Patent GB-1503091-A (GB)
Title: Thiazolo(3,4-b)isoquinoline derivatives
IPC: A61K31/4743
Filed: 1976-08-02
Abstract: 1503091 Thiazolo[3,4-b]isoquinoline derivatives RHONE-POULENC INDUSTRIES 2 Aug 1976 [6 Aug 1975 18 May 1976] 32128/76 Heading C2C Novel compounds of the Formula I wherein A is 3- or 4-pyridyl or 5-isoquinolyl and, when A is 3-pyridyl, X 1  is hydrogen, halogen, dimethylamino or cyano, X 2  is hydrogen or fluorine and X 3  is hydrogen or nitro, at least two of X 1 , X 2  and X 4  being hydrogen, or X 1  and X 2  together are methylenedioxy and X 3  is hydrogen and, when A is 4-pyridyl or 5-isoquinolyl, X 1 , X 2  and X 3  each are hydrogen, and acid addition salts thereof, may be prepared (1) when A is 3- pyridyl or 5-isoquinolyl and, when A is 3- pyridyl, X 1  is hydrogen or halogen only, by cyclizing a compound II wherein A 1  and X 4  have the limited scope of A and X 1  above and X 5  and X 6  correspond to X 2  and X 3 ; (2) provided that when A is 3-pyridyl, X 1  is hydrogen, halogen or cyano, by reacting a compound A-NH 2  with a compound VIII wherein X 7  has the limited scope of X 1  above, R 1  is chlorine, C 1-4  alkylthio or benzylthio and A 2 <SP>(-)</SP> is an anion; (3) when A is 3-pyridyl, X 3  is hydrogen and X 1  and X 2  are different and one of them is hydrogen, by reducing a nitro radical in a compound XIII wherein A 3  is 3-pyridyl and one of X 9  and X 10  is nitro and the other is hydrogen to yield a compound XIV wherein one of X 11  and X 12  is amino and the other is hydrogen, and converting the amino group to halogen, dimethylamino or cyano by known methods, optionally followed by forming an acid addition salt. Intermediates of the Formula II are prepared by reacting a 3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline with a compound A-N:C:S. Intermediates of Formula VIII wherein R 1  is chloro and A 2 <SP>(-)</SP> is chloride are prepared by reacting a 1,5,10,10a-tetrahydrothiazolo[3,4-b] isoquinoline-3-thione with phosgene. The intermediates VIII in which R 1  is methylthio and A 2 <SP>(-)</SP> is iodide are prepared by reacting the same thione with methyl iodide. 3 - Hydroxymethyl - 1,2,3,4 - tetrahydroisoquinolines appropriately substituted in the carbocyclic ring are prepared by reducing the corresponding 3 - ethoxycarbonyl - 1,2,3,4- tetrahydroisoquinoline. The separate isomers of 1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline-3-thione are prepared by reacting 3-hydromethyl-1,2,3,4-tetrahydroisoquinoline with sulphuric acid to yield the sulphate ester and cyclizing this by reaction with carbon disulphide in the presence of base. The corresponding 7-, 8- and 9-nitro derivatives are prepared by nitration of the sulphate ester followed by the cyclization reaction.  5 - Isothiocyanatoisoquinoline is prepared by reacting 5-aminoisoquinoline with carbon disulphide.  (5) - 3 - Ethoxycarbonyl - 7 - nitro - 1,2,3,4- tetrahydroisoquinoline is prepared by nitration of the (5) - 3 - ethoxycarbonyl - 1,2,3,4- tetrahydroisoquinoline. Pharmaceutical compositions of the compounds I with the usual excipients show analgesic, antipyretic and slight anti-inflammatry activity when administered orally, parenterally, rectally or topically.