CH362079A - 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 production of new guanidines, namely the alkylenimino-lower alkyl-guanidines, in which the alkylenimino ring contains 4-10 carbon atoms as ring members and is optionally substituted by hydrocarbons and the lower alkyl radical has the guanido from the imino group by 2- 7 carbon atoms separates.



   The alkyleneimino group of these compounds forms a 5-1 membered ring, but primarily a 7-9-membered ring with 6-8 ring carbon atoms.



   As hydrocarbon residues, for. B. lower alkyl groups, such as methyl or ethyl, are possible.



  The alkyleneimino 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.



   In compounds obtained, the guanidine group can be acylated, especially with 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 trifluoroacetic acid, hydroxyacetic acid or cyclopentylpropionic acid, or alkenoic acids, for example acrylic acid, or aromatic carboxylic acids, e.g. B. monocyclic, aromatic carboxylic acids, for example benzoic acid, hydroxybenzoic acid or aminobenzoic acid, or bicyclic, aromatic carboxylic acids, such as l-naphthoic acid or 2-naphthoic acid, or heterocyclic carboxylic acids, for example nicotinic, isonicotinic or 2-furanic acid.



   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 thiocyanic 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, fumaric 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, 4-amino-salicylic acid, 2-phenoxy-benzoic acid -Acetoxy-benzoic acid, methanesulfonic acid,

     ithanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic 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, particularly in the case of neurogenic or renal hypertension. They are, in particular the alkyleniminoalkylguanidines, 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, like their salts, are distinguished by their long-term effectiveness. 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-heptamethyleneimino-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 in an N (alkylenimino-lower alkyl) -N-cyano urea or thiourea, in which the alkylenimino group contains 21 10 ring carbon atoms and is optionally substituted by hydrocarbons and the lower alkyl radical is the imino of the The cyano urea group is separated by 2-7 carbon atoms, the N-cyano urea or thiourea group is converted into the guanidine group by heating in an acidic aqueous medium.



  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 known methods.



   The conversion according to the invention of the N-cyanurea or thiourea group into the guanidine group is carried out, for example, with dilute aqueous mineral acids, such as aqueous sulfuric acid, and corresponding biuret compounds can also be formed as by-products at the same time.



   The starting materials mentioned are obtained, for example, by the following reaction stages: By reacting an alkyleneimine with a reactive esterified cyano-lower alkanol, e.g. B. a cyano-lower alkyl halide, wherein halogen z. B. for chlorine or bromine, or with a lower alkenyl cyanide, in which the double bond is activated by the C-yan group, one obtains alkylenimino lower alkyl cyanides. In these the cyano group is then converted into the methyleneamino group by reduction, for example by catalytic hydrogenation, such as treatment with hydrogen, in the presence of a catalyst containing a metal of group 8 of the periodic table, e.g. B.

   Palladium black or Raney nickel, or preferably by treatment with a light metal hydride such as lithium, sodium or magnesium aluminum hydride, or with aluminum hydride or aluminum borohydride, if necessary, in the presence of an activator such as aluminum chloride. Equivalent amounts of an alkylenimino-lower alkylamine obtained in this way are then used with a cyanogen halide, such as chlorine or cyanogen bromide, preferably in an inert diluent, e.g. B. diethyl ether, on an alkylenimino-lower alkyl-cyanamide to. The alkylenimino-lower alkyl-cyanamides obtained in this way are then brought with an ammonium or metal cyanate or thiocyanate, preferably an alkali metal, such as sodium or potassium cyanate or thiocyanate, in a neutral medium, e.g.

   B. in the presence of water, for the implementation and receives the desired N- (alkylenimino-lower alkyl) -N-cyano ureas.



   Particularly valuable starting products are those of the formula
EMI2.2
 wherein R is an alkyleneimino group with 6-8 ring carbon atoms, A is a 1,2-ethylene, 1,2-, 2,3- or 1,3-propylene radical and X is an oxygen or sulfur atom, e.g. B. N- (2-heptamethyleneimino-ethyl) -N-cyano-urea or -thiourestotf.



   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.



   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, are 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, ethers 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 example the temperatures are given in degrees Celsius.



   example
A mixture of N- (2-heptamethyleneimino ethyl) -N-cyano urea and 6N aqueous sulfuric acid is heated to 50-80 "for 3 hours; after cooling, the 2-heptamethyleneimino ethyl guanidine sulfate crystallizes out and can crystallize out aqueous ethanol; F. 276-281 "(decomposition).



   The starting material can be obtained as follows:
On 23.4 g of 2-heptamethyleneimino-ethyiamine, dissolved in diethyl ether, 16 g of cyanogen bromide are allowed to act, whereupon the base is liberated from the 2-heptamethyleneimino-ethyl-cyanamide hydro bromide formed by reaction with the stoichiometric amount of an alkali.



   18.1 g of the 2-heptamethyleneimino ethyl cyanamide obtained and 16.2 g of potassium cyanate are dissolved in water and the reduction mixture is left to stand for 24 hours. The excess cyanate is destroyed by adding nitric acid, whereupon the silver salt of the N- (2-hepta methylenimino-ethyl) -N-cyano-urea obtained is precipitated with silver nitrate.



  This is suspended in warm water, hydrochloric acid is added and the precipitated silver chloride is filtered off.



   The 2-piperidino ethyl guanidine sulfate from F. 2032070 (decomposition), the 2-decamethyleneimino-ethyl guanidine sulfate from F. 2602730 (decomposition), the 2-hexamethyleneimino-ethyl guanidine sulfate are obtained in an analogous manner from F. 2332360 (decomposition), the 2-octamethyleneimino-ethyl-guanidine sulfate from F. 272-275 "(decomposition) or the 3-heptamethyleneimino-propyl-guanidine sulfate from F. 248-252" (decomposition).

 

Claims (1)

PATENT CLAIM Process for the preparation of alkylenimino lower alkyl guanidines, in which the alkylenimino ring contains 4-10 10 carbon atoms as ring members and is optionally substituted by hydrocarbons and the lower alkyl radical separates the guanido from the imino group by 2-7 carbon atoms, and their salts, characterized in that the N-cyano urea or thiourea group is converted into the guanidine group by heating in an acidic aqueous medium in a corresponding N- (alkylenimino-lower alkyl) -N-cyano urea or thiourea. SUBCLAIMS 1. The method according to claim, characterized in that the guanidine group is acylated in the compounds obtained. 2. The method according to claim and dependent claim 1, characterized in that such starting materials are used in which the alkyleneimino group contains 6-8 carbon atoms. 3. The method according to claim and the dependent claims 1 and 2, characterized in that those starting materials are used in which the alkyleneimino group contains 6-8 carbon atoms and the lower alkyl radical for 1,2-ethylene, 1,2-, 2,3- or 1 , 3-propylene stands. 4. The method according to claim and the dependent claims 1-3, characterized in that N- (2-heptamethyleneimino-ethyl) -N-cyano urea or thiourea is used as starting materials.