Patent GB-857159-A (GB)
Title: Substituted acridans
Filed: 1957-12-31
Abstract: The invention comprises substituted acridans of the general formula: <FORM:0857159/IV(b)/1> (wherein Y represents halogen, trifluoromethyl, lower alkoxy or lower alkyl, R1 and R2 each represent hydrogen or lower alkyl, A represents an alkylene chain of 3-5 carbon atoms with at least 3 carbon atoms separating the two nitrogen atoms, and R3 and R4 represent lower alkyl groups or form, with the nitrogen atom to which they are attached, a piperazinyl, lower alkyl-piperazinyl, o -di-(lower alkyl) amino-(lower alkyl) piperazinyl, o -hydroxy-(lower alkyl) piperazinyl, o -hydroxy-(lower alkoxy)-(lower alkyl)-piperazinyl, o -acetoxy-(lower alkyl) piperazinyl, pyrrolidinyl, morpholinyl, piperidinyl or thiomorpholinyl ring, the term "lower" indicating throughout that the groups so qualified contain 1-4 carbon atoms, provided that when Y represents halogen, lower alkoxy or lower alkyl, either R2 represents lower alkyl or <FORM:0857159/IV(b)/2> represents lower alkylpiperazinyl, o -di-(lower alkyl) amino-(lower alkyl) piperazinyl, o -hydroxy-(lower alkyl) piperazinyl, o -hydroxy-(lower alkoxy)-(lower alkyl) piperazinyl or o -acetoxy-(lower alkyl) piperazinyl) and their non-toxic acid addition salts, and the preparation thereof by reacting compounds of the general formula : <FORM:0857159/IV(b)/3> with a reactive tertiary-aminoalkyl ester (e.g. halide or arylsulphonate), or, when <FORM:0857159/IV(b)/4> is o -di-(lower alkyl) amino-(lower alkyl) piperazinyl, by reacting the corresponding o -chloro compound with a dialkylamine or, when <FORM:0857159/IV(b)/5> is o -hydroxy-(lower alkyl) piperazinyl, by hydrolysis of the corresponding o -acetoxy compound.  The products are useful as mild sedative agents and antiemetics (see Group VI). 10-Unsubstituted acridans.  The starting materials of the second general formula above are prepared as follows : (a) when R2 is hydrogen, by reduction of the corresponding 2-substituted-acridines or -5-alkylacridines ; (b) when R1 and R2 are both hydrogen, by reduction of the appropriate 2-substituted-5-chloroacridines obtained by treating the corresponding 5-acridones with POCl3 ; (c) when R1 and R2 are both lower alkyl, by treating the appropriate 2-substituted-5-alkylacridines or 2-substituted-acridones with a methyl or ethyl Grignard reagent. 10-[31-(411-Chlorethyl-111-piperazinyl)-propyl] 2-methylacridan is prepared by treating the corresponding 411-hydroxy compound with SOCl2.ALSO:As mild sedative agents and antiemetics may be employed substituted acridans of the general formula:  <FORM:0857159/VI/1> (wherein Y represents halogen, trifluoromethyl, lower alkoxy or lower alkyl, R1 and R2 each represent hydrogen or lower alkyl, A represents an alkylene chain of 3-5 carbon atoms with at least 3 carbon atoms separating the two nitrogen atoms, and R3 and R4 represent lower alkyl groups or form, with the nitrogen atom to which they are attached, a piperazinyl, lower alkylpiperazinyl, o -di-(lower alkyl) amino- (lower alkyl) piperazinyl, o -hydroxy- (lower alkyl) piperazinyl, o -hydroxy- (lower alkoxy)-(lower alkyl) piperzinyl, o -acetoxy-(lower alkyl) piperazinyl, pyrrolidinyl, morpholinyl, piperidinyl or thiomorpholinyl ring, the term "o " lower-indicating throughout that the groups so qualified contain 1-4 carbon atoms, provided that when Y represents halogen, lower alkoxy or lower alkyl, either R2 represents lower alkyl or <FORM:0857159/VI/2> represents lower alkyl (piperazinyl, o -di-(lower alkyl) amino- (lower alkyl) piperazinyl, o -hydroxy- (lower alkyl) piperazinyl, -hydroxy-(lower alkoxy) - (lower alkyl) - piperazinyl), or o  acetoxy- (lower alkyl)- piperazinyl), o  their non-toxic acid addition salts (e.g. those with hydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric nitric, maleic, fumaric benzoic, ascorbic, pamoic, succinic, methylene-bis-salicylic, methanesulphonic, ethanedisulphonic, acetic, propionic, tartanic, sulicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycollic, glutamic, benzenesulphonic or theophyllineautic acid or with 8- halotheophyllines).  The compounds may be administered orally in the form of capsules containing them admixed with solid diluents or pasted with oils, tablets, or aqueous suspensions (e.g. in a medium consisting of water, sodium carboxymethyl-cellulose and a montmorillonite).