CH365080A - Process for the production of new guanidines - Google Patents

Description

       

  



  Process for the production of new guanidines
The present invention relates to a process for the preparation of new guanidines, namely the alkyleneimino-lower-alkyl-guanidines of the general formula I.
EMI1.1
 denotes an unsubstituted or hydrocarbon radical substituted alkyleneimino ring with 4-10 ring carbon atoms, A 'represents a lower alkylene group which the group
EMI1.2
 separates from the guanido group by 2-7 carbon atoms, and Rt is hydrogen or a hydrocarbon radical.



   The alkyleneimino group of these compounds forms a 5-membered ring, but primarily a 7-9-membered ring with 6-8 ring carbon atoms, which is unsubstituted or by hydrocarbon radicals, e.g. B. by lower alkyl, such as methyl or ethyl, may be substituted. The alkylenimino group stands, for example, for pyrrolidino, piperidino, hexa-, hepta-, octa-, nona- or decamethyleneimino or the corresponding ring-substituted groups, as indicated above.



   The alkylene radical connecting the alkyleneimino group to the guanido group can be straight or branched and preferably contains only 2-3 carbon atoms. It therefore stands specifically for 1, 2 ethylene, 1, 2-, 2, 3- or 1, 3-propylene, but also, for example, for 1, 3-, 2, 3- or 1, 4-butylene, 1, 4- or 1,5-pentylene, 1,6-hexylene or 1,7-heptylene.



   The guanido group is preferably unsubstituted, but both the amino and the imino group of the guanido radical can be replaced by hydrocarbon radicals, such as alkyl groups, e.g. B. methyl or ethyl groups may be substituted.



   Salts of the new compounds are especially those with therapeutically useful acids, such as inorganic acids, e.g. B. hydrohalic acids, for example hydrochloric acid or hydrobromic acid, perchloric acid, nitric acid or thiocyanoic acid, sulfuric or phosphoric acids, or organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, maleic acid , Malic acid, tartaric acid, citric acid, ascorbic acid, hydroxymaleic acid, dihydroxymaleic acid, benzoic acid, phenylacetic acid, 4-amino-benzoic acid, 4-hydroxy-benzoic acid, anthranilic acid, cinnamic acid, mandelic acid, salicylic acid, 2-saloxy-benzoic acid zoic acid,

        2-Acetoxy-benzoic acid, methanesulfonic acid, ethanesulfonic acid, HydroxyÏthansulfonsÏure, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-sulfonic acid or sulfanilic acid, or methionine, tryptophan, lysine or arginine. Mono or poly salts can be present.



   The new guanidine derivatives and their salts show antihypertensive activity and can be used as antihypertensive agents, especially in the case of neurogenic or renal hypertension. They are, in particular, the alkylenimino-alkylguanidines in which the alkylenimino group has 6-8 carbon atoms, especially 7 carbon atoms, and which contain no further substituents or only one methyl group as substituents and whose guanido group is unsubstituted, as is their salts, by a long-term effectiveness excellent. Those of the abovementioned alkylenimino-lower alkylguanidines in which the alkyl radical contains 2-3 carbon atoms, as well as their salts, are very effective.

   From this group, 2-heptymethyleneimino-ethyl-guanidine of the formula stands out primarily
EMI2.1
 and its acid addition salts, in particular its sulfate.



   The new compounds are intended to be used as medicinal products in the form of pharmaceutical preparations which combine these compounds with pharmaceutical, organic or inorganic, solid or liquid carriers which are suitable for enteral, e.g. B. oral or parenteral administration are suitable.



   The inventive method is characterized in that compounds of the formula
EMI2.2
 or their salts with compounds of the formula
EMI2.3
 or their salts converts, whereby
EMI2.4
 have the meaning given above, one of the radicals X and Y is a hydrogen atom and the other is a reactive esterified HO-A 'radical in which the esterified hydroxyl group of
EMI2.5
 is separated by 2-7 carbon atoms, and X also represents an alkali metal atom. If desired, the compounds obtained can be acylated and / or the salts obtained can be converted into the free compounds or the free compounds obtained into their salts by methods known per se.



   So you can z. B. alkyleneimines or alkali metal compounds thereof with a reactive ester of a guanido-lower alkanol, in which the guanido group is separated from the esterified hydroxyl group by 2-7 carbon atoms, or react its salts.



   Reactive esters of a guanidone lower alkanol are, for example, those of strong inorganic acids, e.g. B. mineral acids such as hydrochloric acid, hydrobromic or hydroiodic acid or sulfuric acid, or of strong organic acids, e.g. B. organic sulfonic acids such as p-toluenesulfonic acid.



   The inventive reaction is z. B. carried out so that the alkyleneimine or an alkali metal, z. B. sodium or potassium compound thereof, with the reactive guanido-lower alkanol ester or a salt thereof, preferably in the presence of a diluent, reacted. The starting materials mentioned can also be formed under the reaction conditions, e.g. B. the alkali metal compound of alkylenimine when reacting the components in liquid ammonia in the presence of alkali metals such as sodium or potassium, or their carbonates. If a salt of the guanido lower alkanol ester is used, the free base can be set free in an alkaline reaction medium. The diluent is thus chosen with regard to the reaction components, when using the free ester base, for.

   B. an ether such as p-dioxane, or a hydrocarbon such as benzene or toluene, or, if a salt is used, a lower alkanol such as methanol or ethanol. The reaction can be carried out with cooling, but preferably at elevated temperature, if desired, in a closed vessel, under pressure or in an inert gas atmosphere.



   The starting materials can be obtained, for example, as follows: Alkali metal compounds of alkylenimines are z. B. by the action of alkali metals, such as sodium or potassium, alkali metal hydrides or amides, such as sodium or potassium hydride or amide, on the alkyleneimine in the presence of an inert diluent, e.g. B.



  Toluene or p-dioxane.



   The reactive esters of guanido-lower alkanols or their salts can be obtained, for example, by reacting a guanido-lower alkanol with a tbionyl halide such as thionyl chloride, e.g. B. in an inert diluent such as a hydrocarbon, such as benzene or toluene, or with a sulfonyl halide, such as p toluenesulfonyl chloride, in pyridine.



   Preferred starting materials are those of the formula
EMI2.6
 wherein A 'is a 1,2-ethylene, 1,2, 3 or 1,3 propylene radical and Z represents a halogen atom, primarily chlorine, or an arylsulfonyloxy radical, primarily the p-toluene-sulfonyloxy radical, e.g. . B.



     2-guanido-ethyl chloride or 3-p-toluene-sulfonyloxypropyl-guanidine.



   On the other hand, a reactive ester of the abovementioned type of an alkyleneimino-lower alkanol or a salt thereof can also be reacted with a guanidine or its salt by the methods mentioned above.



   The reactive alkyleneimino-lower alkanol esters used as starting materials can be prepared by methods known per se, for example by reacting an alkyleneimine with a halohydrin, such as ethylene chloro- or bromohydrin, or an epoxide, such as ethylene oxide, whereupon the alkyleneimino-lower alkanols obtained, as mentioned above , into the reactive esters, e.g. B. in those of the hydrohalic acids, by treatment with a thionyl halide, converted.



   In the resulting alkylenimino-lower alkylguanidines, the guanido group can be acylated, for example by treating the guanidine compound with a reactive, functional derivative of a carboxylic acid, e.g. B. a halide such as chloride, or an anhydride. Here you can the reaction components in the presence of inert diluents such. B. hydrocarbons such as pentane, hexane, benzene, toluene or xylene, or tertiary organic bases, e.g. B. liquid pyridines, such as pyridine or collidine, or implement in the absence of such, for. B. by heating with the acylating agent, e.g. B. acetic anhydride, alone, in an open or closed vessel under pressure.



   Alcyl derivatives of the new guanidine compounds are those of organic acids, especially carboxylic acids, such as aliphatic carboxylic acids, e.g. B.



  Alkanecarboxylic acids, for example formic acid, acetic acid, propionic acid or trimethyl acetic acid, substituted alkanecarboxylic acids, for example tri fluoroacetic acid, hydroxyacetic acid or cyclopentylpropionic acid, or alkenoic acids, for example acrylic acid, or aromatic carboxylic acids, e.g. B. monocyclic, aromatic carboxylic acids, such as benzoic acid, hydroxybenzoic acid or amino-benzoic acid, or bicyclic, aromatic carboxylic acids, such as 1-naphthoic acid or 2-naphthoic acid, or heterocyclic carboxylic acids, e.g. B. monocyclic, heterocyclic carboxylic acids, for example nicotinic, isonicotinic or 2-furancarboxylic acid.



   The new guanidine compounds are obtained either as free compounds or in the form of their salts. A salt can in a manner known per se, for example by treatment with a strongly alkaline agent, such as aqueous alkali metal hydroxide, e.g. B. lithium, sodium or potassium hydroxide, or with strong anion exchange resins, such as quaternary ammonium exchange resins, can be converted into the free compound. Therapeutically applicable addition salts can be prepared from the free bases with suitable inorganic or organic acids, for example those mentioned at the beginning. The reaction with acids is preferably carried out in suitable diluents, e.g. B.

   Lower alkanols such as methanol, ethanol, n-propanol or i-propanol, breaths such as diethyl ether or dioxane, esters such as ethyl acetate or mixtures of these. Basic, neutral, acidic or mixed salts can be obtained here.



   In the following examples the temperatures are given in degrees Celsius.



   example 1
15.8 g of 2-guanido ethyl chloride hydrochloride in ethanol solution are added to a mixture of 22.6 g of heptamethyleneimine and 75 cm3 of ethanol, the reaction mixture is heated to boiling for a few hours, cooled, filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in water, the solution is made alkaline with dilute sodium hydroxide solution and the base obtained is converted into 2-heptamethyleneimino-ethyl-guanidine sulfate by adding sulfuric acid, mp 276-281 (decomposition).



   The heptamethyleneimine can also be converted into the sodium compound, for example by treatment with sodium amide or sodium hydride in toluene. The sodium compound obtained is allowed to react with 2-guanido-ethyl chloride and the 2-heptamethylene imino-ethyl-guanidine formed is dissolved in water. The filtered solution is passed through an exchange column with a strong anion (sulfate) exchange resin, e.g. B. one of the described in USP No. 2,591,573, the solution is concentrated under reduced pressure and the 2-heptamethyleneimino-ethyl-guanidine sulfate obtained crystallizes from aqueous ethanol.



   Instead of heptamethyleneimine, other alkyleneimines can also be used, for example penta-, hexa-, octa- or decamethyleneimine, which contains the corresponding 2-piperidino-ethyl-guanidine sulfate of F. 205-207 (decomposition), the 2-hexa methylene imino-ethyl-guanidine sulfate from F. 233 to 236 (decomposition; from ethanol-diethyl ether), the 2-octamethyleneimino-ethyl-guanidine sulfate from F. 272 to 275 (decomposition; from water) or the 2-deca methylenimino-ethyl-guanidine sulfate with a temperature of 260 to 273 (decomposition).



   The starting material can be obtained as follows:
16.9 g of thionyl chloride are added with stirring to a mixture of 10.5 g of 2-guanidoethanol hydrochloride and 500 cm3 of toluene, the mixture is left to stand overnight, then heated for 30 minutes, the toluene is decanted and excess thionyl chloride and toluene are evaporated . The remaining 2-guanido ethyl chloride hydrochloride is crystallized from an ethanol-diethyl ether mixture. The free base is obtained by treating the salt with a stoichiometric amount of ammonia in the presence of diethyl ether.



   If, in the above reaction, the 2-guanido ethanol is replaced by the 3-guanido propanol, the corresponding 3-guanido propyl chloride hydrochloride is obtained. If this is reacted with heptamethyleneimine, as indicated above, 3-heptamethyleneimino-propyl-guanidine of the formula is obtained
NH (N-CHs-CHz-CHz-NH-C NH2 as sulfate; it melts after recrystallization from ethanol-diethyl ether and afterwards from ethanol-hexane at 248-252 (decomposition).



   Example 2
A mixture of 19.8 g of 2-hexamethyleneimino ethyl chloride hydrochloride, 21.6 g of guanidine sulfate and water is made slightly alkaline with sodium hydroxide solution, heated on a water bath and further sodium hydroxide solution is added to neutralize the acid formed. After cooling, acidification with sulfuric acid and concentration in vacuo, the 2-hexa methylenimino-ethyl-guanidine sulfate separates out; it can be purified by recrystallization from aqueous ethanol; F. 233-236 (decomposition).



   The other process products mentioned in Example 1 can also be prepared in an analogous manner.



   The starting product is obtained as follows:
A mixture of 26.3 g of hexamethyleneimine, 33.2 g of ethylene bromohydrin, 200 cm3 of benzene and 15 g of anhydrous sodium carbonate is kept boiling overnight with stirring, then filtered, concentrated under reduced pressure and the 2-hexamethyleneiminoethanol obtained is distilled; Kip'13 98 to 101.



   A solution of 5.12 g of thionyl chloride in 150 cm3 of benzene is added dropwise with stirring to a mixture of 5.72 g of 2-hexamethyleneiminoethanol and 50 cm3 of benzene, the mixture is heated to the boil and stirred for a further 2 hours. After cooling, the precipitate is filtered off and the 2-hexamethyleneimino-ethyl chloride hydrochloride obtained is crystallized from methanol-diethyl ether, mp 212 to 216.



   When heptamethyleneimine is reacted with ethylene bromohydrin and the 2-heptamethyleneimino-ethanol formed is treated with thionyl chloride, 2-heptamethyleneimino-ethyl chloride hydrochloride is obtained. This can be converted into 2-heptamethyleneimino-ethyl-guanidine-sulfate by treatment with guanidine sulfate by the method given above.


    

Claims (1)

PATENT CLAIM Process for the preparation of Alkyleniminoniederalkylguanidinen of the formula I. EMI4.1 an unsubstituted or substituted by hydrocarbon radicals alkylenimino ring with 4-10 ring carbon atoms, A 'represents a Niederalky lengruppe which the group EMI4.2 separates from the guanido group by 2-7 carbon atoms, and Ri denotes hydrogen or a hydrocarbon radical, characterized in that compounds of the formula EMI4.3 or their salts with compounds of the formula EMI4.4 or their salts, where one of the radicals X and Y is a hydrogen atom and the other is a reactive esterified HO-A 'radical, in which the esterified hydroxyl group of EMI4.5 is separated by 2-7 carbon atoms, and X also represents an alkali metal atom. SUBCLAIMS 1. The method according to claim, characterized in that the compounds obtained are acylated. 2. The method according to claim, characterized in that the reactive guanido used is lower alkanol ester or alkyleneimino lower alkanol ester, hydrohalic acid or organic sulfonic acid ester. 3. The method according to claim and the dependent claims 1 and 2, characterized in that such starting materials are used in which the remainder EMI4.6 Contains 6-8 carbon atoms. 4. The method according to claim and the dependent claims 1-3, characterized in that such starting materials are used in which the remainder EMI5.1 Contains 6-8 carbon atoms and the lower alkylene radical contained in the radicals X or Y is 1, 2-ethylene, 1, 2-, 2, 3- or 1, 3-propylene. 5. The method according to claim and the sub-claims 1-4, characterized in that such starting materials are used in which the remainder EMI5.2 stand for the heptamethyleneimino group and the lower alkylene radical contained in the radicals X or Y stands for 1,2-ethylene. @@