Patent GB-1410057-A (GB)
Title: Phenylcyclohexenylamines and the preparation thereof
IPC: A61K31/10
Filed: 1972-10-20
Abstract: 1410057 4 - Phenylcyclohexenylamines, derivatives thereof and their pharmaceutical compositions UPJOHN CO 20 Oct 1972 [1 Nov 1971] 48476/72 Addition to 1327691 Heading C2C The invention comprises compounds of Formula I and acid addition salts thereof, wherein the broken line ring is present or absent; R and R‹ are each selected from H, CH 3 , C 2 H 5 , F, Cl, Br, CF 3 , C 1-4  alkylthio + C 1-4  alkoxy radicals; R<SP>1</SP> is H or C 1-4  alkyl; R<SP>2</SP> is H, C 1-4  alkyl, C 1-3  alkanoyl, C 1-3  alkylsulphonyl, C 6-10  arylsulphonyl, (C 1-4  alkyl) carbamoyl, (C 1-4  alkoxy) carbonyl, ring monosubstituted C 6-10  aroyl, C 1-6  alkyl in which the substituent is as defined above for R 1  other than hydrogen, bis-(ring monosubstituted C 6-10  aryl) C 1-6  alkyl or R<SP>1</SP> and R<SP>2</SP> together with the nitrogen atom form a substituted or unsubstituted pyrrolidino, piperidino, hexamethylene imino, morpholino or piperazino ring provided that at least one of the following conditions is satisfied:- (a) the broken line ring is present, (b) R and R‹ are not both hydrogen, (c) R is alkyl thio and (d) NR<SP>1</SP>R<SP>2</SP> is unsubstituted or monosubstituted morpholino or piperazino, and compounds of Formula Ia or an acid addition salt thereof, in which R, R<SP>1</SP> and R<SP>2</SP> are as defined above and R<SP>4</SP> and R<SP>5</SP> are hydrogen or C 1-4  alkyl provided that they are not both hydrogen and that R is alkylthio and/or -NR<SP>1</SP>R<SP>2</SP> is an unsubstituted or monosubstituted morpholino or piperazino ring. Primary 4- substituted phenyl-3-cyclohexen-1-ylamines of Formula I or Ia may be prepared by reducing the correspondingly substituted 4-phenyl-3- cyclohexen-1-ylazide with LiAlH 4 . The amines thus obtained can be reacted as set out below to obtain other compounds of the invention:- (a) heating with a dihaloalkane produces a compound in which NR<SP>1</SP>R<SP>2</SP> is a heterocyclic ring; (b) reaction, in free base form, with an alkylisocyanate yields the corresponding 1-[4-(substituted aryl)-3-cyclohexen-1-yl]alkylurea; (c) reaction with an alkyl sulphony halide in the presence of a tertiary amine yields the N-[4- (substituted aryl)-3-cyclohexen-1-yl]alkyl or aryl sulphonamide, (d) heating with ethyl formate yields the corresponding formamide derivative which is in turn reduced by heating with LiAlH 4  to yield N-methyl-[4-(substituted aryl)-3-cyclohexen-1-yl]-amine which on treatment with an alkyl haloformate gives a corresponding carbamic acid alkyl ester derivative. The carbamic acid ester can be reduced with LiAlH 4  and hydrolysis gives N,N-dimethyl-4- phenyl-3-cyclohexen-l-yl amines, (e) reaction of a primary or secondary amine with the 2,2- dimethyl-1,3-propandiol ketal of a 4-halo alkylphenylketone may be used to obtain 4-[4- phenyl-3-cyclohexen-1-yl amino]alkyl phenyl ketones, (f) reaction of primary or secondary amines with 1,1-bis-phenyl-#-haloalkanes to produce N,N - [bis - (phenyl)alkyl] - 4 - phenyl- 3-cyclohexen-l-ylamines. 1-Phenyl-1,4-cyclohexanediols are prepared by reaction of a phenyl magnesium halide Guignard reagent with a 4-hydroxycyclohexanone and may be oxidized to obtain 4-phenyl-4-hydroxycyclohexanones. These may in turn be treated with strong acid, e.g. CF 3 CO 2 H to obtain 4- phenyl - 3 - cyclohexen - 1 - ones, 4 - phenyl - 3- cyclohexen - 1 - ones with NaBH 4  gives 4- phenyl - 3 - cyclohexen - 1 - ols which may be reacted with aryl or alkyl sulphonyl halides to obtain 4-phenyl-3-cyclohexen-1-yl alkyl or aryl sulphonates. 4-Phenyl-3-cyclohexen-1-ylazides are obtained by reacting the corresponding 1-alkyl or aryl sulphonate with sodium azide and heating. 2 - Alkyl and 2,6 - dialkyl - 4 - oxocyclohexane carboxylates are prepared by reduction of the corresponding 2-cyclohexene compounds and are hydrolysed to obtain the corresponding acids. Reaction of said acids with phenylmagnesium halides produces 4-phenyl-4-hydroxy- 2-alkyl or 2,6-dialkylcyclohexanecarboxylic acids which on treatment with strong acid (e.g. CF 3 CO 2 H) give 4-phenyl 2-alkyl- or 2,6-dialkyl- 3 (or 4)-cyclohexene carboxylic acids. 4-Phenyl 2-alkyl or 2,6-dialkyl-3- (or 4)-cyclohexene-1-carbamic acid esters are obtained by reaction of 4-phenyl-2-alkyl or 2,6-dialkyl-3 (or 4)-cyclohexene carboxylic acids with thionyl chloride, followed by reaction with sodium azide and heating. Pharmaceutical compositions having central nervous system depressant (sedative, muscle relaxant, analgesic, anti-psychotic and anticonvulsant) activity for oral and parenteral application comprise a compound of Formula I, Ia or Ib together with a solid or liquid pharmaceutical carrier.