GB989951A - Anti-inflammatory pharmaceutical compositions containing n-phenyl anthranilic acid derivatives - Google Patents

Abstract

N-Phenylanthranilic acid derivatives of the general formula <FORM:0989951/C2/1> (wherein R1 is a halogen atom or a methyl group; R2 is a halogen atom or a methyl or ethyl group; R3 and R5 are each hydrogen or halogen atoms or methyl groups, R5 not being hydrogen when R3 is halogen; R4 is a hydrogen or halogen atom, R4 and R3 both being hydrogen when R1 and R2 are both methyl; and at least one of R3, R4 and R5 being a hydrogen atom) are prepared by reacting an o-halogenated benzoic acid compound of general formula <FORM:0989951/C2/2> wherein M is hydrogen or a metal and X is halogen, with a compound of the general formula <FORM:0989951/C2/3> in the presence of a copper-containing catalyst and a proton acceptor. Alternatively, compounds of the Formula 1 above may be prepared by the hydrolysis of N-acylated diphenylamines of formula <FORM:0989951/C2/4> wherein R1-5 have the above meanings and R is a carboxy group or a group hydrolysable thereto (e.g. a cyano, carboalkoxy, carboaryloxy, carboarylalkoxy, carbamido or carbonyl halide group), which groups, and also the acyl group, may contain one or more substituents, e.g. C1-4 alkyl, C1-4 alkoxy, halogen, nitro, carboxy and carboalkoxy radicals. N - Phenyl - N - acyl - anthranilic acid compounds of Formula 4 above may be prepared by the following reaction sequences: (a) an anilide of the general formula <FORM:0989951/C2/5> in which R6 is a tertiary alkyl group or an aryl radical optionally substituted by one or more halogen, nitro, C1-4 alkyl, C1-4 alkoxy, carboxy and carboalkoxy groups and R7 is a cyano, carboxy, carboalkoxy, carboaryloxy, carboarylalkoxy or carbamido group is reacted with PCl5 to produce a benzimidoyl chloride of general formula <FORM:0989951/C2/6> which is reacted with a phenol compound of the general formula <FORM:0989951/C2/7> or an alkali metal salt thereof to give an imido imido ester of general formula <FORM:0989951/C2/8> which is heated to arrange intramolecularly to give an N-acylated diphenylamine of formula <FORM:0989951/C2/9> Alternatively, N-acylated diphenylamines of Formula 7 above in which R7 is cyano or carbamido may be prepared by reacting a compound of formula <FORM:0989951/C2/100> in which R8 is a cyano or carbamido group with thionyl chloride to produce the corresponding imino chloride of formula <FORM:0989951/C2/111> which is reacted with a phenol of general formula <FORM:0989951/C2/122> to produce an imidoester of formula <FORM:0989951/C2/133> which is rearranged by heat to obtain an N-acylated diphenylamine of formula <FORM:0989951/C2/144> The N-acylated-N-phenylanthranilic acid starting materials which contain non-oxidizable substituents in the N-phenyl ring can be prepared by the oxidation of a compound of formula <FORM:0989951/C2/155> wherein R9 is a radical oxidizable to a carboxyl group, Ar represents a phenyl ring containing non-oxidizable substituents R1, R2, R3, R4 and R5 and Acyl has the above meaning, such compounds being prepared from the o-R9-substituted -NCOR6 aniline and the corresponding substituted phenol as described above.ALSO:Anti-inflammatory pharmaceutical compositions comprise a carrier and a substantially chemically pure compound (or a pharmaceutically acceptable salt thereof) of general formula <FORM:0989951/A5-A6/1> wherein R1 is a halogen atom or a methyl group; R2 is a halogen atom or a methyl or ethyl group; R3 and R5 each represent a hydrogen atom or a methyl group, R5 being halogen or methyl when R3 is halogen; R4 is a hydrogen or halogen atom, R4 and R3 both being hydrogen when R1 and R2 are methyl groups; and at least one of R3, R4 and R5 is hydrogen. Specified salts are those with sodium, potassium, calcium, ammonium, choline, 2 - hydroxyethyl - ammonium, bis(2-hydroxyethyl)ammonium and tris-(2-hydroxyethyl) ammonium. The compositions may be in conventional forms suitable for oral and parenteral administration and may optionally comprise other anti-inflammatory agents such as corticosteroids, e.g. prednisone, prednisolone, cortisone, hydrocortisone and 9- or 12-halocorticosteroids.