Patent GB-993581-A (GB)
Title: Phenoxyalkylguanidines and their synthesis and pharmaceutical preparations containing them
Inventor: HODSON HAROLD FRANCIS
IPC: C07C51/60
Filed: 1960-03-03
Abstract: The invention comprises guanidine derivatives of the general formula (other than phenoxyethyl guanidine base) <FORM:0993581/C2/1> wherein A is -(CH2)2-, -(CH2)3-, -CH2CH(CH3)- or -CH(CH3)CH2-; Z4 is a hydrogen or halogen atom or an alkyl group containing from one to six carbon atoms and Z2, Z3, Z5 and Z6 are the same or differen and each is a hydrogen or halogen atom or a nitro group or an alkyl or alkoxy group containing from one to four carbon atoms, and acid addition salts thereof, together with processes for their preparation by the reaction of (a) guanidine or a salt thereof with R3X, wherein R3 is a phenoxyalkyl group, and X is a reactive atom or group; (b) ammonia or an ammonium salt with an S-substituted-N-phenoxyalkyl isothiourea of formula R4SC(:NH)NHR3 or salt thereof, or with a cyanamide R3NH.CN, wherein R3 is a phenoxyalkyl group and R4 is a lower alkyl group; (c) a primary amine R3NH2 or a salt thereof with an S-substituted isothiourea R4SC(:NH)NH2 or a salt thereof or with cyanamide itself. Specific compounds displaying a sympatholytic action include 2 - (4 - chloro - 2 - methylphenoxy)-, 2 - (2,5-dimethylphenoxy) - 2 - (4 - bromophenoxy)-, 2 - (2 - methylphenoxy)-, 2 - (2 - isopropylphenoxy)-, 2 - (2 - methoxyphenoxy) - 2 - (2-isopropyl - 5 - methylphenoxy)-, 2 - (2,4,6-trichlorophenoxy) - 2 - (2 - bromophenoxy)-, 2 - (3 - methylphenoxy)-, 2 - (4 - chlorophenoxy)-, 2 - (2,4 - dichlorophenoxy)-, 2 - (2,6-dichlorophenoxy)-, 2 - (2 - chloro - 6 - methylphenoxy)- and 2-(2,6-dimethylphenoxy) ethyl guanidines and 2-(2,6-dimethylphenoxy) propyl guanidines and their acid addition salts. Specific anthelmintic compounds include 2-(2-chlorophenoxy) - 2 - (2 - isopropylphenoxy) ethyl guanidines and 3-(2,4-dichloro-3,5-dimethylphenoxy)- and 3-(4-chloro-3,5-dimethylphenoxy)-propyl guanidines and their acid addition salts.  Starting materials: -1-Amino-2-(4-chloro-2-isopropyl - 5 - methyl - phenoxy) ethane is prepared from the phthalimido derivative of 1-bromo - 2 - (4 - chloro - 2 - isopropyl - 5 - methylphenoxy) ethane, itself obtained by reaction of the bromo compound with potassium phthalimide. Likewise are prepared via the phthalimido derivatives the following 1-amino-2-phenoxy ethanes (substituents in the phenoxy ring given) 2 - isopropyl - 5 methyl, 4 - chloro - 3,5 - dimethyl-, 2-chlorophenoxy-, 5-isopropyl-2-methyl-, 2 - isopropylphenoxy-, 4 - chloro - 3 - methyl-, 4 - t - pentyl-, 3 - chloro - 4 - methyl-, 4 - bromo-, 2,4,6 - trichloro-, 4 - chloro - 5 - isopropyl - 2-methyl-, 4 - chloro - 3,5 - dimethyl-, 2,6 - dimethyl-, 2,6 - dichloro - 2 - bromo-, 2,4 - dichloro-, 2 - chloro - 6 - methyl-, 2 - methoxy-, 2,4 - dichloro - 3,5 - dimethyl-, 2,5 - dimethyl-, 3 - nitro-, 3 - methoxy-, 2,6 - diisopropyl-, 3,5 - dimethyl-, 3,4 - dimethyl-, also 1 - amino-3 - (3 - methylphenoxy)propane and 1 - amino-3 - (4 - chloro - 2 - isopropyl - 5 - methylphenoxy)propane. 1 - Bromo - 2 - (4 - chloro - 3 - methylphenoxy)ethane is prepared from 1,2-dibromoethane and 4-chloro-3-methylphenol; similarly are prepared the following 1-bromo-2-phenoxyethanes: -5 - isopropyl - 2 - methyl-, 4 - t - pentylphenoxy-, 4 - chloro - 3,5 - dimethylphenoxy-, 3 - chloro - 4 - methylphenoxy-, 4-chloro - 3,5 - dimethylphenoxy-, 2,6 - dichlorophenoxy-, 4 - chloro - 5 - isopropyl - 2 - methylphenoxy-, 2 - chloro - 6 - methylphenoxy-, 3-methoxyphenoxy-, 2,4 - dichloro - 3,5 - dimethylphenoxy-, 2,6 - di - isopropylphenoxy- and 1 - bromo - 3 - (4 - chloro - 2 - isopropyl - 5 - methylphenoxy) propane.  1 - Amino - 2 - (4-methylphenoxy)ethane, its 2 - methylphenoxy analogue and 1-amino-2-(2,6-dimethylphenoxy)propane are prepared from the corresponding 1-bromo compounds by treatment with methanolic ammonia. 1 - Bromo - 2 - (2,6 - dimethylphenoxy)propane is obtained from 2-(2,6-dimethylphenoxy)propan-1-ol, itself prepared by LiAlH4 reduction of ethyl 2-(2,6-dimethylphenoxy)propionate formed from 2 - bromopropionate and 2,6 - dimethylphenol.  2 - (3-Methylphenoxy)propylamine is prepared by LiALH4 reduction of 2-(3-methylphenoxy)propionamide, itself prepared from 2-(3-methylphenoxy)propionyl chloride, which is produced from the corresponding acid.ALSO:Pharmaceutical compositions having a specific sympatholytic or an anthelmintic action comprise a phenoxyalkyl guanidine of the general formula <FORM:0993581/A5-A6/1> (A is -(CH2)2-, -(CH2)3-, -CH2CH(CH3)- or -CH(CH3)CH2-; Z4 is hydrogen or halogen or an alkyl group having from one to six carbon atoms, and Z2, Z3, Z5 and Z6 are the same or different and each represents hydrogen, halogen, nitro, alkyl or alkoxy containing from one to four carbon atoms) or addition salts thereof, and an acceptable carrier. The compositions may be formulated as powders, tablets, granules, drafts, syrup, capsules, cachets, suspensions or emulsion for administration per os, or as solution in aqueous or non-aqueous media for injection, or in foods or in suppositories or pessaries, and may incorporate flavouring, preserving, suspending, thickening or emulsifying agents, antioxidants, buffers, bacteriostats, surface active agents, binders and/or lubricants. Examples 31-35 detail specific compositions.