Patent Publication Number: US-4150029-A

Title: 3-Aryl 2-oxazolidinones, their process of preparation and their therapeutical application

Description:
The present invention relates to aryl-3-oxazolidinones-2, a process for preparing them and their application in therapeutics, particularly in the psychotopic field. 
     The compounds of the invention correspond more exactly to the following formula (I): ##STR4## in which R 1  represents: EITHER A HYDROGEN ATOM, IN WHICH CASE R may be: 
     A p-nitro, p-cyano, p-aldehydo or p-acetyl radical; an m-ethyl, m-nitro, or m-bromo group; or two methyl groups in meta and para positions; 
     An m-NH 2  group or ##STR5## IN THE PARA POSITION AND IN WHICH THE COUPLE (R 2 , R 3 ) can have the following meanings: (H, CH 3 ), (CH 3 , CH 3 ), (C 2  H 5 , C 2  H 5 ), ##STR6## or form with the nitrogen atom to which they are bonded a pyrrolidino or piperidino radical; 
     a --SR 4  group in the para position and in which R 4  represents an alkyl radical having 1 to 4 carbon atoms or a cyclohexyl radical; 
     a --OR 5  group in the para position and in which R 5  represents: 
     an alkyl radical having 2 to 7 carbon atoms, 
     a cyclohexyl, cyclohexylmethyl, acetylmethyl, or cyanomethyl radical, 
     an alkene-2 yle radical having 3 to 5 carbon atoms, butene-3 yle or cyclohexene-1 methyl, 
     a propargyl or butyne-2 yle radical, 
     a radical of ##STR7## in which n is equal to 1 and R 6  represents a hydrogen atom, a fluorine atom or a methyl group when it is in the ortho position; a chlorine atom, a fluorine atom, a methyl or trifluoromethyl group when it is in the meta position; and a chlorine, bromine or fluorine atom, a cyano, nitro or dimethyl-amino group when it is in the para position; or n is equal to 2 and R 6  designates a hydrogen atom; or 
     two groups, one methyl in the meta position, the other benzyloxy in the para position; 
     or a CO NH R 7  group where R 7  designates a methyl group in which case R may be: 
     an m-trifluoromethyl or m-bromo group; a p-chloro or p-fluoro radical; two atoms of chlorine in meta and para positions; a p-thiomethyl or p-acetyl radical; 
     a --O R 8  group in the para position and in which R 8  designates: 
     an alkyl radical having from 2 to 5 carbon atoms, a cyanomethyl or acetylmethyl radical, a propargyl radical, or 
     a radical of ##STR8## in which R 9  represents a hydrogen atom, a chlorine, bromine or fluorine atom when it is in the meta position, and a fluorine atom, a chlorine atom or a nitro group when it is in the para position; 
     or where R 7  designates an isopropyl group in which case R designates an m-trifluoromethyl or p-benzyloxy radical. 
     The process for preparing compounds of the invention of formula (I) in which R 1  is a hydrogen atom, consists in cyclizing, by ethyl carbonate action, a 1-phenylamino-2,3-propanediol of formula: ##STR9## in which R&#39; represents: a p-nitro, p-cyano, p-aldehydo- p-acetyl, m-methyl, m-nitro or m-bromo radical; or two methyl groups in meta and para positions; ##STR10## in para position and where the couple (R&#39; 2 , R&#39; 3 ) can have the following meanings: (CH 3 , CH 3 ), (C 2  H 5 , C 2  H 5 ), ##STR11## or form with the nitrogen atom to which they are bonded a pyrrolidino or piperidino radical; 
     an S--R 4  group in the para position and where R 4  has the same meaning as in formula (I); 
     a p-ethoxy or p-benzyloxy group; or 
     two groups, one methyl in the meta position, the other benxyloxy in the para position, 
     which leads to compounds of formula: ##STR12## then possibly to subject the compound of formula (Ia): in which R&#39; represents an m-nitro radical, to a catalytic reduction in an autoclave and in the presence of palladium on charcoal, which leads to the compound of formula: ##STR13## in which R&#39; represents a p-N-methyl N-benzylamino group, to a hydrogenolysis action in alcohol in the presence of palladium on charcoal, which leads to the compound of formula: ##STR14## and in which R&#39; represents a p-benzyloxy group, to a hydrogenolysis action in alcohol in the presence of palladium on charcoal, which leads to the compound of formula: ##STR15## which is condensed with a product corresponding to one of the following formulas: ##STR16## in which R&#39; 5  has the same meaning as R 5  in formula I except for the ethyl and benzyl values, which leads to the compounds of formula: ##STR17## 
     The compounds of formula II, in part novel, are, as to them, obtained by condensation, in methanol or ethanol, of anilines of formula: ##STR18## in which R&#39; has the same meaning as in formula II, with glycidol of formula: ##STR19## 
     The compounds of formula (I) in which R 1  represents a CONHR 7  group where R 7  is a methyl or isopropyl group are, for their part, obtained by the action of an alkyl isocyanate of formula: 
     
         R&#39;.sub.1 --N CO                                            (VI) 
    
     in which R&#39; 1  designates a methyl or isopropyl group on an oxazolidinone of formula (I) in which R 1  represents a hydrogen atom and R can be: 
     an m-trifluoromethyl or m-bromo radical; a p-chloro or p-fluoro radical; two chlorine atoms in meta and para positions; a p-thiomethyl or p-acetyl radical; 
     a --OR 8  group in the para position and in which R 8  designates: 
     an alkyl radical having 2 to 5 atoms of carbone, a cyanomethyl or acetylmethyl radical, a propargyl radical or a radical of ##STR20## in which R 9  represents a hydrogen atom or a chlorine, bromine or fluorine atom when it is in the meta position, and a fluorine atom, a chlorine atom or a nitro group when it is in the para position. 
    
    
     The examples below are given solely as an illustration of the invention. 
     EXAMPLE 1: 3-ethylthiophenylamino 1,2-propanediol 
     Code No. 760465 
     A solution of 12.6 g (0.082 mole) of p-ethylthioaniline and 6.1 g (0.082 mole) of glycidol in 80 ml of ethanol is heated under reflux for 7 hours. Then, it is evaporated and the residue is chromatographed on silica (elution with a mixture of chloroform (80)-acetone(20)). 
     Yield: 43% 
     Melting point: &lt;50° C. 
     Empirical formula: C 11  H 17  NO 2  S 
     Elementary analysis: 
     
         ______________________________________                                    
             C       H         N                                          
______________________________________                                    
Calculated (%) 58.12     7.54      6.16                                   
Obtained (%)   57.96     7.45      6.30                                   
______________________________________                                    
 
    
     EXAMPLE 2: 5-hydroxymethyl-3-metanitrophenyl-2 oxazolidinone 
     Code No. 740511 
     A mixture of 48 g (0.2 mole) of 3-metanitrophenylamino-1,2-propanediol (prepared according to a mode of operation similar to that of example 1), 200 ml of ethyl carbonate and 8 ml of triethylamine is heated at 100°-110° C. for 5 hours. The product obtained is filtered and recrystallised in absolute alcohol. 
     Melting point: 140° C. 
     Yield: 73% 
     Empirical formula: C 10  H 10  N 2  O 5   
     Molecular weight: 238.20 
     Elementary analysis: 
     
         ______________________________________                                    
             C       H         N                                          
______________________________________                                    
Calculated (%) 50.42     4.23      11.76                                  
Obtained (%)   50.54     4.39      11.81                                  
______________________________________                                    
 
    
     In the same way we can obtain compounds corresponding to the following code numbers and shown in table 1 below: 750341 - 750710 - 740564 - 740512 - 760271 - 760133 - 760311 - 760375 - 760474 - 760349 - 760082 - 760466 - 760483 - 760473 - 760600 - 760621 - 760037 - 770017 - 770054 - 760670 - 760167. 
     EXAMPLE 3: 5-hydroxymethyl 3-metaaminophenyl 2-oxazolidinone 
     Code No. 750079 
     A solution of 28 g (0.08 mole) of 5-hydroxymethyl 3-metanitrophenyl 2-oxazolidinone prepared in the previous example is hydrogenated, in an autoclave, under a pressure of 2 to 3 kg, at room temperature and in the presence of palladium on charcoal at 10%, in 400 ml of dioxane. The reaction is finished in 5 hours. Then it is filtered, the filtrate evaporated and the residue crystallised in alcohol. 
     Melting point: 118° C. 
     Yield: 10% 
     Empirical formula: C 10  H 12  N 2  O 3   
     Molecular weight: 208.21 
     Elementary analysis: 
     
         ______________________________________                                    
             C       H         N                                          
______________________________________                                    
Calculated (%) 57.68     5.81      13.46                                  
Obtained (%)   57.39     5.77      13.22                                  
______________________________________                                    
 
    
     EXAMPLE 4: 5-hydroxymethyl 3-p-N-methylaminophenyl 2-oxazolidinone 
     Code No. 760395 
     A solution of 19 g (0.061 mole) of 5-hydroxymethyl 3-p-N-benzyl N-methylaminophenyl 2-oxazolidinone, prepared according to a mode of operation similar to that of example 2, is hydrogenolysed in an autoclave at 50° C., under a pressure of 4 kg for 5 hours, in 400 ml of alcohol, in the presence of 0.6 ml of hydrochloric acid 6.4 N and 3 g of palladium on charcoal at 10%. It is filtered, the filtrate is evaporated, and the residue is taken up with an aqueous solution of bicarbonate of soda, then it is filtered and recrystallised in methanol. 
     Melting point: 174° C. 
     Yield: 6% 
     Empirical formula: C 11  H 14  N 2  O 3   
     Elementary analysis: 
     
         ______________________________________                                    
             C       H         N                                          
______________________________________                                    
Calculated (%) 59.45     6.35      12.61                                  
Obtained (%)   59.29     6.39      12.61                                  
______________________________________                                    
 
    
     EXAMPLE 5: 5-hydroxymethyl 3-p-cyanomethyloxyphenyl 2-oxazolidinone 
     Code No. 760651 
     1st step: 5-hydroxymethyl 3-p-hydroxyphenyl 2-oxazolidinone 
     Code No. 760172 
     A solution of 132.5 g (0.44 mole) of 5-hydroxymethyl 3-p-benzyloxyphenyl 2-oxazolidinone, prepared according to a mode of operation similar to that of example 2, is hydrogenolysed in an autoclave, between 45° and 50° C., under a pressure of 2 kg for 6 hours, in 1.5 litre of alcohol, in the presence of 13 g of palladium on charcoal at 10%. It is filtered, the filtrate is evaporated and recrystallised in isopropyl alcohol. 
     Melting point: 183° C. 
     Yield: 82% 
     Empirical formula: C 10  H 11  NO 4   
     Elementary analysis: 
     
         ______________________________________                                    
             C       H         N                                          
______________________________________                                    
Calculated (%) 57.41     5.30      6.70                                   
Obtained (%)   57.62     5.62      6.69                                   
______________________________________                                    
 
    
     2nd step: 5-hydroxymethyl 3-p-cyanomethyloxyphenyl 2-oxazolidinone 
     Code No. 760651 
     A mixture of 15 g (0.07 mole) of 5-hydroxymethyl 3-p-hydroxyphenyl 2-oxazolidinone prepared in the previous step, 7.6 g (0.1 mole) of chloracetonitrile, 38 g (0.28 mole) of potassium carbonate and 1 g of potassium iodide is brought to reflux for 8 hours in 450 ml of acetone. It is filtered, the filtrate is evaporated and the residue crystallised in absolute alcohol. 
     Melting point: 98° C. 
     Yield: 67% 
     Empirical formula: C 12  H 12  N 2  O 4   
     Molecular weight: 248.23 
     Elementary analysis: 
     
         ______________________________________                                    
             C       H         N                                          
______________________________________                                    
Calculated (%) 58.06     4.87      11.29                                  
Obtained (%)   57.91     4.92      11.21                                  
______________________________________                                    
 
    
     In the same way, we can obtain the compounds corresponding to the following code numbers and listed in table I below: 760116 - 760303 - 760304 - 760414 - 760396 - 760549 - 760534 - 760314 - 770018 - 760306 - 760827 - 760650 - 760535 - 760536 - 760307 - 760877 - 770063 - 770104 - 760337 - 760317 - 760547 - 760556 - 760574 - 760548 - 760537 - 760533 - 760881 - 760622 - 760937 - 760432 - 760453 - 760652. 
     EXAMPLE 6: 5-N-methylcarbamoyloxymethyl 3-p-cyanomethyloxyphenyl 2-oxazolidinone 
     Code No. 760660 
     A solution of 7 g (0.028 mole) of 5-hydroxymethyl 3-p-cyanomethyloxyphenyl 2-oxazolidinone prepared in the 2nd step of example 5, and 4.8 g (0.084 mole) of methyl isocyanate in 30 ml of 1,2-dichlorethane is heated at 110° C. in a sealed tube for 3 hours. Then the solvent is evaporated, the residue crystallised in ether and recrystallised in methanol. 
     Melting point: 90° C. 
     Yield: 70% 
     Empirical formula: C 14  H 15  N 3  O 5   
     Molecular weight: 305.28 
     Elementary analysis: 
     
         ______________________________________                                    
             C       H         N                                          
______________________________________                                    
Calculated (%) 55.08     4.95      13.77                                  
Obtained (%)   54.91     4.84      13.68                                  
______________________________________                                    
 
    
     In the same way we can obtain the compounds corresponding to the following code numbers and listed in table I below: 740704 - 750479 - 750726 - 750685 - 750820 - 740711 - 760786 - 760104 - 760663 - 760662 - 760712 - 760819 - 760658 - 760729 - 760676 - 760717 - 760730 - 760409 - 760723 - 760728 - 760809 - 760733 - 760731. 
     Tables I and II below give respectively the compounds of formula (I) of the invention and new intermediate compounds (II), these later being prepared according to a mode of operation similar to that of example 1. 
     
                                           TABLE I                                 
__________________________________________________________________________
 ##STR21##                                                                
                                      Mel-                                
Code                              Mole-                                   
                                      ting   Elementary analysis          
Num-                      Empirical                                       
                                  cular                                   
                                      point                               
                                         Yield                            
                                             Calculated                   
                                                      Obtained (%)        
ber  R          R.sub.1   formula weight                                  
                                      (° C.)                       
                                         (%) C  H  N  C  H  N             
__________________________________________________________________________
740704                                                                    
    3CF.sub.3   CONHCH.sub.3                                              
                          C.sub.13 H.sub.13 F.sub.3 N.sub.2 O.sub.4       
                                  318.25                                  
                                      115                                 
                                         75  49.06                        
                                                4.12                      
                                                    8.80                  
                                                      48.79               
                                                         3.95             
                                                             8.61         
750479                                                                    
    4Cl         &#34;         C.sub.12 H.sub.13 ClN.sub.2 O.sub.4             
                                  284.70                                  
                                      110                                 
                                         52  50.62                        
                                                4.60                      
                                                    9.84                  
                                                      50.84               
                                                         4.62             
                                                             9.68         
750726                                                                    
    3Br         &#34;         C.sub.12 H.sub.13 BrN.sub.2 O.sub.4             
                                  329.15                                  
                                       90                                 
                                         75  43.79                        
                                                3.98                      
                                                    8.51                  
                                                      43.89               
                                                         4.08             
                                                             8.36         
750685                                                                    
    4F          &#34;         C.sub.12 H.sub.13 FN.sub.2 O.sub.4              
                                  268.24                                  
                                      100                                 
                                         70  53.73                        
                                                4.89                      
                                                   10.44                  
                                                      53.76               
                                                         5.00             
                                                            10.25         
750820                                                                    
    3,4diCl     &#34;         C.sub.12 H.sub.12 Cl.sub.2 N.sub.2 O.sub.4      
                                  319.15                                  
                                      123                                 
                                         66  45.16                        
                                                3.79                      
                                                    8.78                  
                                                      45.04               
                                                         3.63             
                                                             8.49         
740711                                                                    
    3CF.sub.3                                                             
                 ##STR22##                                                
                          C.sub.15 H.sub.17 F.sub.3 N.sub.2 O.sub.4       
                                  346.30                                  
                                      121                                 
                                         61  52.02                        
                                                4.95                      
                                                    8.09                  
                                                      52.26               
                                                         5.06             
                                                             8.03         
750341                                                                    
    3,4diCH.sub.3                                                         
                H         C.sub.12 H.sub.15 NO.sub.3                      
                                  221.25                                  
                                      129                                 
                                         73  65.14                        
                                                6.83                      
                                                    6.33                  
                                                      65.15               
                                                         6.80             
                                                             6.32         
750710                                                                    
    3Br         H         C.sub.10 H.sub.10 BrNO.sub.3                    
                                  272.90                                  
                                      100                                 
                                         64  44.14                        
                                                3.70                      
                                                    5.14                  
                                                      44.21               
                                                         3.94             
                                                             5.20         
740564                                                                    
    4NO.sub.2   H         C.sub.10 H.sub.10 N.sub.2 O.sub.5               
                                  238.20                                  
                                      154                                 
                                         68  50.42                        
                                                4.23                      
                                                   11.76                  
                                                      50.42               
                                                         4.26             
                                                            11.59         
740512                                                                    
    3C.sub.2 H.sub.5                                                      
                H         C.sub.12 H.sub.15 NO.sub.3                      
                                  221.25                                  
                                       97                                 
                                         70  65.14                        
                                                6.83                      
                                                    6.33                  
                                                      64.88               
                                                         6.78             
                                                             6.22         
760271                                                                    
    4CN         &#34;         C.sub.11 H.sub.10 N.sub.2 O.sub.3               
                                  218.21                                  
                                      130                                 
                                         20  60.54                        
                                                4.62                      
                                                   12.84                  
                                                      60.49               
                                                         4.42             
                                                            12.86         
760133                                                                    
     ##STR23##  &#34;         C.sub.12 H.sub.16 N.sub.2 O.sub.3               
                                  236.26                                  
                                      150                                 
                                         25  61.00                        
                                                6.83                      
                                                   11.86                  
                                                      60.72               
                                                         7.07             
                                                            11.77         
760311                                                                    
     ##STR24##  &#34;         C.sub.14 H.sub.20 N.sub.2 O.sub.3               
                                  264.32                                  
                                       95                                 
                                         13  63.61                        
                                                7.63                      
                                                   10.60                  
                                                      63.76               
                                                         7.85             
                                                            10.85         
760375                                                                    
     ##STR25##  &#34;         C.sub.18 H.sub.20 N.sub.2 O.sub.3               
                                  312 142                                 
                                         79  69.21                        
                                                6.45                      
                                                    8.97                  
                                                      69.47               
                                                         6.66             
                                                             9.16         
760474                                                                    
     ##STR26##  H         C.sub.14 H.sub.18 N.sub.2 O.sub.3               
                                  262.30                                  
                                      168                                 
                                         42  64.10                        
                                                6.92                      
                                                   10.68                  
                                                      63.92               
                                                         6.59             
                                                            10.91         
760349                                                                    
     ##STR27##  H         C.sub.15 H.sub.20 N.sub.2 O.sub.3               
                                  276.33                                  
                                      170                                 
                                         39  65.19                        
                                                7.30                      
                                                   10.14                  
                                                      64.89               
                                                         7.27             
                                                            10.44         
760082                                                                    
    4 SCH.sub.3 H         C.sub.11 H.sub.13 NO.sub.3 S                    
                                  239.29                                  
                                      133                                 
                                         62  55.21                        
                                                5.48                      
                                                    5.85                  
                                                      54.95               
                                                         5.38             
                                                             5.92         
760786                                                                    
    4 SCH.sub.3 CONHCH.sub.3                                              
                          C.sub.13 H.sub.16 N.sub.2 O.sub.4 S             
                                  296.34                                  
                                      120                                 
                                         78  52.69                        
                                                5.44                      
                                                    9.45                  
                                                      52.59               
                                                         5.23             
                                                             9.60         
760466                                                                    
    4 SC.sub.2 H.sub.5                                                    
                H         C.sub.12 H.sub.15 NO.sub.3 S                    
                                  253.31                                  
                                      110                                 
                                         66  56.89                        
                                                5.97                      
                                                    5.53                  
                                                      56.82               
                                                         5.85             
                                                             5.48         
760473                                                                    
    4 SC.sub.4 H.sub.9 (n)                                                
                H         C.sub.14 H.sub.19 NO.sub.3 S                    
                                  281.37                                  
                                      106                                 
                                         52  59.76                        
                                                6.81                      
                                                    4.98                  
                                                      59.76               
                                                         6.59             
                                                             4.81         
760483                                                                    
     ##STR28##  &#34;         C.sub.13 H.sub.17 NO.sub.3 S                    
                                  267.34                                  
                                       85                                 
                                         45  58.40                        
                                                6.41                      
                                                    5.24                  
                                                      58.50               
                                                         6.13             
                                                             4.96         
760600                                                                    
    4 SC.sub.3 H.sub.7 (n)                                                
                &#34;         &#34;       &#34;   102                                 
                                         &#34;   &#34;  &#34;  &#34;  58.68               
                                                         6.58             
                                                             5.20         
760621                                                                    
     ##STR29##  &#34;         C.sub.16 H.sub.21 NO.sub.3 S                    
                                  307.40                                  
                                       82                                 
                                         57  62.51                        
                                                6.89                      
                                                    4.56                  
                                                      62.73               
                                                         7.00             
                                                             4.55         
760037                                                                    
    4 OC.sub.2 H.sub.5                                                    
                &#34;         C.sub.12 H.sub.15 NO.sub.4                      
                                  237.25                                  
                                      133                                 
                                         91  60.75                        
                                                6.37                      
                                                    5.90                  
                                                      60.81               
                                                         6.54             
                                                             5.89         
760116                                                                    
     ##STR30##  &#34;         C.sub.13 H.sub.17 NO.sub.4                      
                                  251.27                                  
                                       74                                 
                                         56  62.14                        
                                                6.82                      
                                                    5.57                  
                                                      62.29               
                                                         6.77             
                                                             5.48         
760303                                                                    
    4 OC.sub.3 H.sub.7 (n)                                                
                &#34;         &#34;       &#34;   139                                 
                                         72  &#34;  &#34;  &#34;  61.88               
                                                         7.16             
                                                             5.62         
760304                                                                    
    4 OC.sub.4 H.sub.9 (n)                                                
                &#34;         C.sub.14 H.sub.19 NO.sub.4                      
                                  265.30                                  
                                      122                                 
                                         68  63.38                        
                                                7.22                      
                                                    5.28                  
                                                      63.53               
                                                         7.21             
                                                             5.37         
760414                                                                    
     ##STR31##  &#34;         &#34;       &#34;   110                                 
                                         30  &#34;  &#34;  &#34;  63.41               
                                                         7.25             
                                                             5.19         
760396                                                                    
    4 OC.sub.5 H.sub.11 (n)                                               
                &#34;         C.sub.15 H.sub.21 NO.sub.4                      
                                  279.33                                  
                                      124                                 
                                         48  64.49                        
                                                7.58                      
                                                    5.01                  
                                                      64.43               
                                                         7.75             
                                                             4.86         
760549                                                                    
    4 OC.sub.6 H.sub.13 (n)                                               
                H         C.sub.16 H.sub.23 NO.sub.4                      
                                  293.35                                  
                                      115                                 
                                         76  65.50                        
                                                7.90                      
                                                    4.78                  
                                                      65.55               
                                                         8.00             
                                                             4.50         
760534                                                                    
    4 OC.sub.7 H.sub.15 (n)                                               
                &#34;         C.sub.17 H.sub.25 NO.sub.4                      
                                  307.38                                  
                                      110                                 
                                         65  66.42                        
                                                8.20                      
                                                    4.56                  
                                                      66.44               
                                                         7.91             
                                                             4.54         
760314                                                                    
     ##STR32##  &#34;         C.sub.16 H.sub.21 NO.sub.4                      
                                  291.37                                  
                                      124                                 
                                         15  65.96                        
                                                7.27                      
                                                    4.81                  
                                                      65.73               
                                                         7.29             
                                                             4.91         
770018                                                                    
    4 OC.sub.4 H.sub.9 (t)                                                
                &#34;         C.sub.14 H.sub.19 NO.sub.4                      
                                  265.30                                  
                                       93                                 
                                         52  63.38                        
                                                7.22                      
                                                    5.28                  
                                                      63.41               
                                                         7.25             
                                                             5.19         
760104                                                                    
    4 OC.sub.2 H.sub.5                                                    
                CONHCH.sub.3                                              
                          C.sub.14 H.sub. 18 N.sub.2 O.sub.5              
                                  294.30                                  
                                      110                                 
                                         52  57.13                        
                                                6.16                      
                                                    9.52                  
                                                      57.02               
                                                         6.22             
                                                             9.51         
760663                                                                    
    4 OC.sub.3 H.sub.7 (n)                                                
                &#34;         C.sub.15 H.sub.20 N.sub.2 O.sub.5               
                                  308.33                                  
                                       96                                 
                                         72  58.43                        
                                                6.54                      
                                                    9.09                  
                                                      58.53               
                                                         6.48             
                                                             9.04         
760662                                                                    
    4 OC.sub.4 H.sub.9 (n)                                                
                &#34;         C.sub.16 H.sub.22 N.sub.2 O.sub.5               
                                  322.35                                  
                                       84                                 
                                         80  59.61                        
                                                6.88                      
                                                    8.69                  
                                                      59.60               
                                                         6.91             
                                                             8.66         
760712                                                                    
    4 OC.sub.4 H.sub.9 (iso)                                              
                &#34;         &#34;       &#34;    89                                 
                                         88  &#34;  &#34;  &#34;  59.33               
                                                         6.87             
                                                             8.61         
760819                                                                    
    4 OC.sub.5 H.sub.11 (n)                                               
                CONHCH.sub.3                                              
                          C.sub.17 H.sub.24 N.sub.2 O.sub.5               
                                  336.38                                  
                                       90                                 
                                         56  60.70                        
                                                7.19                      
                                                    8.33                  
                                                      60.45               
                                                         7.22             
                                                             8.44         
760306                                                                    
    4OCH.sub.2CHCH.sub.2                                                  
                H         C.sub.13 H.sub.15 NO.sub.4                      
                                  249.26                                  
                                      109                                 
                                         76  62.64                        
                                                6.07                      
                                                    5.62                  
                                                      62.69               
                                                         6.14             
                                                             5.68         
760827                                                                    
    4OCH.sub.2CHCH                                                        
                H         C.sub.14 H.sub.17 NO.sub.4                      
                                  263.28                                  
                                      150                                 
                                         62  63.86                        
                                                6.51                      
                                                    5.32                  
                                                      63.74               
                                                         6.52             
                                                             5.31         
     CH.sub.3 (trans)                                                     
760650                                                                    
     ##STR33##  &#34;         C.sub.15 H.sub.19 NO.sub.4                      
                                  277.31                                  
                                      100                                 
                                         34  64.96                        
                                                6.91                      
                                                    5.05                  
                                                      64.77               
                                                         6.97             
                                                             4.87         
760535                                                                    
     ##STR34##  &#34;         C.sub.14 H.sub.17 NO.sub.4                      
                                  263.28                                  
                                       82                                 
                                         74  63.86                        
                                                6.51                      
                                                    5.32                  
                                                      64.09               
                                                         6.57             
                                                             5.22         
760536                                                                    
    4 O(CH.sub.2).sub.2                                                   
                H         C.sub.14 H.sub.17 NO.sub.4                      
                                  263.28                                  
                                      116                                 
                                         18  63.86                        
                                                6.51                      
                                                    5.32                  
                                                      63.97               
                                                         6.81             
                                                             5.55         
     CHCH.sub.2                                                           
760307                                                                    
    4 OCH.sub.2C CH                                                       
                &#34;         C.sub.13 H.sub.13 NO.sub.4                      
                                  247.24                                  
                                      130                                 
                                         79  63.15                        
                                                5.30                      
                                                    5.67                  
                                                      63.08               
                                                         5.53             
                                                             5.78         
760658                                                                    
    &#34;           CONHCH.sub.3                                              
                          C.sub.15 H.sub.16 N.sub.2 O.sub.5               
                                  304.29                                  
                                      122                                 
                                         71  59.20                        
                                                5.30                      
                                                    9.21                  
                                                      58.95               
                                                         5.43             
                                                             9.31         
760877                                                                    
    4 OCH.sub.2C C                                                        
                H         C.sub.14 H.sub.15 NO.sub.4                      
                                  261.27                                  
                                      140                                 
                                         58  64.36                        
                                                5.79                      
                                                    5.36                  
                                                      63.98               
                                                         5.80             
                                                             5.18         
     CH.sub.3                                                             
770063                                                                    
     ##STR35##  &#34;         C.sub.17 H.sub.21 NO.sub.4                      
                                  303.35                                  
                                       99                                 
                                         45  67.31                        
                                                6.98                      
                                                    4.62                  
                                                      67.41               
                                                         6.97             
                                                             4.78         
770104                                                                    
     ##STR36##  &#34;         C.sub.17 H.sub.23 NO.sub.4                      
                                  305.36                                  
                                      130                                 
                                         80  66.86                        
                                                7.59                      
                                                    4.59                  
                                                      66.74               
                                                         7.50             
                                                             4.70         
760167                                                                    
     ##STR37##  &#34;         C.sub.17 H.sub.17 NO.sub.4                      
                                  299.31                                  
                                      150                                 
                                         94  68.21                        
                                                5.73                      
                                                    4.68                  
                                                      68.03               
                                                         5.75             
                                                             4.41         
760337                                                                    
     ##STR38##  &#34;         C.sub.17 H.sub.16 ClNO.sub.4                    
                                  333.76                                  
                                      152                                 
                                         66  61.17                        
                                                4.83                      
                                                    4.20                  
                                                      60.98               
                                                         4.70             
                                                             4.44         
760317                                                                    
     ##STR39##  &#34;         C.sub.18 H.sub.19 NO.sub.4                      
                                  313.34                                  
                                      117                                 
                                          7  68.99                        
                                                6.11                      
                                                    4.47                  
                                                      68.70               
                                                         6.11             
                                                             4.51         
770017                                                                    
     ##STR40##  H         C.sub.18 H.sub.19 NO.sub.4                      
                                  313.34                                  
                                      115                                 
                                         73  68.99                        
                                                6.11                      
                                                    4.47                  
                                                      68.83               
                                                         6.39             
                                                             4.39         
760547                                                                    
     ##STR41##  &#34;         C.sub.17 H.sub.16 FNO.sub.4                     
                                  317.31                                  
                                      147                                 
                                         84  64.34                        
                                                5.08                      
                                                    4.41                  
                                                      64.20               
                                                         4.91             
                                                             4.17         
760556                                                                    
     ##STR42##  &#34;         C.sub.18 H.sub.16 F.sub.3 NO.sub.4              
                                  367.32                                  
                                       89                                 
                                         59  58.85                        
                                                4.39                      
                                                    3.81                  
                                                      58.63               
                                                         4.31             
                                                             3.82         
760574                                                                    
     ##STR43##  H         C.sub.17 H.sub.16 BrNO.sub.4                    
                                  378.21                                  
                                      153                                 
                                         75  53.98                        
                                                4.26                      
                                                    3.70                  
                                                      53.81               
                                                         4.17             
                                                             3.46         
760548                                                                    
     ##STR44##  &#34;         C.sub.17 H.sub.16 ClNO.sub.4                    
                                  &#34;   130                                 
                                         67  &#34;  &#34;  &#34;  61.02               
                                                         4.89             
                                                             4.32         
760729                                                                    
    &#34;           CONHCH.sub.3                                              
                          C.sub.19 H.sub.19 ClN.sub.2 O.sub.5             
                                  390.82                                  
                                      109                                 
                                         71  58.39                        
                                                4.90                      
                                                    7.17                  
                                                      58.33               
                                                         4.89             
                                                             7.10         
760537                                                                    
     ##STR45##  H         C.sub.18 H.sub.19 NO.sub.4                      
                                  313.34                                  
                                      135                                 
                                         56  68.99                        
                                                6.11                      
                                                    4.47                  
                                                      69.05               
                                                         6.25             
                                                             4.42         
760533                                                                    
     ##STR46##  H         &#34;       &#34;   123                                 
                                         62  &#34;  &#34;  &#34;  69.20               
                                                         6.37             
                                                             4.60         
760881                                                                    
     ##STR47##  H         C.sub.18 H.sub.16 N.sub.2 O.sub.4               
                                  324.32                                  
                                      159                                 
                                         76  66.66                        
                                                4.97                      
                                                    8.64                  
                                                      66.62               
                                                         4.95             
                                                             8.71         
760622                                                                    
     ##STR48##  H         C.sub.17 H.sub.16 N.sub.2 O.sub.6               
                                  344.31                                  
                                      158                                 
                                         70  59.30                        
                                                4.68                      
                                                    8.14                  
                                                      59.02               
                                                         4.80             
                                                             8.22         
760676                                                                    
    &#34;           CONHCH.sub.3                                              
                          C.sub.19 H.sub.19 N.sub.3 O.sub.7               
                                  401.36                                  
                                      153                                 
                                         89  56.85                        
                                                4.77                      
                                                   10.47                  
                                                      56.64               
                                                         4.63             
                                                            10.53         
760937                                                                    
    4 OCH.sub.2 H         C.sub.19 H.sub.22 N.sub.2 O.sub.4               
                                  342.38                                  
                                      160                                 
                                         56  66.65                        
                                                6.48                      
                                                    8.18                  
                                                      66.61               
                                                         6.35             
                                                             8.29         
     ##STR49##                                                            
760432                                                                    
     ##STR50##  H         C.sub.17 H.sub.16 FNO.sub.4                     
                                  317.31                                  
                                      154                                 
                                         79  64.34                        
                                                5.08                      
                                                    4.41                  
                                                      64.36               
                                                         5.10             
                                                             4.49         
760717                                                                    
    &#34;           CONHCH.sub.3                                              
                          C.sub.19 H.sub.19 FN.sub.2 O.sub.5              
                                  374.36                                  
                                      128                                 
                                         66  60.96                        
                                                5.12                      
                                                    7.48                  
                                                      60.97               
                                                         5.18             
                                                             7.53         
760453                                                                    
     ##STR51##  H         C.sub.16 H.sub. 16 FNO.sub.4                    
                                  317.31                                  
                                      141                                 
                                         81  64.34                        
                                                5.08                      
                                                    4.41                  
                                                      64.60               
                                                         5.01             
                                                             4.33         
760730                                                                    
    &#34;           CONHCH.sub.3                                              
                          C.sub.19 H.sub.19 FN.sub.2 O.sub.5              
                                  374.36                                  
                                      112                                 
                                         50  60.96                        
                                                5.12                      
                                                    7.48                  
                                                      60.99               
                                                         5.19             
                                                             7.77         
760409                                                                    
     ##STR52##  CONHCH.sub.3                                              
                          C.sub.19 H.sub.20 N.sub.2 O.sub.5               
                                  356.37                                  
                                      118                                 
                                         82  64.03                        
                                                5.66                      
                                                    7.86                  
                                                      64.04               
                                                         5.74             
                                                             7.97         
760723                                                                    
    &#34;                                                                     
                 ##STR53##                                                
                          C.sub.21 H.sub.24 N.sub.2 O.sub.5               
                                  384.42                                  
                                      132                                 
                                         83  65.61                        
                                                6.29                      
                                                    7.29                  
                                                      65.91               
                                                         6.83             
                                                             7.12         
760728                                                                    
     ##STR54##  CONHCH.sub.3                                              
                          C.sub.19 ClN.sub.2 O.sub.5                      
                                  390.81                                  
                                      148                                 
                                         68  58.39                        
                                                4.90                      
                                                    7.17                  
                                                      58.38               
                                                         5.08             
                                                             6.92         
760809                                                                    
     ##STR55##  &#34;         C.sub.19 H.sub.19 BrN.sub.2 O.sub.5             
                                  435.27                                  
                                      109                                 
                                         54  52.43                        
                                                4.40                      
                                                    6.44                  
                                                      52.58               
                                                         4.41             
                                                             6.51         
760652                                                                    
    4 OCH.sub.2 COOH.sub.3                                                
                H         C.sub.13 H.sub.15 NO.sub.5                      
                                  265.26                                  
                                      148                                 
                                         66  58.86                        
                                                5.70                      
                                                    5.28                  
                                                      58.56               
                                                         5.69             
                                                             5.17         
760733                                                                    
    &#34;           CONHCH.sub.3                                              
                          C.sub.15 H.sub. 18 N.sub.2 O.sub.6              
                                  322.31                                  
                                      102                                 
                                         62  55.89                        
                                                5.63                      
                                                    8.69                  
                                                      55.63               
                                                         5.76             
                                                             8.60         
770054                                                                    
    4 CHO       H         C.sub.11 H.sub.11 NO.sub.4                      
                                  219.20                                  
                                      123                                 
                                         35  59.72                        
                                                5.01                      
                                                    6.33                  
                                                      59.49               
                                                         4.66             
                                                             6.20         
760670                                                                    
    4 COCH.sub.3                                                          
                H         C.sub.12 H.sub.13 NO.sub.4                      
                                  235.23                                  
                                      155                                 
                                         63  61.27                        
                                                5.57                      
                                                    5.95                  
                                                      61.44               
                                                         5.63             
                                                             5.96         
760731                                                                    
    &#34;           CONHCH.sub.3                                              
                          C.sub.14 H.sub.16 N.sub.2 O.sub.5               
                                  292.28                                  
                                      130                                 
                                         49  57.53                        
                                                5.52                      
                                                    9.59                  
                                                      57.23               
                                                         5.27             
                                                             9.43         
__________________________________________________________________________
 
    
     
                                           table ii                                
__________________________________________________________________________
 ##STR56##                                                                
                     mole-                                                
                          Melting  Elementary analysis                    
Code         Empirical                                                    
                     cular                                                
                          point                                           
                               Yield                                      
                                   Calculated (%)                         
                                            Obtained (%)                  
Number                                                                    
     R       formula weight                                               
                          (° C.)                                   
                               (%) C  H  N  C  H  N                       
__________________________________________________________________________
760472                                                                    
     4-SC.sub.4 H.sub.9 (n)                                               
             C.sub.13 H.sub.21 NO.sub.2 S                                 
                     255.37                                               
                          &lt;50  51  61.14                                  
                                      8.29                                
                                         5.49                             
                                            60.89                         
                                               8.28                       
                                                   5.34                   
760498                                                                    
     4-SC.sub.3 H.sub.7 (iso)                                             
             C.sub.12 H.sub.19 NO.sub.2 S                                 
                     241.35                                               
                          *1   59  59.72                                  
                                      7.94                                
                                         5.80                             
                                            59.23                         
                                               8.54                       
                                                   5.94                   
760599                                                                    
     4-SC.sub.3 H.sub.7 (n)                                               
             &#34;       &#34;    *2   48  &#34;  &#34;  &#34;  59.60                         
                                               8.25                       
                                                   5.48                   
760982                                                                    
      ##STR57##                                                           
             C.sub.15 H.sub.23 NO.sub.2 S                                 
                     281.41                                               
                          82   63  64.02                                  
                                      8.24                                
                                         4.98                             
                                            63.86                         
                                               8.42                       
                                                   4.98                   
760464                                                                    
      ##STR58##                                                           
             C.sub.13 H.sub.20 N.sub.2 O.sub.2                            
                     236.31                                               
                          125  20  66.07                                  
                                      8.53                                
                                         11.86                            
                                            65.78                         
                                               8.49                       
                                                  12.02                   
760355                                                                    
      ##STR59##                                                           
             C.sub.14 H.sub.22 N.sub.2 O.sub.2                            
                     250.33                                               
                          86   23  67.17                                  
                                      8.86                                
                                         11.19                            
                                            67.47                         
                                               9.14                       
                                                  11.02                   
760732                                                                    
     4-CH.sub.3 CO                                                        
             C.sub.11 H.sub.15 NO.sub.3                                   
                     209.24                                               
                          135  48  63.14                                  
                                      7.23                                
                                         6.69                             
                                            63.17                         
                                               7.54                       
                                                  7.06                    
__________________________________________________________________________
 *1: Eb.sub.0.04 = 250° C.                                         
 *2: Eb.sub.0.01 = 250° C.                                         
 
    
     The compounds of formula (I) were studied on laboratory animals and showed activities in the psychotropic field, as potential antidepressants. 
     These activities show up in the following tests. 
     Test A 
     Potentiation in a mouse of generalised trembling caused by an intraperitoneal injection (200 mg/kg) of dl-5-hydroxytryptophane, according to the mode of operation described by GOURET C. and RAYNAUD G. in the J. Pharmacol. (PARIS), (1974), 5, 231. 
     Test B 
     Antagonism in relation to ptosis observed one hour after an intravenous injection (2 mg/kg) of reserpine was given to a mouse, according to the mode of operation described by GOURET C. and THOMAS J. in J. Pharmacol. (PARIS), (1973), 4, 401. 
     Test C 
     Diminution in the density of pontogeniculo-occipital points (P.G.O.) caused by injecting a cat with 0.5 mg/kg of reserpine, according to the mode of operation described by COSTON A. and GOURET C. in J. Pharmacol. (PARIS), (1976), 7, 409. 
     The results of these three tests as well as those of a reference substance TOLOXATONE are given in table III below: 
     
                                           TABLE III                               
__________________________________________________________________________
Tested   Test A    Test B    Test C                                       
compounds                                                                 
         50 DE (mg/kg/p.o.)                                               
                   50 DE (mg/kg/p.o.)                                     
                             50 DE (mg/kg/p.o.)                           
__________________________________________________________________________
a/ According to the invention                                             
740704   42        12        52                                           
740512   68        32        50                                           
750710   62        100       14                                           
740711   19        26        --                                           
750341   100       41        22                                           
740564   38        42        16                                           
740511   55        17        40                                           
760271   20        11        11                                           
760395   39        28        160                                          
760133   11        7.2       4.5                                          
760311   27        32        9                                            
760375   39        28        160                                          
760474   42        68        14                                           
760082   22        18        8.4                                          
760786   &gt;50       40        25.5                                         
760466   40        32        8.25                                         
760473   41        22        11.5                                         
760600   19        15.4      6.26                                         
760621   100       42        40                                           
760037   16        40        5.4                                          
760116   60        50        15                                           
760303   9         14        6.9                                          
760304   5         5         6.1                                          
760414   13        3         5.5                                          
760396   12        1.4       20                                           
760549   26        11        85                                           
760314   19        18        12                                           
760104   48        44        &gt;50                                          
760662   48        17.5      23                                           
760712   48        25        35                                           
760306   14        29        2.5                                          
760827   15        10        5.2                                          
760650   25.5      3.4       7.03                                         
760535   28        50        5.1                                          
760536   8.6       15        6.3                                          
760307   8         14        5                                            
760658   &gt;12.5     27        13.9                                         
760877   25        25        5.6                                          
760167   9.5       3.3       15.2                                         
760337   6         5         120                                          
760317   25        17        45                                           
760556   5         3.2       14.1                                         
760574   21        22        &gt;50                                          
760548   4.4       3.4       33.5                                         
760729   &gt;12.5     23        50                                           
760537   35        17        37.5                                         
760533   41        54        51                                           
760881   12.5      5         29                                           
760622   5.5       2.1       40                                           
760676   &gt;12.5     6.25      22                                           
760432   3.8       2         24                                           
760717   &gt;12.5     12.5      &gt;50                                          
760453   5.5       7         11.6                                         
760409   100       7         &gt;50                                          
760723   &gt;50       17.5      &gt;50                                          
760652   7.1       2.8       13                                           
760651   5.5       2.5       1.5                                          
760660   &gt;12.5     31        12.3                                         
760670   21        10        14                                           
760731   &gt;25       15        17.5                                         
b/ Reference                                                              
TOLOXATONE                                                                
         60        50        28                                           
__________________________________________________________________________
 
    
     as can be seen from the preceding results and those given in table IV below, the difference between lethal doses and active pharmacological doses is sufficient for the compounds of the invention to be used in therapeutics. 
     
                       TABLE IV                                                    
______________________________________                                    
         Acute toxicity in mice                                           
Tested     Dose administered                                              
                         Mortality                                        
                                  50 DL                                   
compounds  (mg/kg/p.o.)  (%)      (mg/kg/p.o.)                            
______________________________________                                    
 a/ according to                                                          
  the invention                                                           
740704     2000          0        --                                      
740711     1000          0        --                                      
740564     --            --       &gt;1000                                   
760271     --            --        1050                                   
760082     --            --       &gt;2000                                   
760037     --            --       &gt;2000                                   
760304     --            --       &gt;2000                                   
760167     --            --       &gt;2000                                   
b/ reference                                                              
TOLOXATONE --            --        1850                                   
______________________________________                                    
 
    
     As can be seen from the preceding tables the compounds of formula (I) have an activity superior or equal to that of the reference compound. 
     They are indicated in endogene and exogene depressive conditions, and will ge given orally in the form of tablets, pills, gelules with a dosage of 500 mg/day on average of active constituent.