Patent GB-1119334-A (GB)
Title: Para-substituted phenylacetic acids, aldehydes and alocohols and their derivatives
IPC: C07D333/22
Filed: 1965-11-22
Abstract: Compounds of the general formula <FORM:1119334/C2/1> (wherein Het represents a thienyl, furyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl radical, R1 represents H or a lower alkyl, alkenyl, alkynyl or haloalkyl radical and R2 represents H, or R1 and R2 together represent a methylene, C2- 5 alkylidene or ethylene radical, R3 and R4 each represent a halogen atom or a lower alkyl, alkylthio, alkylsulphonyl or alkanoylamino, trihalomethyl, SH, NH2, di-(lower alkyl)-amino, CN, NO2, CONH2, di-(lower alkyl)-carbamoyl, di-(lower alkyl)-sulphamoyl, phenyl, acetyl, trifluoroacetyl or trifluoro-methylthio radical, n and m are each 0,1 or 2, X represents COOH; COOM where M is an equivalent of a pharmaceutically non-toxic cation; COOR111 where R111 is lower alkyl, alkenyl or alkynyl, C3- 6 cycloalkyl, aralkyl, morpholinoalkyl, phenyl, (lower alkanoylamino-phenyl, carboxyphenyl, carbamoylphenyl, mono- or poly-(lower alkoxy)-lower alkyl, lower polyhydroxyalkyl or di-(lower alkyl)-amino-lower alkyl; CONY1Y11 where Y1 and Y11 are each H, lower alkyl, mono- or poly-hydroxy-lower alkyl, phenyl-lower alkyl, phenyl, (lower alkoxy)-phenyl, halophenyl, trifluoro-methylphenyl, cyclohexyl, carboxymethyl, 1-carboxy-3-carbamoylpropyl, N, N-di - (lower alkyl) - carbamoylmethyl, N, N-di-(lower alkyl)-amino-lower alkyl, N-(lower alkyl)-pyrrolidyl or N-(lower alkyl)-pyrrolidyl-lower alkyl or Y1 and Y11 jointly form with N amorpho ino, 1-piperazinyl, 4-loweralkyl-1-piperazinyl, 4 - phenyl - 1 - piperazinyl, 4 - (b -hydroxyethyl) - 1 - piperazinyl, 1 - pyrrolidinyl or piperidino radical; CHO; CH2OH; CH2OR6 where R6 is alkyl, alkenyl, aralkyl or alkoxyalkyl or CH(OR7)2 where R7 is alkyl, and the term "lower" means "containing not more than 5 carbon atoms, excluding those in any functional groups such as CO, OCO, COOH, CN or CONH2" are prepared by the following methods: (I) for free acids (X = COOH) wherein R1 = R2 = H, carrying out the following process: <FORM:1119334/C2/2> (wherein R3 and R4 each represent halogen, NO2, di-(lower alkyl)- sulphamoyl, di-(lower alkyl)-carbamoyl, trihalomethyl, lower alkyl, acetyl, trifluoroacetyl, trifluoromethylthio or phenyl); (II) for free acids (X = COOH) wherein R1 and R2 are jointly methylene C2- 5 alkylidene or ethylene, carrying out the following process: <FORM:1119334/C2/3> (wherein neither R3 nor R4 may represent NO2, CN, CONH2 or alkanoylamino); (III) for free acids (X = COOH) wherein R1 is lower alkyl, alkenyl, alkynyl or haloalkyl and R2 is H, carrying out the following process <FORM:1119334/C2/4> (wherein R3 and R4 each represent halogen, NO2, lower alkyl, alkylthio or alkylsulphonyl, di-(lower alkyl) - sulphamoyl, trihalomethyl, phenyl-lower alkyl, di - (lower alkyl) - carbamoyl, acetyl, trifluoroacetyl or trifluoromethylthio); (IV) for free acids (X = COOH) wherein R1 is lower alkyl and R2 is H, hydrogenating the corresponding compounds wherein R1 and R2 are jointly methylene or C2- 5 alkylidene and wherein R3 and R4 are restricted as in (II); (V) after any of the foregoing processes, introducing further desired substituents by one or more of the following steps: nitration; reduction of NO2 to NH2; dialkylating or alkanoylating NH2; replacing NH2 by SH or CN by diazotization and reaction of the diazonium salt with a C1- 5 alkyl xanthate under alkaline conditions or with cuprous cyanide; alkylating SH; oxidizing S-Alkyl to SO2-Alkyl; subjecting SH to the process SH-->SO3H-->SO2Cl-->SO2N(Alkyl)2; acid hydrolysis of CN to CONH2; (VI) for salts (X = COOM), reacting the free acids with inorganic or organic bases containing pharmaceutically nontoxic cations; (VII) for esters (X = COOR111), omitting the hydrolysis step in certain of the foregoing processes, or esterifying the free acids with R111OH; (VIII) for amides (X = CONY1Y11), amidating the free acids with HNY1Y11; (IX) for aldehydes (X = CHO), benzylating any R3 or R4 substituents containing active H in the free acids, converting them to their acid halides, and reducing these (with simultaneous removal of any benzyl groups) by means of H2 in the presence of BaSO4/Pd and quinoline or of an alkali or alkaline-earth metal tri-t-butoxy aluminium hydride; (X) for acetals (X = CH(OR7)2), reacting the aldehydes with a C1- 5 alkanol in the presence of at least a catalytic amount of a strong acid; (XI) for alcohols (X = CH2OH), reducing the corresponding acids with an alkali or alkaline-earth metal aluminium hydride; (XII) for ethers (X = CH2OR6), reacting the alcohols with a strongly basic condensing agent and with an alkyl, alkenyl, aralkyl or alkoxyalky halide.  Starting materials.-The preparation of the starting materials for processes (I) and II) is described, the following compounds being among those formed in the course of these preparations: 2 - (4 - amino - and 4 - cyano - 2 - chlorophenyl) - thiophene, - furan, - thiazole, - pyrazole and - isoxazole; ethyl 4 - (2-, 3-and 4 - pyridyl) - 3 - chlorobenzoate; 2 - phenyl-, 2 - p - nitrophenyl-, 2 - p - aminophenyl- and 2 - p - cyano-phenyl - 6 - chloropyridine; 21 - chloro - 41 - nitro - 2 - chloroacetophenone: 4 - (2 - chloro - 4 - nitrophenyl) - thiazole, -oxazole, -imidazole, -pyrazole and isoxazole; 4 - p - nitrophenyloxazole; 2 - methyl - 4 - chloro- 4 - nitrophenyl) - imidazole; 4 - p - nitrophenylpyrazole; 2 - chloro - 4 - nitrophenyl b -chlorovinyl ketone; 4 - p - nitrophenyl-isoxazole. Pharmaceutical compositions, having antiinflammatory, activity, comprise the compounds of the invention (other than those having an a -C3- 5 alkylidene substituent) together with nontoxic diluents, carriers or coatings.