Patent GB-1304951-A (GB)
IPC: C07D221/16
Filed: 1970-03-18
Abstract: 1304951 Indenopyridines SANDOZ Ltd 18 March 1970 [8 April 1969 6 May 1969 11 June 1969 16 June 1969 9 Sept 1969 10 Dec 1969 11 Dec 1969] 13097/70 Heading C2C Novel (4aRS, 5SR, 96SR) and (4aRS, 5SR, 96RS) indenopyridines of the general formula wherein either R 1 , R 2  and R 3  are each a hydrogen atom or R 1  is a hydrogen atom or a C 1-4  alkyl, C 3-6  alkenyl or C 3-6  alkynyl group, R 2  is a chlorine, bromine or fluorine atom or a C 1-4  alkyl group and R 3  is a hydrogen, chlorine, bromine or fluorine atom or a C 1-4  alkyl, C 1-4  alkylthio, C 1-4  alkoxy or trifluoromethyl group, with the proviso that when R 1  is an isopropyl group, R 2  is a chlorine atom and R 3  is a chlorine atom in the 4-position, the compound is the (4aRS, 5SR, 96RS) isomer, and acid addition salts thereof are prepared (a) when R 1  is a C 1-4  alkyl, C 3-6  alkenyl or C 3-6  alkynyl group, by reacting the corresponding compound wherein R 1  is a hydrogen atom with a compound of the general formula R 1 X, wherein R 1  is a C 1-4  alkyl, C 3-6  alkenyl or C 3-6  alkynyl group and X is a halogen atom or the acid radical of a reactive ester, in the presence of a basic condensation agent; (b) by cyclizing a pyridine derivative of one of the general formulµ or a mixture of pyridine derivatives of the last two formulµ shown with polyphosphoric acid; (c) when R 1  is a hydrogen atom or a C 1-4  alkyl or C 3-6  alkenyl group and R 3  is as R 2  and in the p-position, by cyclizing a 4-piperidyl-methanol of the general formula wherein R 1 <SP>II</SP> is as the desired meaning of R 1 , with polyphosphoric acid; (d) when R 1  is -CH 2 R 1 <SP>III</SP> in which R 1 <SP>III</SP> is a hydrogen atom or a C 1-3  alkyl group, by reduction of the corresponding (4aRS, 5SB, 96SR) or (4aRS, 5SR, 96RS) carbonyl compound of the general formula wherein R 1 <SP>IV</SP> is a hydrogen atom or a C 1-3  alkyl or C 1-6  alkoxy group, with lithium aluminium hydride, aluminium hydride or diborane; (e) when R 1  is a hydrogen atom, by splitting off R 4  from the corresponding (4aRS, 5SR, 96RS) or (4aRS, 5SB, 96SR) compound wherein R 1  is R 4  and R 4  is a methyl or benzyl group; or (f) when R<SP>1</SP> is a hydrogen atom, by heating a (4aRS, 5RS, 96RS) compound of the first general formula above, wherein R 1  is -COOR 5 , in which R 5  is a C 1-6  alkyl, phenyl or benzyl group, or -CN in an alkaline medium to give a (4aRS, 5SR, 96RS) compound; and optionally separating mixtures of isomers to isolate one or each isomer and optionally salifying the product. (4aRS, 5KS, 96RS) indenopyridines of the first general formulaabove are prepared by reducing indenopyridines of one of the general formulµ wherein R 6  is a hydrogen, chlorine, bromine or fluorine atom or a C 1-4  alkyl group and R 7  is as R 1 , or by a process analogous to (e) above. Indenopyridines of the seventh general formula above are prepared (a) when R 1 <SP>IV</SP> is a hydrogen atom or C 1-3  alkyl group, by acylation of an indenopyridine of the first general formula above, wherein R 1  is a hydrogen atom with a reactive acid derivative in the presence of a base or (b) when R 1 <SP>IV</SP> is a C 1-6  alkoxy group, by reacting an indenopyridine of the first general formula above wherein R 1  is a methyl or benzyl group with a chloroformic acid ester of the general formula Cl-COOR 5 , in which R 5  is a C 1-6  alkyl group. Indenopyridines of the first general formula above wherein R 1  is a benzyl group are prepared (a) by reacting the corresponding compound wherein R 1  is a hydrogen atom with benzyl chloride or bromide or (b) by cyclizing a pyridine derivative of the sixth general formula above wherein R 1 <SP>II</SP> is a benzyl group, with polyphosphoric acid. Pyridines of the fourth general formula above are prepared by reacting a piperidinone of the general formula wherein R 7 <SP>I</SP> is a C 1-4  alkyl, C 3-6  alkenyl or C 3-6  alkynyl group, with a phosphorus compound of one of the general formulµ in the presence of an alkali metal alcoholate or amide. Pyridines of the fourth and fifth general formulµ above are prepared by dehydrating a pyridine of the sixth or third general formulµ above, respectively. Pyridines of the sixth general formula above wherein R 1 <SP>II</SP> may also be a benzyl group are prepared by reducing with a complex metal hydride a ketone of the general formula wherein R 7  is as R 1  or a benzyl group, which is prepared by reacting an ester of the general formula wherein R 7 <SP>I</SP> is as R 7 , with at least 2 mols. of a Grignard reagent of the general formula wherein X<SP>I</SP> is a chlorine or bromine atom. Pyridines of the third general formula above are prepared by reacting a piperidinone of the eleventh general formula above with a Grignard reagent of the general formula and hydrolysing the resulting complex. Indenopyridines of the eighth general formula above are prepared by reacting a ketone of the general formula with a Grignard reagent of the general formula and hydrolysing the resulting complex, and dehydrating the hydroxy indenopyridine thus produced of the ninth general formula above. Pharmaceutical compositions having serotonin-antagonistic, analgesic and antiphlogistic activity comprise, as active ingredient, a (4aRS, 5SR, 96SR) or (4aRS, 5SR, 96RS) indenopyridine of the first general formula above or a physiologically acceptable acid addition salt thereof, together with a physiologically acceptable diluent or carrier.