond;   Q is —S(O) 2 —;   Y is NR 9 ;   A 2  is C 1 -C 4 -alkylene   X 1  —O—   X 4  —O— or NR 19 ;   n is 1;   R 6  is hydrogen;   R 2  is hydrogen;   R 3  is hydrogen;   X 2  is CR 12a R 12b ;   X 3  is a bond;   R 5  is phenyl;   Y 1  is a bond;   Y 2  is >CR 15a R 15b ;   R 4a  is hydrogen;   R 4b  is hydrogen;   R 12a  is hydrogen;   R 12b  is hydrogen;   R 15a  is hydrogen;   R 15b  is hydrogen; and   R 19  is C 1 -C 6 -alkyl,   or which is a compound of formula (II) wherein   R 1  is C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, or optionally substituted C 3 -C 12 -heterocyclyl;   W is a bond;   A 1  is a bond;   Q is —S(O) 2 — or —C(O)—;   m is 1or 2;   R 6  is hydrogen;   R 2  is hydrogen;   R 3  is hydrogen;   Y 1  is a bond;   Y 2  is 6  >CR 15a R 15b ;   R 4a  is hydrogen, or C 1 -C 6 -alkyl;   R 4b  is hydrogen or C 1 -C 6 -alkyl;   X 2  is CR 12a R 12b ;   X 3  is a bond;   R 5  is phenyl;   R 12a  is hydrogen;   R 12b  is hydrogen;   R 15a  is hydrogen; and   R 15b  is hydrogen.   
     
     
         18 . The compound as claimed in  claim 1 , which is:
 2-(2-(1-Methyl-1H-imidazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-phenylpropan-1-amine;   2-(2-(1-Methyl-1H-pyrazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-phenylpropan-1-amine;   2-(2-(1-Methyl-1H-pyrazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-phenylpropan-1-amine;   N,N-Dimethyl-2-(2-(1-methyl-1H-imidazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-phenylpropan-1-amine;   N,N,N-Trimethyl-2-(2-(1-methyl-1H-pyrazol-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-phenylpropan-1-amine;   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 .

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