Patent GB-797345-A (GB)
Title: Improvements in or relating to the production of substituted 1, 1, 2-triphenylethylenes
Filed: 1954-08-05
Abstract: The invention comprises compounds of the general formula <FORM:0797345/IV (b)/1> (wherein one R is a carbon-linked guanyl group which may be mono- or di-substituted by alkyl groups of 1 to 6 carbon atoms or may be part of a cyclic structure such as pyrimidinyl, tetrahydropyrimidinyl or imidazolinyl, providing the cyclic group has at most 7 carbon atoms including those of the ring structure and substituents thereon, or the amido nitrogen of the guanyl group may be part of a heterocyclic ring structure such as piperidino, morpholino or pyrrolidinyl, the guanyl group being in the ortho-, meta- or para-position; the other two symbols R are hydrogen or alkyl or alkoxy groups of 1 to 6 carbon atoms in either the ortho-, meta- or para-position; and Y is hydrogen or a cyano group) and acid-addition salts thereof; and their preparation by reacting the corresponding imido-ester compound or an acid-addition salt thereof with ammonia, a monoalkylamine (N-mono-alkyl guanyl compounds being obtained when a limited amount of a monoalkylamine is used and N : N1-di-alkyl guanyl compounds when an excess is used under more vigorous conditions) or a heterocyclic amine or a salt thereof, or, for the compounds in which the guanyl group is part of a cyclic structure, with an alkylene diamine such as ethylene diamine or 2 : 3-diamino butane; or, for compounds in which the guanyl group is part of an oxygen containing ring structure, by reacting an appropriate N-unsubstituted guanyl compound with a 1 : 3-diketone such as acetyl-acetone or a beta-ketoester such as acetoacetic ester; or, for N : N-dialkyl-guanyl-substituted 1 : 1 : 2-triphenylethylenes, by reacting the corresponding cyano-substituted compound with a dialkylamine and a Grignard reagent and decomposing the resulting intermediate compound with an alkali.  Oleates are prepared by treating the free guanyl compound with, preferably an equimolar amount of, oleic acid.  In examples: (1) 1 : 1-di-p-anisyl-2-p-cyanophenyl-ethylene with HCl in anhydrous ethanol gives 1 : 1 - di - p - anisyl - 2 - p - ethoxy - carbiminophenyl-ethylene hydrochloride, the free base of which with aqueous ammonium chloride gives 1 : 1-di-p-anisyl - 2 - p - guanylphenylethylene hydrochloride; (2) 1 : 2-di-p-anisyl-1-m-cyanophenyl-ethylene gives 1 : 2 - di - p - anisyl - 1 -m - ethoxycarbiminophenyl - ethylene hydrochloride as in (1) and this with ethanolic liquid ammonia gives 1 : 2 - di - p - anisyl - 1 - m - guanylphenyl-ethylene hydrochloride; 1-p-anisyl-1-o-anisyl-2-p-ethoxycarbiminophenyl - ethylene hydrochloride and 1 : 1 - di - m - anisyl - 2 - p - ethoxy - carb - iminophenyl - ethylene hydrochloride and the corresponding guanyl compounds are prepared similarly; (3) 1 : 1 - di - p - anisyl - 2 - m - ethoxycarbiminophenyl-ethylene hydrochloride and the corresponding guanyl compound are prepared similarly; (4) 1 : 1-di-p-anisyl-2-o-cyanophenyl-ethylene and diethylaminomagnesium bromide are refluxed in ether-benzene and the mixture is decomposed with sodium hydroxide to give 1 : 1 - di - p - anisyl - 2 - o - (N : N - diethylguanyl) - phenyl - ethylene (hydrochloride also described); (5) 1 : 1 - di - p - anisyl - 1 - p - ethoxycarbiminophenyl-ethylene hydrochloride and the corresponding guanyl compound are prepared as in (2); (6) 1 : 2-diphenyl-1-m-ethoxycarbiminophenyl-ethylene hydrochloride (two geometric isomers described) and the corresponding guanyl compounds are prepared as in (2); (7) 1 : 1 - di - p - anisyl - 2 - p - ethoxycarbiminophenyl-ethylene hydrochloride and ethylene diamine are refluxed in ethanol to give 1 : 1-di-p-anisyl - 2 - (p - 2 - imidazolinylphenyl) - ethylene (hydrochloride described); (8) 1 : 1-di-p-tolyl-2-p - ethoxycarbiminophenyl - ethylene hydrochloride and the corresponding guanyl compound are prepared as in (2); (9) 1 : 1-di-p-anisyl-2-p-ethoxycarbiminophenyl - ethylene and 1 : 3-diaminopropane give 1 : 1 - di - p - anisyl - 2 - p - 2 - (1 : 4 : 5 : 6 - tetrahydropyrimidinyl) - phenyl-ethylene (hydrochloride described); (10) 1 : 1-di - p - anisyl - 2 - p - ethoxycarbiminophenyl-ethylene hydrochloride and piperidine on standing in ethanol give 1 : 1-di-p-anisyl-2-p-piperidinocarbiminophenyl - ethylene (hydrochloride described) and it is stated that the piperidine may be replaced by pyrrolidine or morpholine; (11) 1 : 1-di-p-anisyl-2-p-guanylphenylethylene in aqueous sodium hydroxide and ethyl aceto-acetate in ethanol on standing together at room temperature yield 1 : 1 - di - p - anisyl - 2 - [p-(4 - methyl - 6 - hydroxy - 2 - pyrimidinyl)-phenyl] - ethylene; (12) 1 - p - cyanophenyl-1 : 2-di-p-anisyl-ethylene is reacted with bromine in carbon tetrachloride, the solvent is removed and the residue dissolved in pyridine, cuprous cyanide is added and the mixture refluxed and acidified giving, on working up, 3-p-cyanophenyl - 2 : 3 - di - p - anisylacrylonitrile, this with HCl in anhydrous ethanol gives 3-p-ethoxycarbiminophenyl - 2 : 3 - di - p - anisylacrylonitrile dihydrochloride and this with ammonia in ethanol gives 3-p-guanylphenyl-2 : 3-di-p-anisylacrylonitrile.  Starting materials.  Imidoesters corresponding to the guanyl compounds of the above general formula are prepared by reacting the corresponding cyano compounds (themselves prepared by reacting the corresponding halogen substituted compounds with a heavy metal cyanide in presence of a high boiling tertiary amine) with an alcohol, preferably in the presence of a mineral acid.ALSO:Medicinal compositions for oral, parenteral or topical administration are prepared by dissolving oleates of compounds of the general formula <FORM:0797345/VI/1> (wherein one R is a carbon-linked guanyl group which may be mono- or di-substituted by alkyl groups of 1 to 6 carbon atoms or may be part of a cyclic structure such as pyrimidinyl, tetrahydro pyrimidinyl or imidazolinyl, provided the cyclic group has at most 7 carbon atoms including those of the ring structure and substituents thereon, or the amido nitrogen of the guanyl group may be part of a heterocyclic ring structure such as piperidino, morpholino or pyrrolidinyl, the guanyl group being in the ortho-, meta- or para-position; the other two symbols R are hydrogen or alkyl or alkoxy groups of 1 to 6 carbon atoms in either the ortho-, meta- or para-position; and Y is hydrogen or a cyano group) in oleaginous materials such as olive, sesame, corn or peanut oil.  The compounds are valuable in nonendocrine inflammatory diseases and in endocrine disturbances in which changes in hormonal activity are desirable.