Patent GB-1091403-A (GB)
Title: Therapeutically active phenylalkane derivatives
Inventor: ADAMS STEWART SANDERS
IPC: C07C57/42
Filed: 1964-01-24
Abstract: The invention comprises novel compounds of Formula (I) <FORM:1091403/C2/1> where R1 is hydrogen, halogen, C1- 4 alkyl C1- 4 haloalkyl, C1- 4 alkoxy, C1- 4 alkylthio, nitro or cyano; R2 is hydrogen or fluorine in the 21, 31, 51 or 61 positions; R3 i hydrogen, one or more halogen atoms, one or more C1- 4 alkyl groups, one or more C1- 4 haloalkyl groups, C1- 4 alkoxy, C1- 4 alkylthio, nitro or cyano; A is <FORM:1091403/C2/2> or <FORM:1091403/C2/3> (where R5 is hydrogen, C1- 4 alkyl, or C2- 4 alkenyl); and X is COOR4 (where R4 is hydrogen or C1- 4 alkyl), CH2OH or CONR6R7 (where R6 and R7 are hydrogen or C1- 4 alkyl); together with non-toxic organic and inorganic salts of the compounds in which X is COOH; provided (1) R1, R2 and R3 are all hydrogen, only when A is <FORM:1091403/C2/4> , (2) A-X is not CH2COOH when simultaneously R1 and R2 are hydrogen and R3 is 3-methyl, and (3) R5 is not hydrogen when R1 is a substituent in the 4-position. The acetic acids may be prepared from 4-acetylbiphenyls by the Willgerodt reaction with morpholine and sulphur, followed by hydrolysis of the intermediate thiomorpholide or by the Arndt-Cistert reaction in which a 4-chlorocarbonylbiphenyl is treated with diazomethane and the resulting diazoketone is treated with silver oxide and methanol to give the corresponding methyl 4-biphenylylacetate which is hydrolysed to the acid.  Higher homologous a -biphenylylalkanoic acids may be prepared by reacting a 4-biphenylylacetic acid or an ester thereof with diethyl carbonate in the presence of sodium ethoxide, reacting the sodium derivative of the 2-(4-biphenylyl)-malonic acid ethyl ester formed with an alkyl halide, hydrolysing the 2-alkyl-2-(4-biphenylyl)-malonic acid ethyl ester thus formed and decarboxylating the resultant acid. Compounds in which A-X represents <FORM:1091403/C2/5> may be made by reacting a 2-(4-biphenylyl)-malonic acid with formaldehyde and dimethylamine, refluxing the 2 - (4 - biphenylyl)-2 - dimethylaminomethyl - malonic acid with sodium hydroxide, and acidifying the solution. The salts, esters and amides may be prepared by known methods.  The invention also includes optically active isomers of compounds of Formula (I) where appropriate.  The 4-acetylbiphenyls are made from a biphenyl by a Friedel-Craft reaction.  The biphenyls may be prepared by diazotizing an aniline which may have been produced by reducing the corresponding nitrobenzene, and treating the diazonium salt with benzene. 4-Acetyl-2-methylbiphenyl may be prepared by treating 4-cyano-2-methylbiphenyl (obtained by reacting 4-bromo-2-methylbiphenyl with cuprous cyanide) with methyl magnesium iodide, and decomposing the complex with hydrochloric Acid. 21-Nitro-4-biphenylylacetic acid and ethyl-21 -nitro-4-biphenylylacetate are obtained from 21-nitro-4-biphenylylacetonitrile, which is made by treating 2-nitrobiphenyl with hydrochloric acid, zinc chloride and paraformaldehyde in glacial acetic acid, and reacting the 4-chloromethyl -21-nitrobiphenyl obtained with sodium cyanide.  The 2-(4-biphenylyl)-alkan-1-ols may be prepared by reducing the corresponding esters.  The substituents on the benzene rings may be introduced or interconverted by known methods.  Therapeutic compositions having anti-inflammatory and/or analgesic and/or antipyretic properties which may be administered orally, topically or parenterally, contain as active ingredient a compound of Formula (I) above.