Patent GB-948071-A (GB)
Title: New heterocyclic compounds
Inventor: WRAGG WILLIAM ROBERT
IPC: C07D211/52
Filed: 1959-05-01
Abstract: The invention comprises compounds of the general formula: <FORM:0948071/C2/1> and acid addition salts thereof (wherein X is a straight, saturated or ethylenically unsaturated hydrocarbon chain of two or three carbon atoms, Z is a single bond or a -CH2- or -CO- group, Ar is an unsubstituted phenyl group or a phenyl group substituted by one to three substituents selected from halogen atoms and alkyl groups including halogenoalkyl groups, R1 and R2 are hydrogen atoms or together represent a single bond, R3 represents a group in meta or para position selected from amino, mono-alkylamino, dialkylamino, monohydroxyalkylamino, acylamido, ureido, and alkoxycarbonylamino groups, R4 is a hydrogen atom or an amino or acylamido group in meta or para position, and the tetrahydropyridine or piperidine ring may carry up to four alkyl groups) together with a process for their preparation by reacting a compound of the formula: <FORM:0948071/C2/2> with a compound of the formula: <FORM:0948071/C2/3> (in which Y is the acid residue of a reactive ester, X1 is X as defined above or a similar group wherein one of the methylene groups is replaced by a carbonyl group, R31 represents R3 or a nitro group in the meta or para position) followed, where necessary, by converting X1 to X by reduction of the carbonyl group, and/or reducing a nitro group to a primary amino group, and if desired converting the resultant amino group by known methods into a different grouping within the definition of R3.  The invention is illustrated by 17 detailed Examples.  The piperidine compounds of the general formula: <FORM:0948071/C2/4> are prepared (a) by reacting a compound of the formula: <FORM:0948071/C2/5> (R represents an alkyl group) with NH3 and hydrogen under pressure in the presence of a catalyst and either reducing the resultant piperidone of general formula: <FORM:0948071/C2/6> with lithium aluminium hydride or reacting it with a Grignard reagent RMgX (X is halogen); (b) by reduction of compounds of the general formula: <FORM:0948071/C2/7> themselves prepared by reacting Ar CHO with two molecular proportions of a b -carbonyl ester and NH3 and submitting the resultant compounds of the formula: <FORM:0948071/C2/8> to hydrolysis and decarboxylation. 1-21-(p-Nitrophenyl)ethyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine is prepared from 4-phenyl- 1, 2, 3, 6-tetrahydropyridine and p-nitrophenylethyl bromide, the 4-p-chlorophenyl- and 4-m-trifluoromethylphenyl-analogues are similarly prepared; 1-21- (p-N-b -chloroethoxycarbonylaminophenyl) ethyl -4- phenyl- 1, 2, 3, 6-tetrahydropyridine hydrochloride is obtained from the corresponding amine by treatment with 2-chloroethyl chloroformate, 4-chloro-p-acetamidobutyrophenone is prepared from 4-chlorobutyryl chloride and acetanilide; 4-m-trifluoromethylphenyl- 1, 2, 3, 6-tetrahydropyridine hydrochloride is obtained from m-trifluoromethylbromobenze and 1-benzylpiperid-4-one via 1-benzyl-4-m-trifluoromethylphenyl -4- hydroxy-piperidine hydrochloride and 4-m-trifluoromethylphenyl -4- hydroxy piperidine hydrochloride; 1-21-(4-acetamido -3- nitrophenyl)-ethyl -4- phenyl,-1 2, 3, 6-tetrahydropyridine is prepared from 2-p-nitrophenylethyl bromide via 2-p-acetamidophenylethyl bromide and 2-(4-acetamido -3- nitrophenyl) ethyl bromide; 1-(4-p-nitrophenylbut-2-enyl)-4-m-trifluoromethylphenyl-1, 2, 3, 6-tetrahydropyridine is obtained from 4-p-nitrophenylbut-2-enyl bromide and 4-m-trifluoromethylphenyl -1, 2, 3, 6-tetrahydropyridine. The novel compounds of the invention are useful as antiemetics, hypothermic agents, potentiators of general anesthetics, and in the treatment of psychotic disorders, and may be formulated in compositions suitable for oral or parenteral administration, e.g. as pills, dispersible powders, granules, emulsions, suspensions, syrups, elixirs, capsules, sterile injectible solutions, suspensions and emulsions.  In addition to diluents, the compositions may contain adjuvants such as wetting, dispersing, sterilising, lubricating, emulsifying, sweetening and flavouring agents.