CH480294A - Process for the production of basic thymyl ethers - Google Patents

Description

  

  Process for the preparation of basic thymyl ethers There has already been a process for the preparation of basic thymyl ethers of the general formula
EMI0001.0000
    suggested. The compounds are distinguished by sympatholytic-adrenolytic properties. Doses of 0.5 mg / kg induce an adrenaline reversal or a weakening or abolition of the pressoric noradrenaline effect in the cat's blood pressure. The duration of action is 8 hours and more.



  It has now been shown that the introduction of a pendant methyl group on the ethylene bridge between the oxygen and nitrogen atom reduces the toxicity to a surprising extent, with complete retention or enhancement of the sympatholytic activity. The corresponding compounds are pharmaceutical products that have a wide therapeutic range not previously achieved in this chemical body class.



  For example, the 4-chlorothymyl ethers resulted
EMI0001.0006
  
EMI0001.0007
  
    the following <SEP> values:
<tb> Compound <SEP> R <SEP> R '<SEP> Toxicity <SEP> Smallest <SEP> dose <SEP> Therapeu- <SEP> Relative
<tb> sc.

   <SEP> mg / kg <SEP> for <SEP> adrenaline <SEP> table <SEP> therapeutic
<tb> mouse <SEP> reverse <SEP> on <SEP> width <SEP> width
<tb> cat blood pressure
<tb> WV <SEP> 781 <SEP> H <SEP> H <SEP> 105 <SEP> 1.0 <SEP> mg / kg <SEP> 105 <SEP> 1
<tb> WV <SEP> 0052 <SEP> CH3 <SEP> 11 <SEP> 210 <SEP> 0.5 <SEP> mg / kg <SEP> 420 <SEP> 4
<tb> WV <SEP> 0062 <SEP> H <SEP> CH3 <SEP> 130 <SEP> 0.35 <SEP> mg / kg <SEP> 370 <SEP> 3.5 As can be seen from the table, the The introduction of a side methyl group in the vicinity of oxygen halves the toxicity and doubles the sympatholytic effectiveness.

   This increases the therapeutic range by a factor of four. The effect of a methyl group in the vicinity of the nitrogen is also surprising: toxicity is reduced and sympatholytic efficacy is increased.



  These findings represent a further step forward in the therapy of hypertension and peripheral circulatory disorders.



  To produce the new compounds, a corresponding 4-chloro- or 4-bromo-thymyl-hydroxypropyl ether, which can be prepared from the corresponding halogen thymol and propylene oxide or halo genthymol sodium and halopropanol, is hydrochlorinated and further with ethylamino- Ethanol and thionyl chloride or bromide implemented.



  If thionyl chloride is used, the process described gives the ß-chloroethyl compounds. To prepare the ß-bromoethyl compounds, either thionyl bromide can be used instead of thionyl chloride or the ß-chloroethyl compounds with sodium bromide in alcohol or react with lithium bromide in acetone.



  The hydrochlorides of the new compounds can be converted in the usual manner into salts of other acids, for example into hydrobromides, 1,5-naphthalene disulfonates, maleinates and others. One sets z. B. either with alkali the organic base in free unit, takes up in a suitable organic solvent and neutralized with the desired acid or sets z. B. with suitable solubility conditions, the hydrochloride with the alkali or silver salt of the ge desired acid.

    
EMI0002.0020
  
     The isomeric compound WV 0052 is obtained by the same procedure with 2-chloropropanol-1 as the starting material.



  e) 4-chlorothymyl- [N-ethyl-N-ss-chloroethyl- aminoisopropyl- (1)] - ether-naphthalene-1,5-disulfonate An aqueous solution of substance d) is mixed with saturated aqueous naphthalene 1,5- disulfonic acid ver. The naphthalene disulfonate precipitates in almost quantitative yield.



  M.p. 198-200 C.

 

Claims (1)

PATENT CLAIM Process for the production of basic thymyl ethers of the formula EMI0002.0027 <I> Example </I> a) (2-Hydroxy-propyl-1) - (4-chlorothymyl) -ether An ethanolic solution of 4-chlorothymol-sodium is slowly mixed with an ethanolic solution at the boiling point calculated amount of 1-chloropropanol-2 added. The mixture is boiled for a few hours, the sodium chloride which has separated out is filtered off, the alcohol is distilled off and the residue is subjected to fractional distillation. Kp1 = 126-128 C. b) (2-chloro-propyl-1) - (4-chlorothymyl) -ether A solution of the compound a) in approximately equimolar amounts of pyridine is mixed with a slight excess of thionyl chloride at room temperature with stirring and after the reaction has subsided to 100 C heated. Compound b) is obtained from the reaction mixture by fractional distillation. Kp1 = 127 C. c) (4-Chlorothymyl) - [N-ethyl-N-ss-hydroxyethyl-amino-isopropyl- (1)] -ether-hydrochloride The compound b) is heated with about the same amount of ethylaminoethanol for 6 hours to 160 ° C. and the compound C is isolated as the hydrochloride from the solution in ethyl acetate. M.p. 114-116 C. d) (4-Chloromethyl) - [N-ethyl-N-ss-chloroethyl-amino-isopropyl- (1)] - ether hydrochloride The reaction of c) with thionyl chloride proceeds in the same way as described under 1 d) and leads to the compound or its salts in which R1 and R2 are different and denote hydrogen or a methyl group, while Hal stands for chlorine or bromine, characterized in that a corresponding 4-chloro or 4- Hydrochlorinated bromothymyl hydroxypropyl ether and further reacted with ethylaminoethanol and thionyl chloride or bromide. SUBCLAIMS 1. Process according to claim, characterized in that the ß-bromoethyl compounds are obtained by first introducing chlorine as the halogen atom and converting the ß-chloroethyl compounds obtained in this way with sodium bromide in alcohol. 2. Process according to claim, characterized in that the ss-bromoethyl compounds are obtained by first introducing chlorine as the halogen atom and converting the ss-chloroethyl compounds thus obtained with lithium bromide into acetone.