Patent GB-1252131-A (GB)
IPC: C07D495/04
Filed: 1968-10-31
Abstract: 1,252,131. 1,3,4,10a-Tetrahydro-2H-[1 ]benzopyrano[2,3-c]pyridines. SANDOZ Ltd. 31 Oct., 1968 [1 Dec., 1967; 25 March, 1968; 22 Aug., 1968; 17 Oct., 1968], No. 51674/68. Heading C2C. Novel 1,3,4,10a - tetrahydro - 2H - [1]benzopyrano - [2,3 - c]pyridines of the general formula wherein R 1  is a hydrogen atom or a C1_6 alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 4-6  cycloalkenyl, C 3-6  cycloalkyl-C 1-4  alkyl or C 4-6  cycloalkenyl-C 1-4  alkyl group and R 2  and R 3  are each a hydrogen or halogen atom or a hydroxy, C 1-6  alkyl or C 1-6  alkoxy group, and acid addition salts thereof are prepared (i) by splitting off water from a hydroxy compound of the general formula or (ii) when R 1  is other than a hydrogen atom, by reacting the corresponding compound of the first general formula above wherein R 1  is a hydrogen atom with a compound of the general formula R 1 X, wherein R 1  is other than a hydrogen atom and X is the acid radical of a reactive ester, in the presence of a basic condensation agent, followed optionally by converting any alkoxy groups which may be present in the product into hydroxy groups and/or converting a resulting racemic compound into its optical antipodes and/or salifying. 1,2,3,4,4a,10a - Hexahydro - 5H - [1]benzothiopyrano - [2,3 - c]pyridin - 5 - ols of the second general formula above and acid addition salts thereof are prepared (a) by reducing a ketone of the general formula with sodium, potassium or lithium borohydride; (b) when R 1 is other than a C 2-6  alkenyl, C 2-6  alkynyl, C 4-6  cycloalkenyl or C 4-6  cycloalkenyl- C 1-4  alkyl group, by catalytic hydrogenation or reduction with lithium aluminium hydride or diborane of a ketone of the third general formula above; (c) when R 1  is other than a hydrogen atom, by reacting the corresponding compound of the first general formula above wherein R 1  is a hydrogen atom with a compound of the general formula R 1 X, wherein R 1  is other than a hydrogen atom and X is the acid radical of a reactive ester, in the presence of a basic condensation agent; (d) when R 1  is a -CH 2 R<SP>1</SP> 6  group, in which R<SP>1</SP> 6  is a hydrogen atom or a C 1-5  alkyl, C 3-6  cycloalkyl or C 3-6  cycloalkyl-C 1-3  alkyl group, by reducing a ketone or aldehyde of one of the general formulµ wherein R 6  is a hydrogen atom or a C 1-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl, C 3-6  cycloalkyl, C 4-6  cycloalkenyl, C 3-6  cycloalkyl-C 1-3  alkyl or C 4-6  cycloalkenyl-C 1-3  alkyl group and R 7  is a hydrogen atom or a -COR 6  group, with lithium aluminium hydride or diborane; and (e) when R 1  is a -CHR 13 R 1 XI group in which R 1 XI is a C 2-5  alkenyl, C 2-5  alkynyl, C 4-6  cycloalkenyl or C 4-6  cycloalkenyl-C 1-5  alkyl group and R 13  is a hydrogen atom or R 1 XI and R 13  together form a C 4-6  cycloalkenyl group, by treating the corresponding compound of the second general formula above wherein R 1  is a -CHR 12 R 1 <SP>x</SP> group, in which R 1 <SP>x</SP> is a C 1-5  alkyl group containing at least two carbon atoms substituted once or twice on a single carbon atom, or substituted once on each of two adjacent carbon atoms by fluorine, chlorine or bromine, or a C 2-5  alkenyl group substituted once on one of the carbon atoms of the double bond by fluorine, chlorine or bromine, or a C 4-6  cycloalkyl or C 4-6  cycloalkyl-C 1-3  alkyl group substituted once in the ring by fluorine, chlorine or bromine, and R 12  is a hydrogen atom, or R 1 <SP>x</SP> and R 12  are together a C 4-6  cycloalkyl group substituted once in the ring by fluorine, chlorine or bromine, with a base; followed optionally by salification of the product. Ketones of the third general formula above are prepared (a<SP>1</SP>) when R 1  is a hydrogen atom, by splitting off a methyl or benzyl group from the corresponding compound wherein R 1  is the methyl or benzyl group and (b<SP>1</SP>) when R 1  is a methyl or benzyl group, by condensing the product of (a<SP>1</SP>) with a compound of the general formula R 1 X wherein R 1  is the methyl or benzyl group and X is the acid radical of a reactive ester, in the presence of a basic condensation agent. Thioethers of the general formula wherein R 2 <SP>I</SP> and R 3 <SP>I</SP> are each a hydrogen or halogen atom or a C 1-6  alkyl or alkoxy group, R 1 <SP>VII</SP> is as R 1  except for a hydrogen atom, or additionally a benzyl group, and R 8  is a lower alkyl group, are prepared by condensing a tetrahydroisonicotinic acid ester of the general formula with a thiophenol of the general formula Ketones or aldehydes of the fifth general formula above are prepared by reacting a ketone of the third general formula above wherein R 1  is a hydrogen atom with an acid chloride of the general formula R 6 COCl in the presence of a basis condensation agent. Halo derivatives used as starting materials in process (e) above are prepared analogously to process (c) above. Pharmaceutical compositions having analgetic, antiphlogistic and central nervous system depressing and stimulating activity comprise, as active ingredient, a 1,3,4,10a-tetrahydro-2H-[ 1] benzopyrano[2,3-c]pyridine of the first general formula above or a physiologically acceptable acid addition salt thereof, together with a physiologically acceptable diluent or carrier, and may be administered enterally or parenterally.