Patent GB-1137425-A (GB)
Title: Phenoxyazinyl and acridanyl aminocyclopropanes
IPC: C07D265/18
Filed: 1966-07-22
Abstract: 1,137,425. Phenoxazine and acridan derivatives. SMITH KLINE & FRENCH LABORATORIES. 22 July, 1966 [23 July, 1965 (2)], No. 33211/66. Heading C2C. Novel compounds of Formula I, in which Y is oxygen or =CR 3 R 4 , R 3  and R 4  being hydrogen or C 1-3  alkyl, R is hydrogen, chlorine, bromine, trifluoromethyl, methyl, methoxy or methylthio, each of m and n is 0 or 1, each of R 1  and R 2  is hydrogen or C 1-3  alkyl or R 1  and R 2 , together with the nitrogen atom to which they are attached, represent a 1-pyrrolidinyl, piperidino or 4-methyl-1-piperazinyl ring, and their pharmaceutically acceptable acid addition salts are prepared as follows: (a) the compounds in which m is 0 and n is 1 are prepared by reacting a compound of Formula II with a compound of Formula III and reducing the resulting amide of Formula IV; the compounds where m and n are 1 and -NR 1 R 2  represents a tertiary amino group are prepared by reacting a compound of Formula II with an active ester derivative of an aminocyclopropyl carbinol of Formula V, in which -NR 1 R 2  represents a tertiary amino group; (c) the compounds where n is 1 are prepared by reacting an acid of Formula VI with a C 1-3  alkyl haloformate to give the corresponding cyclopropyl mixed anhydride and then treating this with an amine of formula HNR 1 R 2  to give the cyclopropane-carboxamide and reducing this to the aminomethyl-cyclopropane; (d) the compounds in which n is 0 are prepared by reacting an acid of Formula VI with a C 1-3  alkyl haloformate and then with sodium azide to give the cyclopropyl carboxylic acid azide, thermally decomposing this to give the corresponding isocyanate, treating this with (i) a hydrolysing medium to give the primary aminocyclopropane, or (ii) a C 1-2  alkyl magnesium halide or C 1-3  alkanol to give an N-C 2-3  acyl- or N - C 2-4  carbalkoxy - aminocyclopropane, and either reducing this directly to give an N-C 2-3  alkylaminocyclopropane or N - methylaminocyclopropane, respectively, or further reacting it with a C 1-3  alkyl iodide to give an N-C 1-3  alkyl- N-C 2-3  acyl or N-C 1-3  alkyl-N-C 2-4  carbalkoxyaminocyclopropane, respectively, and reducing this to give an N-C 1-3  alkyl-N-C 2-3  alkylaminocyclopropane or N-C 1-3  alkyl-N-methylaminocyclopropane, respectively; (e) the compounds where -NR 1 R 2  represents a heterocyclic ring are prepared from the corresponding primary amines by reacting them with 1,4-dibromobutane, 1,5-dibromopentane or methyl bis-(#- chloroethyl) amine to give the 1-pyrrolidinyl, piperidino and 4-methyl-1-piperazinyl compounds respectively. The compounds are obtained in the cis and/or trans form depending on the method of preparation. The acid addition salts are prepared by known methods. Cyclopropane-carboxylic acids of Formula VI are prepared by reacting a compound of Formula II with ethyl 2-bromo- or 2-bromomethyl - cyclopropane - carboxylate and hydrolysing the resulting ester. The cis- and transacids of Formula VI in which m is 0 and n is 1, are also prepared by reacting an appropriate 10-vinylphenoxazine or 10-vinyl-acridan with ethyl diazoacetate to give a mixture of cis- and trans - heterocyclic cyclopropane carboxylates, selectively hydrolysing this mixture to give the trans-acid and unhydrolysed cis-ester, and hydrolysing the cis-ester with excess alkali to give the cis-acid. 2 - Chloro - 10 - vinyl - phenoxazine is prepared by reacting 2-chlorophenoxazine with diethylaminoethyl chloride hydrochloride to give 2 - chloro - 10 - (2 - dimethylaminoethyl)- phenoxazine, reacting this with methyl iodide to form the corresponding methiodide and then subjecting this to Hoffman degradation. Pharmaceutical compositions having antidepressant activity, for oral or parenteral administration, comprise one of the novel compounds together with a carrier.