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 . 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrochloride salt with XRDP reflections at 9.41, 12.37, 19.66 and 22.55+/−0.10° (°2θ). 
     
     
         2 . A pharmaceutical composition, comprising a compound according to  claim 1  together with a pharmaceutically acceptable excipient. 
     
     
         3 . The composition according to  claim 2 , said composition being a tablet prepared by wet granulation and comprising anhydrous calcium hydrogen phosphate, corn starch, PVP-VA copolymer, microcrystalline cellulose, sodium starch glycolate, talc and magnesium stearate. 
     
     
         4 . The composition according to  claim 2 , comprising 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   HCl salt 
                   3-8% 
                 
                     
                   Anhydrous calcium hydrogen phosphate 
                   35-45% 
                 
                     
                   Corn starch 
                   15-25% 
                 
                     
                   PVP-VA copolymer 
                   2-6% 
                 
                     
                   Microcrystalline cellulose 
                   20-30% 
                 
                     
                   Sodium starch glycolate 
                   1-3% 
                 
                     
                   Talc 
                   2-6% 
                 
                     
                   Magnesium stearate 
                   0.5-2%.  
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         5 . The composition according to  claim 2 , comprising 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   HCl salt 
                   approximately 5% 
                 
                     
                   Anhydrous calcium hydrogen phosphate 
                   approximately 39% 
                 
                     
                   Corn starch 
                   approximately 20% 
                 
                     
                   PVP-VA copolymer 
                   approximately 3% 
                 
                     
                   Microcrystalline cellulose 
                   approximately 25% 
                 
                     
                   Sodium starch glycolate 
                   approximately 3% 
                 
                     
                   Talc 
                   approximately 4% 
                 
                     
                   Magnesium stearate 
                   approximately 1%. 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         6 . A method of treating a disease selected from the group consisting of affective disorders, depression, major depressive disorder, postnatal depression, depression associated with bipolar disorder, Alzheimer's disease, psychosis, cancer, age or Parkinson's disease, anxiety, general anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, panic attacks, phobia, social phobia, agoraphobia, stress urinary incontinence, emesis, IBS, eating disorders, chronic pain, partial responders, treatment resistant depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, hot flushes, sleep apnoea, alcohol, nicotine or carbohydrate craving, and substance abuse and alcohol or drug abuse, the method comprising administering a therapeutically effective amount of a compound according to  claim 1  to a patient in need thereof. 
     
     
         7 . A process for the preparation of the HCl salt of 
       
         
           
           
               
               
           
         
         the process comprising reacting compound II 
       
       
         
           
           
               
               
           
         
         wherein R′ represents hydrogen or a mono-valent metal ion, 
         with a compound of formula III 
       
       
         
           
           
               
               
           
         
         wherein X 1  and X 2  independently represent halogen, and a compound of formula IV 
       
       
         
           
           
               
               
           
         
         wherein R represents hydrogen or a protecting group, in the presence of a solvent, a base and a palladium catalyst consisting of a palladium source and a phosphine ligand at a temperature between 60° C. and 130° C., followed by reaction with hydrochloric acid to achieve the desired salt. 
       
     
     
         8 . The process according to  claim 7 , wherein compound II and compound III are reacted in a first reaction, and wherein the reaction product 
       
         
           
           
               
               
           
         
         for said first reaction is optionally isolated and purified, followed by a subsequent reaction with the compound IV. 
       
     
     
         9 . The process according to  claim 7 , wherein compound II, compound III and compound IV are mixed together at the start of the process. 
     
     
         10 . The process according to  claim 7 , wherein X 1  and X 2  independently represent Br or I. 
     
     
         11 . The process according to  claim 10 , wherein X 1  represents Br and X 2  represents I. 
     
     
         12 . The process according to  claim 7 , wherein said solvent is an aprotic solvent. 
     
     
         13 . The process according to  claim 7 , wherein the solvent in selected from the group consisting of toluene, xylene, triethyl amine, tributyl amine, dioxin and N-methylpyrrolidone. 
     
     
         14 . The process according to  claim 13 , wherein the solvent is toluene. 
     
     
         15 . The process according to  claim 7 , wherein the palladium source is selected from the group consisting of Pddba 2 , Pd(OAc) 2  and Pd 2 dba 3 . 
     
     
         16 . The process according to  claim 15 , wherein said palladium source is Pddba 2  or Pd 2 dba 3 . 
     
     
         17 . The process according to  claim 7 , wherein said phosphine ligand is selected from the group consisting of
 2,2′-bis-diphenylphosphanyl-[1,1′]binaphtalenyl (rac-BINAP),   1,1′-bis(diphenylphosphino)ferrocene (DPPF),   bis-(2-diphenylphosphinophenyl)ether (DPEphos),   tri-t-butyl phosphine (Fu's salt),   biphenyl-2-yl-di-t-butyl-phosphine,   biphenyl-2-yl-dicyclohexyl-phosphine,   (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine   [2′-(di-t-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and   dicyclohexyl-(2′,4′,6′-tri-propyl-biphenyl-2-yl)-phosphane.   
     
     
         18 . The process according to  claim 17 , wherein said phosphine ligand is rac-BINAP. 
     
     
         19 . The process according to  claim 7 , wherein said base is selected from the group consisting of NaO(t-Bu), KO(t-Bu), Cs 2 CO 3 , DBU and DABCO. 
     
     
         20 . The process according to  claim 19 , wherein said base is NaO(t-Bu). 
     
     
         21 . The process according to  claim 7 , wherein R represents hydrogen. 
     
     
         22 . The process according to  claim 7 , wherein R represents a protecting group selected from the group consisting Boc, Bn, Cbz, C(═O)OEt and Me. 
     
     
         23 . The process according to  claim 7 , wherein R′ is hydrogen. 
     
     
         24 . The process according to  claim 7 , wherein the temperature is between approximately 80° C. and approximately 120° C. 
     
     
         25 . The process according to  claim 9 , comprising the steps of
 a. dissolving or dispersing 1-1.5 equivalents of compounds II, III, and IV in toluene to obtain mixture A;   b. adding 1-2 mole-% of Pddba 2  and 1-2 mole-% of rac-BINAP together with 2-3 equivalents of NaO(t-Bu) to mixture A to obtain mixture B, which is heated to around 100° C. until compound II and III are fully converted;   c. increasing the temperature of the mixture obtained in step b to around 120° C. until compound IV is fully converted; and   d. optionally removing the protecting group by the addition of aqueous acid if compound IV is a protected piperazine.   
     
     
         26 . The process according to  claim 9 , wherein 1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-2-iodo-benzene or 1,2-dibromo-benzene, and piperazine are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd 2 dba 3  and rac-BINAP dispersed in toluene to obtain a mixture which is heated to 100-130° C. for 2-10 hours to obtain the product 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine. 
     
     
         27 . The process according to  claim 9 , wherein 2-5 equivalents of NaO(t-Bu), 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba 2 , and 0.6-1 mole-% rac-BINAP are dispersed in toluene to obtain mixture A′, to which mixture approximately 1 equivalent 2-bromo-iodobezene is added to obtain mixture B′, to which mixture 1 equivalent 2,4-dimethylthiophenol is added and the resulting mixture is heated to reflux for 3-7 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. 
     
     
         28 . The process according to  claim 27 , wherein said resulting mixture is heated to reflux for 4-6 hours, and which process is followed by a subsequent step in which the obtained product is further reacted with aqueous HCl to obtain the corresponding hydrochloric acid addition salt. 
     
     
         29 . A process for the manufacturing of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloric acid addition salt, in which process 1-1.5 equivalents of 2,4-dimethyl-thiol, 1-bromo-2-iodo-benzene or 1,2-dibromo-benzene, and piperazine are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd 2 dba 3  and rac-BINAP dispersed in toluene to obtain a mixture, which is heated to reflux 3-5 hours to obtain the product 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further reacted with aqueous hydrochloric acid. 
     
     
         30 . A process for the manufacturing of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloric acid addition salt in which process 2-5 equivalents of NaO(t-Bu), 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba 2 , and 0.6-1 mole-% rac-BINAP are dispersed in toluene to obtain mixture A′, to which mixture approximately 1 equivalent 2-bromo-iodobezene is added to obtain mixture B′, to which mixture 1 equivalent 2,4-dimethylthiophenol is added and the resulting mixture is heated to reflux for 4-6 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further reacted with aqueous hydrochloric acid.