Patent GB-1386436-A (GB)
Title: Xanthone carboxylic acids and derivatives
IPC: C07D311/86
Filed: 1972-07-12
Abstract: 1386436 Xanthone-2-carboxylic acids and derivatives SYNTEX CORP 12 July 1972 [14 July 1971 12 Jan 1972 5 June 1972] 32533/72 Heading C2C The invention comprises compounds represented by the formulae and the pharmaceutically acceptable, non-toxic esters, amides and salts thereof; wherein each R is a group selected from those of the formulae in which R<SP>1</SP> is hydrogen, C 1 -C 8  alkyl, cycloalkyl, tetrahydrofuran-2-yl, tetrahydropyran-2- yl, tetrahydropyran-4-yl, 4-alkoxytetrahydropyran-4-yl, or carboxylic acyl containing up to 12 carbon atoms, and R<SP>1</SP> is hydrogen, C 1 -C 8  alkyl or cycloalkyl, and R<SP>2</SP> is hydroogen; C 1 -C 8  alkyl; cycloalkyl; phenyl; substituted phenyl in which the substituent is halo, C 1 -C 8  alkyl, C 1- C 8  alkoxy, C 1 -C 8  alkylthio, trifluoromethyl, or cyano; or a monocyclic aromatic heterocyclic group having five or six total members, one or two of which are selected from nitrogen, oxygen, and sulphur. They may be obtained by (1) condensing a o- or p-(carboxylic) acylphenol with a 1,3-dicarboalkoxy-4-halobenzene in the presence of cuprous oxide to give the corresponding 1,3 - dicarboalkoxy - 4 - (o- or p-acylphenyloxy)-benzene, base hydrolysing the latter to give the corresponding 1,3-dicarboxy-4-(o- or p-acylphenyloxy)-benzene, and cyclizing the latter to give the corresponding 5- or 7-acylxanthone-2-carboxylic acid; or (2) condensing an o- or p-(carboxylic)acylphenol with a 1,3-dimethyl-4-halobenzene in the presence of cuprous oxide to give the corresponding 1,3- dimethyl-4-(o- or p-acylphenyloxy)-benzene, oxidizing the latter to give the corresponding 1,3-dicarboxy-4-(o- or p-acylphenyloxy)-benzene, and cyclizing the latter to give the corresponding 5- or 7-acylxanthone-2-carboxylic acid; or (3) oxidizing a compound represented by the formula wherein R<SP>21</SP> is R<SP>2</SP> exclusive of hydrogen and R<SP>3</SP> is C 1 -C 8  alkyl, optionally followed by hydrolysis, to give the corresponding 7-acylxanthone-2- carboxylic acids or the alkyl esters thereof; or (4) treating a 5- or 7-(1,2-oxidoethyl)-xanthone- 2-carboxylic acid alkyl ester with periodic acid or with perchloric acid and sodium periodate optionally followed by hydrolysis to give the corresponding 5- or 7-formylxanthone-2-carboxylic acid or the alkyl esters thereof; or (5) oxidizing a 5- or 7-alkylxanthone-2-carboxylic acid or its alkyl ester with chromium trioxide in acetic acid-acetic anhydride optionally followed by hydrolysis to give the corresponding 5- or 7- acylxanthone-2-carboxylic acid or the alkyl esters thereof; or (6) reducing a 5- or 7-acylxanthone-2-carboxylic acid or ester of steps (1), (2), (3), (4), and (5) optionally followed by hydrolysis to give the corresponding 7- (secondary hydroxyalkyl) xanthone-2-carboxylic acids or the alkyl esters thereof; or (7) treating an appropriate 5- or 7-acylxanthone-2- carboxylic acid or ester of steps (1), (2), (3), (4), and (5) with alkyl or cycloalkyl Grignard reagent optionally followed by hydrolysis to give the corresponding 7-(tertiary hydroxyalkyl)-xanthone-2-carboxylic acids or the alkyl esters thereof; and (8) optionally esterifying a hydroxyalkyl product of steps (6) and (7) to give the corresponding 5- or 7-acyloxyalkylxanthone-2-carboxylic acid; and (9) optionally etherifying a hydroxyalkyl product of steps (6) and (7) to give the corresponding 5- or 7-etherified hydroxyalkylxanthone-2-carboxylic acid; and (10) optionally converting a product of steps (1), (2), (3), (4), (5), (6), (7), (8) and (9) to its pharmaceutically acceptable non-toxic esters, amides and salts. Examples are given for the production of the compounds. Pharmaceutical compositions comprise compounds of Formulµ A or B which may be administered topically, parenterally, orally or by inhalation, in conventional forms, optionally together with other pharmaceuticals. They are useful for inhibiting the effects of allergic reactions, also as smooth muscle relaxants and as vasodilators. The starting compounds of step (3) of Formula (9) above are prepared by the process which comprises reducing xanthone-2-carboxylic acid to give the corresponding xanthene- 2-carboxylic acid, esterifying the latter to the corresponding acid alkyl esters, and acylating the latter with an acid chloride in the presence of aluminium chloride, said xanthone-2-carboxylic acid being optionally prepared by condensing phenol with a 1,3-dicarboalkoxy-4- halobenzene in the presence of cuprous oxide, base hydrolysing the product thereof, and cyclizing the hydrolysed product. The starting compounds of step (4) are prepared by the process which comprises acylating a xanthene-2-carboxylic acid alkyl ester with chloroacetyl chloride, oxidizing the acylated product to the corresponding xanthone compound, reducing the latter to give the 5- or 7- (2 - chloro - 1 - hydroxyethyl) - xanthone - 2- carboxylic acid alkyl ester, and treating the latter with sodium hydride. The starting compounds of step (5) are prepared by the process which comprises condensing a o- or p-alkylphenol with a 1,3-dicarboalkoxy-4-halobenzene in the presence of cuprous oxide, base hydrolysing the product thereof to give the corresponding 1,3-dicarboxy-4-(o- or palkylphenyloxy)-benzene, and cyclizing the latter.