Abstract:
Disclosed are 2-amino-5-phenyl-1,3-benzodiazepines of the formula ##STR1## wherein R 1  and R 2  are hydrogen, halogen, alkyl, or alkoxy; R 2  being able to occupy any of the possible positions on the aromatic ring; R 3  is hydrogen or alkyl; and R 4  is hydrogen, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, dialkylaminoethyl, dialkylaminopropyl, (1-ethyl-2-pyrrolidino) methyl, dialkylamino, alkoxycarbonyl or cyano; or R 3  and R 4  form, with the adjacent nitrogen atom, a heterocycle having 5 to 7 side chains, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen, this latter being able to be substituted by an alkyl group. The majority of the compounds are obtained by condensation of the corresponding 2-methylthio benzodiazepine hydroiodide with an appropriate amine. The compounds are useful as antidepressants.

Description:
BACKGROUND OF THE INVENTION 
     This invention relates to substituted 2-amino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazapines and a process for their preparation. The compounds have therapeutic use as antidepressants. 
     2-amino-7,8-dimethoxy-4,5-3H-dihydro-1,3-benzodiazepines have been described [Rodriquez, et al, J. Org. Chem. 33, 670 (1968)]. Other 2-amino-4,5-3H-dihydro-1,3-benzodiazepines unsubstituted in the 5 position have also been described in U.S. Pat. Nos. 3,780,203 and 3,780,024 as antihypertensive agents and depressants of the central nervous system. Further, 2-anilo-4,5-3H-dihydro-1,3-benzodiazepines have been suggested as diuretic agents in French Patent Application No. 82,13,605 filed by Bayssat, et al. 
     SUMMARY OF THE INVENTION 
     The compounds of the present invention are represented by the general formula I: ##STR2## wherein R 1  and R 2  are hydrogen, a halogen, alkyl, or alkoxy, R 2  being able to occupy any of the possible positions on the aromatic ring; R 3  is hydrogen or alkyl; R 4  is hydrogen, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, dialkylaminoethyl, dialkylaminopropyl, (1-ethyl-2-pyrrolidino)methyl, dialkylamino, alkoxycarbonyl or cyano, with the proviso that when R 4  is cyano, R 3  is hydrogen; or else R 3  and R 4  form, with the adjacent nitrogen atom, a heterocycle having 5 to 7 side chains, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen, which is unsubstituted or substituted with alkyl. The terms alkyl or alkoxy as used herein refer to straight or branched hydrocarbon radicals comprising from 1 to 4 carbon atoms. The term cycloalkyl as used herein refers to rings containing from 4 to 7 carbon atoms. By arylalkyl or heteroarylalkyl is meant the group of formula II 
     
         Ar--alk--                                                  II 
    
     wherein Ar is a benzene ring, optionally mono- or polysubstituted by halogen, alkyl, alkoxy, nitro or amino. Ar can also be the 2-pyridyl, 3-pyridyl, 4-pyridyl or 2-furyl; alk- represents methylene, or an ethylene chain optionally substituted by a hydroxy group. 
     The compounds of formula I wherein R 3  is hydrogen and R 4  is hydrogen or alkoxycarbonyl constitute a particularly attractive class of compounds. 
     Pharmaceutically acceptable salts are of compounds of the formula I within the scope of the invention. These salts include salts prepared from compounds of the formula I with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or from organic acids such as tartaric acid, citric acid, acetic acid, maleic acid, acid, oxalic acid, methanesulfonic acid, fumaric acid. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The compounds of the invention, except those for which R 4  representa an alkoxycarbonyl cyano, are obtained by condensation of the derivatives of general formula III ##STR3## with an amine of general formula IV ##STR4## In formula III and IV, R 1 , R 2 , R 3  and R 4  have the meanings given above. 
     The reaction is carried out in an inert organic solvent, at temperatures between ambient temperature and the boiling temperature of the solvent used, Solvents that have given the best results are alkanols and nitriles having a low molecular weight and N,N-dimethylformamide. Use of acetonitrile has been found to be particularly advantageous. The reaction time is a function of the temperature used and varies from 1 h to 60 h; preferably, temperatures close to the boiling point of the solvent are used where possible to minimize reation time. 
     Preparation of the compounds of formula III is described in French Patent Application 82.10,466[,published] 
     The compounds of the invention wherein R 4  is alkoxycarbonyl and, R 1 , R 2 , and R 3  have the meanings given above, are obtained by condensing a 2-amino-5-phenyl-1,3-benzodiazepine of general formula V ##STR5## with an alkyl chloroformate of formula VI 
     
         Cl--COOR.sub.5                                             VI 
    
     wherein R 5  is alkyl. The reaction is performed in the presence of a base such as dilute soda, dilute potash or an alkaline carbonate. 
     The compounds of the invention wherein R 4  is cyano and R 3  is hydrogen (formula X) are obtained by the series of reactions below, wherein R 1  and R 2  have the meanings given above: 
     a diamine of formula VII whose preparation is described in French Patent Application 82.10,466 (supra): ##STR6## is condensed with a compound of formula VIII: ##STR7## to give the intermediate IX: ##STR8## IX is cyclized into X by heating in an organic solvent having a high boiling point, for example, from 90° C. to 110° C.: ##STR9## The compounds of invention represented by formula I affect the central nervous system and are clinically useful in the treatment of depressive states and psychic disturbances. The mood-modifying activity of the compounds is evaluated by standardized tests such as inhibition of known reserpine ptosis. Reserpine ptosis may be induced by methods such as those described in the literature. For example, Rubin, et al, [J. Pharmacol, Exp. Ther. 120: 125(1957)] induced ptosis in Swiss mice by intraperitoneal injection of 5 mg/kg of reserpine. This ptosis was marked 1 h 30 min later. Compounds to be tested for reserpine inhibition were administered orally at the same time as the reserpine was injected. The effective doses (ED 50 ) obtained for products of the invention and those obtained for the standard antidepressant amitriptyline [5-(3-dimethylaminopropylidene)dibenzo[a,d]-1,4-cycloheptadiene hydrochloride] are given in Table I: 
     
                       TABLE I______________________________________           Reserpine ptosisProducts        ED.sub.50 (mg/kg/PO)______________________________________AMITRIPTYLINE   10Example 1       18Example 3       10Example 4       11Example 8        3Example 48      13______________________________________ 
    
     Lethal doses (LD50) of these products as determined orally in Swiss mice are given in Table II: 
     
                       TABLE II______________________________________Products        LD.sub.50 PO (mg/kg)______________________________________AMITRIPTYLINE     150Example 1         600Example 3         330Example 4       1,200Example 8       2,400Example 48      &gt;3,200______________________________________ 
    
     Compounds of the formula I thus have clinical application as pharmaceuticals, particularly as antidepressants. These pharmaceuticals are conveniently administered orally in the form of plain or sugar-coated tablets or capsules, or rectally in the form of suppositories. The active ingredient is usually combined with various pharmaceutically compatible excipients. Daily dosages typically vary from 10 to 200 mg, depending on the seriousness of the condition being treated and patient idiosyncrasies. 
     Exemplary pharmaceutical formulations are given below: 
     A. Composition of a 100-mg tablet, optionally coated: 
     
         ______________________________________active ingredient 5 mglactose           41 mgwheat starch      41 mggelatin           2 mgalginic acid      5 mgtalc              5 mgmagnesium stearate             1 mg______________________________________ 
    
     B. Composition of a capsule: 
     
         ______________________________________active principle 10 mglactose          32 mgwheat starch     25 mgtalc             2.5 mgmagnesium stearate            0.5 mg______________________________________ 
    
    
    
     The following examples are illustrative of the invention, without limitation: 
     EXAMPLE 1 
     2-Amino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     A mixture of 95.6 g (241.2 mmoles) of 2-methylthio-5-phenyl-4,5,3H-dihydro-1,3-benzodiazepine hydroiodide, 1250 cc of ethyl alcohol and 970 cc of 34% ammonia are refluxed together. About every 4 hours ammonia is bubbled until the reaction medium is saturated the reaction is continued until release of methanethiol stops (about 30 hours). After cooling, insoluble material is filtered and the filtrate is evaporated dry. The residue is dissolved with 500 cc of water then alkalized very strongly with potash pellets. The mixture is stirred for 1 hour with 200 cc of ether. The precipitate of 2-amino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine is filtered, washed with water and dried. It is dissolved in ethyl alcohol and treated with 50 cc of 10N hydrochloric acid. The mixture is evaporated dry and the resulting 2-amino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride is purified by recrystallization in an acetone-ethyl alcohol mixture. Yield: 42.3 g (64%); m.p.=215°-217°  C. 
     IR (KBr): ν (C=N + ): 1680 cm -1 . 
     NMR (DMSO d 6  +D 2  O) δ=3.7-4.1 (complex mass, 2H); 4.4-4.7 (complex 
     mass, 1H); 7.0-7.7 (multiplet, 9H). 
     Analysis by percent: C 15  H 16  ClN 3  ; M=273.76. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  65.80  5.89       12.95 15.35Found       65.94  5.98       12.84 15.18______________________________________ 
    
     The products described in Examples 2 to 10 are obtained by operating under the conditions of example 1. 
     EXAMPLE 2 
     2-Amino-7-chloro-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained from 7-chloro-2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=166°-168° C. (acetone-ethyl alcohol) 
     Analysis by percent: C 15  H 15  Cl 2  N 3  ; M=308.20. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  58.45  4.91       23.01 13.63Found       58.44  4.95       22.99 13.64______________________________________ 
    
     EXAMPLE 3 
     2-Amino-5-(4-methylphenyl)-4,5-3H-hydro-1,3-benzodiazepine hydrochloride 
     Obtained from 5-(4-methylphenyl)-2-methylthio-4,5-3H-dihydro-4,5-3H-benzodiazepine hydroiodide. m.p.=162°-163° C. (acetone-isopropyl alcohol) 
     Analysis by percent: C 16  H 18  ClN 3  ; M=287.78. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  66.77  6.30       12.32 14.60Found       66.90  6.40       12.30 14.61______________________________________ 
    
     EXAMPLE 4 
     2-Amino-5-(4-chlorophenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained from 5-(4-chlorophenyl)2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=163°-166° C. (acetone-ethyl alcohol) 
     Analysis by percent: C 15  H 15  Cl 2  N 3  ; M=308.20. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  58.45  4.91       23.01 13.63Found       58.60  4.93       22.90 13.61______________________________________ 
    
     EXAMPLE 5 
     2-Amino-5-(4-methoxyphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hemioxalate 
     The base is prepared, according to Example 1, from 5-(4-methoxyphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. The hemioxalate is obtained by adding a solution of a demi-equivalent of oxalic acid in acetone to a solution of this base in acetone. m.p.=248°-249° C. (water-ethyl alcohol). 
     Analysis by percent: C 17  H 18  N 3  O 3  ; M=312.33. 
     
         ______________________________________    C %         H %    N %______________________________________Calculated 65.37         5.81   13.46Found      65.06         6.03   13.29______________________________________ 
    
     EXAMPLE 6 
     2-Amino-7-methyl-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained from 7-methyl-2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=159°-161° C. (isopropyl alcohol-diisopropyl ether). 
     Analysis by percent: C 16  H 18  ClN 3  ; M=287.78. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  66.77  6.30       12.32 14.60Found       66.68  6.13       12.26 14.66______________________________________ 
    
     EXAMPLE 7 
     2-Amino-5-(3-methylphenyl)-4,5-3H-dihydro-1,3-benezodiazepine hydrochloride 
     Obtained from 5-(3-methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=137°-139° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 16  H 18  ClN 3  ; M=287.78. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  66.77  6.30       12.32 14.60Found       66.66  6.57       12.36 14.46______________________________________ 
    
     EXAMPLE 8 
     2-Amino-7-methyl-5-(4-methylphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained from 7-methyl-5-(4-methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. 202°-203° C. (isopropyl alcohol-diisopropyl ether). 
     Analysis by percent: C 17  H 20  CIN 3  ; M=301.81. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  67.66  6.68       11.75 13.93Found       67.65  6.55       11.74 13.99______________________________________ 
    
     EXAMPLE 9 
     2-Amino-7-chloro-5-(4-methylphenyl)-4.5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained from 7-chloro-5-(methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=172°-174° C. (isopropyl alcohol-diisopropyl ether). 
     Analysis by percent: C 16  H 17  Cl 2  N 3  ; M=322.23. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  59.64  5.32       22.00 13.04Found       59.96  5.10       21.97 13.09______________________________________ 
    
     EXAMPLE 10 
     2-Amino-5-(2-methylphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained from 5-(2-methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=243°-244° C. (isopropyl alcohol). 
     Analysis by percent: C 16  H 18  ClN 3  ; N=287.78. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  66.77  6.30       12.32 14.60Found       66.89  6.36       12.33 14.43______________________________________ 
    
     EXAMPLE 11 
     2-Dimethylamino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine oxalate 
     2-Dimethylamino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine is obtained from 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide and dimethylamine by operating as in Example 1. The oxalate is obtained by addition of a solution of an equivalent of oxalic acid in acetone to a solution of the base in acetone. m.p.=196°-198° C. (acetone-methyl alcohol). 
     Anaysis by percent: C 19  H 21  N 3  O 4  ; M=355.38. 
     
         ______________________________________    C %         H %    N %______________________________________Calculated 64.21         5.93   11.82Found      63.91         6.17   11.79______________________________________ 
    
     EXAMPLE 12 
     2-Methylamino-5-(4-methylphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     A mixture of 16.4 g of 5-(4-methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide, 100 cc of ethyl alcohol and 20 cc of a 33% methylamine ethyl alcohol solution is refluxed. Every three hours 100 cc of the methylamine ethyl alcohol solution are added until release of methanethiol stops (about 12 hours). The reaction medium is then concentrated dry. The residue is dissolved with water and the mixture made strongly alkaline by addition of potash pellets and then extracted twice with methylene chloride. The collected organic phases are washed with water and dried on sodium sulfate. The methylene chloride is eliminated and 8 cc of 10N hydrochloric acid are added to the residue which is dissolved in ethyl alcohol. After evaporation to dryness, the 2-methylamino-5-(4-methylphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride is recrystallized in an isopropyl alcohol-diisopropylether mixture. m.p.=210°-211° C. Yield: 9.9 g (79%). 
     Analysis by percent: C 17  H 20  ClN 3  ; M=301.81. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  67.66  6.68       11.75 13.93Found       67.63  6.88       11.67 13.82______________________________________ 
    
     EXAMPLE 13 
     2-Methylamino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine oxalate 
     2-Methylamino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine is obtained, after treatment, from 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide by operating as in example 12. After recrystallization in a hexane-ethyl acetate mixture melts at 142°-144° C. 
     An oxalic acid equivalent, dissolved in acetone, is added to this base, dissolved in acetone. The resulting oxalate is filtered and recrystallized in an acetone-ethyl alcohol mixture. m.p.=163°-165° C. Analysis by percent: C 18  H 19  N 3  O 4  ; M=341.35. 
     
         ______________________________________    C %         H %    N %______________________________________Calculated 63.33         5.61   12.31Found      63.40         5.55   12.38______________________________________ 
    
     EXAMPLE 14 
     2-Benzylamino-5-phenyl-4,5-3H-dihdro-1,3-benzodiazepine hydrochloride 
     A mixture of 8 g (20 mmoles) of 2-methylthio-5-phenyl-4,5-3H dihydro-1,3-benzodiazepine hydroidide, 4.3 g (40 mmoles) of benzylamine and 50 cc of acetonitrile is refluxed under nitrogen, until release of methanethiol stops (about 7 hours). After cooling, the reaction mixture is diluted with ether. 2-Benzylamino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide precipitates. It is filtered and put in suspension in water. The mixture is alkalinized with a soda solution and extracted with ether. The organic phase is washed with water and dried on sodium sulfate. The solvent is evaporated and the residue dissolved in ethyl alcohol. 5 cc of a 10N hydrochloric acid solution is added to this solution and concentrated under vacuum. 2-Benzylamino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride is obtained which is purified by recrystallization in ethyl alcohol. 
     Yield: 4.9 g (67%), m.p.=206°-208° C. 
     Analysis by percent: C 22  H 22  ClN 3  ; M=363.88. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  72.61  6.10       9.74  11.55Found       72.39  6.17       9.80  11.60______________________________________ 
    
     The products described in examples 15 to 46 are prepared by operating under the conditions of example 14. 
     EXAMPLE 15 
     2-(4-Chlorobenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 4-chlorobenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=181°-183° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 22  H 21  Cl 2  N 3  ; M=398.33. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  66.34  5.31       17.80 10.55Found       66.30  5.38       17.78 10.55______________________________________ 
    
     EXAMPLE 16 
     2-Benzylamino 7-chloro-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of benzylamine and 7-chloro-2-methylthio-5-phenyl-4,5-3H-dihydro-benzodiazepine hydroiodide. m.p. 169°-170° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 22  H 21  Cl 2  N 3  ; M=398.33. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  66.34  5.31       17.80 10.55Found       66.30  5.48       17.67 10.49______________________________________ 
    
     EXAMPLE 17 
     2-Benzylamino-5-(4-methylphenyl)4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of benzylamine and 5-(4-methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=177°-178° C. (isopropyl alcohol). 
     Analysis by percent: C 23  H 24  ClN 3  ; M=377.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.10  6.40       9.38  11.12Found       72.94  6.49       9.46  11.06______________________________________ 
    
     EXAMPLE 18 
     2-Benzylamino-5-(4-methoxlphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of benzylamine and 5-(4-methoxyphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=120°-122° C. (acetone). 
     Analysis by percent: C 23  H 24  ClN 3  O; M=393.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  70.13  6.14       9.00  10.67Found       70.16  6.06       9.05  10.66______________________________________ 
    
     EXAMPLE 19 
     2-Furfurylamino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hemioxalate 
     Obtained by condensation of furfurylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=220°-222° C. (ethyl alcohol-dimethylformamide). 
     Analysis by percent: C 21  H 20  N 3  O 3  ; M=362.39. 
     
         ______________________________________    C %         H %    N %______________________________________Calculated 69.60         5.56   11.59Found      69.30         5.99   11.44______________________________________ 
    
     EXAMPLE 20 
     2-Benzylamino-5-(4-chlorophenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of benzylamine and 5-(4-chlorophenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. 164°-166° C. (acetone-ethyl alcohol) 
     Analysis by percent: C 22  H 21  Cl 2  N 3  ; M=398.33. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  66.34  5.31       17.80 10.55Found       66.22  5.53       17.66 10.49______________________________________ 
    
     EXAMPLE 21 
     2-(4-Chlorobenzylamino-5-(4-methylphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 4-chlorobenzylamine and 5-(4-methylphenyl)-2-methylthio-4,5-3H-dihyfro-1,3-benzodiazepine hydroiodide. m.p. 202°-203° C. (isopropyl alcohol-diisopropyl ether). 
     Analysis by percent: C 23  H 23  Cl 2  N 3  ; M=412.34. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  67.00  5.62       17.20 10.19Found       66.96  5.96       17.26 10.19______________________________________ 
    
     EXAMPLE 22 
     2-(3-Methylbenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 3-methylbenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=145°-146° C. (acetone-isopropyl alcohol). 
     Analysis by percent: C 23  H 24  ClN 3  ; M=377.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.10  6.40       9.38  11.12Found       72.99  6.45       9.48  11.06______________________________________ 
    
     EXAMPLE 23 
     2-Methoxybenzylamino)5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 4-methoxybenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=202°-204° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 23  H 24  ClN 3  O; M=393.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  70.13  6.14       9.00  10.67Found       70.16  6.06       9.04  10.59______________________________________ 
    
     EXAMPLE 24 
     2-4-Methylbenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 4-methylbenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzoiazepine hydroiodide. m.p. =176°-178° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 23  H 24  ClN 3  ; M=377.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.10  6.40       9.38  11.12Found       73.16  6.10       9.50  11.30______________________________________ 
    
     EXAMPLE 25 
     2-Benzylamino-7-methyl-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of benzylamine and 7-methyl-2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. =153°-155° C. (acetone-isopropyl alcohol). 
     Analysis by percent: C 23  H 24  ClN 3  ; M=377.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.10  6.40       9.38  11.12Found       73.10  6.20       9.41  11.22______________________________________ 
    
     EXAMPLE 26 
     2-(2-Methylbenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 2-methylbenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. 131°-133° C. (acetone-diisopropyl ether). 
     Analysis by percent: C 23  H 24  Cln 3  ; M=377.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.10  6.40       9.38  11.12Found       73.10  6.16       9.39  11.26______________________________________ 
    
     EXAMPLE 27 
     2-Benzylamino-5-(3-methylphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of benzylamine and 5-(3-methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p=159°-161° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 23  H 24  ClN 3  ; M=377.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.10  6.40       9.98  11.12Found       73.05  6.45       9.40  11.06______________________________________ 
    
     EXAMPLE 28 
     2-Benzylamino-5-(2-methylphenyl)4,5-3H-dihydro-1,3-benzo diazepine hydrochloride 
     Obtained by condensation of benzylamine and 5-(2-methylphenyl-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=163°-164° C. (isopropyl alcohol-diisopropyl ether) 
     Analysis by percent: C 23  H 24  ClN 3  ; M=377.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.10  6.40       9.38  11.12Found       72.90  6.60       9.40  11.08______________________________________ 
    
     EXAMPLE 29 
     2-(2,3-Dimethylbenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 2,3-dimethylbenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. 207°-209° C. (ethyl alcohol). 
     Analysis by percent: C 24  H 26  ClN 3  ; M=391.92. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.55  6.69       9.05  10.72Found       73.60  6.69       9.06  10.69______________________________________ 
    
     EXAMPLE 30 
     2-(2,6-Dimethylbenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 2,6-dimethylbenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. 165°-169° C. (ethyl alcohol). 
     Analysis by percent: C 24  H 26  ClN 3  ; M=391.92. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.55  6.69       9.05  10.72Found       73.44  6.88       9.04  10.69______________________________________ 
    
     EXAMPLE 31 
     2-Benzylamino-7-chloro-5-(4-methylphenyl)-4,5-3H-dihyro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of benzylamine and 7-chloro-5-(4-methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=184°-186° C. (ethyl alcohol). 
     Analysis by percent: C 23  H 23  Cl 2  N 3  ; M=412.35. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  67.00  5.62       17.20 10.19Found       67.06  5.88       16.89 10.23______________________________________ 
    
     EXAMPLE 32 
     2-Benzylamino-7-methyl-5-(4-methylphenyl)-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of benzylamine and 7-methyl-5-(4-methylphenyl)-2-methylthio-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. 204°-205° C. (isopropyl alcohol-diisopropyl ether). 
     Analysis by percent: C 24  H 26  ClN 3  ; M=391.92. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.55  6.69       9.05  10.72Found       73.77  6.70       8.98  10.63______________________________________ 
    
     EXAMPLE 33 
     5-Phenyl-2-(2-pyridylmethylamino)-4,5-3H-dihydro-1,3-benzodiazepine dihydrochloride 
     Obtained by condensation of 2-aminomethyopyridine and 2-methylthio-5-Phenyl-4,5-3H-dihydro-1,3-benzodiazapine hydroiodide. m.p.=253°-255° C. (ethyl alcohol-dimethylformamide). 
     Analysis by percent: C 21  H 22  Cl 2  N 4  ; M=401.33. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  62.85  5.53       17.67 13.96Found       62.86  5.66       17.56 13.96______________________________________ 
    
     EXAMPLE 34 
     5-Phenyl-2-(3-pyridylmethylamino)-4,5-3H-dihydro-1,3-benzodiazepine dihydrochloride 
     Obtained by condensation of 3-aminomethylpyridine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide, m.p. 210°-212° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 21  H 22  Cl 2  N 4  ; M=401.33. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  62.85  5.53       17.67 13.96Found       62.90  5.55       17.62 14.03______________________________________ 
    
     EXAMPLE 35 
     5-Phenyl-2-(4-pyridylmethylamino)-4,5-3H-dihydro-1,3-benzodiazepine dihydrochloride 
     Obtained by condensation of 4-aminomethylpyridine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=251°-253° C. (ethyl alcohol). 
     Analysis by percent: C 21  H 22  Cl 2  N 4  ; M=401.33. 
     
         ______________________________________        H %      Cl %    N %______________________________________Calculated  62.85  5.53       17.67 13.96Found       62.89  5.60       17.63 13.98______________________________________ 
    
     EXAMPLE 36 
     2-(4-Nitrobenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine oxalate 
     Obtained by condensation of 4-nitrobenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=160°-162° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 26  H 22  N 4  O 6  ; M=462.45. 
     
         ______________________________________    C %         H %    N %______________________________________Calculated 62.33         4.80   12.09Found      62.38         4.86   12.13______________________________________ 
    
     EXAMPLE 37 
     2-(3-Amino-4-chlorobenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine maleate 
     Obtained by condensation of 3-amino-4-chlorobenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=166°-168° C. (acetone-ethyl alcohol). 
     Analysis percent: C 26  H 25  ClN 4  O 4  ; M=492.95. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  63.35  5.11       7.19  11.37Found       63.21  5.15       7.22  11.23______________________________________ 
    
     EXAMPLE 38 
     2-(4-Aminobenzylamino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine dihydrochloride 
     Obtained by condensation of 4-aminobenzylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=188°-190° C. (ethyl alcohol-ether). 
     EXAMPLE 39 
     2-Cyclopentylamino-5-phenyl-4,5-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of cyclopentylamine and 2-methylthio-5-phenyl-4,5-dihydro-1,3-benzodiazepine hydroiodide. m.p.=181°-183° C. (acetone alcohol). 
     Analysis by percent: C 20  H 24  ClN 3  ; M=341.87. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  70.26  7.07       10.37 12.29Found       70.08  7.08       10.46 12.36______________________________________ 
    
     EXAMPLE 40 
     2-[Amino(3-dimethylaminopropyl)]-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine dihydrochloride 
     Obtained by condensation of 3-dimethylaminopropylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=185°-187° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 20  H 28  Cl 2  N 4  ; M=395.36. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  60.74  7.14       17.93 14.17Found       60.48  7.47       17.86 14.15______________________________________ 
    
     EXAMPLE 41 CL 7-Chloro-2-[amino(3-dimethylaminopropyl)[-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine dioxalate 
     Obtained by condensation of 3-dimethylaminopropylamine and 7-chloro-2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. 186°-188° C. (ethyl alcohol). 
     Analysis by percent: C 24  H 29  ClN 4  O 8  ; M=536.96. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  53.68  5.44       6.60  10.43Found       53.26  5.66       6.61  10.37______________________________________ 
    
     EXAMPLE 42 
     2-[Amino(2-dimethylaminoethyl)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine dihydrochloride 
     Obtained by condensation of 2-dimethylaminoethylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=223°-225° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 19  H 26  Cl 2  N 4  ; M=381.34. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  59.84  6.87       18.60 14.70Found       59.50  7.35       18.48 14.70______________________________________ 
    
     EXAMPLE 43 
     2-Phenethylamino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     Obtained by condensation of 2-phenylethylamine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p. 164°-166° C. (acetone-ethyl alcohol). 
     Analysis by percent: C 23  H 24  ClN 3  ; M=377.90. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  73.10  6.40       9.38  11.12Found       73.06  6.44       9.40  11.06______________________________________ 
    
     EXAMPLE 44 
     2-(4-Methyl-1-piperazinyl)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine dihydrochloride, hydrate 
     Obtained by condensation of N-methylpiperazine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine dydroiodide. m.p.=193°-194° C. (ethyl alcohol-diisopropyl ether). 
     Analysis by percent: C 20  H 27  Cl 2  N 4  O; M=410.36. 
     
         ______________________________________   C %    H %    Cl %      N %  O %______________________________________Calculated     58.53    6.63   17.28   13.65                                  3.90Found     58.23    6.84   17.23   13.52                                  4.04______________________________________ 
    
     EXAMPLE 45 
     2-[Methylamino(1-ethyl-2-pyrrolidinyl)]-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine dihydrochloride 
     Obtained by condensation of 2-aminomethyl-1-ethylpyrrolidine and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=242°-245° C. (ethyl alcohol). 
     Analysis by percent: C 22  H 30  Cl 2  N 4  ; M=421.40. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  62.70  7.18       16.83 13.30Found       62.85  7.13       16.83 13.26______________________________________ 
    
     EXAMPLE 46 
     2-[Amino(2-hydroxy-2-phenylethyl)]-5-phenyl-4,5-3H-dihydro-1,3,benezodiazepine 
     Obtained by condensation of 2-amino-1-phenylethyl alcohol and 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide. m.p.=174°-176° (ethyl alcohol). 
     Analysis by percent: C 23  H 23  N 3  O; M=357.43. 
     
         ______________________________________    C %         H %    N %______________________________________Calculated 77.28         6.48   11.76Found      77.36         6.43   11.86______________________________________ 
    
     EXAMPLE 47 
     2-(2,2-Dimethylhydrazino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydrochloride 
     A mixture of 25 g (63 mmoles) of 2-methylthio-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine hydroiodide, 56.8 g (950 mmoles) of 1,1-dimethylhydrazine and 300 cc of N,N-dimethylformamide is brought to 60° C. for 40 hours. The reaction mixture is concentrated under low pressure. The residue is dissolved in water, strongly alkalized by potash pellets and extracted with methylene chloride. The organic phase is washed with a water and dried on sodium sulfate. After elimination of the solvent, 2-(2,2-dimethylhydrazino)-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine is collected and converted to its hydrochloride by the usual method. m.p.=160°-162° C. (ethyl alcohol-ethyl acetate). 
     Analysis by percent: C 17  H 21  ClN 4  ; M=316.83. 
     
         ______________________________________     C %  H %        Cl %    N %______________________________________Calculated  64.45  6.68       11.19 17.69Found       64.55  6.60       11.19 17.60______________________________________ 
    
     EXAMPLE 48 
     2-amino-(5-Phenyl-4,5-3H-dihydro-1,3-benzodiazepin)yl ethyl carbamate 
     1.95 g (18 mmoles) of ethyl chloroformate are added drop by drop, then a mixture of 50 cc of water and 50 g of crushed ice is added to a suspension of 8.3 g (35 mmoles) of 2-amino-5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine in a mixture of 50 cc of water and 50 g of crush ice. 1.95 g (18 mmoles) of ethyl chloroformate and a solution of 1.5 g (37.5 mmoles) of soda in 10 cc of water are then added simultaneously. it is allowed to return to an ambient temperature and stirred for another hours. The precipitate is filtered, washed with water and dried. It is purified by recrystallization in ethyl alcohol. m.p.=209°-211° C. 
     Yield: 4.9 g (39%). IR: ν(C=0)=1680 cm -1 . 
     Analysis by percent: C 18  H 19  N 3  O 2  ; M=309.35. 
     
         ______________________________________    C %         H %    N %______________________________________Calculated 69.88         6.19   13.58Found      69.98         5.96   13.54______________________________________ 
    
     EXAMPLE 49 
     [2-(5-Phenyl-4,5-3H-dihydro-1,3-benzodiazepin)yl]cyanamide 
     A solution of 25.4 g (120 mmoles of 2-(2-aminophenyl)-2-phenylethylamine in 120 cc of ethyl alcohol is added drop by drop to a solution of 17.5 g (120 mmoles) of dimethyl cyanodithioimidocarbonate in 100 cc of ethyl alcohol. Stirring is continued for 1 hour at ambient temperature and the mixture is left standing overnight. The precipitate is filtered, washed with a little ethyl alcohol and dried. It is put into solution in 200 cc of N,N-dimethylformamide. The solution is refluxed for 30 hours and then evaporated dry under low pressure. The residue is purified by recrystallization in a methyl alcohol-N,N-dimethylformamide mixture. The [2-(5-phenyl-4,5-3H-dihydro-1,3-benzodiazepine)yl]cyanamide melts at 261°-263° C. 
     Yield: 14.8 g (47%). IR: ν (C.tbd.N)=2160 cm -1 . 
     Analysis by percent: C 16  H 14  N 4  ; M=262.30. 
     
         ______________________________________    C %         H %    N %______________________________________Calculated 73.26         5.38Found      73.32         5.25   21.44______________________________________ 
    
     It is to be understood that the present invention is not limited to the embodiments disclosed which are illustratively offered and that modifications may be made without departing from the invention.