Patent GB-1094985-A (GB)
Title: Amidine derivatives, processes for their preparation, and compositions incorporating them
Inventor: HODSON HAROLD FRANCIS
IPC: C07D333/16
Filed: 1964-07-07
Abstract: The invention comprises compounds of the formula <FORM:1094985/C2/1> wherein R1 and R2 are the same or different and each is phenyl or thien-2-yl which may be substituted with halogen C1-C4 alkyl, C1-C4 alkoxy, hydroxy, C1-C4 alkylthio, C1-C4 alkylsulphonyl or C1-C4 alkylsulphinyl, A1 is a divalent straight or branched chain C2-C6 alkylene group containing one or two O or S atoms, provided that there are at least 2 carbon atoms between the divalent atom or atoms and the-NH-group; and A2 is a divalent straight or branched C1-C4 alkylene group and acid addition salts thereof.  They may be prepared by reacting NH3 with a compound of the formula <FORM:1094985/C2/2> wherein Y1 is halogen or SH, alkylthio or alkoxy group; or by reacting a primary amine R1.A1.NH2 with an imidocarbonyl compound of the formula <FORM:1094985/C2/3> wherein Y2 is a hydrogen and Y3 is NH2, SH alkylthio or alkoxy; or Y2 and Y3 form a bond; or by reacting an imidocarbonyl compound of the formulae, the two forms being tautomeric: R2.A2.C(:NOH).NH.A1.R1 R2.A2.C(NH.OH): N.A1.R1 with a reducing agent.  Examples are given for the production of amidines of Formula I.  2 - (4 - Chloro - 3 - methylphenoxy) - ethylamine is obtained by treating 4-chloro-3-methylphenol with 1,2-dibromoethane in the presence of NaOH giving 1-bromo-(41-chloro-31-methylphenoxy) ethane, treating this compound with potassium phthalimide, and then treating the phthalimide derivative with hydrazine hydrate in the presence of ethanol and isolating the above amine.  The following amines may be obtained in a similar manner: 2-31-methoxy-, -methyl-, or -chloro-phenoxyethylamine, 3-31-methoxyphenoxypropyl and 4-31-methoxyphenoxybutylamine.  2-Phenoxypropylamine is obtained by treating 2-chloropropionitrile with phenol in the presence of K2CO3, KI and methylethyl ketone giving 2-phenoxypropionitrile, and reducing the nitrile with LiAlH4.  2-(Substituted-phenoxy) propylamines are obtained in a similar manner.  1 - (3 - Methylphenoxy) prop - 2 - ylamine is obtained by reacting chloroacetone with 3-methylphenol in the presence of K2CO3, KI and ethyl methyl ketone giving 1-(3-methyl-phenoxy)-propan-2-one, converting this ketone to its oxime and reducing with LiAlH4.  1(21 or 31 - methoxyphenoxy) prop - 2 - ylamines 2-phenoxybut - 3 - ylamine and 2 - 31 - methylphenoxy-but-3-ylamine are obtained in a similar manner. 2-Benzyloxypropylamine is obtained by treating sodium 2-aminopropoxide in toluene with benzyl chloride. 2-31-Methylbenzyloxypropylamine and 2-21-thenyloxypropylamine are obtained in a similar manner.  4 - Fluorophenyl - acetamidine p - toluenesulphonate is obtained by treating 4-fluorophenylacetonitrile with hydrogen chloride followed by ethanolic ammonia. Phenylacetamidine p-toluenesulphonate and 2- or 4-methyl-, or 3,4-dimethyl-phenyl-acetamidine are obtained similarly.  3 - Methoxy - phenylacetamidine hydrochloride and other substituted phenylacetamidine hydrochlorides are obtained by treating the appropriate phenylacetonitrile in ethanol with hydrogen chloride followed by ethanolic ammonia.  Pharmaceutical compositions comprise the compounds of the invention and the acid addition salts thereof in admixture with an acceptable carrier therefore.  Acids used to form the acid addition products may be hydrochloric acid, hydriodic acid, sulphuric acid, lactic acid, citric acids, tartaric acids, succinic acid, oxalic acid, p-toluene-sulphonic acid, p-chlorobenzene-sulphonic acid and maleic acid.  The compositions may be administered orally as a draft in water or in a syrup; in capsules or cachets in the dry state, or in tablet form; parenterally in unit dose or multi-dose containers in aqueous or non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the compound or salt isotonic with the blood. Extemporaneous injection solutions may be made from sterile powders, granules or tablets.  The compound or salt may be presented suppositories or pessaries by incorporation in a suppository base.