Patent GB-1043141-A (GB)
Title: Substituted-4-oxo-1, 3, 8-triazaspiro (4, 5) decanes and their therapeutically active non-toxic acid addition salts and the preparation thereof
IPC: C07D471/10
Filed: 1963-06-21
Abstract: The invention comprises 1-R1-2-R2-3-R3-4-oxo - 8 - R4 - 1,3,8 - triaza - spiro(4,5)decanes and the therapeutically active non-toxic acid-addition salts thereof, wherein R1 is a phenyl, lower alkaryl, lower alkyl, lower alkoxyphenyl, cycloalkyl or halophenyl radical; R2 is a hydrogen atom or a lower alkyl radical; R3 is a hydrogen atom or a hydroxymethyl, lower alkyl, lower alkoxycarbonylalkyl, cyanoalkyl, lower alkoxymethyl, lower alkylcarbonyl, carbamoylalkyl, cyclopropylcarbonyl, benzyl or benzoyl radical; R4 is an (R111)(R1111)CH- or Z(CH2)nradical, wherein R111 is a methyl or ethyl radical, R1111 is an aryl or arylethyl radical, n is a positive integer from 1 to 5 and Z is a lower alkyl, hydroxy, hydroxy-lower alkoxy, phenyl, diphenyl-cyanomethyl, diaryl-hydroxymethyl, diphenyl - propionylmethyl, fluorophenyl - hydroxymethyl, aryloxy, 1,4-benzodioxanyl, halo - 1,4 - benzodioxanyl, thienyl, halophenyl, lower alkylphenyl, tri-fluoromethylphenyl, pyridyl, di-lower alkyl-phenyl, lower alkoxyphenyl, cyclopropyl-ethenyl, benzoyl, halobenzoyl, thienoyl, lower alkoxybenzoyl, lower alkylbenzoyl, benzoyloxy, benzyloxy, phenylmethoxymethyl, phenyl-hydroxymethyl, fluorophenyl-lower alkyl-carb-onyloxy -methyl, aryl - cyclopropyl, arylthio, (aryl)(R1)CH-, wherein R1 is a lower alkyl, aryl or aralkyl radical, (aryl)2CH-O-, (lower alkyl)2C=CH-, or (aryl)(R11)C=CH-, where-in R11 is a hydrogen atom or a lower alkyl, aryl or aralkyl radical; said lower alkyl and lower alkoxy groups containing from 1 to 6 carbon atoms and said aryl radical being a phenyl, halophenyl, lower alkylphenyl, lower alkoxy phenyl, trifluoromethylphenyl or 2-thienyl radical. These compounds may be prepared by condensation of a piperidone-4 or 4-hydroxy piperidine alkali metal sulphite appropriately protected at the nitrogen atom by, for example, a benzyl group, with a primary amine and an alkali metal cyanide, conversion of the resulting 1 - substituted - 4 - cyano - 4 - secondary - amino piperidine to the corresponding carboxamide by acid hydrolysis of the nitrile function, cyclization of the carboxamide and, where necessary, saturation of the cyclic double bond at the 2,3-position.  Cyclization may be effected by treatment with formamide, in the absence or presence of an inorganic acid, to yield the 1,3,8 - triazo - spiro(4,5)dec - 2 - ene in cases where the secondary amino group attached to the piperidine ring is alkyl-substituted, and the 1,3,8-triazo-spiro(4,5)decane where the secondary amino group is aryl-substituted.  An exception occurs when the alkyl group is ethyl, in which case the saturated spiro compound is obtained.  Alternatively cyclization may be effected by treatment of the carboxamide with triethoxymethane, in which case a 1,3,8-triazospiro(4,5)dec-2-ene is invariably obtained, or by treatment with an acylating agent, in which case the unsaturated 1,3,8-triazo-spiro(4,5)dec-2-ene bearing a substituent at the 2-position identical to the aliphatic carboxylic acid residue of the anhydride employed is obtained.  Saturation of the cyclic double bond may be achieved by hydrogen activated by a catalyst, e.g. a platinum or nickel catalyst.  The 1,2-disubstituted 1,3,8 - triaza - spiro(4,5)dec - 2 - enes bearing a methyl substituent at the 2-position or the corresponding compound unsubstituted at the 2-position may be advantageously reduced to the spiro(4,5)decane by treatment with a di-light metal hydride, e.g. LiAlH4 or NaAlH4. The benzyl group on the piperidine nitrogen atom may be removed by hydrogenolysis and then replaced by a variety of substituents by reaction of the appropriate halogenated reactant in the presence of a halogen acid acceptor. The debenzylation procedure is applicable to the 2,3-substituted, unsubstituted and 1-substituted compounds except for side reactions such as simultaneous dehalogenation if, for example, the 1-position is occupied by a haloaryl group.  In the case of 2-methyl-substituted dec-2-enes debenzylation may be carried out before or after saturation of the cyclic double bond.  Substituents may be introduced into the nitrogen group at the 3-position before or after debenzylation. For example, reaction with an anhydride introduces an acyl group, reaction with alkyl halide or quaternary ammonium alkylaryl halide introduces an alkyl group, reaction with an aqueous aldehyde introduces hydroxyalkyl group and reaction with an unsaturated nitrile introduces a cyanoalkyl group.  1 - Bromo - 1 - (4 - fluorophenyl) ethane is prepared by reacting 1-(4-fluorophenyl) ethanol with hydrogen bromide. 1-Bromo-1-(4-fluorophenyl) propane is similarly prepared.  1 - Chloro - 4 - (4 - methylphenyl) pentane is prepared by hydrogenating 5 - chloro - 2 - (4-methylphenyl) -2 - pentene.  1 - Bromo - 4 - (4-fluorophenyl) pentane, 1 - chloro - 4 - (4 - methoxyphenyl) pentane, 1 - chloro - 4 - (4 - chlorophenyl) pentane, 1 - chloro - 4,4 - diphenylbutane, 1 - chloro - 5,5 - diphenyl pentane, 1-chloro -4 - (4 - methylphenyl) - 4 - phenyl - butane, 1 - chloro - 4 - (4 - methoxyphenyl) - 4 - phenylbutane, 1 - chloro - 4 - (4 - fluorophenyl) - 4 - phenyl - butane, 1 - chloro - 5 - (4 - fluorophenyl) - 5 - phenyl - pentane, 1 - chloro - 4 - (4 - fluorophenyl) - 4 - (4 - methylphenyl) - butane, 1 - chloro - 4,4 - di -(4 - fluorophenyl) - butane, 1 - chloro - 5,5 - di -(4 - fluorophenyl) - pentane, 1 - chloro - 4 - (4 - fluorophenyl) - 4 - (3 - trifluoromethylphenyl) - butane, 1 - bromo - 4,4 - di - (3 - trifluoromethylphenyl) - butane, 1 - butane, 1 - chloro - 5 - (4 - fluorophenyl) - 4 - phenyl - pentane and 1 - chloro - 4,5 - di - (4 - fluorophenyl) - pentane are similarly prepared.  1 - Bromo - 2 - (4 - fluorophenyl) propane is prepared by reacting fluorobenzene with allyl bromide.  4 - Chlorophenyl - cyclopropyl - methyl - carbinol is prepared by reacting 4-chlorophenyl-cyclopropyl ketone with methylmagnesiumiodide and decomposing the product with an ammonium chloride solution.  Cyclopropylmethyl - 4 - methylphenyl - carbinol, cyclopropyl-4 - methoxyphenyl - methyl - carbinol, cyclopropyl - 4 - methylphenyl - phenyl - carbinol, cyclopropyl - 4 - methoxyphenyl - phenyl - carbinol, cyclopropyl - 4 - fluorophenyl - phenylcarbinol, cyclopropyl - 4 - fluorophenyl - 4 - methylphenyl - carbinol, cyclopropyl - 4 - fluorophenyl-3 - trifluoromethylphenyl - carbinol, cyclopropyl-4 fluorophenyl - 2 - thienyl - carbinol, cyclopropyl - 2 - (4 - fluorophenyl) - 1 - phenyl - ethanol, 1 - cyclopropyl - 1,2 - di - (4 - fluorophenyl)-ethanol, cyclopropyl - phenyl - 3 - trifluoromethylphenyl - carbinol, cyclopropyl - 4 - fluorophenyl-4 - methoxyphenyl - carbinol, 4 - chlorophenyl-cyclopropyl - 4 - fluorophenyl - carbinol, cyclopropyl - 4 - fluorophenyl - 2 - thienyl - carbinol and 5 - chloro - 1 - (4 - fluorophenyl) - 1 - phenyl-pentanol are similarly prepared.  1 - Bromo - 1 - (4 - chlorophenyl) propane is prepared by reacting 1-(4-chlorophenyl) propanol with phosphorus tribromide. 1-Bromomethyl - 2 - phenyl - cyclopropane and 1 - bromo-2 - (4 - fluorophenyl) butane are similarly prepared.  5 - Chloro - 2 - (4 - chlorophenyl) - 2 - pentene is prepared by the action of thionyl chloride on cyclopropyl - 4 - chlorophenyl - methyl - carbinol. 4 - Chloro - 1 - (4 - fluorophenyl) - 1 - butene, 5 - chloro - 2 - (4 - methylphenyl) - 2 - pentene, 5 - chloro - 2 - (4 - methoxyphenyl) - 2 - pentene, 4 - chloro - 1 - (4 - fluorophenyl) - 1 - (4 - methylphenyl) - 1 - butene, 4 - chloro - 1,1 - di - (4-fluorophenyl) - 1 - butene, 4 - chloro - 1 - (4-fluorophenyl) - 1 - (3 - trifluoromethylphenyl) - 1 - butene, fluorophenyl) - 2-phenyl - 2 - pentene, 5 - chloro - 1,2 - di -(4-fluorophenyl) - 2 - pentene, 4 - chloro - 1 - phenyl - 1 -(3 - trifluoromethylphenyl) - 1 - butene, 4 - chloro-1,1 - di -(4 - methylphenyl) - 1 - butene, 4 - chloro-1 1 - (4 - fluoropheny - 1 - (4 - methoxyphenyl) - 1 -butene, 4 - chloro - 1 - (4 - chlorophenyl) - 1 - (4-fluorophenyl) - 1 - butene, 4 - chloro - 1 - (4-fluorophenyl) - 1 - (2 - thienyl) - 1 - butene, 4-chloro - 1 - (4 -methylphenyl) - 1 - phenyl - 1-butene, 4 - chloro - 1 - (4 - methoxyphenyl) - 1-phenyl - 1 - butene and 4 - chloro - 1 - (4 - fluorophenyl) - 1 - phenyl - 1 - butene are prepared similarly.  5 - Bromo - 2 - phenyl - 2 - pentene is prepared by the action of hydrogen bromide on 1-cyclopropyl-1-phenyl ethanol. 5-Bromo-2-(4-fluorophenyl) - 2 - pentene and 4 - bromo 1,1 - di - (3-trifluoromethylphenyl) - 1 - butene are prepared similarly.  5 - Chloro - 1,1 - diphenyl pentanol is prepared by reacting 5-chloro valerate with phenyl-magnesium bromide and decomposing the product with an ammonium chloride solution. 5 - Chloro - 1,1 - di - (4 - fluorophenyl) - pentanol, cyclopropyl - di - (3 - trifluoro - methylphenyl)-carbinol and cyclopropyl - di - (4 - methylphenyl)-carbinol are prepared similarly.  5 - Chloro - 1,1 - diphenyl - 1 - pentene is prepared by the action of concentrated hydro-chloric acid on 5-chloro-1,1-diphenyl pentanol. 5 - Chloro - 1 - (4 - fluorophenyl) - 1 - phenyl - 1-pentene and 5 - chloro - 1,1 - di - (4 - fluorophenyl)-1-pentene are prepared similarly.  1 - Chloro - 4 - (4 - fluorophenyl) - 4 - (2 - thienyl) butane is prepared by reacting cyclopropyl-4 - fluorophenyl -2 - thienyl - carbinol with perchloric acid to form 4 - (4 - fluorophenyl) - 4 -(2 - thienyl) - but - 3 - en - 1 - ol, reducing this compound with lithium tetra-hydroaluminate and treating the resulting 4-(4 - fluorophenyl) - 4 -(2 - thienyl) butanol with thionyl chloride.  1 - Chloro - 3 - (4 - methyl - thio - phenoxy)-propane is prepared by reacting 1-bromo-3-chloro-propane with 4-methyl thiophenol. 2-(4 - Fluoro - thio - phenoxy) -ethanol is similarly prepared.  1 - Chloro - 2 - (4 - fluoro - thio - phenoxy)-ethane is prepared by reacting 2-(4-fluoro-thio-phenoxy)-ethanol with thionyl chloride.  4 - Chloro - 1,1 - di - (4 - methoxyphenyl) - 1-butene is prepared by reacting