1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment

Abstract

1-[2-(2,4-dimethylphenylsulphanyl)phenyl]piperazine exhibits potent activity on SERT, 5-HT3 and 5-HT1A and may as such be useful for the treatment of cognitive impairment, especially in depressed patients.

1 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier; and   a HBr salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine selected from the group consisting of   1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form,   1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form,   1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form,   1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate,   1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate, and mixtures thereof.   
     
     
         2 . The composition of  claim 1 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form. 
     
     
         3 . The composition of  claim 2 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form characterized by an XRPD pattern as shown in  FIG.  2   . 
     
     
         4 . The composition of  claim 2 , wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form is characterized by XRPD peaks at 5.85, 9.30, 17.49, and 18.58+/−0.10° 2θ. 
     
     
         5 . The composition of  claim 1 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form. 
     
     
         6 . The composition of  claim 5 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form characterized by an XRPD pattern as shown in  FIG.  3   . 
     
     
         7 . The composition of  claim 5 , wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form is characterized by XRPD peaks at 6.89, 9.73, 13.78, and 14.62+/−0.10° 2θ. 
     
     
         8 . The composition of  claim 1 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form. 
     
     
         9 . The composition of  claim 8 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form characterized by an XRPD pattern as shown in  FIG.  4   . 
     
     
         10 . The composition of  claim 8 , wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form is characterized by XRPD peaks at 11.82, 16.01, 17.22, and 18.84+/−0.10° 2θ. 
     
     
         11 . The composition of  claim 1 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate. 
     
     
         12 . The composition of  claim 11 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate characterized by an XRPD pattern as shown in  FIG.  5   . 
     
     
         13 . The composition of  claim 11 , wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate is characterized by XRPD peaks at 10.69, 11.66, 15.40, and 17.86+/−0.10° 2θ. 
     
     
         14 . The composition of  claim 1 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate. 
     
     
         15 . The composition of  claim 14 , wherein the 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide ethyl acetate solvate is characterized by XRPD peaks at 8.29, 13.01, 13.39, and 16.62+/−0.10° 2θ. 
     
     
         16 . The composition of  claim 1 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is a mixture of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate and 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form characterized by an XRPD pattern as shown in  FIG.  6   . 
     
     
         17 . The composition of  claim 1 , wherein the composition is a tablet. 
     
     
         18 . A method of treating a disease, the method comprising administering a therapeutically effective amount of the composition of  claim 1  to a patient in need thereof;
 wherein the disease is selected from the group consisting of affective disorders, depression, major depressive disorder, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, and panic attacks. 
 
     
     
         19 . The method of  claim 7 , wherein the disease is major depressive disorder.