Patent Publication Number: US-4368199-A

Title: Novel derivatives of 3,4,5-trimethoxy cinnamoyl piperazine, their salts, the process for preparing the same and their application in therapeutics

Description:
The present invention relates to new derivatives of 3,4,5-trimethoxy cinnamoyl piperazine, the salts thereof and the process for preparing same and application thereof in therapeutics. 
     The new compounds correspond more exactly to the general formula: ##STR1## in which --X-- represents: either an alkylene radical --(CH 2 ) n  -- wherein n assumes the value 1,2 or 3, a methylcarbonyl chain (--CH 2  --CO--) or a 1-hydroxy ethyl chain ##STR2## these two chains being bonded to the piperazine radical by their CH 2  group, in which cases Ar represents: 
     a phenyl radical of structure ##STR3##  where m is either equal to 1 or 2, R 1  then representing a hydrogen atom, a halogen atom or an alkyl group of 1 to 5 carbon atoms, or is equal to 1, R 1  then representing an amino, nitro, alkylcarbonylamino, alkylsulfonylamino or alkylaminocarbonylamino group whose alkyl groups each comprise from 1 to 5 carbon atoms; 
     an aromatic radical of structure ##STR4##  in which the set (R 2 , R 3 , p) assumes any one of the following values: (H, H, 1 or 2), (H, alkyl from 1 to 5 C, 1 or 2), (OH, H, 2), (OH, alkyl from 1 to 5 C, 1 or 2), (alkyloxy from 1 to 5 C, H, 2), (alkyloxy from 1 to 5 C, alkyl from 1 to 5 C, 2), (H, alkylcarbonyl from 2 to 5 C, 1 or 2); 
     the radicals of structures ##STR5## an aromatic radical of structure: ##STR6##  in which R 4  represents a hydroxy or alkyloxy group of 1 to 5 carbon atoms; or 
     a naphthyl nucleus; 
     or a chain of formula ##STR7## bonded to the piperazine radical by the CH 2  group, in which cases Ar represents: 
     an aromatic group of structure ##STR8## where R 5  represents a hydrogen or chlorine atom, or an alkyl group of 1 to 5 carbon atoms or an alkyloxy group of 1 to 5 carbon atoms and q assumes the value 1, 2 or 3; 
     an aromatic radical of structure: ##STR9##  in which R 6  represents an alkyl group of 1 to 5 carbon atoms or an alkyloxy group of 1 to 5 carbon atoms; 
     the nuclei of structures: ##STR10## the naphthyl nucleus; the --X--Ar chain being also able to be represented by the structure: ##STR11## where n and R 5  have the same meanings as before, or the structure: ##STR12## 
     where p=1 or 2 and R 3  represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms or an alkylcarbonyl group of 2 to 5 carbon atoms. 
     As was mentioned above, the present invention also relates to the salts of the compounds of formula (I), which salts may be formed with pharmaceutically acceptable mineral acids, such as hydrochloric acid or organic acids such as oxalic acid. 
     In accordance with the present invention, the compounds of formula (I) are obtained by processes which differ depending on the meaning of the symbols X and Ar. Thus: 
     A. The compounds of formula (I) in which X represents an alkylene radical of structure (--CH 2 ) n  -- in which n=1, 2 or 3, are obtained by condensation of 3,4,5-trimethoxy cinnamoyl piperazine of formula: ##STR13## with the chlorides, bromides, tosylates or mesylates of formula: 
     
         Ar.sub.1 --(CH.sub.2).sub.n --Y                            (III) 
    
     in which Y represents a chlorine or bromine atom or the tosyloxy or mesyloxy groups, n=1, 2 or 3 and Ar 1  has the same meaning as Ar in the formula (I) when X represents the alkylene group (--CH 2 ) n  --. 
     This condensation is preferably carried out at reflux in an organic solvent such as acetone, acetonitrile or DMF in the presence of a basic agent such as potassium carbonate. 
     B. The compounds of formula (I) in which X represents the --CH 2  --CO-- chain, except for the case where Ar represents the group of formula: ##STR14## are obtained by condensation of the compound of formula (II) with the compounds of formula: 
     
         Ar.sub.2 --CO--CH.sub.2 --Y&#39;                               (IV) 
    
     in which Y&#39;=Cl or Br and Ar 2  has the same meaning as Ar 1  in formula (III), except for the values: ##STR15## this condensation reaction being preferably carried out under the same conditions as the condensation of the compound of formula (II) with the compounds of formula (III). 
     The compound of formula (IV) having the particular form: ##STR16## is new and it is obtained by action of cupric bromide in solution in a mixture of ethyl acetate and chloroform, on the compound of formula: ##STR17## 
     This latter is also new and is obtained by action of methyl sulfate, preferably in an acetone medium and in the presence of potassium carbonate, on 8-hydroxy 5-acetyl 1,4-benzodioxane. 
     The compound of formula (I) where the --X--Ar chain represents the ##STR18## group is obtained by hydrolysis by means of potassium carbonate in a methanol medium of the compound of formula: ##STR19## 
     The compound of formula (Ia), which is new, is obtained by condensation of the compound of formula (II) with the compound of formula: ##STR20## the operation method for carrying out this condensation being identical to that used for condensation of the compound of formula (II) with the compounds of formula (III). 
     The compound (IVc) is also new and is obtained by the process used for the synthesis of the compound of formula (IVa), but from the compound of formula: ##STR21## 
     This latter is itself new and is obtained by action of benzyl chloride on 5-acetyl 8-hydroxy, 1,4-benzodioxane, in an organic solvent medium such as THF and in the presence of a base such as triethylamine. 
     C. The compounds of formula (I) in which X represents (--CH 2  --CH 2  --CO--) are obtained by reaction of the compound of formula (II) with the chlorhydrates of the compounds of formula: ##STR22## in which Ar 3  has the same meaning as Ar in formula (I) when X represents (--CH 2  --CH 2  --CO--). 
     This reaction is carried out preferably at reflux in an alcohol solvent such as ethanol, isopropyl alcohol or butanol. 
     The compounds of formula (V) are obtained by so-called &#34;MANNICH&#34; reaction of piperidine with the compounds of formula: 
     
         CH.sub.3 --CO--Ar.sub.3                                    (VI) 
    
     in which Ar 3  has the same meanings as in formula (V). 
     D. The compounds (I) in which X represents the chains ##STR23## are obtained by reduction, preferably by means of sodium borohydride, in the presence of NaOH and in an alcohol medium (preferably methanol), respectively of the compounds of formula (I) in which X represents the chain (--CH 2  --CO--) and the chain (--CH 2  --CH 2  --CO--) prepared according to the processes set forth in points B and C above. 
     The compound of formula (I) in which the chain --X--Ar represents the ##STR24## may also be obtained by reduction preferably by means of sodium in a methanol medium and in the presence of NaOh, of the compound (Ia). 
     E. The compounds of formula (I) in which X represents the chain ##STR25## are obtained by condensation, preferably in an organic solvent such as acetonitrile, of the compound of formula (II) with those of formula: ##STR26## where Ar 3  has the same meanings as in formula (V). 
     The compounds of formula (VII) or (VIIa) are obtained by opening epibromhydrin or epichlorhydrin, in a T.H.F. medium and in the presence of cuprous iodide, by means of the magnesians of the compounds of formula 
     
         Br--Ar.sub.3                                               (VIII) 
    
     in which Ar 3  has the same meanings as in the formulae (VII) and (VIIa). 
     F. The compounds of formula (I) in which X represents the chain ##STR27## are obtained by condensation of compound of formula (II), preferably in an acetone, acetonitrile, T.H.F. or D.M.F. medium and in the presence of potassium carbonate, with the compounds of formula: ##STR28## in which Ar 3  has the same meanings as in formula (V). 
     The compounds of formula (IX) are obtained by saponification by means of potassium carbonate in a methanol medium of the compounds of formula: ##STR29## in which Ar 3  has the same meanings as in formula (IX). 
     The compounds of formula (X) are obtained by action of succinimide bromide in a benzene medium and in presence of azobisisobutyronitrile on the compounds of formula: ##STR30## in which Ar 3  has the same meanings as in formula (X). 
     The compounds of formula (XI) are themselves obtained by condensation of benzaldehyde in a benzene medium and in the presence of paratoluenesulfonic acid with the compounds of formula: ##STR31## in which Ar 3  has the same meanings as in formula (XI). 
     G. The compounds of formula (I) in which the --X--Ar chain is ##STR32## are obtained by condensation of the chloride of 3,4,5-trimethoxy cinnamoyl acid, preferably in a T.H.F. or D.M.F. medium and in the presence of triethylamine, on the compounds of formula: ##STR33## in which R 3  and p have the same meanings as in formula (I). 
     The compounds of formula (XIII) in which R 3  represents the hydrogen atom are obtained by demethylation by means of 48% bromhydric acid, of the compounds of formula (XIII) in which R 3  represents the methyl group. 
     The compounds of formula (XIII) in which R 3  represents an alkyl group of 1 to 5 carbon atoms are obtained by a two-step synthesis which consists in condensing piperazine in a benzene medium and in presence of paratoluene sulfonic acid with the compounds of formula: ##STR34## in which R&#39; 3  represents an alkyl group of 1 to 5 carbon atoms and p=1 or 2, then in reducing the intermediate compounds thus formed, by means of sodium borohydride in an ethanol medium. 
    
    
     The following preparations are given by way of example to illustrate the invention. 
     EXAMPLE 1 
     1-benzyl-4-(3,4,5-trimethoxy) cinnamoyl piperazine hydrochloride hydrate (I) 
     Code number: 21 
     A suspension of 6.1 g of formula (II) compound, 3.2 g of benzyl chloride and 8.3 g of potassium carbonate in 70 ml of acetonitrile was brought to reflux for 5 hours. Then it was filtered, the filtrate diluted with 70 ml of acetone, chlorhydric ethanol was added, the precipitate was filtered and recrystallized in methanol. 4.8 g of the expected compound were isolated. 
     Yield: 56% 
     Melting point: 230° C. 
     Molecular weight: 440.14 
     Empirical formula: C 23  H 29  ClN 2  O 5  +2/5 H 2  O 
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             62.76       6.82   6.36                                      
Obtained (%) 62.93       7.37   6.49                                      
______________________________________                                    
 
    
     By the same process, but from the corresponding reagents, the compounds of formula (I) and of code numbers: 1 to 4, 22 to 57, 101 and 105 given in table I below were obtained. 
     EXAMPLE 2 
     2-[4-(3,4,5-trimethoxy) cinnamoyl piperazinyl]1-phenyl ethanone (I) 
     Code number: 58 
     A suspension of 15.4 g of formula (II) compound, 10 g of α-bromoacetophenone and 13.8 g of potassium carbonate in 100 ml of acetonitrile was brought to reflux for 30 minutes. Then it was filtered, the filtrate evaporated and the residue crystallized in isopropyl ether. Thus 17.7 g of the desired compound were isolated. 
     Yield: 84% 
     Melting point: 103° C. 
     Molecular weight: 424.48 
     Empirical formula: C 24  H 28  N 2  O 5   
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             67.90       6.65   6.60                                      
Obtained (%) 67.73       6.55   6.43                                      
______________________________________                                    
 
    
     By the same process, but from the corresponding reagents, the compounds of formula (I) of code numbers: 5 to 10, 12, 59 to 78 given in table I below are obtained. 
     EXAMPLE 3 
     1-(3,4,5-trimethoxy phenyl) 3-[4&#39;-(3,4,5-trimethoxy cinnamoyl) 1&#39;-piperazinyl]propanone hydrochloride hydrate (I) 
     Code number: 99 
     A solution of 10.2 g of 3-piperidino 1-(3,4,5-trimethoxy)phenyl propanone (in chlorhydrate form) and 9 g of formula (II) compound in 30 ml of water and 30 ml of ethanol was brought to reflux for 8 hours. Then the solvents were evaporated, the residue taken up in chloroform, washed with water, dried on sodium sulfate, filtered, the filtrate was evaporated and the residue crystallized in ethanol (Melting point: 156° C.). 
     The precipitate was dissolved in ethanol, chlorhydric ethanol was added and the hydrochloride obtained was filtered. 
     Yield: 70% 
     Melting point: 162° C. 
     Molecular weight: 597.93 
     Empirical formula: C 28  H 37  ClN 2  O 8  +5.5% H 2  O 
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             56.24       6.86   4.69                                      
Obtained (%) 56.17       6.33   4.74                                      
______________________________________                                    
 
    
     EXAMPLE 4 
     2-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl]1-phenyl ethanol hydrochloride (I) 
     Code number: 79 
     A solution of 8.1 g of formula (I) compound, code number 58, described in example 2, in 200 ml of methanol and 0.1 ml of concentrated NaOH was brought to reflux, then 3.8 g of sodium borohydride were slowly added and left 1 hour at reflux. Then the solvent was evaporated, the residue taken up in ethyl acetate, washed with water, dried on sodium sulfate, filtered, the filtrate was evaporated, the residue dissolved in acetone, chlorhydric ethanol was added, diluted with ether and the precipitate obtained was filtered. 7.4 g of the expected compound were obtained. 
     Yield: 63% 
     Melting point: 226° C. 
     Molecular weight: 462.96 
     Empirical formula: C 24  H 31  ClN 2  O 5   
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             62.26       6.75   6.05                                      
Obtained (%) 62.07       6.71   6.01                                      
______________________________________                                    
 
    
     By the same process, but from the corresponding reagents, the compounds of formula (I) of code numbers: 13 to 19, 80 to 98 and 100 appearing in table I below, were obtained. 
     EXAMPLE 5 
     3-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl]1-(3,4-dimethoxy)phenyl 2-propanol hydrochloride hydrate (I) 
     Code number: 102 
     1st stage: 1-chloro 3-(3,4-dimethoxy) phenyl 2-propanol (VIIa) 
     To a suspension of 2.4 g of magnesium in the minimum of T.H.F. were added 21.7 g of 4-bromo-veratrole in 200 ml of T.H.F., while maintaining the reflux of the T.H.F. Then it was cooled to &#34;40° C. and 0.2 g of CuI was added, stirring was carried out for 30 minutes and then 13.9 g of epichlorhydrin were slowly added. It was left to stir for 1 hour at 20° C., then washed with a saturated solution of ammonium chloride, dried on magnesium sulfate, filtered, the filtrate was evaporated and the residue distilled: Eb 0 .05 : 150°-152° C. 
     2nd stage: 3-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl] 1-(3,4-dimethoxy)-phenyl-2-propanol hydrochloride hydrate (I) 
     Code number: 102 
     A suspension of 10 g of formula (VIIa) compound obtained in the preceding stage, 15.9 g of formula (II) compound, 6.4 g of sodium iodide and 17.8 g of potassium carbonate in 200 ml of acetonitrile was brought to reflux for 8 hours. Then it was filtered, the filtrate evaporated, the residue was taken up in methylene chloride, washed with water, dried on magnesium sulfate, filtered and the filtrate was evaporated. The raw product obtained was dissolved in ethanol, chlorhydric ethanol was added and the precipitate formed was filtered. 
     Yield: 30% 
     Melting point: 162° C. 
     Molecular weight: 546.88 
     Empirical formula: C 27  H 37  ClNO 7  +1.8% H 2  O 
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             59.29       7.02   5.13                                      
Obtained (%) 59.21       7.03   5.02                                      
______________________________________                                    
 
    
     By the same process, but from the corresponding reagents, the compounds of formula (I) of code numbers 20 and 103 given in table I below were obtained. 
     EXAMPLE 6 
     3-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl] 2-phenyl 1-propanol hydrochloride hydrate (I) 
     Code number: 104 
     1st stage: 2,5-diphenyl 1,3-dioxanne (XI) 
     A solution of 85 g of 2-phenyl 1,3-propanediol, 59.3 g of benzaldehyde and 2 g of paratoluenesulfonic acid in 400 ml of benzene was brought to reflux for 6 hours, while removing the water formed. Then it was washed with water, dried on magnesium sulfate, filtered, the filtrate was evaporated and the residue crystallized in isopropyl ether. Thus, 84.7 g of the expected compound were obtained. 
     Yield: 63% 
     Melting point: 123° C. 
     Molecular weight: 240.29 
     Empirical formula: C 16  H 16  O 2   
     Elementary analysis 
     
         ______________________________________                                    
                C    H                                                    
______________________________________                                    
Calculated (%)    79.97  6.71                                             
Obtained (%)      79.89  6.54                                             
______________________________________                                    
 
    
     2nd stage: 1-bromo 3-benzoyloxy 2-phenyl propane (X) 
     To a solution of 84 g of formula (XI) compound obtained in the preceding stage and 11.5 g of azobisisobutyronitrile in 400 ml of benzene were slowly added 68.4 g of succinimide bromide. Then it was left to agitate for an hour at ambient temperature then for 2 hours at reflux. Then it was diluted with ether, washed with water, the solvents were evaporated and the residue was chromatographed on a silica column (eluent:methylene chloride). 89 g were obtained (Yield: 79%) of an oily product. 
     3rd stage: 3-bromo 2-phenyl 1-propanol (IX) 
     A suspension of 16 g of the formula (X) compound obtained in the preceding stage and 1 g of potassium carbonate in 200 ml of methanol was left under agitation for 3 hours, then the mixture was brought to reflux for 2 hours, the methanol was evaporated, the residue was taken up in methylene chloride, washed with water, dried on magnesium sulfate, filtered, the filtrate was evaporated and the residue chromatographed on a silica column (eluent:heptane-ethyl acetate: 80-20). 5.9 g (Yield: 50%) of oily product were obtained. 
     4th stage: 3-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl] 2-phenyl 1-propanol hydrochloride hydrate (I) 
     Code number: 104 
     A suspension of 28 g of formula (IX) compound obtained in the preceding stage, 30.6 g of compound (II) and 18 g of potassium carbonate in 300 ml of acetonitrile was brought to reflux for 5 hours. Then it was filtered, the filtrate evaporated, the residue was taken up in 1 N hydrochloric acid, washed with ether, basified by means of concentrated NaOH, extracted with ethyl acetate, washed with water, dried on sodium sulfate, filtered, the filtrate was evaporated, the residue was dissolved in ethyl acetate, chlorhydric ethanol was added, the precipitate formed (26 g) was filtered and recrystallized in ethyl acetate. 
     Yield: 45% 
     Melting point: 152° C. 
     Molecular weight: 492.30 
     Empirical formula: C 25  H 33  ClN 2  O 5  +2% H 2  O 
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             60.99       7.01   5.69                                      
Obtained (%) 60.95       7.02   5.80                                      
______________________________________                                    
 
    
     EXAMPLE 7 
     2-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl] 1,2,3,4-tetrahydro 6,7-dihydroxy naphthyl hydrate (I) 
     A solution of 12.5 g of piperazine, 10 g of 6,7-dimethoxy 1,2,3,4-tetrahydro naphthalene 2-one and 1 g of paratoluenesulfonic acid in 200 ml of benzene was brought to reflux for 5 hours while removing the water formed. Then the solvent was evaporated, the residue was taken up in 200 ml of ethanol, 7.3 g of sodium borohydride were slowly added and the solution was brought up to reflux for one hour. Then the solvent was evaporated, the residue was taken up in chloroform, washed with water, dried on sodium sulfate, filtered, the filtrate was evaporated, the residue was dissolved in ethanol, chlorhydric ethanol was added and the precipitate formed was filtered. 9 g of the expected compound were obtained. 
     Yield: 68% 
     Melting point: &gt;260° C. 
     Molecular weight: 349.29 
     Empirical formula: C 16  H 26  Cl 2  N 2  O 2   
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             55.01       7.21   8.02                                      
Obtained (%) 54.83       7.43   8.04                                      
______________________________________                                    
 
    
     By the same process, but from the corresponding reagents, 2-(1-piperazinyl) 5,6-dimethoxy 1,2,3,4-tetrahydro naphthyl-dihydrochloride (XIII) was obtained. 
     Melting point: &gt;260° C. 
     Elementary analysis 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             55.01       7.50   8.02                                      
Obtained (%) 54.90       7.86   7.98                                      
______________________________________                                    
 
    
     2nd stage: 2-(1-piperazinyl) 6,7-dihydroxy 1,2,3,4-tetrahydro naphthyl dibromohydrate (XIII) 
     A solution of 7 g of formula (XIII) compound obtained in the preceding stage (in base form) in 200 ml of 48% bromhydric acid was brought to reflux for one hour. Then the solvents were evaporated and the residue crystallized in acetone. 
     Yield: 73% 
     Melting point: &gt;260° C. 
     Empirical formula: C 14  H 20  N 2  O 2  +2.25 HBr 
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             37.88       5.39   6.31                                      
Obtained (%) 37.86       5.35   6.60                                      
______________________________________                                    
 
    
     By the same process, but from the corresponding reagents 2-(1-piperazinyl) 5,6-dihydroxy 1,2,3,4-tetrahydro naphthyl dibromhydrate (XIII) was obtained. 
     Melting point: &gt;260° C. 
     Empirical formula: C 14  H 20  N 2  O 2  +2 HBr+0.8% H 2  O 
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             40.66       5.45   6.78                                      
Obtained (%) 40.57       5.37   6.93                                      
______________________________________                                    
 
    
     3rd stage: 2-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl] 1,2,3,4-tetrahydro 6,7-dihydroxy naphthyl hydrate (I) 
     Code number: 108 
     To a suspension cooled to -20° C. of 5.8 g of formula (XIII) compound, prepared in the preceding stage, in 300 ml of D.M.F. and 7 g of triethylamine were added 6 g of 3,4,5-trimethoxy cinnamoic acid chloride and it was left under agitation for 30 minutes at -20° C. Then after 2 hours at ambient temperature, it was filtered, the filtrate was evaporated and the residue was chromatographed on a silica column, and eluted with the chloroform (90)--methanol (10) mixture. 27% of product was obtained. 
     Melting point: &gt;260° C. 
     Molecular weight: 472.31 
     Empirical formula: C 26  H 32  N 2  O 6  +0.8% H 2  O 
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             66.12       6.91   5.93                                      
Obtained (%) 65.77       7.03   5.90                                      
______________________________________                                    
 
    
     By the same process, but from the corresponding reagents, the compounds of formula (I) of code numbers: 106, 107 and 109 given in table I below were obtained. 
     EXAMPLE 8 
     2-bromo 4&#39;-methoxy 2&#39;,3&#39;-ethylenedioxy acetophenone (IVa) 
     1st stage: 5-acetyl 8-methoxy 1,4-benzodioxane (IVb) 
     To a suspension of 39 g of 5-acetyl 8-hydroxy 1,4-benzodioxane and 55 g of potassium carbonate in 350 ml of acetone were slowly added 28.6 ml of dimethylsulfate. Then the reaction mixture was brought to reflux for 90 minutes, filtered, the filtrate was evaporated, the residue was taken up in chloroform, washed with water and with a 30% NaOH solution. Then it was dried on sodium sulfate, filtered, the solvent was evaporated and the product filtered on a silica column (eluent:ethyl ether). 33.1 g of the expected product were obtained. 
     Yield: 80% 
     Melting point: 67° C. 
     Molecular weight: 208.21 
     Empirical formula: C 11  H 12  O 4   
     Elementary analysis: 
     
         ______________________________________                                    
                C    H                                                    
______________________________________                                    
Calculated (%)    63.45  5.81                                             
Obtained (%)      63.58  5.93                                             
______________________________________                                    
 
    
     2nd stage: 2-bromo 4&#39;-methoxy 2&#39;,3&#39;-ethylene dioxy acetophenone (IVa) 
     To a suspension of 7.5 g of cupric bromide in 25 ml of ethyl acetate was slowly added a solution of 4.1 g of the compound (IVb) prepared in the preceding stage in 25 ml of chloroform. Then it was brought to reflux for 6 hours, filtered and the filtrate evaporated, the residue was taken up in chloroform and washed with a sodium bicarbonate solution then with water. It was dried on sodium sulfate, filtered and the filtrate evaporated. 4.2 g of the expected product were obtained (Yield: 73%--Melting point: 135° C.) which was immediately used in the synthesis of the corresponding compound (I), after thin layer chromatography verification. 
     EXAMPLE 9 
     2-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl] (4&#39;-hydroxy 2&#39;,3&#39;-ethylene dioxy)acetophenone hydrochloride (I) 
     Code number: 11 
     1st stage: 5-acetyl 8-benzoyloxy 1,4-benzodioxane (IVd) 
     To a solution cooled to 0° C. of 80 g of 5-acetyl 8-hydroxy 1,4-benzodioxane and 72 ml of triethylamine in 500 ml of T.H.F. were slowly added 51.2 g of benzoyl chloride. Then it was left for 1 hour at room temperature, the solvent was evaporated, the residue was taken up in methylene chloride, washed with water, with dilute hydrochloric acid, then again with water and dried on sodium sulfate. It was filtered, the solvent was evaporated and 128 g of raw product were obtained (Yield˜100%) which, after checking by thin film chromatography, was used in the following stage. 
     2nd stage: 4&#39;-benzoyloxy 2&#39;,3&#39;-ethylenedioxy 2-bromo acetophenone (IVc) 
     This product was obtained with a process identical to the one used in the 2nd stage of example 8, but from compound (IVd). The raw product obtained was purified by silica column chromatography (eluent:methylene chloride), then used immediately in the following stage. 
     3rd stage: 2-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl] (4&#39;-benzoyloxy 2&#39;,3&#39;-ethylenedioxy)acetophenone hydrochloride trihydrate (Ia) 
     This compound was obtained with a process identical to the one used in example 2 for preparing compound (I) of code number 10, but from compound (IVc). The raw product obtained was dissolved in alcohol and 6,5 N chlorhydric ethanol was added, the precipitate formed was filtered and recrystallized in alcohol. 
     Yield: 40% 
     Melting point: 186° C. 
     Molecular weight: 693.13 
     Empirical formula: C 33  H 35  ClN 2  O 9   
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             57.18       5.96   4.04                                      
Obtained (%) 56.80       5.55   3.89                                      
______________________________________                                    
 
    
     4th stage: 2-[4-(3,4,5-trimethoxy cinnamoyl) 1-piperazinyl] (4&#39;-hydroxy 2&#39;,3&#39;-ethylenedioxy)acetophenone hydrochloride (I) 
     A suspension of 15 g of the compound (Ia) obtained in the preceding stage and 0.005 g of potassium carbonate in 100 ml of methanol was agitated under a nitrogen flow, at room temperature, for 12 hours, then was brought to reflux for 3 hours, the methanol was evaporated, the residue was taken up in 2 N hydrochloric acid, washed with ethyl ether, then with ethyl acetate. It was alkalized with ammonia and extracted, the residue was dissolved in isopropyl alcohol and ˜5.8 N chlorhydric ethanol was added and the precipitate obtained was filtered. 
     Thus, 12 g of the expected product were isolated. 
     Melting point: 213° C. 
     Molecular weight: 566.51 
     Empirical formula: C 26  H 31  ClN 2  O 8  +1.75 H 2  O 
     Elementary analysis: 
     
         ______________________________________                                    
           C         H      N                                             
______________________________________                                    
Calculated (%)                                                            
             55.12       5.96   4.95                                      
Obtained (%) 55.00       5.87   4.69                                      
______________________________________                                    
 
    
     
                                           TABLE I                                 
__________________________________________________________________________
 ##STR35##                                                   (I)          
                                             Melt-                        
Code                                     Molec-                           
                                             ing     ELEMENTARY           
Num-                            Empirical                                 
                                         ular                             
                                             point                        
                                                 Yield                    
                                                     ANALYSIS             
ber XAr                Form     formula  weight                           
                                             (°C.)                 
                                                 (%) (%)CHN               
__________________________________________________________________________
     ##STR36##         Chlorhydrate                                       
                                C.sub.24 H.sub.31 ClN.sub.2 O.sub.5       
                                         462.95                           
                                             250 22  Cal.62.26 6.75 6.05  
                                                     Obt. 62.00 6.68      
                                                     5.91                 
2                                                                         
     ##STR37##         Chlorhydrate                                       
                                C.sub.25 H.sub.33 ClN.sub.2 O.sub.6       
                                         492.99                           
                                             218 14  Cal.60.90 6.75 5.68  
                                                     Obt. 60.84 6.89      
                                                     5.54                 
3                                                                         
     ##STR38##         Base     C.sub.24 H.sub.30 N.sub.2 O.sub.5         
                                         426.49                           
                                             175 38  Cal.67.58 7.09 6.57  
                                                     Obt. 67.34 7.21      
                                                     6.61                 
4                                                                         
     ##STR39##         Hydrated Chlorhydrate                              
                                C.sub.24 H.sub.30 N.sub.2 O.sub.6, HCl,   
                                9/8 H.sub.2 O                             
                                         499.23                           
                                             252 16  Cal.57.74 6.71 5.61  
                                                     Obt. 57.99 6.33      
                                                     5.84                 
5                                                                         
     ##STR40##         di-chlorhy- drate                                  
                                C.sub.24 H.sub.30 Cl.sub.2 N.sub.2        
                                O.sub.6  513.41                           
                                             220 25  Cal.56.14 5.89 5.46  
                                                     Obt. 56.21 5.58      
                                                     5.36                 
6                                                                         
     ##STR41##         oxalate  C.sub.26 H.sub.32 N.sub.2 O.sub.7,        
                                (COOH).sub.2                              
                                         574.57                           
                                             172 60  Cal.58.53 5.96 4.88  
                                                     Obt. 58.59 5.43      
                                                     4.65                 
7                                                                         
     ##STR42##         hydrated chlorhydrate                              
                                C.sub.27 H.sub.35 ClN.sub.2 O.sub.8,      
                                H.sub.2 O                                 
                                         569.04                           
                                             148 22  Cal.56.99 6.55 4.92  
                                                     Obt. 56.81 6.45      
                                                     4.87                 
8                                                                         
     ##STR43##         hydrated chlorhydrate                              
                                C.sub.27 H.sub.35 ClN.sub.2 O.sub.8, 1/1  
                                H.sub.2 O                                 
                                         570.84                           
                                             188 75  Cal.56.81 6.57 4.91  
                                                     Obt. 57.14 6.42      
                                                     4.93                 
9                                                                         
     ##STR44##         hydrated base                                      
                                C.sub.24 H.sub.28 N.sub.2 O.sub.7, 4/5    
                                H.sub.2 O                                 
                                         470.89                           
                                             134 43  Cal.61.21 6.34 6.14  
                                                     Obt. 61.31 6.20      
                                                     5.92                 
10                                                                        
     ##STR45##         base     C.sub.27 H.sub.32 N.sub.2 O.sub.8         
                                         512.54                           
                                             175 80  Cal.63.27 6.29 5.47  
                                                     Obt. 63.09 6.33      
                                                     5.44                 
11                                                                        
     ##STR46##         hydrated chlorhydrate                              
                                C.sub.26 H.sub.31 ClN.sub.2 O.sub.8, 1.75 
                                H.sub.2 O                                 
                                         566.51                           
                                             213 71  Cal.55.12 5.96 4.95  
                                                     Obt. 55.00 5.87      
                                                     4.69                 
12                                                                        
     ##STR47##         hydrated base                                      
                                C.sub.25 H.sub.31 N.sub.3 O.sub.7, 2/5    
                                H.sub.2 O                                 
                                         524.79                           
                                             240 67  Cal.57.21 6.11 8.01  
                                                     Obt. 57.47 6.38      
                                                     8.21                 
13                                                                        
     ##STR48##         chlorhydrate                                       
                                C.sub.24 H.sub.31 ClN.sub.2 O.sub.6       
                                         478.96                           
                                             254 74  Cal.60.18 6.52 5.85  
                                                     Obt. 59.82 6.61      
                                                     6.03                 
14                                                                        
     ##STR49##         hydrated chlorhydrate                              
                                C.sub.26 H.sub.35 ClN.sub.2 O.sub.7, 7/6  
                                H.sub.2 O                                 
                                         544.03                           
                                             150 54  Cal.57.40 6.92 5.15  
                                                     Obt. 57.90 7.04      
                                                     5.02                 
15                                                                        
     ##STR50##         hydrated base                                      
                                C.sub.27 H.sub.36 N.sub.2 O.sub.8, 11/10  
                                H.sub.2 O                                 
                                         536.39                           
                                             137 74  Cal.60.45 7.18 5.22  
                                                     Obt. 60.16 6.98      
                                                     5.23                 
16                                                                        
     ##STR51##         hydrated chlorhydrate                              
                                C.sub.27 H.sub.37 ClN.sub.2 O.sub.8, 5/4  
                                H.sub.2 O                                 
                                         575.56                           
                                             195 50  Cal.56.34 6.92 4.87  
                                                     Obt. 56.21 6.87      
                                                     4.92                 
17                                                                        
     ##STR52##         hydrated chlorhydrate                              
                                C.sub.24 H.sub.30 N.sub.2 O.sub.7, HCl,   
                                1/4 H.sub.2 O                             
                                         499.46                           
                                             216 50  Cal.57.71 6.36 5.60  
                                                     Obt. 57.40 6.61      
                                                     5.61                 
18                                                                        
     ##STR53##         hydrated chlorhydrate                              
                                C.sub.26 H.sub.33 ClN.sub.2 O.sub.8, 2/3  
                                H.sub.2 O                                 
                                         549.01                           
                                             190 82  Cal.56.87 6.30 5.10  
                                                     Obt. 57.20 6.25      
                                                     4.90                 
19                                                                        
     ##STR54##         hydrated base                                      
                                C.sub.25 H.sub.33 N.sub.3 O.sub.7 S 0.55  
                                H.sub.2 O                                 
                                         529.51                           
                                             222 31  Cal.56.70 6.49 7.94  
                                                     Obt. 56.43 6.67      
                                                     8.15                 
20                                                                        
     ##STR55##         chlorhydrate                                       
                                C.sub.25 H.sub.33 ClN.sub.2 O.sub.5       
                                         476.99                           
                                             148 35  Cal.60.88 7.11 5.68  
                                                     Obt. 61.08 7.14      
                                                     5.49                 
21                                                                        
     ##STR56##         HCl + 2/5 H.sub.2 O                                
                                C.sub.23 H.sub.29 ClN.sub.2 O.sub.5 + 2/5 
                                H.sub.2 O                                 
                                         440.14                           
                                             230 56  Cal.62.76 6.82 6.36  
                                                     Obt. 62.93 7.37      
                                                     6.49                 
22                                                                        
     ##STR57##         HCl      C.sub.23 H.sub.28 Cl.sub.2 N.sub.2        
                                O.sub.4  467.38                           
                                             218 59  Cal.59.10 6.04 5.99  
                                                     Obt. 59.40 6.32      
                                                     5.97                 
23                                                                        
     ##STR58##         Hydrated hydrochloride                             
                                C.sub.23 H.sub.28 ClFN.sub.2 O.sub.4 +    
                                1/3 H.sub.2 O                             
                                         450.93                           
                                             213 96  Cal.60.45 6.32 6.13  
                                                     Obt. 60.51 6.53      
                                                     6.21                 
24                                                                        
     ##STR59##         Base     C.sub.23 H.sub.27 ClN.sub.2 O.sub.4       
                                         430.92                           
                                             128 64  Cal.64.10 6.32 6.50  
                                                     Obt. 64.02 6.49      
                                                     6.41                 
25                                                                        
     ##STR60##         Base     C.sub.24 H.sub.30 N.sub.2 O.sub.4         
                                         410.49                           
                                             130 59  Cal.70.22 7.37 6.82  
                                                     Obt. 70.37 7.56      
                                                     6.74                 
26                                                                        
     ##STR61##         HCl      C.sub.24 H.sub.31 ClN.sub.2 O.sub.5       
                                         462.95                           
                                             246 37  Cal.62.26 6.75 6.05  
                                                     Obt. 61.99 6.90      
                                                     5.91                 
27                                                                        
     ##STR62##         Hydrated Hydrochloride                             
                                C.sub.24 H.sub.31 ClN.sub.2 O.sub.5 + 1/4 
                                H.sub.2 O                                 
                                         462.96                           
                                             226 67  Cal.61.66 6.79 5.99  
                                                     Obt. 61.75 6.78      
                                                     5.82                 
28                                                                        
     ##STR63##         Hydrated Hydrochloride                             
                                C.sub.24 H.sub.29 ClN.sub.2 O.sub.6 + 2/3 
                                .sub.2 O 488.96                           
                                             239 83  Cal.58.95 6.15 5.73  
                                                     Obt. 59.11 6.24      
                                                     5.89                 
29                                                                        
     ##STR64##         Base     C.sub.24 H.sub.30 N.sub.2 O.sub.6         
                                         442.49                           
                                             206 46  Cal.65.14 6.83 6.33  
                                                     Obt. 65.19 6.95      
                                                     6.34                 
30                                                                        
     ##STR65##         Hydrated Sulfate                                   
                                C.sub.26 H.sub.36 N.sub.2 O.sub.11 S +    
                                3/4 H.sub.2 O                             
                                         598.14                           
                                             130 10  Cal.52.20 6.32 4.68  
                                                     Obt. 52.23 6.75      
                                                     4.39                 
31                                                                        
     ##STR66##          Hydrated Methane- Sulfonate                       
                                C.sub.27 H.sub.38 N.sub.2 O.sub.10 S +    
                                1/3 H.sub.2 O                             
                                         588.66                           
                                             170 61  Cal.55.09 6.62 4.76  
                                                     Obt. 54.99 6.68      
                                                     4.80                 
32                                                                        
     ##STR67##         Hydrated Base                                      
                                C.sub.26 H.sub.34 N.sub.2 O.sub.7 + 1/2   
                                H.sub.2 O                                 
                                         495.56                           
                                             128 26  Cal.63.01 7.12 5.65  
                                                     Obt. 62.70 7.26      
                                                     5.50                 
33                                                                        
     ##STR68##         Hydrated Methane- Sulfonate                        
                                C.sub.26 H.sub.36 N.sub.2 O.sub.10 S +    
                                2/5 H.sub.2 O                             
                                         575.836                          
                                             245 32  Cal.54.22 6.44 4.87  
                                                     Obt. 54.48 6.42      
                                                     4.90                 
34                                                                        
     ##STR69##         Base     C.sub.23 H.sub.28 N.sub.2 O.sub.5         
                                         412.47                           
                                             173 23  Cal.66.97 6.84 6.79  
                                                     Obt. 66.85 7.18      
                                                     6.66                 
35                                                                        
     ##STR70##         Base     C.sub.23 H.sub.28 N.sub.2 O.sub.5         
                                         412.47                           
                                             182 12  Cal.66.97 6.84 6.79  
                                                     Obt. 66.66 6.98      
                                                     6.73                 
36                                                                        
     ##STR71##         Base     C.sub.23 H.sub.28 N.sub.2 O.sub.5         
                                         412.47                           
                                             225 18  Cal.66.97 6.84 6.79  
                                                     Obt. 66.80 6.79      
                                                     6.45                 
37                                                                        
     ##STR72##         HCl      C.sub.24 H.sub.32 ClN.sub.3 O.sub.6       
                                         526.04                           
                                             220 44  Cal.54.79 6.13 7.99  
                                                     Obt. 54.58 6.14      
                                                     7.94                 
38                                                                        
     ##STR73##         Base     C.sub.25 H.sub.32 N.sub.4 O.sub.5         
                                         468.54                           
                                             160 36  Cal.64.08 6.88 11.96 
                                                     bt. 63.80 7.15       
                                                     11.84                
39                                                                        
     ##STR74##         Hydrated Sulfate                                   
                                C.sub.23 H.sub.29 N.sub.3 O.sub.10 S +    
                                1/6 H.sub.2 O                             
                                         542.55                           
                                             250 80  Cal.50.91 5.45 7.75  
                                                     Obt. 51.18 5.22      
                                                     7.74                 
40                                                                        
     ##STR75##         Hydrated diHCl                                     
                                C.sub.23 H.sub.31 Cl.sub.2 N.sub.3        
                                O.sub.4 + 1.25 H.sub.2 O                  
                                         506.94                           
                                             230 60  Cal.54.49 6.66 8.29  
                                                     Obt. 54.53 6.60      
                                                     8.31                 
41                                                                        
     ##STR76##         Hydrated Oxalate                                   
                                C.sub.27 H.sub.33 N.sub.3 O.sub.9 + 3/5   
                                H.sub.2 O                                 
                                         554.37                           
                                             150 30  Cal.58.49 6.22 7.58  
                                                     Obt. 58.16 6.29      
                                                     7.50                 
42                                                                        
     ##STR77##         Base     C.sub.23 H.sub.28 N.sub.2 O.sub.6         
                                         428.47                           
                                             217 25  Cal.64.47 6.59 6.54  
                                                     Obt. 64.35 6.88      
                                                     6.38                 
43                                                                        
     ##STR78##         Hydrated Hydrochloride                             
                                C.sub.24 H.sub.31 ClN.sub.2 O.sub.4 + 1/3 
                                .sub.2 O 452.97                           
                                             188 26  Cal.63.63 7.05 6.19  
                                                     Obt. 63.63 7.26      
                                                     6.33                 
44                                                                        
     ##STR79##         Hydrated Hydrochloride                             
                                C.sub.24 H.sub.30 Cl.sub.2 N.sub.2 O.sub. 
                                4 + 2/5 H.sub.2 O                         
                                         488.62                           
                                             218 74  Cal.58.99 6.35 5.73  
                                                     Obt. 58.92 6.23      
                                                     5.77                 
45                                                                        
     ##STR80##         HCl      C.sub.24 H.sub.30 ClFN.sub.2 O.sub.4      
                                         464.95                           
                                             219 33  Cal.61.99 6.50 6.03  
                                                     Obt. 61.86 6.53      
                                                     6.00                 
46                                                                        
     ##STR81##         Hydrated Hydrochloride                             
                                C.sub.25 H.sub.33 ClN.sub.2 O.sub.5 + 1/5 
                                H.sub.2 O                                 
                                         480.59                           
                                             219 73  Cal.62.48 7.00 5.83  
                                                     Obt. 62.47 6.94      
                                                     5.98                 
47                                                                        
     ##STR82##         Base     C.sub.25 H.sub.32 N.sub.2 O.sub.5         
                                         440.55                           
                                             90  56  Cal.68.16 7.32 6.36  
                                                     Obt. 68.32 7.49      
                                                     6.51                 
48                                                                        
     ##STR83##         Base     C.sub.25 H.sub.32 N.sub.2 O.sub.5         
                                         440.55                           
                                             137 35  Cal.68.16 7.32 6.36  
                                                     Obt. 68.03 7.56      
                                                     6.12                 
49                                                                        
     ##STR84##         Oxalate  C.sub.28 H.sub.36 N.sub.2 O.sub.10        
                                         560.58                           
                                             200 42  Cal.59.99 6.47 5.00  
                                                     Obt. 59.95 6.64      
                                                     5.07                 
50                                                                        
     ##STR85##         HCl      C.sub.27 H.sub.37 ClN.sub.2 O.sub.7       
                                         537.04                           
                                             230 46  Cal.60.38 6.94 5.22  
                                                     Obt. 60.08 7.04      
                                                     5.03                 
51                                                                        
     ##STR86##         Hydrated Base                                      
                                C.sub.24 H.sub.30 N.sub.2 O.sub.5 + 1/6   
                                H.sub.2 O                                 
                                         429.49                           
                                             177 20  Cal.67.11 7.12 6.52  
                                                     Obt. 66.88 7.11      
                                                     6.28                 
52                                                                        
     ##STR87##         Hydrated Hydrochloride                             
                                C.sub.24 H.sub.31 ClN.sub.2 O.sub.5 +     
                                H.sub.2 O                                 
                                         480.98                           
                                             250 10  Cal.59.93 6.92 5.82  
                                                     Obt. 59.65 6.66      
                                                     5.52                 
53                                                                        
     ##STR88##         Base     C.sub. 25 H.sub.33 N.sub.3 O.sub.6        
                                         503.60                           
                                             214 50  Cal.59.62 6.61 8.34  
                                                     Obt. 59.32 6.76      
                                                     8.08                 
54                                                                        
     ##STR89##         Base     C.sub.26 H.sub.34 N.sub.4 O.sub.5         
                                         482.56                           
                                             220 72  Cal.64.71 7.10 11.61 
                                                     bt. 64.52 7.23       
                                                     11.42                
55                                                                        
     ##STR90##         Hydrated Hydrochloride                             
                                C.sub.24 H.sub.30 ClN.sub.3 O.sub.6 +     
                                H.sub.2 O                                 
                                         509.98                           
                                             200 85  Cal.56.52 6.32 8.24  
                                                     Obt. 56.54 6.19      
                                                     8.22                 
56                                                                        
     ##STR91##         Hydrated diHCl                                     
                                C.sub.24 H.sub.33 Cl.sub.2 N.sub.3        
                                O.sub.4 + H.sub.2 O                       
                                         516.46                           
                                             &gt;260                         
                                                 96  Cal.55.81 6.83 8.14  
                                                     Obt. 56.10 6.72      
                                                     8.11                 
57                                                                        
     ##STR92##         Base     C.sub.26 H.sub.33 N.sub.3 O.sub.5         
                                         467.55                           
                                             191 54  Cal.66.79 7.11 8.99  
                                                     Obt. 66.30 7.30      
                                                     8.65                 
58                                                                        
     ##STR93##         Base     C.sub.24 H.sub.28 N.sub.2 O.sub.5         
                                         424.48                           
                                             103 84  Cal.67.90 6.65 6.60  
                                                     Obt. 67.73 6.55      
                                                     6.43                 
59                                                                        
     ##STR94##         Base     C.sub.24 H.sub.27 ClN.sub.2 O.sub.5       
                                         458.93                           
                                             135 70  Cal.62.81 5.93 6.10  
                                                     Obt. 62.77 5.90      
                                                     6.14                 
60                                                                        
     ##STR95##         Hydrated Oxalate                                   
                                C.sub.26 H.sub.29 FN.sub.2 O.sub.9 + 2/3  
                                H.sub.2 O                                 
                                         544.52                           
                                             134 45  Cal.57.35 5.62 5.15  
                                                     Obt. 57.22 5.43      
                                                     5.14                 
61                                                                        
     ##STR96##         HCl      C.sub.24 H.sub.27 Cl.sub.3 N.sub.2        
                                O.sub.5  529.84                           
                                             212 40  Cal.54.40 5.14 5.29  
                                                     Obt. 52.88 5.08      
                                                     5.22                 
62                                                                        
     ##STR97##         Base     C.sub.28 H.sub.30 N.sub.2 O.sub.5         
                                         474.54                           
                                             121 68  Cal.70.87 6.37 5.90  
                                                     Obt. 70.66 6.48      
                                                     5.72                 
63                                                                        
     ##STR98##         Base     C.sub.25 H.sub.30 N.sub.2 O.sub.6         
                                         454.51                           
                                             146 83  Cal.66.06 6.65 6.16  
                                                     Obt. 66.04 6.79      
                                                     5.88                 
64                                                                        
     ##STR99##         Hydrated Hydrochloride                             
                                C.sub.25 H.sub.31 ClN.sub.2 O.sub.6 + 1/2 
                                .sub.2 O 499.97                           
                                             136 10  Cal.60.05 6.57 5.71  
                                                     Obt. 60.02 6.95      
                                                     6.06                 
65                                                                        
     ##STR100##        Base     C.sub.25 H.sub.30 N.sub.2 O.sub.6         
                                         454.51                           
                                             113 94  Cal.66.06 6.65 6.16  
                                                     Obt. 65.76 6.47      
                                                     6.13                 
66                                                                        
     ##STR101##        HCl      C.sub.25 H.sub.29 ClN.sub.2 O.sub.7       
                                         504.95                           
                                             260 20  Cal.59.46 5.79 5.55  
                                                     Obt. 59.26 5.80      
                                                     5.51                 
67                                                                        
     ##STR102##        Hydrated Hydrochloride                             
                                C.sub.25 H.sub.31 ClN.sub.2 O.sub.7  +    
                                1.75 H.sub.2 O                            
                                         538.49                           
                                             198 32  Cal.55.76 6.46 5.20  
                                                     Obt. 55.31 6.09      
                                                     5.06                 
68                                                                        
     ##STR103##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.33 ClN.sub.2 O.sub.7 + 3/5 
                                H.sub.2 O                                 
                                         531.81                           
                                             208 84  Cal.58.72 6.48 5.27  
                                                     Obt. 58.88 6.38      
                                                     5.34                 
69                                                                        
     ##STR104##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.33 ClN.sub.2 O.sub.7 + 1/5 
                                H.sub.2 O                                 
                                         524.60                           
                                             214 79  Cal.59.52 6.42 5.34  
                                                     Obt. 59.61 6.50      
                                                     5.32                 
70                                                                        
     ##STR105##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.33 ClN.sub.2 O.sub.7 + 3/5 
                                H.sub.2 O                                 
                                         531.81                           
                                             210 67  Cal.58.72 6.48 5.27  
                                                     Obt. 58.63 6.29      
                                                     5.18                 
71                                                                        
     ##STR106##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.33 ClN.sub.2 O.sub.7 + 1%  
                                H.sub.2 O                                 
                                         526.26                           
                                             225 62  Cal.59.34 6.43 5.33  
                                                     Obt. 59.00 6.76      
                                                     5.13                 
72                                                                        
     ##STR107##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.33 ClN.sub.2 O.sub.7 +     
                                3.5% H.sub.2 O                            
                                         539.89                           
                                             158 59  Cal.57.84 6.53 5.19  
                                                     Obt. 57.53 6.53      
                                                     5.34                 
73                                                                        
     ##STR108##        Hydrated Hydrochloride                             
                                C.sub.27 H.sub.35 ClN.sub.2 O.sub.8 + 1%  
                                H.sub.2 O                                 
                                         556.59                           
                                             205 52  Cal.58.26 6.45 6.03  
                                                     Obt. 58.25 6.55      
                                                     5.03                 
74                                                                        
     ##STR109##        hemi-oxalate                                       
                                C.sub.25 H.sub.29 N.sub.2 O.sub.8         
                                         485.49                           
                                             212 57  Cal.61.84 6.02 5.77  
                                                     Obt. 61.34 6.18      
                                                     5.74                 
75                                                                        
     ##STR110##        Hydrated Base                                      
                                C.sub.24 H.sub.28 N.sub.2 O.sub.6 + 4/5   
                                H.sub.2 O                                 
                                         454.89                           
                                             190 40  Cal.63.36 6.56 6.16  
                                                     Obt. 63.28 6.89      
                                                     6.03                 
76                                                                        
     ##STR111##        Hydrated Base                                      
                                C.sub.26 H.sub.32 N.sub.4 O.sub.6 + 1.1%  
                                H.sub.2 O                                 
                                         502.07                           
                                             128 65  Cal.62.20 6.55 11.16 
                                                     bt. 61.89 6.58       
                                                     11.06                
77                                                                        
     ##STR112##        Hydrated Base                                      
                                C.sub.24 H.sub.28 N.sub.2 O.sub.7 + 3/4   
                                H.sub.2 O                                 
                                         469.99                           
                                             245 54  Cal.61.32 6.33 5.96  
                                                     Obt. 60.99 6.37      
                                                     5.91                 
78                                                                        
     ##STR113##        HCl      C.sub.26 H.sub.31 ClN.sub.2 O.sub.7       
                                         518.98                           
                                             220 58  Cal.60.17 6.02 5.40  
                                                     Obt. 59.82 6.25      
                                                     5.58                 
79                                                                        
     ##STR114##        HCl      C.sub.24 H.sub.31 ClN.sub.2 O.sub.5       
                                         462.96                           
                                             226 63  Cal.62.26 6.75 6.05  
                                                     Obt. 62.07 6.71      
                                                     6.01                 
80                                                                        
     ##STR115##        HCl      C.sub.24 H.sub.30 Cl.sub.2 N.sub.2        
                                O.sub.5  497.41                           
                                             208 60  Cal.57.95 6.08 5.63  
                                                     Obt. 57.67 5.77      
                                                     5.65                 
81                                                                        
     ##STR116##        Hydrated Hydrochloride                             
                                C.sub.24 H.sub.30 ClFN.sub.2 O.sub.5 +    
                                1/4 H.sub.2 O                             
                                         485.46                           
                                             200 69  Cal.59.37 6.33 5.77  
                                                     Obt. 59.40 6.17      
                                                     5.68                 
82                                                                        
     ##STR117##        Base     C.sub.24 H.sub.28 Cl.sub.2 N.sub.2        
                                O.sub.5  495.39                           
                                             118 42  Cal.58.18 5.70 5.66  
                                                     Obt. 58.30 5.64      
                                                     5.65                 
83                                                                        
     ##STR118##        HCl      C.sub.28 H.sub.33 ClN.sub.2 O.sub.5       
                                         513.02                           
                                             221 70  Cal.65.55 6.48 5.46  
                                                     Obt. 65.34 6.52      
                                                     5.48                 
84                                                                        
     ##STR119##        Hydrated Hydrochloride                             
                                C.sub.25 H.sub.33 ClN.sub.2 O.sub.6 + 1/5 
                                H.sub.2 O                                 
                                         496.59                           
                                             194 67  Cal.60.46 6.78 5.64  
                                                     Obt. 60.50 6.73      
                                                     5.29                 
85                                                                        
     ##STR120##        Hydrated Hydrochloride                             
                                C.sub.25 H.sub.33 ClN.sub.2 O.sub.6 + 1/3 
                                .sub.2 O 498.99                           
                                             220 63  Cal.60.17 6.80 5.61  
                                                     Obt. 60.16 6.82      
                                                     5.74                 
86                                                                        
     ##STR121##        HCl      C.sub.25 H.sub.33 ClN.sub.2 O.sub.6       
                                         492.99                           
                                             218 65  Cal.60.90 6.75 5.68  
                                                     Obt. 60.83 6.49      
                                                     5.63                 
87                                                                        
     ##STR122##        Base     C.sub.25 H.sub.32 N.sub.2 O.sub.7         
                                         472.52                           
                                             197 50  Cal.63.54 6.83 5.93  
                                                     Obt. 63.44 6.85      
                                                     5.66                 
88                                                                        
     ##STR123##         Hydrated Hydrochloride                            
                                C.sub.26 H.sub.35 ClN.sub.2 O.sub.7 + 2/5 
                                H.sub.2 O                                 
                                         537.51                           
                                             156 83  Cal.58.09 6.75 5.21  
                                                     Obt. 58.19 7.13      
                                                     5.10                 
89                                                                        
     ##STR124##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.35 ClN.sub.2 O.sub.7 +     
                                1/10 H.sub.2 O                            
                                         524.21                           
                                             210 79  Cal.59.50 6.76 5.34  
                                                     Obt. 59.30 7.01      
                                                     5.37                 
90                                                                        
     ##STR125##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.35 ClN.sub.2 O.sub.7 +     
                                9/40 H.sub.2 O                            
                                         527.07                           
                                             230 80  Cal.59.24 6.69 5.31  
                                                     Obt. 58.84 6.69      
                                                     5.25                 
91                                                                        
     ##STR126##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.35 ClN.sub.2 O.sub.7  + 1% 
                                H.sub.2 O                                 
                                         528.29                           
                                             196 69  Cal.59.10 6.79 5.31  
                                                     Obt. 58.97 6.81      
                                                     5.26                 
92                                                                        
     ##STR127##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.35 ClN.sub.2 O.sub.7 + 2%  
                                H.sub.2 O                                 
                                         533.69                           
                                             164 55  Cal.58.51 6.86 5.25  
                                                     Obt. 58.30 6.62      
                                                     5.22                 
93                                                                        
     ##STR128##        Hydrated Base                                      
                                C.sub.24 H.sub.30 N.sub.2 O.sub.6 + 1/2   
                                H.sub.2 O                                 
                                         451.50                           
                                             142 58  Cal.63.84 6.92 6.21  
                                                     Obt. 64.03 6.42      
                                                     6.17                 
94                                                                        
     ##STR129##        Hydrated Hydrochloride                             
                                C.sub.24 H.sub.31 ClN.sub.2 O.sub.6 + 1/2 
                                .sub.2 O 487.97                           
                                             236 27  Cal.59.07 6.61 5.74  
                                                     Obt. 59.30 6.82      
                                                     5.62                 
95                                                                        
     ##STR130##        Hydrated C.sub.26 H.sub.35 ClN.sub.4 O.sub.6 +     
                                2.5% H.sub.2 O                            
                                         548.58                           
                                             198 38  Cal.56.92 6.71 10.21 
                                                     bt. 56.62 6.46       
                                                     10.09                
96                                                                        
     ##STR131##        Hydrated Base                                      
                                C.sub.24 H.sub.30 N.sub.2 O.sub.7 + 1.25  
                                H.sub.2 O                                 
                                         481.02                           
                                             148 42  Cal.59.92 6.81 5.82  
                                                     Obt. 59.67 6.36      
                                                     5.74                 
97                                                                        
     ##STR132##        Hydrated Hydrochloride                             
                                C.sub.27 H.sub.35 ClN.sub.2 O.sub.8 + 2/5 
                                H.sub.2 O                                 
                                         551.02                           
                                             210 55  Cal.58.09 6.46 5.02  
                                                     Obt. 57.61 6.91      
                                                     4.83                 
98                                                                        
     ##STR133##        Base     C.sub.26 H.sub.32 N.sub.2 O.sub.7         
                                         484.53                           
                                             158 67  Cal.64.45 6.66 5.78  
                                                     Obt. 64.17 6.65      
                                                     5.71                 
99                                                                        
     ##STR134##        Hydrated Hydrochloride                             
                                C.sub.28 H.sub.37 ClN.sub.2 O.sub.8 +     
                                5.5% H.sub.2 O                            
                                         597.93                           
                                             162 70  Cal.56.24 6.86 4.69  
                                                     Obt. 56.17 6.33      
                                                     4.74                 
100                                                                       
     ##STR135##        Hydrated Hydrochloride                             
                                C.sub.28 H.sub.39 ClN.sub.2 O.sub.8 +     
                                4.4% H.sub.2 O                            
                                         593.16                           
                                             145 70  Cal.56.69 7.12 4.72  
                                                     Obt. 56.42 6.85      
                                                     4.74                 
101                                                                       
     ##STR136##        Hydrated Hydrochloride                             
                                C.sub.28 H.sub.39 ClN.sub.2 O.sub.7 + 1.9 
                                H.sub.2 O                                 
                                         585.29                           
                                             144 25  Cal.57.47 7.37 4.79  
                                                     Obt. 57.46 6.57      
                                                     4.88                 
102                                                                       
     ##STR137##        Hydrated Hydrochloride                             
                                C.sub.27 H.sub.37 ClNO.sub.7 + 1.8%       
                                H.sub.2 O                                 
                                         546.88                           
                                             162 30  Cal.59.29 7.02 5.13  
                                                     Obt. 59.21 7.03      
                                                     5.02                 
103                                                                       
     ##STR138##        Hydrated Hydrochloride                             
                                C.sub.28 H.sub.39 ClN.sub.2 O.sub.8 +     
                                3.1% H.sub.2 O                            
                                         585.15                           
                                             156 28  Cal.57.47 7.07 4.79  
                                                     Obt. 57.73 7.12      
                                                     4.38                 
104                                                                       
     ##STR139##        Hydrated Hydrochloride                             
                                C.sub.25 H.sub.33 ClN.sub.2 O.sub.5 + 2%  
                                H.sub.2 O                                 
                                         492.30                           
                                             152 45  Cal.60.99 7.01 5.69  
                                                     Obt. 60.95 7.02      
                                                     5.80                 
105                                                                       
     ##STR140##        HCl      C.sub.26 H.sub.32 ClN.sub.3 O.sub.4       
                                         485.99                           
                                             252 37  Cal.64.25 6.64 8.65  
                                                     Obt. 63.99 6.94      
                                                     8.35                 
106                                                                       
     ##STR141##        Hydrated Base                                      
                                C.sub.28 H.sub.36 N.sub.2 O.sub.6 +       
                                H.sub.2 O                                 
                                         514.60                           
                                             116 46  Cal.65.35 7.44 5.44  
                                                     Obt. 65.39 7.64      
                                                     5.76                 
107                                                                       
     ##STR142##        Hydrated Hydrochloride                             
                                C.sub.28 H.sub.37 ClN.sub.2 O.sub.6 +     
                                0.3% H.sub.2 O                            
                                         534.65                           
                                             &gt;260                         
                                                 61  Cal.62.90 7.01 5.24  
                                                     Obt. 62.82 7.27      
                                                     5.26                 
108                                                                       
     ##STR143##        Hydrated Base                                      
                                C.sub.26 H.sub.32 N.sub.2 O.sub.6 + 0.8%  
                                H.sub.2 O                                 
                                         472.31                           
                                             &gt;260                         
                                                 27  Cal.66.12 6.91 5.93  
                                                     Obt. 65.77 7.03      
                                                     5.90                 
109                                                                       
     ##STR144##        Hydrated Hydrochloride                             
                                C.sub.26 H.sub.33 ClN.sub.2 O.sub.6 +     
                                1.2% H.sub.2 O                            
                                         511.03                           
                                             &gt;260                         
                                                 34  Cal.61.10 6.82 5.48  
                                                     Obt. 60.80 7.15      
__________________________________________________________________________
                                                     5.21                 
 
    
     The compounds of formula (I) were studied on laboratory animals and showed cardiac contractile force stimulating properties, without activity on the cardiac frequency, as well as coronarian vasodilatory and hypotensive properties. 
     Tests were carried out on dogs anaesthetized with sodic pentobarbital (30 mg/kg/i.v.) and the compounds of formula (I) were administered intravenously. The activity on the cardiac contractile force was measured with a BRODIE and WALTON stress gauge fixed to the left ventricle. 
     The arterial pressure was measured at the femoral artery with a SANBORN pressure sensor. 
     The cardiac frequency was automatically counted by means of a cardiotachymeter from the pulse pressure wave. 
     The coronary flow was measured by means of an electromagnetic probe of the STATHAM or BIOTRONEX type at the coronary artery. 
     The acute toxicity was assessed in accordance with the MILLER and TAINTER method (Proc. Sci. Exp. Biol. Med. 1944, 57, 261) 
     To illustrate the invention some results obtained with the compounds of formula (I) are given in table II below. 
     
                                           TABLE II                                
__________________________________________________________________________
                  Variation                        Increase               
                  of the    Variation  Increase    of the                 
           Administered                                                   
                  average   of the     of the      cardiac                
Tested                                                                    
    LD 50  dose   arterial  cardiac    coronary    contractile            
Com-                                                                      
    (mouse)                                                               
           (dog)  pressure                                                
                       Duration                                           
                            frequency                                     
                                  Duration                                
                                       flow   Duration                    
                                                   force  Duration        
pounds                                                                    
    (mg/kg/i.v.)                                                          
           (mg/kg/i.v.)                                                   
                  (%)  (mn) (%)   (mn) (%)    (mn) (%)    (mn)            
__________________________________________________________________________
2    105   0.625  -12   1 to 20                                           
                            +6    &lt;5   +93    &lt;20  +71    5 to 30         
           2.5    -25   1 to 20                                           
                            +8    1 to 40                                 
                                       +76 to +398                        
                                              &gt;30  +58 to                 
                                                          &gt;308            
3   &gt;200   0.625  -9    1 to 30                                           
                             0         +26      5  +47     30             
           2.5    -36  &gt;30  +7    5 to 30                                 
                                       +62    5 to 10                     
                                                   +62     5 to 30        
7    1000  0.625  -22   5 to 30                                           
                            -2 to +15                                     
                                  5 to 30                                 
                                       +277   &lt;5   +69    15 to 30        
    (p.o. 0%)                                                             
           2.5    -35  15 to 30                                           
                            -8 to +9                                      
                                  5 to 30                                 
                                       +416   &lt;20  +51    &lt;10             
10   180   0.625  -7   &lt;5   +2    &lt;5   +39     1 to 15                    
                                                   +9     &lt;10             
           2.5    -16  &gt;30  +12   &gt;30  +46    20 to 30                    
                                                   +53     10             
41  &gt;200   2.5    -36  21 to 40                                           
                            -16   0 to 30                                 
                                        --      -- +35    20 to 30        
54  &gt;200   2.5    -9   20 to 30                                           
                            +4    0 to 30                                 
                                       +181   10 to 30                    
                                                   +48    5 to 30         
62    45   2.5    -14   10  +4     5    --      -- +43    &gt;30             
70   168   2.5    -21  20 to 30                                           
                            +5    0 to 20                                 
                                       +27    10 to 20                    
                                                   +50    5 to 10         
89  &gt;100   2.5    -38  &gt;30  -10   0 to 30                                 
                                        --      -- +51    0 to 30         
90   1000  2.5    -11  20 to 30                                           
                             0         +15    15 to 30                    
                                                   +42    5 to 20         
    (p.o. 80%)                                                            
95  &gt;200   2.5    -20  20 to 30                                           
                            +8    1 to 30                                 
                                       +27    10 to 20                    
                                                   +21     10             
102 &gt;200   2.5    -26  &gt;30  -4    1 to 5                                  
                                       +34    15 to 30                    
                                                   +13     10             
105 &gt;200   2.5    -34  &gt;30   0         +55     1 to 30                    
                                                   +17    1 to 10         
108 200 (20%)                                                             
           2.5    -20  &gt;30  +3    0 to 5                                  
                                       +29     5 to 20                    
                                                   +44    5 to            
__________________________________________________________________________
                                                          20              
 
    
     As can be seen from the results given in table II, the compounds of formula (I) have a substantial stimulating activity on the cardiac contractile force with no (or little) activity on the cardiac frequency as well as coronary vasodilator and hypotensive effects. 
     Because of these properties and because of their low toxicity, the compounds of the invention find their application in therapeutics and they will be used in particular in the treatment of troubles due to cardiac deficiency. 
     They will be administered, alone or in combination, possibly associated with pharmaceutically acceptable vehicles, either orally, in the form of pills, tablets or capsules, in doses up to 200 mg/day (taken at one or several times), or intravenously, in the form of an injectable phial, in doses up to 25 mg/day.