Patent GB-582043-A (GB)
Title: Improvements in or relating to therapeutically active hydrazo-compounds containing arsenic radicals and process for preparing same
IPC: C07D231/34
Filed: 1943-10-27
Abstract: Hydrazo-compounds and their derivatives, all containing residues of 1-substituted naphthalene sulphonic acid derivatives and residues of phenyl-arsenic compounds containing tri- or pentavalent arsenic according to the general formula <FORM:0582043/IV/1> wherein G represents a hydrogen atom or -SO3H radical; C6H2 represents the residue of a benzene nucleus; Y represents -OH, -NH2, -NH acyl, -NH alkyl, -NHCO2 alkyl, -O- alkyl, -O-CO2-alkyl, -O- acyl; A and B represent H, -OH, -O- alkyl, -O- acyl, -NO2, alkyl, -NH2, -NH alkyl, -NH acyl, -NH.NH2, -NH-NH acyl, -N acyl -NH2, -N acyl -NH acyl, -NH-NH- alkyl, -N alkyl -NH2, -N alkyl -NH- alkyl, and may be identical or different; D represents -O3H2, =O, =dihalogen and =S or a radical of the formula <FORM:0582043/IV/2> are prepared by reduction of the corresponding azo compounds using in particular a metallic powder, e.g. zinc or iron dust, in alkaline solution.  Such azo compounds are prepared (a) by coupling according to classical methods an aromatic diazo-compound containing a radical of tri- or pentavalent arsenic with the desired naphthol- or naphthylamine-derivative; (b) by condensing a phenylhydrazine derivative containing tri- or pentavalent arsenic with a 1 : 2-naphthoquinone-sulphonic acid derivative; (c) by coupling a diazotised b -naphthylamine-sulphonic acid derivative with a phenyl-arsenic derivative carrying a tri- or pentavalent arsenic radical and a hydroxy- and/or amino group.  The compounds are employed therapeutically.  Hydrazo-compounds in which the nitrogen atoms of the hydrazo-linkage carry a hydrogen atom are stabilized against the action of molecular oxygen (i) by substituting for such hydrogen atom a stabilizing radical, e.g. by mono- or di-alkylation and acylation, the stabilized compounds containing e.g. the following linkages between the naphthalene and benzene nuclei: -N(COCH3)-N(COCH3-N(COCH3)-NH-, -N(CO2 alkyl)-N(CO2 alkyl)-, -N(CO2 alkyl)-NH-, -N(COC6H5) -N(COC6H5)-, -N(COC6H5)-NH-; (ii) by condensation with carbonyl-compounds, such as aliphatic or cyclic aldehydes and ketones.  Such carbonyl - compounds, which form divalent radicals, may condense with one hydrazo-compound, or one molecule of a carbonyl compound, e.g. formaldehyde, may combine with 2 moles. of a hydrazo derivative; (iii) condensation, in bimolecular or mono-molecular proportions, by reaction with an acid chloride of a dibasic acid, e.g. malonyldichloride; (iv) by reaction with isocyanic acid and its derivatives, e.g. phenyl isocyanate; or (v) by reaction with acetylene dicarboxylic esters, producing addition compounds.  In examples: (1) the red azo-dye obtained by coupling diazotised arsanilic acid with 1-naphthol-4 : 8-disulphonic acid, according to U.S.A. Specification 2,244,293, is treated, in N/1 sodium hydroxide solution, with zinc dust until decolorized and the monosodium salt of [benzene arsonic acid-4]-(1-hydrazo-2)-[a -naphthol-4 : 8-disulphonic acid] is isolated from the filtrate and by replacing arsanilic acid by 4-hydroxy-3-aminophenyl (arsonic acid and proceeding similarly, the monosodium salt of [4-hydroxy-phenylarsonic acid]-(3-hydrazo-2)-[1-naphthol-4 : 8-disulphonic acid] is obtained; (2) the azo dye obtained (a) by coupling diazotised 2 : 1-aminonaphthol-4 : 6 : 8-trisulphonic acid with p-oxy-phenylarsinoxide, or (b) by coupling diazotised 3-amino-4-hydroxy-phenylarsinoxide with 1-naphthol-4 : 6 : 8-trisulphonic acid, is treated, in 20 per cent aqueous ammonia, with hydrogen sulphide until decolorized and the resultant ammonium salt of [4-hydroxy-phenylarsinsulphide] - (3 - hydrazo - 2) - [a  - naphthol - 4 : 6 : 8-trisulphonic acid], in 90 per cent aqueous acetic acid solution, is salted out with sodium chloride as the sodium salt, which is subsequently converted into the corresponding arsinoxide by dissolving in an excess of aqueous sodium hydroxide solution in an atmosphere of hydrogen, acidifying with acetic acid and salting out with sodium chloride; (3) the azo dye obtained by coupling p-diazobenzene-arsinoxide with 1-naphthol-4 : 8-disulphonic acid is treated, in N/1 sodium hydroxide solution, with iron powder until decolorized and the filtrate is shaken in hydrogen with benzoyl chloride, the product being isolated as its mono-sodium salt; (4) benzenearsonic acid-4-(1 - hydrazo - 2) - 1 - naphthol - 4 : 8 - disulphonic acid, prepared according to (1), is dissolved in N/1 sodium hydroxide and treated in hydrogen with chlorocarbonic ethyl ester, the product being isolated as its sodium salt as in (3); (5) the monosodium salt of benzene-arsonic acid-4-(1 - hydrazo - 2) - 1 - naphthol - 4 : 8 - disulphonic acid, prepared as in (1), is dissolved in air-free water and shaken, in hydrogen with benzoyl chloride in the presence of calcium carbonate, and the monosodium salt of the product is obtained on acidification with acetic acid, followed by addition of sodium acetate.  Replacement of benzoyl chloride by a 20 per cent solution of malonyldichloride in chloroform produces a malonyl derivative; (6) benzene-arsonic acid-4-(1-hydrazo-2)-1-naphthol-4 : 8-disulphonic acid is dissolved in aqueous sodium bicarbonate and shaken in hydrogen with acetaldehyde, and the product is pptd. on acidification with acetic acid; a bimolecular compound is obtained by replacing acetaldehyde with neutral 30 per cent formaldehyde; (7) 4-hydroxy-phenylarsinoxide-1-(3-hydrazo-2)-1-naphthol-4 : 8-disulphonic acid prepared as in (2), is shaken with acetic anhydride to yield 4 - hydroxy - phenylarsinoxide - 1 - (3 - mono - N - acetyl-hydrazo-2)-1-na4hthol-4 : 8-disulphonic acid.  By acetylation with excess acetic anhydride, the corresponding diacetyl derivative is obtained; (8) benzenearsonic acid-4-(1-hydrazo-2)-1-naphthol-4 : 8-disulphonic acid is treated, in aqueous sodium bicarbonate, with phenylisocyanate and the product is pptd. on acidification with acetic acid; (9) the azo dye obtained by coupling diazotised m-arsanilic acid with 1-naphthylamine-4 : 8-disulphonic acid is treated, in N/1 sodium hydroxide, with iron powder, and the filtrate is shaken with dimethyl sulphate; (10) the azo dye obtained by coupling diazotised 1-hydroxy-2-diazo-naphthalene-4 : 8-disulphonic acid in alkaline solution with 4-hydroxy-phenyl-arsinoxide, is dissolved in N/1 sodium hydroxide and treated with zinc dust and the product is isolated as in (2); (11) 4 : 41-dihydroxy-arsenobenzene-3 : 31-bis-[azo-2]-1-naphthol-4 : 8-disulphonic acid, prepared as in U.S.A. Specification 2,235,478, and dissolved in aqueous sodium bicarbonate, is treated with zinc dust at room temperature and the product is pptd. on acidification and stabilized by re-dissolving in dilute aqueous alkali and treatment with chlorocarbonic methyl ester; (12) a stabilized hydrazo-compound is obtained by reducing an acetylated trivalent arsenic compound, prepared as in (7), or a stabilized hydrazo-compound containing a pentavalent arsenic radical, prepared as in (4) with sodium hydrosulphite to obtain the corresponding arseno-derivatives; (13) the azo-compound obtained by coupling diazotised 4 - hydroxy - 3 - aminophenyl - 1 - arsinoxide with 1-naphthol-4 : 8-disulphonic acid is reduced in aqueous sodium hydroxide with excess zinc dust in hydrogen, and the resulting hydrazo compound is stabilized by treating with phenyl isocyanate as in (8).  Analogously, phenylarsinoxide - (4 - azo - 2) - 1 - naphthol - 4 : 8 - disulphonic acid, obtained by coupling p-diazophenylarsinoxide with 1-naphthol-4 : 8-disulphonic acid, is reduced to the corresponding hydrazo-compound.  1 : 2-Amino-naphthol-4 : 6 : 8-trisulphonic acid is obtained by diazotising 1-amino-naphthol-4 : 6 : 8-trisulphonic acid and heating in aqueous solution, diazotising the resulting naphthol-trisulphonic acid and reducing the product with iron powder and hydrochloric acid. Specification 539,528 is referred to.