Patent Publication Number: US-5023266-A

Title: Method of treatment of psychotic disorders

Description:
The present invention is directed to the use of Ifenprodil and analogues thereof in a method for the treatment of psychotic disorders. 
     The compounds to be used correspond to general formula (I) below, wherein 
     R 1  denotes a halogen atom or a hydroxy group, 
     R 2  denotes a hydrogen atom or a methyl group, and 
     R 3  denotes a hydrogen or halogen atom. 
     According to whether R2 de h or methyl, the compounds of general formula (I) comprises one or two chiral centers. The compounds can hence exist in various stereochemical forms. TheY can exist also in the form of free bases or acid addition salts. 
     The compounds of general formula (I) are disclosed in U.S. Pat. No. 3,509,164, in French patent 2546166, in European patent 0109317, in French patent 2628740, and in C.A., 94, 83708b (1981). 
     The compounds have been submitted to pharmacological tests showing their antipsychotic activity. 
    
    
     In particular their inhibitory activity on the binding of [ 3  H](+)3(3-hydroxyphenyl)-N-(1-propyl)-piperidine, or [ 3  H]-(+)-3-PPP, to the σ-receptor in the cerebral cortex of rats has been studied, essentially as described in J. Pharmacol. Exp. Ther., 238, 739-748, (1986). Male Sprague-Dawley rats (150-200 g) were sacrificed, and the cerebral cortex was homogenized in 25 volumes of ice-cold Tris-HCl buffer (pH 7.4 at 25° C.) with the use of an Ultra-Turrax™ polytron. The homogenate was washed twice by centrifugation (10 min at 45,000g) and intermittent resuspension of the resulting pellet in fresh buffer. The final pellet was resuspended in 20 volumes of 50mM Tris-HCl buffer (pH 8.0 at 22° C.). A 75 μl aliquot of this membrane preparation was then incubated in a final volume of 250 μl with 2nM [ 3  H]-(+)-3-PPP (specific activity 90 Ci/mmol; New England Nuclear) for 90 min at 25° C., in the absence or in the presence of competing drugs. After incubation, the membranes were recovered by filtration over 0.05% polyethyleneimine-pretreated Whatman™ GF/B filters using a Skatron™ Cell Harvester, and washed with ±2.5 ml of ice-cold 50mM Tris-HCl buffer (pH 7.7 at 0° C.). Non-specific binding was defined with 1μM haloperidol. 
     Data were analyzed by conventional graphical techniques and least-squares regression analysis where appropriate. 
     The following Table indicates the IC 50  of the compounds, i.e. the concentration (μM) which inhibits 50 percent of the [ 3  H]-(+)-3-PPP. 
     
                       TABLE                                                       
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 ##STR1##                      (I)                                        
                                    Salt or                               
N°                                                                 
      R1     R2       R3   Form     base   IC.sub.50                      
______________________________________                                    
1     OH     CH.sub.3 H    (±) erythro                                 
                                    HCl    0.008                          
2     OH     CH.sub.3 H    (±) threo                                   
                                    base   0.01                           
3     OH     CH.sub.3 H    (-) erythro                                    
                                    Bz.    0.015                          
4     OH     CH.sub.3 H    (+) erythro                                    
                                    Bz.    0.007                          
5     Cl     H        F    (±)   HCl    0.003                          
6     Cl     H        F    (+)      base   0.0092                         
7     Cl     H        F    (-)      base   0.0098                         
______________________________________                                    
 Note: &#34;HCl&#34; denotes the hydrochloride salt, and &#34;Bz.&#34; denotes the benzoat
 salt.                                                                    
 
    
     The results of the pharmacological tests show that the compounds of general formula (I) have high affinity for the σ-receptor, and that they are potential antipsychotics for the human. 
     Therefore they are useful for the treatment of psychoses, and especially of schizophrenia. 
     They can be presented in any form suitable for enteral or parenteral administration, in combination with any suitable excipient, for example in the form of tablets, gelatin capsules, capsules, oral or injectable solutions or suspensions. 
     The daily dosage can range from 1 to 120 mg of active substance.