CH532041A - 4-indolyl - amino ethers prepn - Google Patents

Abstract

4-Indolyl-amino ethers prepn. Cpds. (I), useful as beta-adrenergic blocking agents: (where R is 1-6C alkyl, 3 or 4-C cycloalkyl, or 3-phenylpropyl; R2 and R3 are H or Me) are prepd. either by acylating the corresponding free hydroxy cpd. or by hydrogenolysis of the corresponding N-benzyl cpd., in turn prepd. by acylating the N-benzyl free hydroxy cpd.

Description

  

  
 



  Process for the production of new indole derivatives
The invention relates to a process for the preparation of new indole derivatives of the formula I in which R1 is lower alkyl, a cycloalkyl group of 3 or 4 carbon atoms or the 3-phenylpropyl group and R2 and R3 are each hydrogen or the methyl group, and their acid addition salts.



   If R1 stands for lower alkyl, this alkyl radical contains in particular up to 6 carbon atoms.



   Of the compounds of the formula I in which R1 is lower alkyl, those are preferred in which the alkyl group is branched, in particular branched on the sc carbon atom, e.g. the isopropyl, sec-butyl, tert-butyl, tert-pentyl, 3-pentyl, etc.



   According to the invention, the compounds of the formula I and their acid addition salts are obtained by debenzylating compounds of the formula II in which R1, R2 and R are as defined above and, if desired, converting the resulting compounds of the formula I into their acid addition salts.



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



   The debenzylation according to the invention is carried out, for example, by hydrogenation in the presence of a catalyst, preferably a palladium catalyst, in an organic solvent which is inert under the reaction conditions, e.g. Ethyl acetate, a cyclic or open-chain ether such as diethyl ether, etc., and is preferably carried out at room temperature and normal pressure. After the hydrogenation has ended, the catalyst is filtered off and the filtrate is evaporated to dryness.



   The compounds of formula II are new and can e.g. by treating the compounds of the formula III, in which Rl, R and R3 have the above meanings, with excess pivalic anhydride at a temperature of about 20 to 1000. The reaction is preferably carried out in the presence of an alkali metal salt of pivalic acid as a buffer substance.



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



   The work-up stage should of course be carried out gently, since otherwise the pivaloyloxy ester group would also be split again.



   The compounds of the formula III are known or can be prepared from compounds of the formula IV by processes known per se.



   Of the compounds of the formula IV, 4-hydroxy -2,3-dimethylindole is new. For its preparation, 4-benzyloxy-2-methylindole can be aminomethylated under the conditions of a Mannich reaction to give compounds of the formula V in which R4 and R4 'are lower alkyl, and the compounds of the formula V thus obtained can be catalytically hydrogenated, e.g. in the presence of a palladium catalyst in a lower alkanol.



   If the preparation of the starting compounds is not described, they are known or can be prepared by processes known per se or analogously to those described here or analogously to processes known per se.



   The compounds of the formula I and their acid addition salts have not yet been described in the literature. In animal experiments, they have interesting pharmacodynamic properties and can therefore be used as medicinal products.



   They show an inhibition of the positive-inotropic adrenaline effect in the spontaneously beating, isolated guinea pig atrium, this antagonistic effect occurring at bath concentrations of 0.03 to 1 mg / l. In the anesthetized whole animal (cat, dog) they lead to a strong inhibition of the tachycardia and lowering of blood pressure caused by isoproterenol [1- (3,4- -dihydroxyphenyl) -2-isopropylaminoethanol. The compounds accordingly have a blocking effect on the adrenergic p-receptors. Due to their anti-arrhythmic effect, they are also suitable for the treatment of cardiac arrhythmias. The doses to be used naturally vary depending on the type of substance used, the administration and the condition to be treated.

  In general, however, satisfactory results are obtained in test animals at a dose of 0.1 to 0.6 mg / kg body weight; if necessary, this dose can be administered in 2 to 3 portions or as a sustained-release form. For larger mammals, the daily dose is around 10 to 500 mg. For oral applications, the partial doses contain about 3 to 250 mg of the new compounds in addition to solid or liquid carriers or diluents.



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



   In the following example, which explains the invention in more detail but is not intended to limit its scope in any way, all temperatures are given in degrees Celsius and are uncorrected.
EMI2.1

EMI2.2




   Example I 4- (3-isopropylamino-2-pivaloylaxypropaxy) indole 5 g of 4- (3-benzylisopropylamino-2-pivaloyloxypropoxy (indole are dissolved in 100 ml of glacial acetic acid and in the presence of 1 g of a palladium catalyst (5% palladium on carbon) with hydrogen The catalyst is filtered off, the glacial acetic acid is evaporated off under reduced pressure, the residue is dissolved in water and made alkaline with concentrated aqueous ammonia while cooling thoroughly with ice.



  It is extracted with ether, the extracts are dried over magnesium sulfate and evaporated under reduced pressure.

 

   The hydrogen maleate of the title compound crystallizes from acetone, mp 123 to] 260.



   By reacting 4- (3-benzylisopropylamino-2-hydroxypropoxy) indole with pivalic anhydride, the 4- (3-benzylisopropylamino-2-pivaloyloxypropoxy) indole required as starting material is obtained as a tough resin.



   The following compounds were prepared analogously to the process described in Example 1:
Example 2 4- (3-Isopropylamino-2-pivaloyloxypropoxy) -2-methylindole hydrogen malonate, mp 132-1340.



   Example 3 4- (3-tert-butylamino-2-pivaloyloxypropoxy) indole hydrogen maleate with a melting point of 155 to 1570.



   Example 4 4- [3- (3-Phenylpropylamino) -2-pivaloyloxypropoxy] indole oxalate of mp 183-1850.

 

Claims (1)

PATENT CLAIM Process for the preparation of new indole derivatives of the formula I, in which R1 is lower alkyl, a cycloalkyl group of 3 or 4 carbon atoms or the 3-phenylpropyl group and R2 and R5 are each hydrogen or the methyl group, and their acid addition salts, characterized in that. that compounds of the formula II, in which R1, R. and R3 have the above meanings, are debenzylated and, if desired, the compounds of the formula I obtained are converted into their acid addition salts.