Patent GB-978542-A (GB)
Title: New piperidine derivatives and processes for preparing the same
IPC: A61K31/00
Filed: 1963-01-30
Abstract: The invention comprises piperidine derivatives of the formula I <FORM:0978542/C1/1> in which R represents a hydrogen atom or a hydroxy, alkoxy or alkyl group in the 3- or 4-position of the phenyl group, R1 represents a methyl or ethyl group and A represents a straightchained alkylene group containing 3 or 4 carbon atoms, or a straight-chained alkenylene group containing 3 or 4 carbon atoms in which the double bond of the alkenylene group is in conjugation with the adjacent benzene nucleus, and non-toxic acid addition salts thereof. The compounds may be prepared by (a) reacting a compound of the formula <FORM:0978542/C1/2> with a compound of the formula <FORM:0978542/C1/3> in which A1 represents the group A as defined above or a group which, in the product of the reaction, can be converted to the group A without modifying any other part of the molecule, and X represents a substituent selected to react with the N-hydrogen atom of the compound of formula II to form a =N-A1-linkage with elimination of HX, or (b) condensing 3-hydroxybenzyl cyanide with a tertiary amine of the formula <FORM:0978542/C1/4> and hydrolysing and esterifying the resulting compound having the formula <FORM:0978542/C1/5> or (c) reacting a substituted pentane of the formula <FORM:0978542/C1/6> in which Hal represents halogen, with a primary amine of the formula <FORM:0978542/C1/7> or (d) for compounds in which A represents an alkylene group, condensing a compound of the formula <FORM:0978542/C1/8> with a compound of the formula X1-CH2-CH2-X11 in which X1 and X11 represent halogen atoms, or bisulphate arylsulphonate or alkylsulphonate groups, and hydrolysing, esterifying and reducing the resulting quaternary ammonium compound having the formula <FORM:0978542/C1/9> or (e) for compounds in which A represents a propylene or propenylene group, condensing a compound of the formula II with formaldehyde and a carbonyl compound of the formula <FORM:0978542/C1/100> converting the product thus formed to a compound of formula I by ketone-specific reduction to replace the group <FORM:0978542/C1/111> by the group <FORM:0978542/C1/122> dehydration to produce a compound of Formula I in which A represents a propenylene group, and, if desired, subsequent hydrogenation to produce a compound of formula I in which A represents a propylene group or (f) as in (e) but wherein the compound of formula X is replaced by a compound of the formula <FORM:0978542/C1/133> and wherein the resulting compound is partially or wholly hydrogenated to form a compound of formula I in which A is a propenylene or propylene group, respectively.  4-(31-Hydroxyphenyl) -4- carbalkoxy-piperidines of formula II are prepared by treating 1-tosyl -4- (31-alkoxyphenyl) -4- cyano piperidine with concentrated hydrobromic acid in the presence of phenol to produce 4-(31-hydroxyphenyl) -piperidine -4- carboxylic acid and subsequently esterifying this compound with methanol or ethanol.  Starting materials of formula VIII are prepared by reacting 3-hydroxybenzyl cyanide with a substituted ethane of formula  <FORM:0978542/C1/144> 3-(m-Hydroxyphenyl)-propyl bromide is prepared by boiling 3-(m-methoxyphenyl)-propanol with 48% hydrobromic acid.  1-[3-(411-Methoxyphenyl) -3- oxo-propyl], -4-(31-hydroxyphenyl) -4- carbethoxy-piperidine hydrochloride is prepared by reacting 4-(31-hydroxyphenyl) -4- carbethoxy-piperidine hydrochloride with formaldehyde and p-methoxyacetophenone, or with p-methoxy -b - bromopropiophenone.  1-[3-(411-Methoxyphenyl) -3- hydroxypropyl]- 4- (31-hydroxyphenyl) -4- carbethoxy piperidine is prepared by reducing the corresponding 3-oxo-propyl compound, and 1-(311-phenyl -311-hydroxy propyl) -4- (31-hydroxyphenyl) -4- carbethoxy-piperidine hydrochloride is prepared by reacting 4-(31-hydroxyphenyl) -4- carbethoxy-piperidine hydrochloride with 3-phenyl -3- hydroxy -1- bromo-propane.  Pharmaceutical compositions, having central analgesic and morphine antagonistic action, for oral, rectal or parenteral administration comprise a compound of the invention together with a pharmaceutical carrier or excipient. The compositions may be formulated as tablets, capsules, ampoules or suppositories.  Specification 748,874 is referred to.