Patent GB-1409341-A (GB)
Title: Thioxanthone carboxylic acids and derivatives
IPC: C07D409/12
Filed: 1973-01-03
Abstract: 1409341 Thioxanthones carboxylic acids and derivatives SYNTEX (USA) Inc 3 Jan 1973 [19 July 1972 21 Nov 1972] 387/73 Heading C2C The invention comprises compounds of formula and the pharmaceutically acceptable, non-toxic esters, amides and salts thereof, wherein each m is the integer 0, 1 or 2, each R is C 1-5  alkyl; -O-(C 1-5 ) alkyl; -OH and the conventional esters thereof; halo, mercapto, C 1-5  alkylthio, -CF 3 ; or a group selected from in which R<SP>1</SP> is H, C 1-5  alkyl, cycloalkyl, tetrahydrofuran-2-yl, tetrahydro, pyran-4-yl, 4- alkoxytetrahydropyran-4-yl, or acyl containing up to 12 carbon atoms, R<SP>1</SP> is H, C 1-15  alkyl or cycloalkyl; R<SP>2</SP> is H, C 1-5  alkyl, cycloalkyl, phenyl, substituted phenyl (in which the substitutuent is halo, C 1-5  alkyl, C 1-5  alkoxy, C 1-5  alklthio, -CF 3  or -CN), or a monocyclic 5- or 6-membered heterocyclic group having one or two hetero atoms selected from N, O and S; n is the integer 1 or 2; R<SP>3</SP> is C 1-5  alkyl when n is 1 and R<SP>3</SP> is C 1-5  alkyl, -OH, -N 2 , mono C 1-5  alkylamino or di C 1-5  alkylamino when n is 2. These compounds may be obtained by (1) condensing an o-mercaptobenzoic acid with a phalobenzoic acid or an o-halobenzoic acid with a p-mercaptobenzoic acid in the presence of copper powder with potassium carbonate to prepare the corresponding 4-(o-carboxyphenylthio)-benzoic acid; or (2) condensing a mercaptobenzene with a 1,3-dicarboxy-4-halobenzene in the presence of copper powder with potassium carbonate to prepare the corresponding 1,3- dicarboxy-4-(phenylthio)benzene; or (3) conducting the procedures of Steps (1) and (2) with the corresponding alkyl esters of the benzoic acid reagents using cuprous oxide followed by base hydrolysis to give the same products; and (4) optionally oxidizing a product of Steps (1), (2) and (3) to give the corresponding S-oxo and S,S-dioxo compounds; and (5) cyclizing a product of Steps (1), (2), (3), and (4) to give the corresponding 5, 6 or 7, monosubstituted or 5, 7 di-substituted thioxanthone-2-carboxylic acid or the 10-oxo or 10, 10-dioxo compounds thereof; and (6) optionally oxidizing, if necessary, a product of Step (5) to give the corresponding 10-oxo and 10,10-dioxo compounds and (7) optionally cleaving a methoxy substituted product of Steps (5) and (6) to give the corresponding hydroxy compound and treating the latter with lower alkyl halide in the presence of base optionally followed by hydrolysis to give the corresponding alkoxy substituted compounds; and (8) optionally esterifying any hydroxy substituted compounds, and (9) oxidizing an (alkyl)thioxanthone-2-carboxylic acid with chromic oxide in acetic acid-acetic anhydride to give the corresponding (alkanoyl)- thioxanthone-2-carboxylic acids; and (10) reducing an acyl substituted thioxanthone-2- carboxylic acid ester of Steps (5), (6), and (9) optionally followed by hydrolysis to give the corresponding (secondary hydroxyalkyl)-thioxanthone-2-carboxylic acid or the alkyl esters thereof; or (11) treating an appropriate acyl substituted thioxanthone 2-carboxylic acid ester of Steps (5), (6), and (9) with alkyl or cycloalkyl Grignard reagent optionally followed by hydrolysis to give the corresponding (tertiary hydroxyalkyl)thioxanthone-2-carboxylic acid or the alkyl esters thereof; or (12) oxidizing an alkylthio substituted thioxanthone-2-carboxylic acid or an alkyl ester thereof with a peracid optionally followed by hydrolysis to give the corresponding (alkylsulfinyl)thioxanthone-2- carboxylic acid or the alkyl esters thereof; or (13) oxidizing an alkylthio substituted thioxanthone-2-carboxylic acid or an alkyl ester thereof with hydrogen peroxide optionally followed by hydrolysis to give the corresponding (alkylsulfonyl)thioxanthone-2-carboxylic acid or the alkyl esters thereof; or (14) treating an alkylthio substituted thioxanthone-2-carboxylic acid ester with chlorine under acidic conditions optionally followed by hydrolysis to give the corresponding (chlorosulfonyl)thioxanthone - 2 - carboxylic acid or the alkyl esters thereof; and (15) treating a chlorosulfonyl substituted thioxanthone-2-carboxylic acid with base to give the corresponding (sulfro)thioxanthone-2-carboxylic acid; or (16) treating a chlorosulfonyl substituted thioxanthone-2-carboxylic acid with ammonia, monoalkylamine, or dialkylamine to give the corresponding sulfamoyl-, monoalkylsulfamoyl-, and dialkylsulfamoyl substituted thioxanthone- 2-carboxylic acid; and (17) optionally esterifying a hydroxyalkyl product of Steps (10) and (11) to give the corresponding (acyloxy alkyl)-thioxanthone-2-carboxylic acid; and (18) optionally esterifying a hydroxyalkyl product of steps (10) and (11) to give the corresponding (etherified hydroxyalkyl)-thioxanthone-2- carboxylic acid; and (19) optionally converting a product of Steps (5), (6), (7), (8), (9), (10), (11), (12), (13), (15), (16), (17), and (18) to it pharmaceutically acceptable, non-toxic esters, amides, and salts. The following intermediate compounds are prepared: 4-(2-Carboxy-4-methylphenylthio)-benzoic acid by the reaction of 4-bromobenzoic acid with 2 - mercapto - 5 - methylbenzoic acid in Example I; and 1,3-Dicarbomethoxy-4-(p- (methoxy) - thiophenyloxy) - benzene is prepared by reacting 1,3-dicarbomethoxy-4-bromobenzene with p - (methoxy) - thiophenol in Example 5. The two ester groups of this intermediate are converted into free carboxylic groups by conventional methods. The invention also comprises a pharmaceutical composition useful for inhibiting the effects of allergic reaction and for treating bronchopulmonary disorders which contains as an active ingredient a compound according to the invention in admixture with a pharmaceutically acceptable non-toxic carrier.