CH628885A5 - Piperidine derivative - Google Patents

Abstract

The piperidine derivative of formula: <IMAGE> in which the various symbols are defined in Claim 1, is obtained by reacting a derivative of benzoic acid of formula: <IMAGE> with a piperidine derivative of formula: <IMAGE> The piperidine derivative of formula (I) constitutes the active ingredient of pharmaceutical compositions intended for counteracting the effects of dopamine and for stimulating serotoninergic mechanisms.

Description

       

  
 

** ATTENTION ** start of the DESC field may contain end of CLMS **. 

 in which R, R 'and R2 are defined as in claim 1 with a piperidine derivative of general formula:
EMI2. 1

 in which the various symbols are defined as in the
 claim l.    



   21.  Method according to claim 20, characterized in that
 uses as active derivative a halide, an alkyl ester, an anhy
 dride or a mixed anhydride of benzolque acid.    



   22.  Method according to one of claims 20 or 21, characterized
 in that the reaction is carried out in the presence of an organic solvent
 inert at a temperature between and 120 C.    



   23.  Process according to claim 20, characterized in that one does
 react a benzoic acid according to the general formula (1V) with a
 derivative of general formula (V), in the presence of a dehydrating agent
 in an inert organic solvent at a temperature between
 20 and 110 C.    



   24.  Process according to claim 20 for the preparation of a piperidine derivative of general formula (I), in which R represents a hydroxy group, characterized in that a compound obtained reacting corresponding to this formula, but in which R
 is a methoxy group, with boron tribromide or trichloride
 aluminum, using methylene chloride or benzene as solvent, at a temperature between 20 and 80 C, in order to
 transform the methoxy group into hydroxy. 



   25.  Process according to Claim 20 for the preparation of a piperidine derivative of the general formula, in which R is a hydroxy group, characterized in that a compound obtained corresponding to this formula is submitted, where R is an acyloxy group, less than 1 acid or alkaline hydrolysis with hydrochloric acid or sodium hydroxide, using a mixture of water and alcohol containing 1 to 4 carbon atoms, as solvent, at a temperature between 20 and 90 vs. 



   26.  Process according to one of Claims 20 to 23 for the preparation of a piperidine derivative of general formula (I), in which R1 is an amino group, characterized in that the amino group of the benzoic acid reagent of general formula (IV) ) is protected by an acyl group, and in that after reaction with the piperidine derivative of general formula (V), the acyl protecting group of the N-acylated intermediate product is removed by acid or alkaline hydrolysis to give a corresponding compound having the general formula (I), wherein R1 represents an amino group. 



   27.  Method according to one of claims 20 to 26, characterized in that a piperidine derivative of general formula (I) is transformed into a pharmacologically acceptable acid addition salt. 



   28.  Process according to one of Claims 20 to 26, characterized in that the transformation of a piperidine derivative of general formula (I) in which R represents a hydroxy group, into an alkali metal or alkali metal salt is carried out. pharmacologically acceptable earthy. 



   29.  Process according to Claim 20, characterized in that the transformation of a piperidine derivative of general formula (I) obtained into a pharmacologically acceptable quaternary ammonium salt is carried out. 



   30.  Process according to claim 20, characterized in that a piperidine derivative of general formula (I) obtained is transformed into an N-oxide derivative. 



   31.  Use of the piperidine derivative of formula (I) of an acid addition salt, of an alkali or alkaline earth metal salt or of a pharmacologically acceptable quaternary ammonium salt of this derivative, or of an N-oxide thereof according to claim 1 as an active ingredient, combined with a pharmacologically acceptable carrier or diluent, in a pharmaceutical composition. 



   The invention relates to a piperidine derivative for therapeutic use, to its preparation process, as well as to its use in a pharmaceutical composition. 



   The piperidine derivative according to the invention is characterized in that it has the following general formula:
EMI2. 2
 wherein R represents a halogen atom, or a hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy or aralkoyloxy group, or a lower acyloxy group, in which the acyl moiety is derived from a carboxylic acid; R1 represents a hydrogen atom or an amino group, lower alkylamino, lower dialkoylamino or a lower acylamino group, in which the acyl moiety is derived from a carboxylic acid;

  R2 represents a nitro or trifluoromethyl or lower thioalkyl group or a lower alkylsulfinyl group, or else Rl and R2 together form a triazo group; R3 represents a hydrogen atom or a lower alkyl or lower alkenyl group, or a cycloalkyl or cycloalkenyl group having from 3 to 7 carbon atoms in the nucleus, or a phenyl group, R4 represents a cycloalkyl group having from 3 to 7 atoms carbon in the nucleus, or an aroyl, aryl or heterocyclyl group;

  ; R5, R6 and Ri each represents a hydrogen atom, a lower alkyl, lower alkenyl, or benzene group, and W represents a single bond or a lower alkylene or lower alkenyl group, provided that when W is a single bond, R3 is other than a cycloalkenyl group, as well as the acid addition salts, alkali metal salts, alkaline earth metal salts and pharmacologically acceptable quaternary ammonium salts of this derivative or its N-oxide derivative . 



   The aryl group represented by R4 can be a phenyl group of general formula:
EMI2. 3
 wherein R8, R9 and R10 each represents a hydrogen or halogen atom or a lower alkoxy, hydroxy, nitro, amino, lower alkylamino, lower dialkoylamino, trifluoromethyl or lower alkyl group, or R8 and R9 may together form a group methylenedioxy, in which case R1 represents a hydrogen atom. 



   The lower designation currently used for alkoxy, alkenyloxy, alkynyloxy, alkyl, alkenyl, alkyl, alkenylene, thioalkyl, alkylsulfinyl, acyl, acyloxy and alkanoyl means that the group in question contains at most 6 carbon atoms. 

 

   Preferred compounds of general formula I are those having the more specific formula:
EMI2. 4
 wherein R 'represents a halogen atom (preferably chlorine) or a hydroxy, lower alkoxy group (preferably methoxy or ethoxy), an allyloxy, propargyloxy, acetoxy or benzyloxy group; R1 'represents a hydrogen atom or an amino group or a lower acylamino group in which the acyl fraction is derived from a carboxylic acid (preferably acetamido) and RZ represents a nitro, methylsulfinyl or thiomethyl group, or else Rl' and R2, together form a triazo group; R3 'represents a hydrogen atom, or a lower alkyl group (preferably



  methyl) or a phenyl group; R4 represents a cyclohexyl group or a phenyl group optionally substituted by 1 or 2 halogen atoms, lower alkyl or lower alkoxy groups, or by a methylenedioxy or trifluoromethyl group, or by three methoxy groups, or R4 represents a thienyl group or naphthyl (preferably -naphthyl) or a benzoyl group optionally substituted by a halogen atom (preferably p-fluorobenzoyl); R5 ,, R6- and R7- each represent a hydrogen atom or a lower alkyl group (preferably methyl or ethyl), and W 'represents a single bond or a methylene, ethylene or vinylene group, as well as the salts of addition of pharmacologically acceptable acids of these compounds. 



   Compounds of great importance are those of general formula III, in which R 'represents a lower alkoxy group (methoxy or ethoxy), allyloxy or propargyloxy, Rl' represents an amino group, R2, represents a nitro group, R3 'a hydrogen atom, R4 a phenyl group optionally substituted by a halogen atom or a methyl or methoxy group (preferably in the para position), R5 ,, R6 and R7, each represent a hydrogen atom, and W 'represents a methylene group or preferably a single bond. 



   Particularly preferred compounds are N- (1-benzyl piperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide, N- (lp-me thylbenzylpiperide-4-yl) -2-methoxy-4 -amino-5-nitrobenzamide, the
N- (1-p-chlorobenzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenz-amide, N- (benzylpiperide-4-yl) -2-ethoxy-4-amino-5-nitrobenz - amide, and N- (1-phenethylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide and their pharmacologically acceptable acid addition salts. 



   The subject of the invention is also a process for the preparation of the above-mentioned piperidine derivative, characterized in that a reactive derivative of a benzoic acid of the following general formula is reacted:
EMI3. 1
 in which R, R1 and R2 are defined as above, with a piperidine derivative of general formula:
EMI3. 2
 in which the various symbols are defined as above. 



  The reactive derivative of said benzoic acid can be a halide (preferably a chloride), an alkyl ester (preferably a methylester), an anhydride or a mixed anhydride. 



   The reaction is preferably carried out in the presence of an inert organic solvent, for example benzene, toluene, chloroform, tetrahydrofuran, N, N-dimethylformamide or dioxane, at a temperature between -5 and 1209 C.    



   The benzoic acid halides of general formula IV can be prepared by reacting the acid with thionyl chloride or a phosphorus halide in the presence of an inert organic solvent such as benzene, toluene or halogenated hydrocarbon. 



  Mixed anhydrides of benzoic acids of general formula IV can be prepared by reacting the acid with, for example, an alkyl chloroformate in the presence of an organic nitrogenous base, for example triethylamine, in an organic solvent, for example tetrahydrofuran, N, N-dimethylformamide or methylene chloride, and at a temperature between - 20 and +250 C.     Esters and anhydrides of benzoic acids of formula IV, which can be used as starting materials in the above process, can be prepared from benzoic acids, according to known methods. 



   The piperidine derivatives of general formula V, in which R7 is a hydrogen atom, can be prepared by reduction of the corresponding 4-piperidone-oximes with lithium / aluminum hydride in the presence of diethyl ether or tetrahydrofuran, or by amination reducing the corresponding 4-piperidones dissolved in an organic solvent, for example an alcohol containing from 1 to 4 carbon atoms, in the presence of platinum or Raney nickel as catalyst.  The piperidine derivatives of general formula V, where R7 is a lower alkyl, lower alkenyl or benzyl group, can be prepared from the corresponding N-acylated substituted compounds, by reduction of the carbonyl group to methylene, using lithium hydride /aluminum. 



   Other piperidine derivatives of general formula V can be prepared by known methods. 



   The piperidine derivatives of general formula I can also be prepared, by direct reaction of a benzoic acid of general formula IV with a piperidine derivative of general formula V, in the presence of an appropriate dehydrating agent.  Such agents are: silicon tetrachloride, a mono-, di- or trialcoylsilylchloride, titanium tetrachloride, N, N'-dicyclohexylcarbodiimide, thionyl chloride, sulfuric anhydride in methyl sulfoxide, chloride of chloride toluene-p-sulfonyl, dimethylacetal acetone or a polymeric drying agent.  The reaction is carried out in an inert organic solvent, for example methylene chloride, acetone, pyridine, ethyl acetate or dioxane, at a temperature between 20 and 110 ° C.    



   The piperidine derivatives of general formula I, where R represents a hydroxy group, can also be prepared from the corresponding O-methylated derivatives of general formula I (where R represents a methoxy group) by reacting these compounds with tribromide. boron or aluminum trichloride, using methylene chloride or benzene as solvent, at a temperature between 20 and 80 C.  The O-methylated compounds used as starting materials in this process can be prepared according to the methods previously described using starting materials in which R represents a methoxy group. 



   The piperidine derivatives of general formula I, where R represents a hydroxy group, can also be prepared from the corresponding O-acy derivatives of general formula I, where R represents an acyloxy group.  In this case, the O-acy! És derivatives are hydrolyzed by hydrochloric acid diluted by sodium or potassium hydroxide in aqueous alcoholic solution, at a temperature between 20 and 90 "C
 In the preparation of the compounds of general formula I in which R1 represents an amino group, it is sometimes advisable to use, as starting materials, corresponding compounds in which the amino group is protected by an acyl group, this protective acyl group preferably being an acetyl, chloroacetyl, trilluoroacetyl or phthaloyl group. 

  After the reaction, the N-acylated intermediate products are subjected to acid or alkaline hydrolysis, with a view to providing the corresponding compounds of general formula I in which R 1 represents an amino group.  The acid hydrolysis of the N-acylated compounds can be carried out by heating with dilute hydrochloric acid, preferably at the boiling point of the reaction mixture, while the alkaline hydrolysis is preferably carried out at a temperature between 20 and 900 C, with sodium or potassium hydroxide in aqueous alcoholic solution. 

 

   The piperidine derivatives of general formula I have, as pharmacologically main properties, the ability to oppose the effects of dopamine or dopaminergic agents of endogenous or exogenous origin, and to provoke the stimulation of serotonergic mechanisms.  In the case where homeostatic control is a balance between dopaminergic and serotonergic mechanisms, these two actions are synergistic, and the precise contribution of each of them in the final biological response is difficult to determine.  In grouped form, these compounds have exhibited activities which can be considered favorable in the treatment of various brain dysfunctions, obesity and gastrointestinal disorders in mammals, including humans. 



  Their characteristic properties manifested in experimental animals are: the antagonism of the effects of dopaminergic agents such as apomorphine, induction of catatonia, production of local anesthesia, stimulation of gastrointestinal transit and induction of both spasmogenic and spasmolytic effects on smooth muscles, in accordance with the initial resting tone. 



   However, since the serotonergic and local anesthesia properties do not necessarily act in parallel in the anti-dopaminergic series, the clinical applications of the various derivatives may be very different.  In grouped form, these compounds can be used in the treatment of a variety of conditions affecting the central nervous system, such as acute and chronic psychosis, manic psychosis, schizophrenia, serious behavioral disorders, non-melancholic depressive states and migraines, and are effective in the treatment of nausea and vomiting of various origins, originating for example from gastrointestinal disorders, congestive heart failure, postoperative states, etc. , as well as in the treatment of other gastrointestinal disorders such as dyspepsia, flatulence, biliary insufficiency, hiatal hernias, peptic ulcers,

   esophageal reflux, gastritis, duodenitis and cholelithiasis.  These compounds can also be used in the treatment of obesity and associated conditions where the administration of an appetite suppressing agent is authorized. 



   For therapeutic uses, the compounds of general formula I can be used in the form of addition salts with inorganic or organic acids which are biologically and pharmaceutically acceptable, such as sulfates, hydrohalides (for example hydrochlorides), phosphates, lower alkanesulfonates, arylsulfonates and salts of aliphatic or aromatic acids of 1 to 20 carbon atoms which may contain one or more double bonds or other functional groups such as hydroxy, lower alkoxy, amino or keto, for example fumarates. 



   The piperidine derivatives of general formula I, in which R represents a hydroxy group, can also form pharmacologically acceptable salts with alkali or alkaline earth metals, these salts being obtained by reacting the derivatives of formula I, where R is a hydroxy group, with an alkali or alkaline earth metal carbonate or hydroxide using water, methanol or ethanol as solvent, at a temperature between 40 and 100 C.    



   These salts can also be used for therapeutic purposes in the form of pharmacologically acceptable quaternary ammonium salts, such as the salts formed by reaction of the compounds of general formula I, with sulphates or lower alkyl halides or in the form oxygenated derivatives in which the oxygen is linked to the nitrogen atom of the piperidine nucleus, namely the N-oxides. 



   The acid addition salts, the quaternary ammonium salts and the pharmacologically acceptable N-oxides of the compounds of general formula I can be prepared according to known methods. 



   A subject of the invention is also the use, in a pharmaceutical composition, of the piperidine derivative of formula I or of an acid addition salt, of an alkali metal or alkaline earth metal salt or of a pharmacologically acceptable quaternary ammonium salt of this derivative, or of an N-oxide of the latter as active ingredient associated with a pharmaceutically acceptable carrier or diluent.  Preferably, the compositions are prepared in a form suitable for oral, topical, percutaneous or parenteral administration. 

  The pharmaceutically acceptable vehicles or diluents which are mixed with the active compound (s) or the salts or N-oxides of these compounds, with a view to forming the compositions of the invention, are well known in themselves and the excipients used are functions inter alia of the method applied for the administration of said compositions.  These compositions are preferably suitable for administering bones.  In this case, the compositions for oral administration may be in the form of effervescent tablets, capsules, pastilles or granules, or of liquid preparations such as mixtures, elixirs, syrups or suspensions all containing one or more compounds of the invention ; these preparations are obtained according to methods well known in the art. 



   The diluents which can be used in the preparation of these compositions include liquid and solid diluents which are compatible with the active ingredient, together with coloring or flavoring agents if desired.  Tablets or capsules may advantageously contain from 0.1 to 20 mg and, preferably, from 0.1 to 5 mg of active ingredient or the equivalent amount of an acid addition salt, of alkali or alkali metal - earthy or quaternary ammonium or an N-oxide of these compositions. 



   Liquid compositions suitable for oral use may be in the form of solutions or suspensions.  The solutions can be aqueous solutions of a soluble salt or another derivative of the active compound combined with, for example, sucrose to form a syrup.  The suspensions may contain an insoluble active compound according to the invention or an acid addition salt, an alkali or alkaline earth metal salt or a quaternary ammonium salt of this compound, combined with water, together with a suspending agent or a flavoring agent. 



   The compositions for parenteral injection can be prepared from the soluble salts, which may or may not be lyophilized and dissolved in water or in a fluid suitable for parenteral injection. 



   The compounds can be mixed with other active antacid and antiulcer agents (excluding anticholinergic agents) for oral use or, in appropriate cases, parenterally. 



   The dosages of the most interesting compounds, used for tranquilizing and antiemetic effects, seem to be between 0.5 and 50 mg / d.  The dosages used for gastrointestinal indications are also in the same range. 



   The following examples illustrate the process for preparing the piperidine derivative according to the invention. 



  Example 1:
 To a solution of 2-methoxy-4-amino-5-nitrobenzoic acid (6.4 g; 0.03 mol) in N, N-dimethylformamide (175 ml), a solution of triethylamine (3 g; 0.03 mol) in N, N-dimethylformamide (5 ml).     The mixture is cooled to 5 to -10 ° C. and a solution of ethyl chloroformate (3.3 g; 0.03 mol) in N, N-dimethylformamide (5 ml) is added.     The reaction mixture is stirred at the same temperature for 0.5 h, then a solution of 1-benzyl-4-amipopiperidine (5.7 g;

   0.03 mol) in N, Ndimethylformamide (15 ml).     After stirring for 1 h at -5 to
   - 10 "C, the temperature is brought back to ambient temperature overnight.  The solvent is removed in vacuo and the residue is poured into an aqueous solution of sodium bicarbonate.  The solid formed is extracted on exhaustion with methylene chloride, the organic layers are washed with an aqueous solution of sodium bicarbonate, then with water, dried (Na2 804), then the solvent is removed in vacuo. 

  N- (1-benzylpiperide-4-yl) - 2-methoxy-4-amino-5-nitrobenzamide (9.3 g) is obtained, which is converted into its hydrochloride by treatment with a saturated hydrochloric acid solution. in ethanol; the hydrochloride melts at 218-220 "C (dec. ). 

 

   The following derivatives are prepared in a similar manner: N- (1-cyclohexylmethylpiperide-4-yl) -2-methoxy-4-amino-5-nitro-benzamide, the hydrochloride of which melts at 215-217 "C (dec . ); N- [1- (1-phenylethyl) piperide-4-yl] -2-methoxyXamino-5-nitro-benzamide, the hydrochloride of which melts at 235-236 "C; N- (1-m-methylbenzylpiperide-4 -yl) -2-methoxy4-amino-5-nftrobenzamide, the hydrochloride monohydrate melts at 178-180 "C; N- (lp-methylbenzylpiperide4-J! 1) -2-met benzamide, whose hydrochloride melts at 202-204 "C; N- (l -p-chlorobenzylpiperide-4-yI) -2-methoxy-4- amino-5-nitro-benzamide, the hydrochloride of which melts at 238-241 "C (dec. );

   N- [1- (2-methoxy-5-chlorobenzyl) piperide-4-yl] -2-methoxy-4-amino-5-nitrobenzamide, the fumarate of which melts at 219-221 "C (dec. ); N- [1-3,4,5-trimethoxybenzyl) piperide-4-yl] -2-methoxy-4-amino-5-nitrobenzamide, the hydrochloride of which melts at 181-183 "C (dec. ); N- (1-phenethylpiperide-4-yl) -2-methoxy-4-amino-5. nitrobenz amide, the hydrochloride of which melts at 240-242 "C (dec. ); N- (1-cinnamylpiperide-4. yl) -2-methoxy-4-amino-5-nitrobenzamide, the fumarate of which melts at 236-238 "C (dec. ); N-methyl-N- (1-diphenylmethylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide, the hydrochloride of which melts at 267-269 "C (dec. ); N- [1- (2-thienylmethy!) piperide-4-yl] -2-methoxy-4-amino-5-nitro-benzamide, the hydrochloride of which melts at 208-210 "C (dec. );

   N-methyl-N- (1-benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitro-benzamide, the fumarate of which melts at 141-143 "C; N- (1-benzyl- 3-methylpiperide-yl) -2-methoxy-4-amino-5-nitro-benzamide, the fumarate of which melts at 210-212 "C; the N- (1 -m. trifluoromethylbenzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide, whose hydrochloride monohydrate melts at 177-1799C (dec. ); N- (1-benzylpiperide-4-yl) -2-methoxy-4-acetamido-5-nitrobenzamide, the fumarate of which melts at 204-206 "C; N- (1 -p-methylbenzvlpiperide-4- yl) -2-methoxy-4-acetamido-5-nitrobenzamide, the fumarate of which melts at 199-200 "C (dec. ); N- (1-p-ehlorobenzylpiperide-4-yl) -2-methoxy-4-acetamido-5-nitrobenzamide, the fumarate of which melts at 186-188 "C (dec. );

   N- [1- (2-methoxy-5-chlorobenzyl) pipedde-4-yl] -2-methoxy-4-acet-amido-5-nitrobenzamide, whose fumarate melts at 191-193 "C; N- [1- (3,4,5-trimethoxybenzyl) piperide-4-yl] -2-methoxy-4-acet-amido-5-nitrobenzamide, the fumarate of which melts at 220-222 "C (dec. ); N-! 1 - (1-phenylethyl) piperide-4-ylj-2-methoxy-acetamido-5-nitrobenzamide, the fumarate of which melts at 213-214 "C; bis [N- (1-phenethylpiperide) fumarate 4-yl) -2-methoxy-4-acetamido-5-nitrobenzamide], p. f.    209-21 1 "C (dec. ); N- (1-cinnamylpiperide-yl) -2-methoxy-acetamido-5-nitrobenzamide, the fumarate of which melts at 201-203 "C;

   N- [1- (2-thieny! methyl) piperide-4-yl] -2-methoxy-4-acetamido-5-nitrobenzamide, the fumarate of which melts at 203-205 "C; N-methyl-N- (1-benzylpiperide-4-yl) -2-methoxy-4-acetamido-S-nitrobenzamide, the fumarate of which melts at 142-144 "C; N- (1-cyclohexylmethylpiperide-4-yl) -2-methoxy-4-acetamido-5-nitrobenzamide, the fumarate of which melts at 217-219 "C; N- (1-benzylpiperide-4-yl) -2 -methoxy-4,5-azimidobenzamide, the hydrochloride of which melts at 244 246 "C (dec. ); bis fumarate [N- (1-p-methylbenzylpiperide-4-yl) -2-methoxy-4,5-azimidobenzamide], p. f.    243-245 "C (dec. );

   bis fumarate [N- (1-p-chlorobenzylpiperide-4-yl) -2-methoxy-4,5-azimidobenzamide], p. f.    214-216 "C (dec. ); N- [1- (1-phenylethyl) piperide-4-yl-2-methoxy-4,5-azimidobenz-amide, the fumarate of which melts at 203-205 "C; N- (1-cyclohexylmethylpiperide-4- yl) -2-methoxy-4,5-azimidobenzamide, of which the hydrochloride monohydrate melts at 239-241 "C; N- (1-benylpiperide-4-y!) - 2-methoxy-5-nitrobenzamide, whose fumarate melts at 145-147 "C; N - (- benzylpiperide-4-yl) -2-allyloxy-4 -amino-5-nitrobenzamide, the fumarate of which melts at 191-193 "C;

  ; N- (1-cyclohexylmethylpiperide-4-yl) -2-allyloxy-4-amino-5-nitro-benzamide, the fumarate of which melts at 203-205 "C (dec. ); N- (1 -benzvlpiperide-yl) -2-propargyloxy-4-amino-5-nitrobenzamide, the fumarate of which melts at 213-215 "C (dec. ); N- (1-benzylpiperide-4-yl) -2-chloro-4-amino-5-nitrobenzamide, the fumarate of which melts at 236-238 "C (dec. );

   N- (1-benzylpiperide-4-yl) -2-acetoxy-4-acetamido-5-nitrobenzamide, p. f.    191-193 "C; N- (1-benzylpiperide-4-yl) -2-hydroxy-4-acetamido-5-nitrobenzamide, p. f.    220-222 "C;
 N- [1- (3-phenylpropyl) piperide-4-yl] -2-methoxy-4-amino-5-nitro-
 benzamide, the hydrochloride of which melts at 174,176 "C (dec. );
 N- (1-cyclohexylmethyl-3-methylpiperide-4-yl) -2-methoxy-
 4-amino-5-nitrobenzamide, the fumarate of which melts at 178-180 "C;
 N- (1-ss-naphthylmethylpiperide-4-yl) -2-methoxy-4-amino-5-nitro-
 benzamide, whose hydrochloride monohydrate melts at 185-187 "C;

  ;
 N-1- (3-phenylpropyl) piperide-y-2-methoxy-4-acetamido-5-
 nitrobenzamide, whose fumarate melts at 202-204 C (dec. );
 N- (1-benzylpiperide-4-yl) -2-propargyloxy-5-methylthiobenz-
 amide, the fumarate of which melts at 175-177 "C;
 N- (1-benzylpiperide-4-yl) -2-hydroxy-5-methylthiobenzamide,
 whose hydrochloride melts at 246-248 "C;
 N- (1-benzylpiperide-4-yl) -2-benzyloxy-5-methylthiobenzamide,
 whose hydrochloride melts at 193-195 "C;
 N- (1-benzylpiperide-4-yl) -2-benzyloxy-5-methylsulfinylbenz-
 amide, the hydrochloride of which melts at 166-168 "C;
 N- (1 p-methoxybenzylpiperide-4-y1) -2-methoxy-amino-5-nitro-
 benzamide, whose hydrochloride melts at 220-222 C (dec. );

  ;
 N- (1-phenethylpiperide-4-yl) -2-propargyloxy-5-methylthiobenz-
 amide, the fumarate of which melts at 196-198 "C (dec. );
 N- (1-benzylpiperideXyl) -2-ethoxy-4-amino-5-nitrobenzamide,
 whose fumarate melts at 228-230 "C (dec. );
 N- [1 - (3-p-fluorobenzoypropyl) piperide-4-ylj-2-methoxy-4-amino-
 5-nitrobenzamide, of which the hydrochloride monohydrate melts at
 222-224 "C (dec. );
 N- [1-3,4-methylenedioxybenzyl) piperide-4-yl] -2-methoxy-
 4-amino-5-nitrobenzamide, the fumarate of which melts at 231-233 "C
 (Dec. ), and
 N-ethyl-N- (1-benzylpiperide-4-yl) -2-methoxy-5-nitrobenzamide,
 whose hydrochloride melts at 210-212 "C (dec. ). 



   The fumarates mentioned above are obtained by
 addition of fumaric acid in stoichiometric amount to a
 hot ethanolic solution based on piperidine.  The hot solution
 obtained is cooled and the fumarate is crystallized. 



   Example 2:
 Boiled under reflux for 3 h a mixture of N- (1-benzyl-
 piperide-yl) -2-acetoxyacetamido-5-nitrobenzamide (1.4 g;
 0.0031 mol) (prepared according to the procedure described in the example
 ple 1), sodium hydroxide (0.3 g; 0.0062 mol), water (25 ml) and
   ethanol (12.5 ml).     Then dilute this mixture with water,
 neutralizes with dilute hydrochloric acid, the solid is separated by
 filtration, washing with water and then with diethyl ether, which allows obtaining
 1.1 g of N- (1-benzylpiperide-4-yl) -2-hydroxy-4-acetamido-5-nitro
 benzamide (p. f.    220-222 "C).    



   Example 3:
 A mixture of N- (1-benzy! - piperide-4-yi) -2-hydroxy-4-acetamldo-5-nitrobenzamide (1 g;
   0.0024 ME) (prepared as described in Example 2), sodium hydroxide (0.2 g; 0.0048 ME), water (25 ml) and ethanol (12.5 ml) .    



  The mixture is then diluted with water, neutralized with dilute hydrochloric acid and the precipitate is collected by filtration. 



  This precipitate is washed with water and then with diethyl ether, which gives 0.9 g of N- (1-benzylpiperide-4-yl) -2-hydroxy-4-amino-5-nitrobenzamide.  This compound is treated with a saturated solution of hydrochloric acid in methanol, which provides the hydrochloride which is recrystallized from ethanol.     The N- (1-benzylpiperide-4-yl) -2-hydroxy-4-amino-5-nitrobenzamide hydrochloride is thus obtained (p. f. 

 

     248-250 "C, dec. )
Example 4:
 A mixture of N (1 -benzylpiperide-4-yl) -2-methoxy-4-acetamido-5-nitrobenzamide (4.26 g; 0.01 mol) (boiled according to the process described in Example 1), concentrated hydrochloric acid (5 ml), methanol (40 ml) and water (40 ml).     The solvent is removed in vacuo and the solid is recrystallized from methanol to give 3.4 g of N (i benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide hydrochloride (p. f. 



     218-220 C, dec. )
Example 5:
 A suspension of N (1 -benzylpiperide-4-yl) -2-acetoxy-4-acetamido-5-nitrobenzamide (4.5 g; 0.01 mol) (boiled according to the process described in Example 1) in ethanol (25 ml), concentrated hydrochloric acid (4.5 ml) and water (50 ml).     The mixture is diluted with water, made alkaline with sodium bicarbonate and extracted with chloroform.  The organic solution is dried (Na2SO4), the solvent is removed in vacuo and the residue is triturated with diethyl ether, which gives a solid product, which is treated with a saturated solution of hydrochloric acid in ethanol. 

  After crystallization from ethanol, 3 g of N- (1-benzylpiperide-4-yl) -2-hydroxy-4-amino-5-nitrobenzamide hydrochloride (p. f.    248-250 C, dec. ). 



  Example 6:
 A solution of N- (1-benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide (3.8 g; 0.01 mol) (prepared as described in Example 1) in chloride methylene (70 ml) is added to another solution of boron tribromide (2.84 ml; 0.03 mol) in methylene chloride (20 ml).     The mixture is stirred at room temperature for 24 h, then poured into a mixture of a saturated solution of sodium bicarbonate in water (250 ml) and methylene chloride (100 ml).     The decanted organic solution is dried and the solvent is removed in vacuo to give a paste which is triturated with petroleum ether. 

  The residue obtained is treated with a solution of hydrochloric acid in ethanol, which gives 3 g of N- (1 -benzylpiperide-4-yl) -2-hydroxy-4-amino-5-nitro-benzamide hydrochloride (p. f.    248-250 C, dec. ). 



     Example 7:
 N, N'-dicyclohexylcarbodiimide (4.12 g; 0.02 mol) and 1-benzylEaminopiperidine (3.8 g; 0.02 mol) are successively added to a 2-methoxy-4 acid solution. -acetamido5-nitrobenzoic acid (5.1 g; 0.02 mol) in methylene chloride (125 ml).     After stirring overnight at room temperature, the insoluble N, N'-dicyclohexylurea is filtered off, the solution is washed with water, dried (Na2SO4) and the solvent is removed in vacuo to obtain a product solid. 

  The latter is suspended in hot methanol and treated with the stochiometric amount of fumaric acid, which gives a solution from which the fumarate of N- (1-benzylpiperide 4-yl) -2-methoxy- is crystallized. 4-acetamido-5-nitrobenzamide (6.2 g).  After recrystallization from methanol, this compound melts at 204-206 C. 



  Example 8:
 A solution of 2-methoxy-4-acetamido-5-nitrobenzoyl chloride (8.2 g; 0.03 mol) dissolved in anhydrous tetrahydrofuran (45 ml) is gradually added to another solution of 1-benzyl 4 -aminopiperidine (5.25 g; 0.028 mol) and triethylamine (3.87 ml; 0.028 mol) in anhydrous tetrahydrofuran (45 mi) at room temperature.  Once this addition is complete, the mixture is left at room temperature, with stirring overnight, then concentrated in vacuo, poured into water and extracted with chloroform.  The organic solution is dried (Na2SO4) and the solvent is removed in vacuo. 

  The residue is suspended in hot methanol and treated with the stoichiometric amount of fumaric acid to give a solution from which the fumarate of N (1-benzylpiperide-4-yl) -2-methoxy-4- is crystallized. acetamido-5-nitrobenzamide (13.1 g) (p. f.    204-206 C).    



  Example 9:
 To a solution of N- (1-benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide (3.8 g; 0.01 mol) (prepared as described in Examples 1 or 4) in acetone (100 ml) and chloroform (100 ml), methyl iodide (1.25 ml; 0.02 mol) is added.  After stirring at room temperature for 8 h, an additional quantity of methyl iodide (1.25 ml; 0.02 mol) is added and the mixture is left at room temperature for 15 h, then filtered and collected. a solid product which is washed with diethyl ether to give 4.8 g of N- (1-benzylpiperide-4-yl) -2-methoxy4-amino-5-nitrobenzamide iodide.  After recrystallization from a mixture of water / methanol, the product melts at 232-234 "C C (dec. ).    



  Example 10:
 To a solution of N- (1-benzylpiperide-4-yl) -2-methoxy- 4-acetamido-5-nitrobenzamide (3.7 g; 0.0087 mol) (prepared according to the process described in Example 1) in glacial acetic acid (25 ml), a 30% hydrogen peroxide solution (2.0 ml) is added.     The mixture is heated for 12 h at a temperature between 70 and 75 "C, the solvent is removed in vacuo and the residue is treated with water, it is made alkaline with a dilute aqueous solution of sodium hydroxide and extracted with methylene chloride. 

  The organic solution is washed with water, dried (Na2SO4), and the solvent is removed in vacuo to give a residue which, triturated with diethyl ether, provides the N-oxide of N- (1-benzylpiperide-4-yl ) -2-methoxy-4-acetamido-5-nitrobenzamide (1.6 g) (p. f.    184-186 C, dec. ). 



   The following examples illustrate the pharmaceutical compositions according to the invention. 



  Example 11:
 50,000 capsules each containing 0.5 mg of N (I-benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide hydrochloride are prepared in accordance with the following formulation:
 N- (1-benzylpiperide-4-yl) hydrochloride -
 2-methoxy-4-amino-5-nitrobenzamide 25 g
 citric acid 50g
 magnesium stearate 5000 g
 dry powdered lactose 11 175 g
 Pluronic F-68 2000 g
 sodium lauryl sulfate 1750 g
Procedure:
 We mix the N- (1 -benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide, citric acid, sodium lauryl sulfate, lactose and Pluronic F-68, and pass this mix through a sieve with a mesh opening of 0.6 mm. 

  The magnesium stearate is added and the mixture is encapsulated in gelatin capsules of appropriate size. 



  Example 12:
 100,000 tablets each containing 1 mg of hydrochloride
N- (1 -benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide are prepared from the following formulation:
 N- (1 -benzylpiperide-4-yl) hydrochloride -
 2-methoxy-4-amino-5-nitrobenzamide 100 g
 microcrystalline cellulose 1850 g
 dry sprayed lactose 9820 g
 carboxymethylated starch 570 g
 sodium stearyl fumarate 80 g
 colloidal silica 80g
Procedure:
 All the powders are passed through a sieve with a mesh width of 0.6 mm.  They are then mixed in a suitable mixing device for 30 min and compressed into 125 mg tablets using 6 mm discs and flat beveled punches.  The disintegration time of these tablets is approximately 60 s. 

 

  Example 13:
 10,000 suppositories, each containing 1 mg of N- (1 -benzylpiperide-4-yl) -2-methoxy-4-amino-5-nikobenzamide hydrochloride are prepared as follows:
 N- (l -benzylpiperide-4-yl) hydrochloride -
 2-methoxy-4-amino-5-nitrobenzamide 10 g
 theobromine oil 19990 g
Procedure:
 Theobromine oil is melted and the active compound is suspended therein.  The mixture is then poured into suitable suppository molds, so as to obtain suppositories of 2.0 g. 



  Example 14:
 50,000 ampoules, each containing 0.5 mg hydrochloride
N- (1 -benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide are prepared using the following formulation:
 N- (l -benzylpiperide-4-yl) hydrochloride -
   2-methoxy-4-amino-5-nitrobenzamide 25 g
 sodium chloride 500 g
 water, injectable quality, q. s.  1001
Procedure:
 N- (1-benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide hydrochloride and sodium chloride are dissolved in about 801 of water while heating slightly.  The solution is diluted with water to 1001, passed through a filter retaining the bacteria and distributed in 2 ml glass ampoules, - in a known manner. 

  The production of the solution for injection can be done under sterile conditions.    It is also possible to operate under normal conditions and then hot sterilize the filled ampoules. 



  Example 15:
 1000 vials (150 ml capacity) each containing 15 mg of N- (1-benzylpiperide-4-yl) -2-methoxy-4-amino-5-nitrobenzamide hydrochloride are prepared as follows:
 N- (1 -benzylpiperide-4-yl) hydrochloride -
 2-methoxy-4-amino-5-nitrobenzamide 15 g
 sorbitol 70,000 g
 sorbic acid 125g
 citric acid 125g
 distilled water, q. s.  1501
 flavoring agent q. s. 

 

  Procedure:
 N- (1-benzylpiperide-4-yl) -2-methoxy- 4-amino-5-nitrobenzamide hydrochloride and sorbic acid are dissolved in 1001 of water, then sorbitol, citric acid and the flavoring agent, with stirring, until dissolved.  The mixture is diluted to 1501 and distributed in the bottles. 



   Compositions similar to those described in examples 1 1 to 15 can be prepared by containing, as active ingredient, piperidine derivatives of general formula I other than N (1 -benzylpiperide). 4-yl) -2-methoxy-4-amino-5-nitrobenzamide, for example other products conforming to the formulas mentioned in examples 1 to 10 or at the end of these examples.  


    

Claims (31)

 CLAIMS  1. Therapeutically active piperidine derivative, characterized in that it has the general formula: EMI1.1  wherein R represents a halogen atom, or a hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy or aralkoyloxy group, or a lower acyloxy group, in which the acyl moiety is derived from a carboxylic acid; R1 represents a hydrogen atom or an amino group, lower alkylamino, lower dialklamino or a lower acylamino group, in which the acyl moiety is derived from a carboxylic acid; R2 represents a nitro or trifluoromethyl or lower thioalkyl group or a lower alkylsulfinyl group, or else R1 and R2 together form a triazole group; R3 represents a hydrogen atom or a lower alkyl or lower alkenyl group, or a cycloalkyl or cycloalkenyl group having from 3 to 7 carbon atoms in the nucleus, or a phenyl group; R4 represents a cycloalkyl group having from 3 to 7 carbon atoms in the nucleus, or an aroyl, aryl or heterocyclyl group; ; Rs, R6 and R7 each represent a hydrogen atom, a lower alkyl, lower alkenyl or benzyl group, and W represents a single bond or a lower alkylene or lower alkenylene group, provided that, when W is a single bond, R3 is other than a cycloalkenyl group, as well as acid addition salts, alkali metal salts, alkaline earth metal salts and pharsnacologically acceptable quaternary ammonium salts of this derivative or its N-oxide derivative .  2. Piperidine derivative according to claim 1, characterized in that R4 represents a phenyl group of general formula: EMI1.2  in which R8, R9 and R10 each represent a hydrogen or a halogen atom or a lower alkoxy, hydroxy, nitro, amino, lower alkylamino, lower dialkoylamino, trifluoromethyl or lower alkyl group, or else R8 and R9 together form a methylenedioxy group , in which case R10 represents a hydrogen atom.  3. Piperidine derivative according to claim 1, characterized in that it has the general formula: EMI1.3  wherein R 'represents a halogen atom or a hydroxy, lower alkoxy, allyloxy, propargyloxy, acetoxy or benzyl oxy group; R1 'represents a hydrogen atom or an amino group or a lower acylamino group in which the acyl fraction is derived from a carboxylic acid and R2, represents a nitro, methylsulfinyl or thiomethyl group, or else R1' and R2, form together a triazo group; R3 'represents a hydrogen atom, a lower alkyl or phenyl group; R4 represents a cyclohexyl group or a phenyl group optionally substituted by 1 or 2 halogen atoms, lower alkyl or lower alkoxy groups, or by a methylenedioxy or trifluoromethyl group or by three methoxy groups, or else R4 represents a thienyl group or naphthyl or a benzoyl group optionally substituted by a halogen atom; R5 ', R6' and R7 'each represent a hydrogen atom or a lower alkyl group, and W' represents a single bond or a methylene, ethylene or vinylene group, as well as the pharmacologically acceptable acid addition salts of this derivative.  4. Piperidine derivative according to one of claims 1, 2 or 3, characterized in that W or W 'represents a single bond and the pharmacologically acceptable acid addition salts of this derivative.  5. Piperidine derivative according to claim 3, characterized in that R 'represents a lower alkoxy, allyloxy or propargyloxy group, R1' represents an amino group, R2, represents a nitro group, R3, represents a hydrogen atom, R4 represents a phenyl group optionally substituted by a halogen atom or by a methyl or methoxy group, Rr, R6 'and R7' each represent a hydrogen atom and W 'represents a single bond or the methylene group, as well as the pharmacologically acceptable acid addition salts of this derivative.  6. Piperidine derivative according to claim 5, characterized in that R 'represents the methoxy or ethoxy group.  7. Piperidine derivative according to one of claims 5 or 6, characterized in that W 'represents a single bond.  8. Piperidine derivative according to claim 1, characterized in that it has the formula: N- (l-benzylpiperide-4-yl) -2-methoxy- 4-amino-5-nitrobenzamide.  9. Piperidine derivative according to claim 1, characterized in that it has the formula: N- (1-p-methyl! Benzylpiperide-4-yl) - 2-methoxy-4-amino-5-nitrobenzamide.  10. Piperidine derivative according to claim 1, characterized in that it has the formula: N- (l-p-chlorobenzylpiperide-yl) - 2-methoxy-4-amino-5-nitrobenzamide.  11. Piperidine derivative according to claim 1, characterized in that it has the formula: N- (l -benxylpiperide-4-yl) -2-ethoxy-4-amino- 5-nitrobenzamide.  12. Piperidine derivative according to claim 1, characterized in that it has the formula: N- (l-phenetylpiperide-4-yl) -2-methoxy4-amino-5-nitrobenzamide.  13. Piperidine derivative according to claim 1, characterized in that it has the formula: N- (1-benzylpiperide-4-y1) -2-hydroxy- 4-amino-5-nitrobenzamide.  14. Piperidine derivative according to claim 1 or one of claims 8 to 13, characterized in that it is salified with a pharmacologically acceptable acid.  15. Piperidine derivative according to claim 1 or one of claims 8 to 13, characterized in that it is in the form of a pharmacologically acceptable quaternary ammonium salt.  16. Piperidine derivative according to claim 1 or one of claims 8 to 13, characterized in that it is in the form of a derivative N-oxide.  17. Piperidine derivative according to claim 1, having a hydroxy group, characterized in that it is salified with an alkali metal or an alkaline earth metal pharmacologically acceptable.    18. Piperidine derivative according to claim 1, characterized in that it has the formula: N- (l-benzylpiperide-4y1) - 2-methoxy-4-amino-5-nitrobenzamide iodide iodide.  19. Piperidine derivative according to claim 1, characterized in that it has the formula: N'-oxide of N- (i-benzvlpiperid-4-yl) - 2-methoxy-4-acetamido-5-nitrobenzamide.  20. Process for the preparation of the piperidine derivative or of a quaternary ammonium salt thereof or of its N-oxide derivative according to claim 1, characterized in that a reactive derivative of a benzoic acid having the general formula: EMI1.4    in which R, R 'and R2 are defined as in claim 1 with a piperidine derivative of general formula: EMI2.1  in which the various symbols are defined as in the  claim l.  21. The method of claim 20, characterized in that  uses as active derivative a halide, an alkyl ester, an anhy  dride or a mixed anhydride of benzolque acid.  22. Method according to one of claims 20 or 21, characterized  in that the reaction is carried out in the presence of an organic solvent  inert at a temperature between and 120 C.  23. The method of claim 20, characterized in that one does  react a benzoic acid according to the general formula (1V) with a  derivative of general formula (V), in the presence of a dehydrating agent  in an inert organic solvent at a temperature between  20 and 110 C.  24. The method of claim 20 for the preparation of a piperidine derivative of general formula (I), in which R represents a hydroxy group, characterized in that a compound obtained reacting corresponding to this formula, but in which R  is a methoxy group, with boron tribromide or trichloride  aluminum, using methylene chloride or benzene as solvent, at a temperature between 20 and 80 C, in order to  transform the methoxy group into hydroxy.  25. The method of claim 20 for the preparation of a piperidine derivative of general formula, in which R is a hydroxy group, characterized in that a compound obtained corresponding to this formula is submitted where R is an acyloxy group, lower acid or alkaline hydrolysis with hydrochloric acid or sodium hydroxide, using a mixture of water and alcohol containing 1 to 4 carbon atoms, as solvent, at a temperature between 20 and 90 C.  26. Method according to one of claims 20 to 23 for the preparation of a piperidine derivative of general formula (I), in which R 1 is an amino group, characterized in that the amino group of the benzoic acid reagent of general formula (IV) is protected by an acyl group, and in that after reaction with the piperidine derivative of general formula (V), the acyl protecting group of the N-acylated intermediate product is removed by acid or alkaline hydrolysis to give a corresponding compound having the general formula (I), wherein R1 represents an amino group.  27. Method according to one of claims 20 to 26, characterized in that a piperidine derivative of general formula (I) is transformed into a pharmacologically acceptable acid addition salt.  28. Method according to one of claims 20 to 26, characterized in that one performs the transformation of a piperidine derivative of general formula (I) where R represents a hydroxy group, into an alkali metal or metal salt pharmacologically acceptable alkaline earth.  29. Process according to claim 20, characterized in that the transformation of a piperidine derivative of general formula (I) obtained into a pharmacologically acceptable quaternary ammonium salt is carried out.  30. Method according to claim 20, characterized in that a piperidine derivative of general formula (I) obtained is transformed into an N-oxide derivative.  31. Use of the piperidine derivative of formula (I) of an acid addition salt, of an alkali or alkaline earth metal salt or of a pharmacologically acceptable quaternary ammonium salt of this derivative, or of an N-oxide thereof according to claim 1 as an active ingredient, combined with a pharmacologically acceptable carrier or diluent, in a pharmaceutical composition.  The invention relates to a piperidine derivative for therapeutic use, to its preparation process, as well as to its use in a pharmaceutical composition.  The piperidine derivative according to the invention is characterized in that it has the following general formula: EMI2.2  wherein R represents a halogen atom, or a hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy or aralkoyloxy group, or a lower acyloxy group, in which the acyl moiety is derived from a carboxylic acid; R1 represents a hydrogen atom or an amino group, lower alkylamino, lower dialkoylamino or a lower acylamino group, in which the acyl moiety is derived from a carboxylic acid; R2 represents a nitro or trifluoromethyl or lower thioalkyl group or a lower alkylsulfinyl group, or else Rl and R2 together form a triazo group; R3 represents a hydrogen atom or a lower alkyl or lower alkenyl group, or a cycloalkyl or cycloalkenyl group having from 3 to 7 carbon atoms in the nucleus, or a phenyl group, R4 represents a cycloalkyl group having from 3 to 7 atoms carbon in the nucleus, or an aroyl, aryl or heterocyclyl group; ; R5, R6 and Ri each represents a hydrogen atom, a lower alkyl, lower alkenyl, or benzene group, and W represents a single bond or a lower alkylene or lower alkenyl group, provided that when W is a single bond, R3 is other than a cycloalkenyl group, as well as the acid addition salts, alkali metal salts, alkaline earth metal salts and pharmacologically acceptable quaternary ammonium salts of this derivative or its N-oxide derivative .  The aryl group represented by R4 can be a phenyl group of general formula: EMI2.3  wherein R8, R9 and R10 each represents a hydrogen or halogen atom or a lower alkoxy, hydroxy, nitro, amino, lower alkylamino, lower dialkoylamino, trifluoromethyl or lower alkyl group, or R8 and R9 may together form a group methylenedioxy, in which case R1 represents a hydrogen atom.  The lower designation currently used for alkoxy, alkenyloxy, alkynyloxy, alkyl, alkenyl, alkyl, alkenylene, thioalkyl, alkylsulfinyl, acyl, acyloxy and alkanoyl means that the group in question contains at most 6 carbon atoms.  Preferred compounds of general formula I are those having the more specific formula: EMI2.4  wherein R 'represents a halogen atom (preferably chlorine) or a hydroxy, lower alkoxy group (preferably methoxy or ethoxy), an allyloxy, propargyloxy, acetoxy or benzyloxy group; R1 'represents a hydrogen atom or an amino group or a lower acylamino group in which the acyl fraction is derived from a carboxylic acid (preferably acetamido) and RZ represents a nitro, methylsulfinyl or thiomethyl group, or else Rl' and R2, together form a triazo group; ; R3 'represents a hydrogen atom, or a lower alkyl group (preferably ** ATTENTION ** end of the CLMS field may contain start of DESC **.