Patent GB-1334070-A (GB)
Title: Tris- and tetrakis- 1,2,3,4-tetrahydroisoquinoline and -3,4- dihydroisoquinoline compounds
Inventor: RAJAGOPALAN P
IPC: C07D217/16
Filed: 1970-12-30
Abstract: 1334070 Tris and tetrakis-(1,2,3,4-tetrahydro or 3,4 - dihydro - isoquinolines) ENDO LABORATORIES Inc 30 Dec 1970 [6 Jan 1970] 61841/70 Heading C2C Novel compounds of the general Formula I wherein A and B is each hydrogen or taken together are a single bond; R 1  and R 2  are the same or different and are hydrogen or C 1-6  alkyl; R 3 , R 4  and R 5  are the same or different and are hydrogen or alkyl, alkoxy, alkenoxy, or alkynoxy containing up to 6 carbon atoms or halogen, hydroxy, C 2-6  acyloxy, aryloxy, phenyl C 1-6  alkoxy or any adjacent pair of the groups are together C 1-3  alkylenedioxy; n is 3 or 4 and Z is an organic group having a valence of 3 or 4 consisting of carbon and hydrogen and optionally up to 4 hetero atoms selected from oxygen, sulphur and nitrogen and optionally up to 3 substituents selected from amino, nitro, halo, hydroxy, C 1-6  alkyl or alkoxyl, benzyloxy, trifluoro methyl and C 1-3  alkylenedioxy (on adjacent carbon atoms, and wherein all 3 or 4 R 3  substituents on the tetrahydroisoquinoline or dihydroisoquinoline groups are the same, all 3 or 4 R 4  substituents on said groups are the same and all 3 or 4 R 5  substituents on said groups are the same) may be prepared when A and B are hydrogen atoms by reduction of the compound I in which A and B are together a single bond which in turn is prepared by cyclizing an appropriately substituted N-phenethyl substituted amide with phosphorus oxychloride. The amide is formed by reacting a tri- or tetracarboxylic acid ester or acid chloride of Z with an appropriately substituted phenethylamine. The substituents on the compounds I may be modified for example by demethylation of methoxy groups or debenzylation of benzyloxy groups to produce further compounds I. The tri- and tetra-carboxylic acids, ester and acid chlorides of Z may be prepared by esterifying the free acid or forming the acid chloride and/or (a) ring opening 2-oxo cyclopentane carboxylic acid mixed methyl and ethyl esters in the presence of ethyl 4-bromobutenoic acid or 1,3-dibromopropane to form triethyl 1,4,7- heptanetricarboxylate and tetraethyl 1,4,8,11- undecanetetracarboxylate respectively; (b) reducing 2 - oxo - 1,3 - cyclopentanediylidenetetrapropionic acid to 1,3-cyclopentanediylidenetetrapropionic acid; (c) condensing sodium thioglyoxylate, from ethyl thioglyoxylate and sodium ethoxide with ethyl 2-oxo-3-bromocyclohexanecarboxylate to form 3[(carboxymethyl)thio] - 2 - oxocyclohexane carboxylic acid diethyl ester and ring opening by base hydrolysis to form the triethyl ester of 2[(carboxymethyl) thio]-heptane dioic acid; (d) cyanoethylation of (i) 4<SP>1</SP>-chloroacetophenone, (ii) 4-oxotetrahydrothiopyran, or (iii) glycerol followed by hydrolysis of the cyano groups to the carboxylic acid groups to yield (i) 4-(2-carboxyethyl)-4-(p-chlorobenzoyl) heptane dioicacid, (ii) 4-oxo-thiopyrandiylidene 3,5-tetrapropionic acid and (iii) 3,3<SP>1</SP>,3<SP>11</SP>- (1,2,3 - propanetriyltrioxy) tripropionic acid respectively, followed in the case of (i) by Wolf Kishner reduction of the benzoyl group to benzyl and (ii) by hydrazine hydrate reduction of the 4-oxo group to a methylene group; (e) Wolf Kishner reduction of acyl groups to alkyl and benzyl groups to yield acyclic tricarboxylic acid esters; (f) condensing mixed ethyl and methyl esters of 2-oxocyclohexane carboxylic acid with 1,4-dibromobutane to yield the mixed ethyl and methyl esters of 1,1<SP>1</SP>-tetramethylene bis- [2 - oxocyclohexane carboxylic acid] which on ring opening by basic hydrolysis yield tetramethyl 1,5,10,14-tetradecanetetracarboxylate. Pharmaceutical compositions of the compounds I inhibit blood clot formation and dissolve blood clots when administered parenterally, orally or rectally with the usual excipients.