CH545783A - Novel indole derivs - prepn by reacting 4-(2-hydroxy-3-isopropylaminopropoxy) indoles and acid anhy-drides - Google Patents

Abstract

Derivatives of formula (I) (where R2 and R3 are H, or CH3, and either (a) R1 is 1,1-dimethyl-2-propynyl or allyl and R4 is cycloalkyl opt. mono- or polysubstd. by lower alkyl, phenyl opt. substd. by CH3, OCH3, F and/or Cl, chloroalkyl or alkyl, or (b) R1 is lower alkyl, 3-6C cycloalkyl or phenylalkyl and R4 is chloroalkyl or phenyl opt. substd. by CH3, OCH3, F and/or Cl) and their acid addn. salts, which have beta-adrenergic receptor blocking and antiarrhythmic activity and can be used for the treatment and prophylaxis of coronary diseases and for the treatment of disturbances in heart rhythm, are prepd. by reacting cpds. of formula (I; OCOR4 is OH) with anhydrides of (R4CO)2O in the presence of R4COOH.

Description

  

  
 



   The invention relates to a process for the preparation of new indole derivatives of the formula 1, in which R2 and R3 each represent hydrogen or methyl and either R1 is dimethyl-2-propynyl or allyl and R4 is a cycloalkyl group which can be substituted by one or more lower alkyl groups , a phenyl radical which can carry one or more substituents from the group methyl, methoxy, fluorine or chlorine, a chloroalkyl or alkyl group or R, lower alkyl, a cycloalkyl group of 3 to 6 carbon atoms or a phenylalkyl group and R4 a phenyl radical, the one or can carry several substituents from the group methyl, methoxy, fluorine or chlorine or denote a chloroalkyl group and their acid addition salts.



   Of the compounds of the formula I, those are preferred in which the radical Rl is compactly branched, in particular in the a-position to the carbon atom, such as. B. the isopropyl; sec. butyl, tert. Butyl, tert. Pentyl, 3-pentyl, etc.



   If R4 is an alkyl group, this preferably contains 1 to 7 carbon atoms.



   If R4 stands for a cycloalkyl group, this preferably contains 3 to 7 carbon atoms.



   Any alkyl substituents of this cycloalkyl group contain in particular 1 to 4 carbon atoms; of the alkyl substituents, the methyl group is preferred, such as e.g. B. im 1 -methylcyclohexyl.



   If R4 represents a substituted phenyl radical, it stands in particular for p-tolyl, p-chlorophenyl, 3,4,5-trimethoxyphenyl, p-fluorophenyl, 2,6-dichlorophenyl, etc.



   According to the invention, the compounds of the formula I and their acid addition salts are obtained by acylating compounds of the formula II in which R1, R2 and R3 have the above meaning with acid anhydrides of the formula III in which R4 has the above meaning in the presence of the corresponding acids and the Wins compounds of the formula I as free bases or as acid addition salts.



   Acid addition salts can be prepared from the free bases in a known manner and vice versa.



   In practice you go z. B. so that compounds of the formula II are mixed with excess acid R4COOH, in which R4 has the above meaning, and after adding an excess of its acid anhydride, the mixture is stirred for several hours at room or slightly elevated temperature.



   The reaction mixture thus obtained can, for. B. be worked up by pouring it on ice, alkaline with alkali or ammonia and with a water-immiscible, inert under the prevailing conditions organic solvent such. B. ethyl acetate, a cyclic or open-chain ether such as diethyl ether, etc., shakes out.



   The subsequent treatment with alkali or ammonia saponifies any portion of the 1-acylation product that may have formed; the work-up stage should of course be carried out gently, since otherwise the R4COOH ester group formed would also be cleaved again.



   Some of the compounds of formula 11 are also new and can, for. B. be prepared by reacting compounds of the formula IV, in which R2 and R3 have the above meaning, as a salt or in the presence of a base with epihalohydrins and the reaction products thus obtained with amines of the formula V, in which R has the above meaning, condensed.



   The compounds of formula IV can, for. B. be prepared by hydrogenolytic debenzylation of the corresponding 4-benzyl oxyindole derivatives.



   4-Benzyloxy-2-methylindole can, for example, by reacting 4-benzyloxy-2-indolecarboxylic acid chloride with a dialkylamine, subsequent reduction of the amide obtained with z. B. lithium aluminum hydride to 2-dialkylaminomethyl4-benzyloxyindole, subsequent quaternization of the nitrogen and repeated reduction with z. B. lithium aluminum hydride can be obtained. The 3-methyl4-benzyloxyindole derivatives can, for example, by aminomethylation of 4-benzyloxyindole or 4-benzyloxy-2-methylindole under the conditions of a Mannich reaction, subsequent quaternization of the nitrogen and subsequent reduction with z. B. lithium aluminum hydride can be produced.



   If the production of the starting products is not described, they are known or can be produced by processes known per se or analogously to those described here or analogously to processes known per se.



   The new compounds of the formula I or their acid addition salts have not yet been described in the literature. They are distinguished by interesting pharmacodynamic properties, so they can be used as remedies.



   The new compounds show an inhibition of the positively ionotropic adrenaline effect in the spontaneously beating, isolated guinea pig atrium, this antagonistic effect occurring at bath concentrations of 0.1 to 2 mg / l.



  In the anesthetized whole animal (cat, dog) they lead to a long-lasting, strong inhibition of the tachycardia and lowering of blood pressure caused by isoproterenol [1 3,4-dihydroxyphenyl> 2-isopropylaminoethanol]. The compounds therefore have a blocking effect on the adrenergic receptors and can therefore u. a. be used for prophylaxis and therapy of coronary diseases. Due to their antiarrhythmic effect, they are also suitable for the treatment of cardiac arrhythmias.



   The new compounds of the formula I or their physiologically tolerable acid addition salts can be administered as medicaments alone or in a suitable pharmaceutical form with pharmacologically inert adjuvants.



   In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all temperatures are given in degrees Celsius and are uncorrected.
EMI1.1
  
EMI2.1




  Example 1: 4 <2-Benzoyloxy-3-isopropylaminopropoxy) indole
A suspension of 7.14 g of benzoic anhydride in 50 ml of hexametapole is added dropwise to a suspension of 7.44 g of 442-hydroxy-3-isopropylaminopropoxy) indole and 66 g of benzoic acid in 100 ml of hexametapole and the mixture is stirred for 24 hours at 0 to The mixture is then poured onto ice, about 500 ml of ether are added and the mixture is stirred for 1 hour.



  With good cooling, make alkaline with 100% ammonia solution, separate the ethereal phase and dry it over magnesium sulfate. The evaporation residue of this ethereal phase is chromatographed on silica gel with methylene chloride and the oily title compound is finally converted into its hydrogen oxalate, skewers of ethanol / ethyl acetate (melting point 178 to 181 ").



  Example 2: 4 {244-chlorobutyryloxyS3-isopropylaminopropoxy] indole
The procedure is analogous to Example 1, but instead of benzoic acid or anhydride, 4-chlorobutyric acid or its anhydride is used here. The hydrogen oxalate of the title compound crystallizes from ethanol / benzene (melting point 159 to 161 ").

 

  Example 3: 4 {342-methyl-3-butyn-2-ylamino) -2-pivaloyloxypropoxy] indole
The procedure is analogous to Example 1, but instead of benzoic acid or anhydride, pivalic acid / anhydride is used. The hydrogen oxalate of the title compound crystallizes from ethanol / benzene (melting point 192 "to 194").



  Example 4: 4i2 (2,6-dichlorobenzoyloxy) -3-isopropylaminopropoxy] indole
The procedure is analogous to Example 1, but instead of benzoic acid or anhydride, 2,6-dichlorobenzoic acid or its anhydride is used. The hydrogen oxalate of the title compound crystallizes from glacial acetic acid / ethyl acetate (melting point 98).

 

Claims (1)

PATENT CLAIM Process for the preparation of new indole derivatives of the formula 1, in which R2 and R3 are each hydrogen or methyl and either Rl is 1,1-dimethyl-2-propynyl or allyl and R4 is a cycloalkyl group which may be substituted by one or more lower alkyl groups Phenyl radical, which can carry one or more substituents from the group methyl, methoxy, fluorine or chlorine, is a chloroalkyl or alkyl group or R1 is lower alkyl, a cycloalkyl group of 3 to 6 carbon atoms or a phenylalkyl group and R4 is a phenyl radical of one or more substituents Group can carry methyl, methoxy, fluorine or chlorine or mean a chloroalkyl group and their acid addition salts, characterized in that compounds of the formula II in which R1, R2 and R3 have the above meaning acylated with acid anhydrides of the formula III, in which R4 has the above meaning, in the presence of the corresponding acids and the compounds of the formula I are obtained as free bases or as acid addition salts.