Patent GB-1154345-A (GB)
Title: Substituted p-Cyclohexylphenylacetic Acids and their Derivatives, and Reduction Products
IPC: C07D295/13
Filed: 1966-06-08
Abstract: 1,154,345. Araliphatic acids, salts, esters, amides, aldehydes, acetals, alcohols and ethers, MERCK & CO. Inc. 8 June, 1966 [11 June, 1965], No. 25565/66. Heading C2C. Compounds of the general formulae (wherein R represents an alkoxy, OH, keto, NH 2  or mono- or di-alkylamino group, R m  represents a halogen atom or a trihalomethyl, NH 2 , di-(C 1-5  alkyl)-amino, C 1-5  alkoxy, alkylthio or alkylsulphonyl, di-(C 1-5  alkyl)-sulphamoyl, OH, SH, CN, NO 2 , CONH 2  or C 1-5  alkanoylamino group, at least one R m  being in the 3- or 5-position and any trihalomethyl substituent being in the 3-position, R α1  represents H and R α2  a C 1-5  alkyl group or R α1  and R α2  jointly represent = CH 2  or = CHCH 3 , and X represents COOH or a pharmaceutically acceptable salt thereof; COOR 1  where R 1  is C 2-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl, C 3-6  cycloalkyl, phenyl, (C 1-6  alkanoylamino)-phenyl, carboxyphenyl, carbamoylphenyl, mono- or poly- (C 1-5  alkoxy)-C 1-5  alkyl, C 3-6  cycloalkoxy- C 1-5  alkyl, polyhydroxy-C 1-5  alkyl, di-(C 1-5  alkyl)-amino-C 1-5  alkyl or C 3-6  cycloalkylamino-C 1-5 -alkyl; CONYY<SP>1</SP> wherein Y and Y<SP>1</SP> each represent H or a C 1-5  alkyl, mono- or poly-hydroxy-C 1-5  alkyl, phenyl substituted C 1-5  alkyl, phenyl, (C 1-5  alkoxy)-phenyl, halophenyl, trifluoromethylphenyl, cyclohexyl, carboxymethyl, benzyloxycarbonylmethyl, 1-carboxy - 3 - carbamoylpropyl, N-di-(C 1-5  alkyl)- carbamoylmethyl, N-di-(C i - 5  alkyl)-amino-C 1-5  alkyl, N-(C 1-5  alkyl)- pyrrolidyl or N-(C 1-5  alkyl) - pyrrolidyl - C 1-5  alkyl group or NYY<SP>1</SP> represents a morpholino, piperazino, N-(C 1-5  alkyl)-piperazino, N-phenylpiperazino, N-(#- hydroxyethyl)-piperazino, pyrrolidino or piperidino radical; CHO; CH 2 OH; or mono- or dialkoxy-methyl) and (wherein R α1  represents H, R α2  represents a C 1-5  alkyl group, R m  represents a halogen atom or a trihalomethyl, NH 2 , di-(C 1-5  alkyl)-amino, NO 2  or C 1-5  alkylsulphonyl at least one R  m  being in the 3- or 5-position and any trifluoromethyl group being in the 3-position, and X represents COOH or a pharmaceutically acceptable salt thereof, or a (C 1-5  alkoxy)-carbonyl or phenoxycarbonyl group) are prepared by the following methods: (1) for compounds (I), carrying out the processes shown in the following reaction schemes: (wherein R a  represents and alkyl or aryl group, R b  represents a hydroxy or acyloxy group, R 2  and R 3  each represent an alkyl group and R c  represents a C 1-5  alkyl group); (2) thereafter, if desired, carrying out one or more of the following steps on the free acids or their C 1-5  alkyl or phenyl esters or, in the case of (c) their salts: (a) oxidizing the secondary alcohol group(s) in the cyclohexane ring to keto; (b) converting ketones to primary amines via their oximes (R m  in this case not being NO 2 , CN or alkanoylamino); (c) mono- or di-alkylating the NH 2  group(s) (R m  in this case not being SH or alkanoylamino); (3) for compounds (II), dehydrating the corresponding 4-hydroxycyclohexyl compounds; (4) for compounds in which R is alkoxy, by alkylating compounds in which R is hydroxy; (5) converting to their pharmaceutically acceptable salts any of the products capable of forming salts. The products in some cases contain an asymmetric carbon atom and they are ordinarily present as racernate mixtures which may be resolved by standard methods into the d- and l-isomers, the d-isomer having anti-inflammatory activity. Therapeutic compositions having anti-inflammatory, antipyretic and analgesic activity contain as the active ingredient a compound of the first formula above. The compositions may be administered orally. 4<SP>1</SP> - (4<SP>11</SP> - Acetoxycyclohexyl) - 31 - nitroaceto - phenone by reacting 4-phenylcyclohexonol with acetic anhydride, reacting the resulting 4- acetoxy-1-phenylcyclohexane with acetyl chloride in the presence of carbon disulphide and aluminium chloride and nitrating the resulting 4<SP>1</SP> -(4<SP>11</SP> - acetoxycyclohexyl) - acetophenone. By a similar procedure 41 - (4<SP>11 </SP>- acetoxycyclohexyl) - 3<SP>1</SP> - nitropropiophenone and 4<SP>1 </SP>- (4<SP>11</SP> - propionyloxy-cyclohexyl-, 4<SP>1 </SP>- (2<SP>11 </SP>- acetoxycyclohexyl)-, 4<SP>1 </SP>- (3<SP>11</SP> - benzoyloxycyclohexyl)- and 4<SP>1</SP> - (2<SP>11</SP>, 4<SP>11</SP> - diacetoxycyclohexyl)- 31 - nitroacetophenone. 4<SP>1</SP> - (4<SP>11</SP> - Acetoxycyclohexyl) - 3<SP>1</SP>- chloroacetophenone is prepared by reducing the corresponding 3<SP>1</SP> - nitro compound, diazotizing the corresponding 3<SP>1 </SP>- amino compound and then treating the product with cuprous chloride. By a similar procedure 41 - (411 - acetoxycyclohexyl) - 3 - bromo - acetophenone and 4<SP>1</SP> - (4<SP>11</SP> - acetoxycyclohexyl) - 3<SP>1 </SP>- chloropropiophenone and the corresponding 4<SP>11 </SP>- butyryloxycyclohexyl compound. 2 - (4<SP>1</SP> - [4<SP>11</SP> - acetoxycyclohexyl] - 31 - chlorophenyl) - propionitrile is prepared by reacting 4<SP>1</SP> - (4<SP>11</SP> - acetoxycyclohexyl) - 3<SP>1 </SP>- chloroacetophenone with sodium borohydride and treating the resulting 2-(4<SP>1</SP> - acetoxycyclohexyl)- 5 - (α - hydroxyethyl) - chlorobenzene with thionyl chloride.