Certain substituted 1-aryl-3-piperazine-1'-yl propanones

Abstract

Disclosed are compounds of formula I: wherein X is a carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl; Z is nitrogen or CH; Ar 1 and Ar 2 independently represent aryl groups; and Y is hydrogen; or Y and R 1 or R 2 together represent CH 2 ;CH 2 CH 2 ; CH 2 O; CH 2 S forming a five or six membered ring and such ring may be optionally substituted with loweralkyl or phenyl; or the pharmaceutically acceptable salts thereof, useful in the treatment of neoplastic diseases, and bacterial or fungal infections, and in preventing or decreasing the production of abnormally phosphorylated paired helical filament (PHF) epitopes associated with Alzheimer's Disease and, therefore, useful for treating Alzheimer's Disease.

What is claimed is:  
     
         1 . A compound of the formula:  
                   or the pharmaceutically acceptable salts thereof wherein 
 X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;  
 Z is nitrogen or CH with the proviso that when Ar 1  is phenyl or substituted phenyl Z is nitrogen;  
 Ar 1  is a group of the formula:  
                 
 
   wherein 
 R 1 , R 2  and R 3  independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, amino, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamiine, alkylsulfonylamnino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy, optionally substituted phenylsulfide, provided that R 1 , R 2  and R 3  are not all hydrogen; or two of R 1 , R 2  and R 3  taken together can form an ethylenedioxy, ethyleneoxy, or a lower straight alkylene chain alkyl bridge of 3-5 atoms optionally substituted by loweralkyl; or  
 R 1 , R 2  and R 3  are the same or different and represent a group of the, formula:  
                 
 
   Ar 1  is a group of the formula:  
                 
   wherein 
 X 2  is oxygen or sulfur;  
 R 5  is hydrogen, halo, loweralkyl, loweralkoxy or thioloweralkoxy;  
 R 6  is hydrogen, halo, or loweralkyl;  
 R 7  is hydrogen, lowerakyl, halo, nitro, cyano, optionally substituted thienyl, optionally substituted phenyl morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl;  
 R 8  is loweralkyl or phenyl;  
 R 9  and R 10  are independently selected from hydrogen, halo, loweralkoxy, hydroxy;  
 R 14  is selected from hydrogen, loweralkyl, nitro or halo;  
 R 19  and R 20  are independently selected from hydrogen, loweralkyl, halo, nitro, or optionally substituted phenyl;  
 R 21  is hydrogen, loweralkyl, nitro, halo, cyano, phenyl, thienyl, or phenylethynyl;  
 R 22  is hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;  
 R 23  is hydrogen or loweralkyl;  
 R 24  is hydrogen; or when Y is other than hydrogen R 24  is hydrogen, loweralkyl, or optionally substituted phenyl;  
 R 25  is hydrogen, loweralkyl or thioalkoxy;  
 R 26  is loweralkyl, optionally substituted phenyl or optionally substituted phenylrmnethylenyl; and  
 R 27  is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and  
 R 28  is hydrogen, optionally substituted phenyl, loweralkyl, or optionally substituted thienyl; and  
 R 29  is hydrogen, nitro, or loweralkyl; and 
 provided that R 7 , R 14  and R 29  are not all hydrogen; and  
 provided that R 23  and R 28  are not both hydrogen; and  
 
   Ar 2  is a group of the formula:  
                 

 where R 11  and R 12  independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;  
 or R 11  and R 12  together form a methylenedioxy or ethylenedioxy bridge; or Ar 2  is naphthyl, optionally substituted thienyl, furyl, 1,2,3-thiadiazolyl, or a group of the formula:  
                 
 
   wherein 
 each R 4  independently represents hydrogen, halo, or loweralkyl;  
 R 13  is hydrogen or halo; and  
   Y is hydrogen, or Y and R 1 , R 2 , R 3 , R 19 , R 20 , R 22 , R 23 , or R 29  together represent CH 2 , C(R 24 ) 2 CH 2 , C(R 24 ) 20 , or C(R 24 ) 2 S forming a five or six membered ring.    
     
     
         2 . A compound of the formula:  
                   or the pharmaceutically acceptable salts thereof wherein 
 X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;  
 Ar 1  is a group of the formula:  
                 
 
   wherein 
 R 1 , R 2  and R 3  independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, amino, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamino, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy, optionally substituted phenylsulfide, provided that R 1 , R 2  and R 3  are not all hydrogen; or two of R 1 , R 2  and R 3  taken together can form an ethylenedioxy, ethyleneoxy, or a lower straight alkylene chain alkyl bridge of 3-5 atoms optionally substituted by loweralkyl; or  
 R 1 , R 2  and R 3  are the same or different and represent a group of the formula:  
                 
 
   wherein 
 R 24  is hydrogen; or when Y is other than hydrogen R 24  is hydrogen, loweralkyl, or optionally substituted phenyl;  
   Ar 2  is a group of the formula:  
                 

 where R 11  and R 12  independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;  
 or R 11  and R 12  together form a methylenedioxy or ethylenedioxy bridge; or  
   Ar 2  is naphthyl, optionally substituted thienyl, furyl, 1,2,3-thiadiazolyl, or a group of the formula:  
                 
   wherein 
 R 4  independently represents hydrogen, halo, or loweralkyl,  
 R 13  is selected from hydrogen or halo; and  
   Y is hydrogen, or Y and R 1 , R 2 , or R 3 , together represent CH 2 ; C(R 24 ) 2 CH 2 ; C(R 24 ) 2 O; or C(R 24 ) 2 S forming a five or six membered ring.    
     
     
         3 . A compound according to    claim 1    which is:  
                 

 or the pharmaceutically acceptable salts thereof wherein 
 X represents carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl;  
 Z is nitrogen or CH;  
 Ar 1  is a group of the formula:  
                 
 
 
 wherein 
 X 2  is oxygen or sulfur;  
 R 5  is hydrogen, halo, loweralkyl, loweralkoxy or thioloweralkoxy;  
 R 6  is hydrogen, halo, or loweralkyl;  
 R 7  is hydrogen, lowerakyl, halo, nitro, cyano, optionally substituted thienyl, optionally substituted phenyl morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl;  
 R 8  is loweralkyl or phenyl;  
 R 9  and R 10  are independently selected from hydrogen, halo, loweralkoxy, hydroxy;  
 R 14  is selected from hydrogen, loweralkyl, nitro or halo;  
 R 19  and R 20  are independently selected from hydrogen, loweralkyl, halo, nitro, or optionally substituted phenyl;  
 R 21  is hydrogen, loweralkyl, nitro, halo, cyano, phenyl, thienyl, or phenylethynyl;  
 R 22  is hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl;  
 R 23  is hydrogen or loweralkyl;  
 R 24  is hydrogen; or when Y is other than hydrogen R 24  is hydrogen, loweralkyl, or optionally substituted phenyl;  
 R 25  is hydrogen, loweralkyl or thioalkoxy;  
 R 26  is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and  
 R 27  is loweralkyl, optionally substituted phenyl or optionally substituted phenylmethylenyl; and  
 R 28  is hydrogen, optionally substituted phenyl, loweralkyl, or optionally substituted thienyl; and  
 R 29  is hydrogen, nitro, or loweralkyl; and 
 provided that R 7 , R 14  and R 29  cannot simultaneously be hydrogen; and  
 provided that R 23  and R 28  cannot simultaneously be hydrogen; and  
 
 
 Ar 2  is a group of the formula:  
                 

 where R 11  and R 12  independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, loweralkoxy, thioloweralkoxy, or loweralkyl;  
 or R 11  and R 12  together form a methylenedioxy or ethylenedioxy bridge; or  
 
 Ar 2  is naphthyl, optionally substituted thienyl, furyl, 1,2,3-thiadiazolyl, or a group of the formula:  
                 
 
 wherein 
 R 4  independently represents hydrogen, halo, or loweralkyl;  
 R 13  is selected from hydrogen or halo; and  
 
 Y is hydrogen, or Y and R 19 , R 20 , R 22 , R 23 , or R 29  together represent CH 2 ; C(R 24 ) 2 CH 2 ; C(R 24 ) 2 O; or C(R 24 ) 2 S forming a five or six membered ring.  
 
     
     
         4 . A compound according to    claim 1    which is:  
                 

 wherein 
 X represents carbonyl, sulfonyl, or methylene;  
 Z is nitrogen or CH with the proviso that when Ar 1  is phenyl or substituted phenyl Z is nitrogen;  
 Ar 1  is a group of the formula:  
                 
 
 
 wherein 
 R 1 , R 2  and R 3  independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, aminoacetyl, morpholino, cyano, piperidinyt, trifluoroalkoxy, alkylsulfonylarnino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenylarnino, optionally substituted phenoxy, optionally substituted phenylsultide; provided that R 1 , R 2  and R 3  are not all hydrogen; or  
 
 Ar 1  is a group of the formula:  
                 
 
 wherein 
 R 6  is hydrogen, halo, or loweralkyl;  
 R 9  and R 10  are independently selected from hydrogen, halo, loweralkoxy, hydroxy; and  
 
 Ar 2  is a group of the formula:  
                 

 where R 11  and R 12  independently represent hydrogen, halo, trifluoromethyl, amino, nitro, cyano, acetyl, thioloweralkoxy, loweralkyl, or taken together form a methylenedioxy bridge.  
 
 
     
     
         5 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 11  and R 12  independently represent hydrogen, halo, trifluoromethyl, nitro, cyano, acetyl, amino, thioloweralkoxy, loweralkyl, or taken together form a methylenedioxy bridge;  
 Ar 1  is a group of the formula:  
                 
 
 
 wherein 
 R 1 , R 2  and R 3  independently represent hydrogen, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, acetyl, amino, morpholino, cyano, piperidinyl, loweralkyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy, optionally substituted phenylsulfide, provided that R 1 , R 2  and R 3  are not all hydrogen; or  
 R 1 , R 2  and R 3  are the same or different and represent a group of the formula:  
                 
 
 
 
     
     
         6 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 1  and R 2  are independently selected from hydrogen, nitro, iodo, or fluoro; provided that  
 R 1  and R 2  are not both -hydrogen; and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, nitro; or optionally substituted thienyl groups.  
 
 
     
     
         7 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 1  represents hydrogen, loweralkyl, halogen, cyano, nitro, optionally substituted thienyl, optionally substituted phenyl, morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl; and  
 R 2  is hydrogen, nitro, loweralkyl or halogen; and  
 R 3  is hydrogen, nitro, or loweralkyl; and 
 provided that R 1 , R 2  and R 3  are not all hydrogen; and  
 
 Ar 2  represents thienyl, phenyl or phenyl mono or disubstituted with halogen, cyano, nitro, loweralkyl, or loweralkoxy groups; or Ar 2  is a group of the formula:  
                 
 
 
 wherein R 4  and R 5  are independently selected from hydrogen, halo, or loweralkyl groups.  
 
     
     
         8 . A compound according to    claim 1    which is:  
                 

 wherein 
 X represents methylene, carbonyl or sulfonyl;  
 R 1  represents halogen, loweralkyl, nitro or cyano; and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, or nitro groups.  
 
 
     
     
         9 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 1  and R 2  are independently selected from hydrogen, halogen, loweralkyl, nitro, or optionally substituted phenyl; and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.  
 
 
     
     
         10 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 1  represents hydrogen, optionally substituted phenyl, carbomethoxy or loweralkyl; and  
 R 2  hydrogen, or loweralkyl; and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.  
 
 
     
     
         11 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 1  represents hydrogen, carbomethoxy, optionally substituted phenyl or loweralkyl, and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy, or nitro groups.  
 
 
     
     
         12 . A compound according to    claim 1    which is:  
                 

 wherein 
 X represents carbonyl or sulfonyl; and  
 Ar 1  is a group of the formula:  
                 
 
 
 wherein 
 R 1 , R 2  and R 3  independently represent hydrogen, fluorine, iodine, phenyl, nitro, trifluoroalkyl, thioloweralkoxy, cyclohexyl, acetyl, morpholino, cyano, piperidinyl, trifluoroalkoxy, arylsulfonylamine, alkylsulfonylamino, optionally substituted phenylethynyl, 4,5-dihaloimidazole, optionally substituted phenoxy, optionally substituted phenylsulfide, provided that R 1 , R 2  and R 3  are not all hydrogen; and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, or nitro groups; or  
 Ar 2  is a group of the formula:  
                 
 
 
 wherein 
 R 4  independently represents hydrogen, halo, or loweralkyl.  
 
 
     
     
         13 . A compound according to    claim 1    which is:  
                 

 wherein 
 X represents carbonyl or sulfonyl;  
 R 1  represents hydrogen, loweralkyl, halogen, nitro, or cyano; and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.  
 
 
     
     
         14 . A compound according to    claim 1    which is:  
                 

 wherein 
 X represents carbonyl or sulfonyl;  
 R 1  represents hydrogen, loweralkyl, halogen, cyano, nitro, optionally substituted thienyl, optionally substituted phenyl, morpholino, piperidinyl, piperazinyl, optionally substituted phenylmethylenylpiperazinyl, optionally substituted phenylsulfonylpiperazinyl, or optionally substituted phenylcarbonylpiperazinyl; and  
 R 2  is hydrogen, nitro, loweralkyl or halogen; and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, loweralkoxy or nitro groups.  
 
 
     
     
         15 . A compound according to    claim 1    which is:  
                 

 wherein 
 X represents carbonyl or sulfonyl; and  
 Ar 1  is a group of the formula:  
                 
 
 
 wherein 
 R 1  and R 2  independently represent hydrogen, halogen, nitro, cyano, phenyl, or loweralkyl; and  
 Ar 2  represents phenyl or phenyl mono or disubstituted with halogen, cyano, loweralkyl, or nitro groups; or thienyl or thienyl optionally substituted with halo, loweralkyl, cyano or nitro groups.  
 
 
     
     
         16 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 1  and R 2  independently represent hydrogen, halogen, cyano, loweralkoxy or loweralkyl groups.  
 
 
     
     
         17 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 1  and R 2  independently represent hydrogen, halogen, or loweralkyl groups.  
 
 
     
     
         18 . A compound according to    claim 1    which is:  
                 

 wherein 
 R 1  and R 2  independently represent hydrogen, halogen, or loweralkyl, or taken together form a methylenedioxy bridge.  
 
 
     
     
         19 . A compound of the formula:  
                   wherein 
 Z is CH or nitrogen;  
 X is carbonyl, sulfonyl, or methylene;  
 M is CH 2 , C(R 1 ) 2 CH 2 , C(R 1 ) 2 O, or C(R 1 ) 2 S;  
 R 1  is hydrogen, loweralkyl, optionally substituted phenyl;  
 Ar 2  is optionally substituted phenyl, optionally substituted thienyl, or furyl; and  
 A represents an aryl or heteroaryl ring having from zero to three hetero atoms selected from the group consisting of oxygen, sulfur or nitrogen.  
   
     
     
         20 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(p-Iodophenyl)-3-(4′-benzyl 1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(p-Fluorophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(o-Fluorophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-p-Iodophenyl)-3-[4′-(o-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (e) 1-(o-Fluorophenyl)-3-[4′-(o-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (f) 1-(o-Fluorophenyl)-3-[4′-(p-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (g) 1-(p-Fluorophenyl)-3-[4′-(p-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (h) 1-(m-Fluorophenyl)-3-[4′-(p-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (i) 1-(p-Iodophenyl)-3-[4′-(p-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (j) 1-(6″-Fluoro-2″-methylphenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (k) 1-(m-Fluorophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (l) 1-o-Iodophenyl-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         21 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(2″,3″-Dihydro-1″,4″-benzodioxan-6″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(1″,2″,3″,4″-Tetrahydronaphth-6″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         22 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(4″-Fluoronaphth-1″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-p-Biphenyl-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-p-Cyclohexylphenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-(Fluoren-2″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (e) 1-(p-Methanesulfonamidophenyl)-3-(2″,5″-difluorobenzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-(m-Methanesulfonarnidophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride,  
 (g) 1-(4″-Methoxy-1″-naphthalenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (h) 1-(6″-Methoxy-2″-naphthalenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (i) 1-(Biphenylen-2″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone;  
 (j) 1-p-Phenylthiophenyl-3-(4′-benzyl-1′-piperazinyl)-3-propanone dihydrochloride.  
 
     
     
         23 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(p-Nitrophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrocholoride;  
 (b) 1-(m-Nitrophenyl)-3-(4+-benzyl-1′-piperazinyl)-1-propanone dihydrocholoride;  
 (c) 1-(m-Nitrophenyl)-3-[4′-(p-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrocholoride;  
 (d) 1-(m-Nitrophenyl)-3-[4′-(o-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (e) 1-(p-Nitrophenyl)-3-[4′-(o-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (f) 1-p-Nitrophenyl)-3-[4′-(2″,5″-difluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (g) 1-p-Nitrophenyl)-3-[4′-(m-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (h) 1-(p-Nitrophenyl)-3-[4′-(p-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (i) 1-p-Nitrophenyl)-3-[4′-(3″,4″-difluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (j) 1-(o-Nitrophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (l) 1-(p-Nitrophenyl)-3-(4′-piperonyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (k) 1-(2″-Bromo-5″-nitrophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (l) 1-(3″-Nitrophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         24 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(p-Methylthiophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrocholoride;  
 (b) 1-[3″,5″-Bis-(trifluoromethyl)phenyl]-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochlonde;  
 (c) 1-(p-Trifluoromethoxyphenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrocholoride;  
 (d) 1-[3″-(p-Chlorophenyl)sulfonamidophenyl]-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrocholoride;  
 (e) 1-(p-Methylthiophenyl)-3-(4′-(2″,6″-difluorobenzyl)-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-[3″,5″-Bis(trifluoroethoxy)phenyl]-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         25 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(1″-Methyl-1″-H-pyrazol-4″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrocholoride;  
 (b) 1-(5″-Methyl-2″-furanyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone hydrochloride;  
 (c) 1-(2-Thiazolyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-(N-Phenylsulfonylpyrrol-2-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (e) 1-(p-Nitrophenyl)-3-[4′-(4″-methyl-1″,2″,3″-thiadiaz-5″-oyl)]-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-[4″-(5′″,4′″-Dichloroimidazol-1′″-yl)phenyl]-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (g) 1-(5″-Methyl-3″-phenylisoxazol-4″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (h) 1-(5″-Methyl-3″-phenylisoxazol-4″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (i) 1-(2″-Phenylthiazol-4″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (j) 1-(2″,4″-Dimethylthiazol-5″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         26 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(3″-Thienyl)-3-[4′-(m-fluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (b) 1-(3″-Thienyl)-3-[4′-(2′″,5′″-difluorobenzyl)-1′-piperazinyl]-1-propanone dihydrochloride.  
 
     
     
         27 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(p-Nitrophenyl)-3-(4′-(o-tnrfluoromethyl)benzoyl-1′-piperazinyl)-1-propanone;  
 (b) 1-(p-Nitrophenyl)-3-[4′-(2″,6″-difluorobenzoyl)-1′-piperazinyl]-1-propanone hydrochloride;  
 (c) 1-(o-Fluorophenyl)-3-[4′-(2″,6″-difluorobenzoyl)1′-piperazinyl]-1-propanone hydrochloride;  
 (d) 1-(o-Fluorophenyl)-3-[4′-(o-trifluoromethylbenzoyl)-1′-piperazinyl]-1-propanone hydrochloride;  
 (e) 1-(p-Nitrophenyl)-3-(4′-o-fluorobenzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-(p-Nitrophenyl)-3-[4′-(2″,3″-difluorobenzoyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (g) 1-(2″-Chloro-3″-nitrothien-5″-yl)-3-(4′-o-trifluoromethylbenzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (h) 1-(p-Nitrophenyl)-3-(4′-[4′″-methyl-1″,2″,3″-thiadiaz-5″-oyl]-1′-piperazinyl)-1-propanone dihydrochloride;  
 (i) 1-(5″-Chloro-4″-nitro-2″-thienyl)-3-[4′-(4′″-methyl-1′″,2″′,3′″-thiadiaz-5′″-oyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (j) 1-(5″-Nitro-3″-thienyl)-3-(4′-o-fluorobenzoyl-1′-piperazinyl)-1-propanone dihydrocholoride;  
 (k) 1-(5″-Bromo-2″-thienyl)-3-(4′-o-fluorobenzoyl-1′-piperazinyl)-1-propanone dihydrocholoride.  
 
     
     
         28 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1,4-Bis-[3′-(4″-benzyl-1″-piperazinyl)-propanoyl] benzene;  
 (b) 1-(p-Acetylphenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(8″-Acetylphenoxathiin-2″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 2,8-Bis-[3′-(4″-benzyl-1″-piperazinzyl)propanoyl] phenoxathiin.  
 
     
     
         29 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(5″-Phenyl-2″-thienyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(5″-Bromo-2″-thienyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(5″-Chloro-2″-thienyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-(5″-Nitro-3″-thienyl)-3-(4′-benzyl-1-piperazinyl)-1-propanone dihydrochloride;  
 (e) 1-(5″-(2′″-thienyl]-2″-thienyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-(5″-Bromo-2″-thienyl)-3-(4′-o-fluorobenzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (g) 1-(5′-Cyano-2″-thienyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (h) 1-(5″-Chloro-4″-nitro-2″-thienyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (i) 1-(5″-Methyl-2″-thienyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         30 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(5′″-Bromo-2′″-thienyl)-3-[4′-(2″,6″-difluorobenzoyl)-1′-piperazinyl]-1-propanone hydrochloride;  
 (b) 1-(2″-Thienyl)-3-[4′-(o-fluorobenzoyl)-1′-piperazinyl]-1-propanone hydrochloride;  
 (c) 1-(5″-Bromo-2″-thienyl)-3-(4′-[2′″-chloro-6′″-methylpyrido-4′″-yl]-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         31 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(p-N-Morpholinophenyl)-3-(4′-p-iodobenzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(p-N-Morpholinophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(p-N-Piperidinophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         32 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(m-Cyanophenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(p-Cyanophenyl)-3-(4-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         33 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(5″-Bromo-2″-thienyl)-3-[4′-(1′″-p-chlorophenyl-1′″-phenylmethyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (b) 1-(2″-Thienyl)-3-(4′-(1′″-p-chlorophenyl-1′″-phenylmethyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (c) 1-(p-Nitrophenyl)-3-(4′-(1″-p-chlorophenyl-1″-phenylmethyl)-1′-piperazinyl]-1-propanone dihydrochloride.  
 
     
     
         34 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(Benzofur-2″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(5″-Chloro-3″-methylbenzo[b]-2″-thienyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(5″-Bromo-2″-thienyl)-3-[4′-(3′″-chlorobenzo[b]-2′″-thienoyl)-1′-piperazinyl]-1-propanone dihydrochloride;  
 (d) 1-[5″-(Phenylethynyl)-2″-thienyl]-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         35 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 3-(4′-Benzyl-1′-piperazinomethyl)-thiochroman-4-one dihydrochloride;  
 (b) 1 -(6″-Bromocoumarin-3″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(6″-Bromocoumarin-3″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-(Coumarin-3″-yl)-3-(4′-benzyl-1′-piperzinyl)-1-propanone dihydrochioride,  
 (e) 1-(Coumarin-3″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         36 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(5″-Cyano-4″-methyl-2″-(methylthio)thien-3″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(5″-Cyano-4″-methyl-2″-(methylthio)thien-3″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(p-(2″,4″-Dichlorophenoxy)-phenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-(p-(2″,4″-Dichcorophenoxy)-phenyl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (e) 1-(5′″-(2″,4″-Difluorophenoxy)-fur-2′″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-(5′″-(2″,4″-Difluorophenoxy)-fur-2′″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (g) 1-(1″,1″-Dimethyl-6″-tert-butylindan-4″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (h) 1-(1″,1″-Dimethyl-6″-tert-butylindan-4″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         37 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(2″,3″-Dihydrobenzo[b]fur-5″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(2″,3″-Dinydrobenzo[b]fur-5″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(3″,5″-Dimethylbenzo[b]thien-2″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-(3″,5″-Dimethylbenzo[b]thien-2″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (e) 1-(2″,4″-Dimethylthien-5″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-(2″,4″-Dimethylthien-5″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         38 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(p-[Phenylthio]phenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(p-[Phenylthio]phenyl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         39 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(3″-Methoxycarbonyl-5″-methylisoxazol-4″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(3″-Methoxycarbonyl-5″-methylisoxazol-4″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(5″-(2′″-Carbomethoxythien-3′″-yl)-furan-2″-yl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-(5″-(2′″-Carbomethoxythien-3′″-yl)-furan-2″-yl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (e) 1-(p-(4″-Methoxyphenoxy)-phenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-(p-(4″-Methoxyphenoxy)-phenyl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         40 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(p-(4″-Nitrophenoxy)-phenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) -(p-(4″-Nitrophenoxy)-phenyl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(m-Nitro-p-(phenylthio)-phenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (d) 1-(m-Nitro-p-(phenylthio)-phenyl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (e) 1-(m-Nitro-p-(1″-piperidinyl)-phenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (f) 1-(m-Nitro-p-(1″-piperidinyl)-phenyl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (g) 1-(m-Nitro-p-(4″-morpholino)-phenyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (h) 1-(m-Nitro-p-(4″-morpholino)-phenyl)-3-(4′-benzoyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (i) 1-(p-Nitrophenyl)-3-(4′-(5″-(1′″-methyl-3′″-trifluoromethylpyrazol-5′″-yl)-thien-2″yl)-1′-piperazinyl)-1-propanone dihydrochloride.  
 
     
     
         41 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(2″-Thienyl)-3-(4′-benzyl-1′-piperidinyl)-1-propanone hydrochloride;  
 (b) 1-(5″-Bromo-2″-thienyl)-3-(4′-p-fluorobenzoyl-1′-piperidinyl)-1-propanone hydrochloride;  
 (c) 1-(4″-Nitro-2″-thienyl)-3-(4′-p-fluorobenzoyl-1′-piperidinyl)-1-propanone hydrochloride;  
 (d) 1-(5″-Bromo-2″-thienyl)-3-(4′-benzyl-1′-piperidinyl)-1-propanone hydrochloride;  
 (e) 1-(m-Nitrophenyl)-3-(4′-benzyl-1′-piperidinyl)-1-propanone hydrochloride.  
 
     
     
         42 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-(p-Nitrophenyl)-3-(4′-benzenesulfonyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1-(5″-Bromo-2″-thienyl)-3-(4′-benzenesulfonyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (c) 1-(5″-Bromo-2″-thienyl)-3-(4′-p-bromobenzenesulfonyl-1′-piperazinyl)-1-propanone hydrochloride;  
 (d) 1-(5″-Bromo-2″-thienyl)-3-(4′-p-toluenesulfonyl-1′-piperazinyl)-1-propanone hydrochloride;  
 (e) 1-(p-Nitrophenyl)-3-(4′-p-bromobenzenesulfonyl-1′-piperazinyl)-1-propanone hydrochloride;  
 (f) 1-(p-Nitrophenyl)-3-(4′-p-toluenesulfonyl-1′-piperazinyl)-1-propanone hydrochloride;  
 (g) 1-(5″-Chloro-4″-nitro-2″-thienyl)-3-(4′-benzenesulfonyl-1′-piperazinyl)-1-propanone hydrochloride.  
 
     
     
         43 . A compound according to    claim 1    which is selected from the group consisting of: 
 (a) 1-[5″-Cyano-4″-methyl-2″-(methylthio)-3″-thienyl]-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride;  
 (b) 1 -(2″,4″-Dimethyl-5″-thiazolyl)-3-(4′-benzyl-1′-piperazinyl)-1-propanone dihydrochloride.