CH524618A - Coronary dilatory hypotensive 1-(3',4',5'- - Google Patents

Abstract

Coronary dilatory, hypotensive 1-(3',4',5'-trimethoxycinnamoyl)-4-(R- oxycarbonylmethyl)-piperazi- nes. Title cpds. (where R is a 1,3 or 4C atom optionally branched aliphatic or 5 or 6c atom cycloaliphatic group) are prepared by reacting trimethoxycinnamoyl halide with a piperazineacetic acid ester.

Description

       

  Process for preparing novel amides derived from esters of piperazine-1 acetic acid The main patent relates to a process for preparing novel amides derived from esters of piperazine-1 acetic acid.



  These amides correspond to the general formula
EMI0001.0004
    in which R ,, R2, R3, R4 and R5 represent either hydrogen or a halogen (F, Cl, Br), or an alkyl residue comprising from 1 to 5 carbon atoms, or a lower alkoxy residue, a group methylene-dioxy, a nitro radical, R ,, R2, R3, R4 and R5 may be identical or different and R represents an alkyl residue of 1 to 6 carbon atoms, linear or branched, saturated or unsaturated.



  According to the main patent, the compounds of formula (1) above are obtained by reaction of an acid halide of formula
EMI0001.0015
    Hal being a halogen atom, on a piperazine compound of formula
EMI0001.0017
    
EMI0002.0000
    
EMI0003.0000
  
       The pharmacological study of the compounds described in the main patent has shown that the most interesting of them meets the formula
EMI0004.0002
    By keeping the same substitution on the phenyl ring (R1 = R5 = H, Rf # = R3 = R4 = OCH3),

      the holder continued his work by varying the nature of the ester formed and consequently giving R a value other than ethyl, that is to say allcyl, comprising two carbon atoms.



  The subject of the present invention is therefore a process for the preparation of novel amides of formula (1), in which Rl and R5 represent a hydrogen atom, R2, R3 and R4 a methoxy group and R is a linear or branched alkyl residue comprising 1, 3 or 4 carbon atoms, or a cycloIphatic hydrocarbon chain comprising 5 or 6 carbon atoms.



  The amides therefore correspond to the general formula
EMI0004.0015
  
EMI0004.0016
  
       The amides of formula (II) are prepared by the action of a (3,4,5-trimethoxy) cinnamoyl halide of formula
EMI0005.0003
    on an ester of piperazine-1 acetic acid of formula
EMI0005.0005
    R having the same meaning as in formula (II) and Hal representing a halogen.



  The compounds listed in Table I were prepared according to this process, the applied procedure having been described in detail in the main patent. When tested on laboratory animals, the compounds of formula (II) exhibited coronary artery dilation and hypotensive properties.



  <I> 1 - Coronarodilator properties </I>



  Measurement of the coronary venous sinus flow rate in the anesthetized dog shows that intravenous administration of the compounds of formula (II) causes coronary artery dilatation and a decrease in coronary resistance. In addition, there is an increase in p02, that is to say the partial pressure of oxygen (which corresponds to the oxygen dissolved in the plasma) in the blood of the coronary venous sinus.



  The results obtained are listed in Table II as a function of the values of the radical R.
EMI0005.0011
  
       <I> 2 - Hypotensive properties </I>



  Intravenous administration of the compounds of formula (II) in anesthetized dogs and cats causes a drop in blood pressure.



  The results obtained are listed in Table III as a function of the values of R.



  As emerges from Table IV and from Tables II and III above, the difference between the pharmacologically active doses and the lethal dose of the same compound is sufficiently large to allow the use of said compounds in therapy.



  The compounds of formula (I) are indicated in the basic treatment of coronary insufficiency in various forms: angina, angina status, prevention and treatment of the sequelae of myocardial infarction. They are also indicated in all forms of arterial hypertension.



  They can be administered in the form of tablets containing 50 to 200 mg of active principle, long-acting tablets containing 150 to 600 mg of active principle, injectable ampoules containing 50 to 200 mg of active principle.


    

Claims (1)

CLAIM Process for the preparation of compounds corresponding to the formula EMI0006.0009 in which R is a linear or branched allyl residue comprising 1, 3 or 4 carbon atoms, or a cycloaliphatic hydrocarbon chain comprising 5 or 6 carbon atoms, characterized in that an acid halide of formula is reacted EMI0006.0014 where Hal is a halogen atom, to an ester of piperazine-1 acetic acid of the formula EMI0006.0016 in the presence of an alkaline agent acceptor of acid HHal, at a temperature between room temperature and the boiling point of the reaction medium. SUB-CLAIM Process according to claim, characterized in that one uses, as piperazine of formula (IV), a piperazine in which the radical R is chosen from the following radicals <B>: </B> methyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, tert-butyl, cyclopentyl and cyclohexyl.