N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor

Abstract

The present invention relates to N-phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) compounds, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating diseases that respond to modulation of the serotonin 5-HT 6 receptor.

1 - 30 . (canceled) 
     
     
         31 . A non-prophylactic method for treating acute or chronic signs, symptoms and/or malfunctions of an addictive disease, said method comprising administering an effective amount of a N-Phenyl-(piperazinyl or homopiperazinyl)-benzenesulfonamide or benzenesulfonyl-phenyl-(piperazine or homopiperazine) of formula (I) or (I′) 
       
         
           
           
               
               
           
         
         wherein 
         X is a bond or a group N—R 4 ; 
         R 1  is hydrogen or methyl; 
         R 2  is hydrogen or methyl; 
         R 3  is hydrogen, C 1 -C 3  alkyl, fluorine, C 1 -C 2  alkoxy or fluorinated C 1 -C 2  alkoxy; 
         R 4  is hydrogen, C 1 -C 4  alkyl, C 3 -C 4  cycloalkyl, or C 3 -C 4  cycloalkyl-CH 2 —; 
         R 5  is hydrogen, fluorine, chlorine, C 1 -C 2  alkyl, fluorinated C 1 -C 2  alkyl, C 1 -C 2  alkoxy or fluorinated C 1 -C 2  alkoxy; 
         R 6  is hydrogen, fluorine or chlorine; and 
         n is 1 or 2, 
         or a physiologically tolerated acid addition salt or an N-oxide thereof. 
       
     
     
         32 . The method of  claim 31 , wherein the addictive disease is caused by the abuse of a psychotropic substance. 
     
     
         33 . The method of  claim 32 , wherein the psychotropic substance is a sedative, an anxiolytic, a hypnotic, or a narcotic. 
     
     
         34 . The method of  claim 32 , wherein the psychotropic substance is an opioid, cocaine, nicotine, alcohol, a substance which interacts with the GABA chloride channel complex, a sedative, a hypnotic, a tranquilizer, lysergic acid diethylamide, a cannabinoid, a psychomotor stimulant, an amphetamine or amphetamine-like substance, or caffeine. 
     
     
         35 . The method of  claim 31 , wherein the addictive disease is an addiction to gaming. 
     
     
         36 . The method of  claim 31 , wherein the addictive disease is an addiction to gambling, a computer or video game addiction, or an internet addiction. 
     
     
         37 . The method of  claim 31 , wherein X is a group N—R 4 . 
     
     
         38 . The method of  claim 31 , wherein n is 1. 
     
     
         39 . The method of  claim 31 , wherein R 3  is methyl or methoxy. 
     
     
         40 . The method of  claim 31 , wherein R 4  is hydrogen. 
     
     
         41 . The method of  claim 31 , wherein R 5  is methyl, methoxy or difluoromethoxy. 
     
     
         42 . The method of  claim 31 , wherein R 6  is hydrogen. 
     
     
         43 . The method of  claim 31 , wherein
 X is a bond or a group N—R 4 ;   R 1  is hydrogen or methyl;   R 2  is hydrogen;   R 3  is hydrogen, C 1 -C 2  alkyl, or C 1 -C 2  alkoxy;   R 4  is hydrogen, methyl, ethyl, n-propyl, isopropyl or cyclopropylmethyl;   R 5  is hydrogen, methyl or methoxy;   R 6  is hydrogen; and   n is 1 or 2.   
     
     
         44 . The method of  claim 31 , wherein the OCHF 2 -radical in formula I is located on the benzene ring in the ortho-position with respect to X. 
     
     
         45 . The method of  claim 31 , wherein the OCHF 2 -radical in formula I is located on the benzene ring in the meta-position with respect to X. 
     
     
         46 . The method of  claim 31 , wherein the OCHF 2 -radical in formula I is located on the benzene ring in the para-position with respect to X. 
     
     
         47 . The method of  claim 31 , wherein the compound of formula (I) or (I′) is selected from the group consisting of:
 N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide; 
 1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methyl-phenyl]-piperazine; 
 N-(2-difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamide; 
 N-(2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzene-sulfonamide; 
 N-(3-Difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzene-sulfonamide; 
 N-(4-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-methyl-3-piperazin-1-yl-benzene sulfonamide; 
 N-cyclopropylmethyl-N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-cyclopropylmethyl-N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzene-sulfonamide; 
 N-(3-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-N-propyl-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide; 
 N-(3-difluoromethoxy-phenyl)-4,N-dimethyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-N-ethyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide; 
 N-(2-difluoromethoxy-phenyl)-N-methyl-4-methyl-3-piperazin-1-yl-benzene sulfonamide; 
 N-(2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzene-sulfonamide; 
 N-(4-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 3-[1,4]diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide; 
 3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-N-ethyl-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-4-methoxy-N-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-N-propyl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-N-isopropyl-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-N-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-N-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 1-[3-(3-difluoromethoxy-benzenesulfonyl)-phenyl]-piperazine; 
 1-[3-(3-difluoromethoxy-benzenesulfonyl)-phenyl]-4-methyl-piperazine; 
 1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine; 
 1-[5-(3-difluoromethoxy-benzenesulfonyl)-2-methoxy-phenyl]-4-methyl-piperazine; 
 1-[5-(3-difluoromethoxy-4-methoxy-benzenesulfonyl)-2-methoxy-phenyl]-piperazine; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3,4-bis-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(3,4-bis-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(5-chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(5-chloro-2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(5-chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methyl-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3,4-bis-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(5-chloro-2-difluoromethoxy-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((R)-3-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-((S)-3-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(5-chloro-2-difluoromethoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N(2-difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methoxy-phenyl)-4-methyl-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methyoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(4-difluoromethoxy-3-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(4-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(4-difluoromethoxy-3-methoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(4-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide; 
 3-[1,4]diazepan-1-yl-N-(2-difluoromethoxy-phenyl)-4-methyl-benzenesulfonamide; 
 3-[1,4]diazepan-1-yl-N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-benzenesulfonamide; 
 N-(3-difluoromethoxy-4-methyl-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide; 
 N-(3-difluoromethoxy-phenyl)-4-methyl-3-(4-methyl-[1,4]diazepan-1-yl)-benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-yl benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-N-methyl-3-piperazin-1-yl benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methylphenyl)-4-fluoro-3-piperazin-1-yl benzenesulfonamide; 
 N-(5-difluoromethoxy-2-methylphenyl)-4-fluoro-N-methyl-3-piperazin-1-yl benzenesulfonamide; and 
 the physiologically tolerated acid addition salts thereof and the N-oxides thereof. 
 
     
     
         48 . The method of  claim 31 , wherein the compound of formula (I) or (I′) is selected from the group consisting of:
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-difluoromethoxy-5-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(5-Chloro-2-difluoromethoxy-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(5-Difluoromethoxy-2-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide; 
 N-(2-Difluoromethoxy-4-fluoro-phenyl)-4-methoxy-3-(4-methyl-piperazin-1-yl)-benzenesulfonamide; 
 N-(5-Difluoromethoxy-2-methylphenyl)-4-difluoromethoxy-3-piperazin-1-yl benzenesulfonamide; and 
 the physiologically tolerated acid addition salts thereof and the N-oxides thereof. 
 
     
     
         49 . The method of  claim 31 , wherein the compound of formula (I) or (I′) is N-(2-difluoromethoxy-4-methyl-phenyl)-4-ethoxy-3-piperazin-1-yl-benzenesulfonamide, or a physiologically tolerated acid addition salt or N-oxide thereof. 
     
     
         50 . The method of  claim 31 , wherein the compound of formula (I) or (I′) is N-(2-difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide, or a physiologically tolerated acid addition salt or N-oxide thereof.