1461777 2 - Phenyl - 4 - oxo - 4H - 1 benzopyran derivatives FISONS Ltd 28 May 1974 [8 June 1973] 27379/73 Heading C2C Novel compounds of the Formula I in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  which may be the same or different each represent hydrogen, alkyl, alkoxy, halogen, alkenyl, amino, hydroxy, -CF 3 , -CN, alkylamino, alkoxyalkoxy, hydroxyalkoxy, -NO 2  or R 6  and R 7  together form a -(CH 2 ) 4 - or -(CH 2 ) 3 O- chain, and E is a carboxylic acid group, a 1H-tetrazol-5-yl group, a N-(1H- tetrazol-5-yl) carboxamide group, a group -CH 2 COOH, a group -CONHOH, or a group -CO-CHR 2 CO-R 1 , R 1  represents alkyl C 1-6 , alkoxy C 1-6 , phenyl, amino, or mono- or dialkyl C 1-6  amino, R 2  represents hydrogen or -CORx, and Rx represents alkyl C 1-6 , alkoxy C 1-6 , amino or mono- or di-alkyl C 1-6  amino, or R 1  and R 2  together form a 3- or 4-membered alkylene chain which is optionally interrupted by an -NH- group, and which chain is optionally substituted by one or more alkyl C 1-6  groups and/or, on the carbon atom a to the methine proton, by a carbonyl oxygen atom, and pharmaceutically acceptable salts, esters and amides of the group E thereof where E is capable of priming such a derivative, provided that (i) when E is a -COOH group, or a pharmaceutically acceptable salt, ester or amide thereof, and R 3 , R 8 , R 9 , R 10 , R 11  and R 12  are all hydrogen then (A) R 5  is not hydrogen or alkoxy, or (B) R 6  is not hydrogen, hydroxy, alkyl or alkoxy, or (C) R 7  is not hydrogen or alkoxy, or (ii) when E is a -COOH group, or a pharmaceutically acceptable salt, ester or amide thereof, E is not in the 2<SP>1</SP>-position, may be prepared by (a) cyclizing a compound of Formula II in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , E and the provisos are as defined above, with the further proviso that E and either of the groups on adjacent carbon atoms do not form a cyclizable pair of groups, Z is a reactive halogen atom or a group -OM, and M is hydrogen or an alkali metal cation, (b) producing a compound of Formula Ia in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12  and the provisos are as defined above, by hydrolysing a compound of Formula III in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12  and the provisos are as defined above, and Ry represents a group which is hydrolysable to a -COOH group, (c) producing a compound of Formula Id in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are as defined above, by reacting a compound of Formula VI  in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are as defined above, with an azide in a solvent which is inert under the reaction conditions, (d) producing a compound of Formula Ie in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are as defined above, by reacting an anhydride, ester or acid halide of a compound of Formula Ia, with hydroxylamine, (e) producing a compound of Formula I in which E is a group by (1) reacting an acid halide or a mixed anhydride of a compound of Formula Ia, with a compound of formula CH 2 R 2 COR 1 , or an enamine thereof, and if an enamine is used, hydrolysing the resulting compound, or (ii) hydrolysing a compound of Formula VII in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are as defined above, and Ra and Rb, which may be the same or different, each represent an alkyl C 1-6  group, or together with the nitrogen atom form a 5, 6 or 7 membered heterocyclio ring which optionally contains an oxygen atom, (f) producing a compound of Formula Ih in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are as defined above, by treating a compound of Formula VIII in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are as defined above, with water, (g) producing a compound of Formula I in which R 3  is a halogen atom by selective halogenation of a corresponding compound of Formula I in which R 3  is a hydrogen atom, (h) producing a compound of Formula I in which R 3  is an -OH group by oxidative cyclization of a compound of Formula X in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  ,R 12 , E and M are as defined above, (i) producing a compound of Formula I in which one or more of R 3  to R 12  is an alkoxy group or a hydroxyalkoxy group, subject to the provisos defined above, by reacting a corresponding compound of Formula I in which one or more of R 3  to R 12  is an -OH group, subject to proviso (i) (B) only, with an alkylating agent, or with an alkylene oxide respectively, (j) selectively dehydrogenating a corresponding flavanone compound of Formula XV in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , E and the provisos are as defined above, (k) producing a compound of Formula I in which at least one of R 3  to R 12  is an amino group, by selective reduction of a corresponding compound of Formula I in which at least one of R 3  to R 12  is a -NO 2  group, (1) producing a compound of Formula Il in which R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are as defined above, by reacting an anhydride, ester or acid halide of a compound of Formula Ia, with 5-aminotetrazole, or (m) producing a compound of Formula I in which R 3  to R 12  and the provisos are as defined above, save that one of R 3  to R 12  is an -OH group, by dealkylation of a corresponding compound of Formula I in which R 3  to R 12  are as defined above (but the provisos do not apply except as regards R 6 ), save that one of R 3  to R 12  except R 6  is an alkoxy group and where desired or necessary converting the compound of Formula I to a pharmaceutically acceptable salt, ester or amide of the group E thereof or vice versa. Intermediates of the Formula II are prepared by rearrangement under basic conditions of the corresponding 2 - (E - substituted benzoyloxy)- acetophenone which in turn is produced by acylation of a 2-hydroxy acetophenone, using an E-substituted benzoic acid derivative. Under certain conditions the diketo II is formed directly from the esterification process. Also compounds of the Formula I may be prepared directly from the acetophenone above without isolation of the compound II. Intermediates of the Formula III in which Ry is cyano are prepared (1) from a compound of the Formula II in which E is nitro by cyclization to produce a compound I in which E is nitro followed by reduction of the nitro group to amino followed by diazotization and reaction with copper cyanide or (2) cyclization of a compound of the Formula II in which E is acetamido followed by hydrolysis of this grouping to amino and then diazotization and reaction with copper cyanide. In both preparations the compound of the Formula II is prepared from the corresponding 2-hydroxy acetophenone and an E-substituted benzoic acid derivative as described in the previous paragraph. Intermediates of the Formula VIII are prepared by reacting a compound of the Formula I in which E is -COCl with diazomethane. Intermediates of the Formula X are prepared by reacting 2-hydroxy acetophenone with an E-substituted benzaldehyde. 2-Chloro-6-hydroxyacetophenone is prepared by diazotization of 2-amino-6-chloroacetophenone. 2 - Bromo - 6 - hydroxyaoetophenone is prepared by forming the acid chloride from 2- bromo-6-nitrobenzoic acid followed by reaction of the acid chloride with diethylmalonate/Mg to yield diethyl 2 - bromo - 6 - nitrobenzoylmalonate which is decarboxylated to yield 2-bromo-6- nitroacetophenone which is reduced to 2-amino-6- bromoacetophenone which is diazotized to yield the required compound. 3,4 - Dichloro - 2 - hydroacetophenone and 3,6- dichloro-2-hydroacetophenone are prepared by reacting the appropriate dichlorophenol with dimethyl acetylene-dicarboxylate to yield a dichlorophenoxyfumaric acid (and also the maleic acid) which is cyclized to yield a dichloro-4-oxo- 4H-1-benzopyran-2-carboxylic acid which on hydrolysis yields the required compounds. 4 - Carbomethoxy - 3 - nitrobenzoyl chloride is prepared by partial hydrolysis of dimethyl nitroterephthalate to yield 4-carbomethoxy-3- nitrobenzoic acid followed by formation of the acid chloride. Chloroterephthalic acid is formed as a byproduct from the reaction of 3-chloro-2- hydroxy-acetophenone and 3-chloro-4-carbomethoxy benzoic acid. Pharmaceutical compositions of the compounds I with the usual excipients show bronchodilatory activity and are useful in treatment of other diseases caused by antigen-antibody reactionswhen administered orally or by inhalation.