Patent GB-848341-A (GB)
Title: New isoquinolines and process for their manufacture
IPC: A61K31/00
Filed: 1957-04-25
Abstract: The invention comprises isoquinolines having in the 1-position a hydroxy group etherified with a polyethylene glycol containing 4-20 ethylene radicals (particularly a substituent of the formula :- <FORM:0848341/IV(a)/1> wherein n is 4-20, R represents hydrogen or a C1-3 alkyl radical and R1 hydrogen or, in some of the units, is C1-3 alkyl or oxa-alkyl radical), and optionally further substituted in the ring by alkyl, cycloalkyl or condensed alkylene radicals of less than 10 carbon atoms, and the manufacture thereof in accordance with the examples (i.e. by reacting above 90 DEG  C an appropriate 1-chloroisoquinoline with an appropriate polyethylene glycol or monoalkyl ether thereof, preferably in the form of a metal (e.g. sodium) salt thereof and advantageously in excess of the polyethylene glycol compound as solvent).  A mixed polyalkyleneglycol ether of the formula :-  <FORM:0848341/IV(a)/2> (wherein n and m represent average values of 16 and 3 respectively) is prepared by reacting a commercial polyethylene glycol monoethyl ether of average molecular weight 750 with 1 : 2-propylene oxide in the presence of powdered KOH at 150 DEG -160 DEG  C.ALSO:The invention comprises isoquinolines having in the 1-position a hydroxy group etherified with a polyethylene glycol containing 4-20 ethylene radicals (particularly a substituent of the formula:  <FORM:0848341/IV(b)/1> wherein n is 4-20, R represents hydrogen or a C1-3 alkyl radical and R1 hydrogen or, in some of the units, a C1-3 alkyl or oxaalkyl radical), and optionally further substituted in the ring by alkyl, cycloalkyl or condensed alkylene radicals of less than 10 carbon atoms; pharmaceutical preparations containing these compounds (see Group VI); and the manufacture thereof in accordance with the examples (i.e. by reacting above 90 DEG  C. an appropriate 1-chloroisoquinoline with an appropriate polyethylene glycol or monoalkyl ether thereof, preferably in the form of a metal (e.g. sodium) salt thereof and advantageously in excess of the polyethylene glycol compound as solvent).  The second reactant may be a mixture of compounds with different chain lengths, in which case the product is also a mixture, which may be separated into its constituents if desired.  Polyethylene glycol monoalkyl ethers are prepared by a process which may be represented by the following reaction scheme:  <FORM:0848341/IV(b)/2> <FORM:0848341/IV(b)/3> A mixed polyalkyleneglycol ether of the formula:  <FORM:0848341/IV(b)/4> (wherein n and m represent average values of 16 and 3 respectively) is prepared by reacting a commercial polyethylene glycol monomethyl ether of average molecular weight 750 with 1 : 2-propylene oxide in the presence of powdered KOH at 150 DEG -160 DEG  C.  Octaethylene glycol is prepared by diesterifying diethylene glycol with benzenesulphonyl chloride and caustic soda and reacting the product with a solution of sodium in excess of triethylene glycol.  1-Chloroisoquinolines are prepared by the action of POCl3 on the corresponding 1 : 2-dihydroisoquinolones-(1), obtained in some cases by dehydrogenation of the corresponding 1 : 2 : 3 : 4-tetrahydro compounds.  4-n-Butyl-, 4-cycloheryl-, 4-n-heptyl-and 7-n-pentyl-1 : 2 : 3 : 4-tetahydroisoquinolones-(1) are prepared by ring closure with Al Cl3 of the appropriate isocyanates produced by the action of COCl2 on the amines obtained by catalytic hydrogenation of, respectively, a -phenylcapronitrile (from benzyl cyanide and n-butyl benzenesulphonate in liquid ammonia in the presence of sodium), a -cyclohexylphenylacetonitrile a -phenylnonanonitrile and p-n-pentylbenzyl cyanide (from n-pentylbenzene by reaction with formaldehyde and HCl to form p-n-pentylbenzyl chloride and reaction of this with KCN).  3 : 4-Tetramethylene-1 : 2 : 3 : 4-tetrahydroisoquinolone-(1) is prepared similarly from 2-phenylcyclohexylamine via 2-phenylcyclohexyl isocyanate.ALSO:Pharmaceutical preparations, e.g. for use as local anaesthetics or anti-coughing agents, contain, in admixture with a pharmaceutical carrier, an isoquinoline having in the 1-position a hydroxy group etherified with a polyethylene glycol containing 4-20 ethylene radicals (particularly a substituent of the formula: <FORM:0848341/VI/1> wherein n is 4-20, R represents hydrogen or a C1-3 alkyl radical and R1 hydrogen or, in some of the units, a C1-3 alkyl or oxaalkyl radical), and optionally further substituted in the ring by alkyl, cycloalkyl or condensed alkylene radicals of less than 10 carbon atoms.  The preparations may be in forms suitable for oral, enteral, parenteral or topical administration, e.g. tablets, dragees, salves, creams, solutions, suspensions or emulsions.  They may be sterilized and may contain auxiliary substances, such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers, or other therapeutically valuable substances.