Patent GB-1410783-A (GB)
Title: N-substituted 4-amidopyridines tetrahydropyridines and piperidines
IPC: C07D213/75
Filed: 1972-01-20
Abstract: 1410783 Substituted 4-amidopiperidines JOHN WYETH & BRO Ltd 22 Jan 1973 [20 Jan 1972] 2721/72 Heading C2C The invention comprises novel compounds having the general Formula I in which II represents a ring system of the Formula IIa, IIb or IIc A represents a direct bond, a C 1 -C 6  alkylene radical, a mono- or di-keto C 1 -C 6  alkylene radical, a hydroxy-C 1 -C 6  alkylene radical, a radical -OCH 2 CH(OH)CH 2 - or -O-(C 1 -C 6  alkylene)-; W represents one of the following radicals-1, 2, 3, 4-tetrahydronaphthyl, naphthyl, indenyl, indolyl, benzo-[b]-thienyl, piperidyl, pyrimidinyl, quinolyl, benzo-1,4-dioxanyl, and benzindolyl any of which may be substituted, and when A is or -O-(lower alkylene)-, W may also represent phenyl and when A is other than lower alkylene W may be a C 5 -C 7  cycloalkyl radical or a pyridyl radical; R represents an optionally substituted aryl C 1 -C 6  alkyl group, C 5 -C 7  cycloalkyl group or a C 1 -C 6  alkyl group; R<SP>1</SP> represents hydrogen or C 1 -C 6  alkyl; R<SP>2</SP> represents an optionally substituted aryl group and X- denotes an ion and the acid addition and quaternary ammonium salts of those compounds having ring systems IIb or IIc. The compounds of the invention may be prepared by (a) when the compounds have ring system II(a) or II(b), acylating a compound of Formula V in which the ring system has Formula Va or Vc with a reactive derivative of an acid of general Formula RCO 2 H, or with an acid of said formula in the presence of a known condensing agent, e.g. a carbodiimide, or with said acid after first activating the amino function, e.g. as phosphazo derivative; (b) reacting a compound of general Formula VIa, VIb or VIc with an agent of formula W-A-Y in which W and A are as defined above and Y is a halogen atom or similar replaceable group or atom, e.g. a tosyl group, or with a compound of formula W-A<SP>1</SP>-H wherein A<SP>1</SP> represents an epoxy substituted lower alkenyl radical or a radical of Formula IX when the product has chain A is an hydroxy lower alkylene or radical or with a compound of formula W-B wherein B is a straight or branched chain alkenyl radical, preferably a vinyl radical, to give a compound of Formula I in which A is a straight or branched chain alkylene radical, (d) a Mannich reaction between an aldehyde, a compound of Formula VIb-VIc and a compound of formula W-H or a derivative thereof in which chain A has been at least partially formed and contains a site of the type known to participate in the Mannich reaction; (e) reacting a compound of Formula XIIa or XIIb wherein T is a known precursor of W with another molecule known for the formation of W ; (f) reacting a compound of formula W-A-OH in which A is C 1 -C 6  alkylene with a compound of Formula VIb or VIc in the presence of a catalyst, e.g. Raney nickel; (g) reacting a compound of formula W-H with an acidhalide of Formula XVII to obtain a compound of Formula I in which A is (h) by treating a compound of Formula III under mild conditions so as to remove the group R<SP>4</SP>, hydrogenolysis may be used in which case other reducible functions may also be reduced during the reaction; (i) Fischer indole synthesis on a compound of Formula XIX to produce a product of Formula I in which W is an optionally substituted indole; (j) reacting a compound of formula W-H wherein W is an unsubstituted piperidyl radical and the H is attached to the nitrogen atom thereof with a compound Hal-A-Hal where A is C 1 -C 6  alkylene and Hal is halogen and a compound of Formula VIa-VIc to produce a compound of Formula I in which W is a piperidyl radical. Methods are disclosed for the synthesis of the intermediates referred to above without examples being provided. Pharmaceutical compositions having analgesic, anti-oxotremorine, hypotensive, anti-inflammatory, central nervous system or blood platelet aggregation inhibition activity for oral, intramuscular, intraperitoneal or subcutaneous administration comprise a compound of Formula I together with a pharmaceutically acceptable carrier.