1,2,3,4,5,6-HEXAHYDRO-8-HYDROXY-3-BENZAZOCINE DERIVATIVES,THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

摘要

1448243 1,2,3,4,5,6 - Hexahydro - 8 - hydroxy-benzazocines F HOFFMANN-LA ROCHE & CO AG 23 Oct 1973 [24 Oct 1972 6 April 1973 27 July 1973] 49201/73 Heading C2C Novel 1,2,3,4,5,6 - hexahydro - 8 - hydroxybenzazocines of the general formula wherein R 2 is a C 1-7 alkyl, C 3-7 cycloalkyl-C 1-7 alkyl, C 2-7 alkenyl, C 3-7 alkynyl or aryl-C 1-7 alkyl group and each of R 3 and R 4 is a hydrogen atom or C 1-7 alkyl group, at least one of R 3 and R 4 being a C 1-7 alkyl group and at least one of R 2 , R 3 and R 4 being other than a methyl group (present as racemates or optical antipodes when R 3 and R 4 are not alike), and pharmaceutically acceptable acid addition salts thereof are prepared (a) by reacting a 1,2,3,4,5,6-hexahydro-8- alkoxy - benzazocine of the general formula wherein R 1 is a C 1-7, alkyl group, or an acid addition salt thereof with an ether-cleaving agent; or (b) by reacting the corresponding compound in which R 2 is a hydrogen atom or an acid addition salt thereof with agents yielding the group R 2 e.g. an acylating agent, which gives an N-acyl- 8-acyloxybenzazocine, followed by a reducing agent; followed optionally by separation of a resulting reacemate into the optical antipodes and by conversion of a resulting base into a pharmaceutically acceptable acid addition salt. 1,2,3,4,5,6 - Hexahydro - 8 - alkoxy - benzazocines of the general formula II are prepared by alkylating, alkenylating or alkynylating the corresponding compound in which R 2 is a hydrogen atom and 1,2,3,4,5,6-hexahydro-8- hydroxy - benzazocines of the general Formula I wherein R 2 is a hydrogen atom are prepared from the same starting materials by treatment with an ether-cleaving agent. 1,2,3,4,5,6 - Hexahydro - 8 - alkoxy - benzazocines of the general Formula II wherein R 2 is a hydrogen atom are prepared (i) by condensing an amino acid of the general formula and reducing the resulting lactam of the general formula or (ii) by benzylating the amino acid (16), condensing the resulting N-benzyl-amino acid, reducing the resulting lactam and removing the benzyl group from the resulting N-benzylbenzazocine by hydrogenolysis. Amino acids (16) are prepared by reacting a p-R 1 O-benzaldehyde with CH 3 COCHR 3 R 4 , reducing the resulting ketone of the general formula heating the resulting alcohol of the general formula under acidic conditions, oxidizing the resulting tetrahydronaphthalene of the general formula nitrosating the resulting naphthalenone (characterized as the 2,4-dinitrophenylhydrazone) of the general formula ring-opening the resulting oxime of the general formula reducing the resulting nitrile of the general formula to give an amino acid and then an amino alcohol of the respective general formulµ introducing an acetyl group R 5 and a phthaloyl group R 6 into the amino alcohol, chlorinating the resulting acetate of the general formula reacting the resulting chloride of the general formula with an alkali metal cyanide, and removing the phthaloyl group from and hydrolysing the resulting cyanide of the general formula Pharmaceutical compositions having analgesic activity comprise, as active ingredient, a 1,2,3,4,5,6 hexahydro - 8 - hydroxy - benzazocine of the general Formula I or a pharmaceutically acceptable acid addition salt thereof, in association with compatible pharmaceutical carrier suitable for parenteral or enteral administration.