Patent GB-1094470-A (GB)
Title: Isoquinoline derivatives and preparation thereof
IPC: C07D217/16
Filed: 1966-07-28
Abstract: The invention comprises compounds of the formula <FORM:1094470/C2/1> where R1 and R2 are H, a C1 to C4 alkyl group, a methoxy or ethoxy group, Cl or Br or together constitute a methylenedioxy group, and R3 to R8 denote H, and alkyl group which may be substituted by Cl, Br, OH, alkoxy, aryloxy, amino or alkylated amino and which has a total of 1 to 10 carbon atoms, an aryl group which may or may not be substituted by alkyl, F, Cl, Br, OH, alkoxy, methylenedioxy, or dialkylamino and which has a total of 6 to 10 carbon atoms, or an aralkyl group which may be substituted by alkyl, F, Cl, Br, OH, alkoxy, methylenedioxy or dialkylamino and which has a total of 7 to 10 carbon atoms, and acid addition salts or quarternary ammonium salts thereof. The novel compounds may be made by treating a compound of the formula <FORM:1094470/C2/2> <FORM:1094470/C2/3> <FORM:1094470/C2/4> <FORM:1094470/C2/5> where one of the radicals Y is free OH group, the other is Z and Z is an OH group which may, if desired, be esterified or etherified, Cl, Br or I, with a cyclising HZ-liberating agent. Alternatively, a compound of Formula I but in which one or both of the heterocyclic rings contain(s) one or more carbonyl or hydroxy groups in the free positions or, in the case of a carbonyl group, in the 4-position and/or one or more double bonds, the compound being in the form of a quarternary ammonium salt when there is a double bond in the 5,11b-position, is treated with a reducing agent.  The preparation of the following intermediate is also exemplified: 1 - hydroxymethyl - isoquinoline is hydrogenated and reacted with chloracetyl chloride to give 1,3,4,6,7,11b - hexahydro - 4 - oxo - 1,4 - oxazino [3,4-a] isoquinoline; 1-hydroxymethyl-1,2,3,4 -tetrahydroisoquinoline is reacted with (a) ethylene oxide, (b) 1-chloro-2-methyl-propanol-(2) or (c) 1-chloro-2-bromoethane to give the corresponding 2-(2-hydroxyethyl)-, 2-(2-hydroxy - 2 - methylpropyl)- or 2 - (2 - chloroethyl) - 1 - hydroxymethyl - 1,2,3,4 - tetrahydroisoquinoline; homoveratryl amine is reacted with 2-chloroethanol to form N-2-hydroxyethyl-homoveratrylamine which is reacted with chloroacetyl chloride forming N-chloroacetyl-N-(2-hydroxyethyl) - homoveratrylamine which is cyclised to N-homoveratrylmorpholinone-(2); 1 - phenyl - hydroxymethylisoquinoline is hydrogenated and the product reacted with ethylene oxide to from 1-phenylhydroxymethyl-2 - (2 - hydroxymethyl) - 1,2,3,4 - tetrahydroisoquinoline hydrochloride; 1 - cyano - 2 - benzoyl 1,2-dihydroisoquinoline is reacted with phenyl-lithium to form 1,1-diphenylhydroxymethylisoquinoline which is hydrogenated to the tetrahydro compound and reacted with ethylene oxide to form 1,1-diphenyl hydroxymethyl - 2 - (2 - hydroxyethyl) - 1,2,3,4 - tetrahydroisoquinoline; 1 - hydroxymethyl - isoquinoline is reacted with 2-chloroethanol, hydrogenated and reacted with thionyl chloride to give 1-(2-chloroethoxymethyl)-1,2,3,4-tetrahydroisoquinoline; 3 - [o - (2 - hydroxyethyl)-phenyl]-morpholine is reacted with thionyl chloride to give 3-[o-(2-chloroethyl)-phenyl]-morpholine; 3 - (o - carboxymethylphenyl) morpholine is reacted with thionyl chloride and then triethylamine to give 1,3,4,6,7,11b-hexahydro - 6 - oxo - 1,4 - oxazino [3,4-a] isoquinoline; 3 - phenyl - 4 - carboxymethylmorpholine is reacted with aluminium chloride to give 1,3,4,6,7,11b - hexahydro - 7 - oxo - 1,4 - oxazino [3,4-a] isoquinoline; 7 - hydroxy - 1,3,4,6,7, 11b - hexahydro - 1,4 - oxazino [3,4-a] isoquinoline is made by reduction of the corresponding 7-oxo compound with sodium borohydride; 1,3,4,11b - tetrahydro - 1,3 - oxazino [3,4-a] isoquinoline is made by conversion of 7 - hydroxy - 1,3,4,6,7,11b - hexahydro - 1,4 - oxazino [3,4-a] isoquinoline to the p-toluenesulphonate, followed by treatment with potassium-t-butylate and processing.  Pharmaceutical compositions for use in human or veterinary medicine to improve cardiac circulation comprise a compound of Formula I with an inert physiologicaly-acceptable carrier.  The compositions may be solutions, suspensions, emulsions or implants for parenteral application; tablets or dragees for enteral application; and ointments or creams for topical application.