Patent GB-788130-A (GB)
Title: Benz(c) acridine compounds and methods for obtaining the same
Inventor: MOORE ALEXANDER MAZYCK
Filed: 1955-12-14
Abstract: The invention comprises benz(c)acridine compounds of the general formula <FORM:0788130/IV (b)/1> and acid addition salts thereof, wherein R represents a divalent alkyl group containing from 2 to 6 carbon atoms, R1 represents an alkyl or hydroxyalkyl group containing from 2 to 12 carbon atoms or a cycloalkyl-alkyl or aralkyl group containing from 7 to 12 carbon atoms or a cycloalkyl or a hydroxy-substituted cycloalkyl group containing from 5 to 7 carbon atoms, and Z represents hydrogen or a halogen or a methyl, ethyl, methoxy, or ethoxy group, and the preparation thereof by condensing a monoalkylaminoalkylamine of the general formula NH2-R-NH-R1 with a 7-substituted benz(c)acridine of the general formula <FORM:0788130/IV (b)/2> or a naphthoylaminobenzoyl halide of the general formula <FORM:0788130/IV (b)/3> and in the latter case where an amide is produced having the formula <FORM:0788130/IV (b)/4> reacting said amide with a cyclizing agent such as phosphorus oxychloride or pentachloride, or sulphuric or phosphoric acid, wherein R, R1 and Z have the above significance, Y represents a halogen or a lower alkoxy, phenoxy, lower alkylmercapto or phenyl mercapto group, and X represents a halogen.  If desired, an excess of either reactant may be used. Although not necessary, an anhydrous inert organic solvent such as benzene, toluene, xylene, dioxane or petroleum ether may be used as a reaction solvent.  The reaction is favoured by temperatures in excess of 75 DEG  C.-preferably in the range of 75 DEG  to 150 DEG C.  A condensation catalyst such as copper dust or a copper salt, particularly cuprous chloride, may be used in the above reaction. The reaction using a 7-halo-benz(c)acridine reactant is preferably carried out in the presence of an excess of phenol, the corresponding 7-phenoxy-benz(c)acridine being first formed, e.g., 10-chloro-7-phenoxy- or 7-phenoxy-benz(c)acridine, which need not be isolated before the reaction is continued.  An alternative method for the preparation of benz(c) acridine compounds of the above general formula is by condensing an alkylamine of the formula NH2-R1 with a 7-haloalkylamino-benz(c)acridine of the general formula <FORM:0788130/IV (b)/5> or an acid addition salt thereof, wherein R, R1, Z and X have the above significance.  If desired, an excess of the alkylamine may be used.  Although not necessary, an anhydrous inert organic solvent such as a hydrocarbon, lower aliphatic alcohol or ketone, cyclic ketone or tertiary amine may be used as a reaction solvent, e.g. benzene, toluene, xylene, petroleum ether, ethanol, n-propanol, n-butanol, isobutanol, n-pentanol, acetone, diethyl ketone, dioxane or pyridine.  This process is preferably carried out at a temperature between 50 DEG  and 100 DEG C. The acid addition salts may be formed from organic or inorganic acids to form salts such as the hydrochloride, hydrobromide, sulphate, phosphate, arsonate, arsanilate, oxalate, sulphamate, sulphonate, acetate, lactate, tartrate, gluconate, citrate, salicylate, 5,51-methylene disalicylate, benzoate, pamoate, cresotinate, methylene-di-o-cresotinate, and naphthoate, and salts derived from 8-hydroxy-7-ioso-5-quinoline sulphonic acid, p-ureido-benzene-arsonic acid, N-acetyl-4-hydroxy-m-arsanilic acid, N-glycolylarsanilic acid, and N,N1-ethylene bis (p-arsanilic acid).  The preferred salts are the penicillinates, particularly the benzyl penicillinates.  A specific penicillin salt prepared in the bispenicillin G salt of 7-(3-octyl-aminopropylamino) benz(c)acridine.  In the examples and description benz(c)acridine compounds of the above general formula are referred to in which Z represents hydrogen or 1- or 4-methoxy substituent, a 2-methoxy or -ethoxy substituent, or a 10-methyl, -ethyl, -methoxy, -bromo or -chloro substituent, and the substituent in the 7-position is a 2-ethylaminoethylamino, 2-octylaminoethylamino, 2-(2-hydroxy-ethylamino) ethylamino, 3 - isopropylamino-propylamino, 3 - hexylaminopropylamino, 3 - heptylaminopropylamino, 3-octylaminopropylamino, 3 - nonylaminopropylamino, 3 - decylaminopropylamino, 3 - undecylaminopropylamino, 3 - dodecylaminopropylamino, 3 - cyclohexylaminopropylamino, 3 - cyclohexylethyl-aminopropylamino, 3 - (1 - ethylhexylamino) propylamino, 3 - (1 - methylheptylamino) - propylamino, 3 - (1 - propylpentylamino) propylamino, 3 - (1 - ethyl - pentylamino) propylamino, 3 - (3 - phenylpropylamino) propylamino, 3 - (2 - ethylhexylamino) propylamino, 3 - (3 - hydroxypropylamino) - propylamino, 3 - (6 - hydroxyhexylamino) propylamino, 3 - (10 - hydroxydecylamino) propylamino, 3-(2-hydroxyethylamino) propylamino, 3 - (2 - hydroxycyclopentylamino) propylamino, 3 - (4-hydroxycyclohexylamino) propylamino, 3-(4-hydroxy-1-methylbutylamino) amylamino, 5-ethylaminoamylamino, 5 - hexylaminoamylamino, 5-octylaminoamylamino, or 6-amylaminohexylamino group.  A naphthoylaminobenzoyl halide of the above general formula prepared in one of the examples is 2-(a -naphthylamino) benzamidopropylamino-octane (prepared from 2-(a -naphthylamino) benzoyl chloride and 3-octylaminopropylamine). Intermediate compounds.  2 - (a  - Naphthylamino) benzoyl chloride is prepared from the reaction of the corresponding free acid and phosphorus pentachloride.  3-(1-Ethylpentylamino)-, 3-(1-propylpentylamino)-, 3-nonylamino-, 3-(3-phenylpropylamino)-, 3-(2-ethylhexylamino)- and 3-dodecylamino-propylamine are prepared by the reaction of 1,3-diaminopropane with 3-bromo-pentane, 4-chloro-octane, nonyl bromide, 3-phenylpropyl chloride, 2-ethylhexyl chloride and dodecyl bromide respectively. 5-Octylaminoamylamine is prepared by the reaction of octyl chloride and 1,5-diaminopropane. 3-Heptylaminopropylamine is prepared by the reaction of acrylonitrile with n-heptylamine and the resulting N-(b -cyanoethyl) heptylamine is hydrogenated under pressure in the presence of Raney nickel.  7 - Phenylmercapto -, 7 - ethylmercapto-, and 2-methoxy-7-methylmercapto-benx(c)acridine are prepared by the reaction of the required 7-chloro-benz(c)acridine and thiophenol, ethanethiol and methanethiol respectively in the presence of sodium and ethanol. 7-Chloro-10-methylbenz(c)acridine is prepared by the reaction of 2-chloro-4-methylbenzoic acid and 1-naphthylamine to form 4-methyl-2-(a -naphthylamino) benzoic acid which is then treated with phosphorus oxychloride followed by concentrated ammonium hydroxide and an ice solution.