CH509273A - Phenoxyalkyl amidines having blood pressure reducing - Google Patents

Abstract

(A) Phenoxyalkyl amidines of the general formula (I): - where Z3 and Z4=hydrogen, halogen, alkoxy (1 to 4C atoms) or trifluoromethyl, but one of the two groups Z3 or Z4 must be hydrogen. - (B) Pharmaceutical preparations contng. (I). - The compounds have blood pressure reducing properties and are active orally.

Description

  

  Process for the preparation of propionamidines The pharmacological effect of the phenoxyacet amidines has already been investigated. For example, the complete specification of British patent no. 476611 describes 3-methoxy- and 4-methoxy-phenoxyacetamidines as useful drugs, and the complete specfication of British patent No. 654521 describes that phenoxyacetamidine and 4-chlorophenoxyacetamidine determine the amplitude of contraction enlarge the heart of animals. Further work in this area has been done by Craver, B. N. et al. (J. Pharm. & Exp.

   Ther., 99, [1950], 353), who examined the cardiac effect of 4-chlorophenoxyacetamidine and its 3-nitro derivative.



  Trials have now shown that the phenoxypropionamidines of the formula
EMI0001.0009
    wherein one of Z3 and Z4 is hydrogen, halogen, alkoxy with 1 to. 4 carbon atoms or the trifluoromethyl radical and the other is hydrogen, and their acid addition salts A reduce the central and peripheral level or catecholamines, z.

   B. the noradrenaline level in the heart and brain, without exerting a depressive effect on the sympathetic pressure. They are therefore useful in the treatment or prophylaxis of conditions in which the catecholamines are harmful, e.g. B. in cardiac arrhythmia. You can therefore z. B. used in the treatment of ventricular fibrillation.



  Particularly useful compounds of the formula I are: 2-m-methoxyphenoxypropionamidine, 2-m-chlorophenoxypropionamidine, 2-p-chlorophenoxypropionamidine, 2-m-trifluoromethylphenoxypropionamidine, 2-m-fluorophenoxypropionamidine, 2-m-bromophenoxypropionamidine and their acid addition salt.



       According to the invention, the compounds of the formula I are prepared by adding an imidocarbonyl derivative of the form
EMI0001.0031
    , with ammonia, its salt with an aliphatic or aromatic sulfonic acid, an ammonium thiocyanate, an alkali metal amide or with thiourea.



  You can use an ammonium salt of an aromatic tables or aliphatic sulfonic acid, for. B. benzenesulfonic acid, p-taluenesulfonic acid or p-chloro benzenesulfonic acid. A substituted ammonium thiocyanate or thiourea can be used in place of the sulphonic acid salts and the nitrile can be replaced by a functional group providing the cyanide group, e.g. B. by an amide.

   It is preferable to work in the absence of a solvent at a temperature which increases by 18.0 ° C. This type of reaction is known per se, see e.g. B. E. H. Rodd, Chemistry of Cambon Compounds, 1st edition JA, pages 609 ff. You can also use a nitrile of the formula II with an alkali metal amide, eg. B. potassium amide, implement.



  This type of reaction can also be carried out with an ammonium salt and the corresponding nitrite in liquid ammonia under .eck. You can z. B. use ammonium sulfate, chloride or thiocyanate, but prefer the bromide. One can use a solvent for the ammonia or the ammonium salt, e.g. B. methanol or ethanol, also use, but this is not absolutely necessary.



  The process product is a base or its acid addition salt, and this can be converted into salts or bases by double reaction with an acid or its acid or with a base or its salt.

   This can be done: in solution or in an ion exchanger, before isolation or after: isolation and cleaning of the product. You can z. B. Hydroiodides, hydrochlorides, sulfates, lactates, chrates, tartrates, succinates, oxalates, p-toluenesulfanates, p-chlorbenzenesulfonates and maleates of the bases produce.



  The compounds of Formula I and their salts can be incorporated into pharmaceutical preparations in a known manner.



  The tests carried out indicate that the effective and useful dosage of the compounds mentioned in adults is between 20 and 200 mg / kg weight.



  In the following example the temperatures are given in C -.



  <I> Example </I> A mixture of 5.45 g of 2-m-chlorophenoxypropionitrile and 5.2 g of ammonium benzene sulfonate is stirred and heated to 270-280 ° C. in a nitrogen atmosphere for 11/2 hours. The mixture is allowed to cool down and extracted -with about 30 ml of boiling water. The aqueous solution is cooled and filtered. A crystalline solid is obtained, melting point 21.6 to 221 C.

   Two further extractions with boiling water yield two further fractions of the material, both with a melting point of 222-223'C. The three fractions are combined and recrystallized from Äthähol / water. Pure 2-m-chlorophenoxypropionamidine benzenesulfonate is obtained, melting point 223-224 C. This salt is identical in terms of melting point and mixed melting point, infrared spectrum, thin-layer chromatography to Odem material which was obtained by a different process.

 

Claims (1)

PATENT CLAIM Process for the preparation of propionamidines of the formula. EMI0002.0061 wherein one of Z3 and Z4 is hydrogen, halogen alkoxy having 1 to 4 carbon atoms or the trifluoromethyl radical and the other is hydrogen, or of their acid addition salts, characterized by the reaction of a nitrile of the formula EMI0002.0068 with ammonia, its salt with an aliphatic or aromatic sulfonic acid, an ammonium thiocyanate, an alkali metal amide or with thiourea. SUBCLAIMS 1. Method according to claim, characterized in that the reaction is carried out in the absence of a solvent. 2. The method according to claim, characterized in that the reaction is carried out in an inert atmosphere. 3. The method according to claim, characterized in that the ammonium salt of an aromatic sulfonic acid is used. 4. The method according to claim, characterized in that: the nitrile used is m-chlorophenoxy propionitrile. 5. The method according to claim, characterized in that potassium amide is used. 6. The method according to dependent claim 5, characterized in that the nitrile used is m-chlorophenoxy prapianitnil. <I> Note from the </I> Federal <I> Office for Intellectual Property: </I> If parts of the description are inconsistent with the definition of the invention given in the claim, it should be remembered that according to Art. 51 of the Patent Act, the patent claim is authoritative for the material scope of the patent.