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-HT 3 and 5-HT 1A and may as such be useful for the treatment of cognitive impairment, especially in depressed patients.

1 . A method of alleviating a symptom or complication of generalized anxiety disorder, or delaying progression of generalized anxiety disorder, comprising:
 administering to a patient in need thereof a pharmaceutical composition comprising a hydrobromide salt of a 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,
 wherein said method alleviates a symptom or complication of generalized anxiety disorder, or delays the progression of generalized anxiety disorder, in said patient. 
 
     
     
         2 . The method of  claim 1 , wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt alpha form. 
     
     
         3 . The method of  claim 2 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-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 method 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 method of  claim 1 , wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt beta form. 
     
     
         6 . The method of  claim 5 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-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 method 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 method of  claim 1 , wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt gamma form. 
     
     
         9 . The method of  claim 8 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-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 method 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 method of  claim 1 , wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt hemihydrate. 
     
     
         12 . The method of  claim 11 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-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 method of  claim 11 , wherein the 1-[2-(2,4-dimethylphenyl sulfanyl)-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 method of  claim 1 , wherein said hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-phenyl]piperazine is 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide salt ethyl acetate solvate. 
     
     
         15 . The method of  claim 14 , wherein the 1-[2-(2,4-dimethylphenyl sulfanyl)-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 method of  claim 1 , wherein the hydrobromide salt of 1-[2-(2,4-dimethylphenyl sulfanyl)-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 method of  claim 1 , wherein the hydrobromide salt of a 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine is administered at a daily dose of from 1 mg to 20 mg.