Patent GB-1447032-A (GB)
Title: Tricyclic sulphones and pharmaceutical compositions containing  them
IPC: C07D333/76
Filed: 1972-05-19
Abstract: 1447032 Tricyclic sulphones WELLCOME FOUNDATION Ltd 17 Aug 1973 [19 May 1972 6 Sept 1972 4 May 1973] 19552/76 and 19553/76 Divided out of 1447031 Heading C2C The invention comprises compounds of the formula wherein Z<SP>1</SP> is carboxyl, a carboxylate salt a (C 1 -C 6 ) -alkylcarboxylate or a carboxamide optionally substituted by (C 1 -C 6 )-alkyl, Z<SP>3</SP> is a bond, -CO-, -O-, -S-, -SO-, or -CH 2 - and Z<SP>2</SP> is H, a carboxylate salt, (C 1 - C 6 )-alkylsulphonyl, alkylsulphinyl, alkylthio, alkyl or alkoxy, (C 2 -C 7 )-alkanoyl or alkanoylamino, amino, NO 2 , CN or halogen, with the proviso that (1) when Z<SP>2</SP> is H or a carboxylate salt then Z<SP>1</SP> is a carboxylate salt, and (2) when Z<SP>3</SP> is -CO- and Z<SP>1</SP> is in the 2-position then Z<SP>2</SP> when in the 5-, 6- or 7-position, is other than halogen, alkanoyl, alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl; and except for 7 - nitro - 2 - carboxythioxanthone - 10,10- dioxide and its amide, 9-nitro-4-carboxyphenoxathiin - 10,10 - dioxide, 8 - chloro - 2 - carboxyphenoxathiin - 10,10 - dioxide and its methyl ester, 4,6-dicarboxydibenzothiophene- 5,5-dioxide disodium salt, and 8-chloro-2- carboxythioxanthone-10,10-dioxide. They may be obtained by (a) when Z<SP>1</SP> is carboxyl or a carboxylate salt, or both Z<SP>1</SP> and Z<SP>2</SP> are carboxylate salts, hydrolysing a compound of the formula wherein Y<SP>1</SP> is a carboxyl group precursor or is the same as Z<SP>1</SP> and Y<SP>2</SP> is carboxyl group precursor or is the same as Z<SP>2</SP>, with a base or with a dilute aqueous mineral acid optionally in the presence of an organic acid; (b) oxidizing a compound of the formula wherein Y<SP>5</SP> is alkyl, alkanoyl or is the same as Z<SP>1</SP>, Y<SP>3</SP> is the same as Z<SP>3</SP>, Y<SP>4</SP> is -S-, -SO-, or -SO 2 -, and Y<SP>6</SP> is alkyl, alkanoyl or is the same as Z<SP>2</SP>, provided that when Y<SP>5</SP> is the same as Z<SP>1</SP> and Y<SP>6</SP> is the same as Z<SP>2</SP> then at least Y<SP>4</SP> is - or Y<SP>3</SP> is -CH 2 - or -S-,-S-or-SO with an appropriate oxidizing agent; (c) when Z<SP>3</SP> is -O- or -S-, cyclizing a compound of the formula wherein one of R<SP>2</SP> and R<SP>3</SP> is SH, OH or an ester thereof and the other is a leaving group, with a base; (d) cyclizing a compound of the formula using a Lewis acid; (e) cyclizing a compound of the formula with C1SO 3 H; (f) when Z<SP>3</SP> is -S- or -CH 2 -, reducing the corresponding compound of Formula I wherein Z<SP>3</SP> is -SO- or -CO-, with an appropriate reducing agent; (g) when Z<SP>3</SP> is -S-, reacting a compound of the formula wherein R<SP>5</SP> and R<SP>6</SP> are each leaving groups, with sodium sulphide; or (h) when Z<SP>3</SP> is -CO-, cyclizing a compound of the formula wherein R<SP>1</SP> is -COOH or a derivative thereof or is -CHO, in the presence of a Lewis or protonic acid; and when a salt, an amide or an alkyl ester is required converting the products obtained above by appropriate reactions. Pharmaceutical compositions comprise the compounds of Formula I and in addition the compounds excluded by proviso (1) and those compounds specifically named, in association with an acceptable carrier. They are useful as inhibitors of allergic reactions associated with asthma, hay fever, conjunctivitis, urticaria and eczema and may be applied orally, rectally, ophthalmically, pulmonarily, nasally, dermally, topically or parenterally. The preparation of the following intermediates and other products is described: Prep. (1) 2-carboxydibenzothiophene-5,5-dioxide from dibenzothiophene via 2-acetyldibenzothiophene and dibenzothiophene-2-carboxylic acid; Prep. (2) 2,8-dicarboxyphenoxathiin-10,10-dioxide from 2,8-diacetylphenoxathiin via its 10,10-dioxide; Prep. (3) 2-methoxycarbonylphenoxathiin-1.0,10-dioxide from the corresponding free acid; Prep. (4) 3-carboxythioxanthone- 10,10-dioxide from benzene sulphonyl chloride and p-xylene via 2,5-dimethyldiphenyl sulphone and diphenyl sulphone-2,5-dicarboxylic acid; Prep. (5) 2-carbozyphenozathiin-10,10-dioxide by a route analogous to prep. (1); Preps. (6) and (7) 2-carboxythioxanthone-10,10-dioxide by a route analogous to prep. (4) or from toluene and omercaptobenzoic acid via methylthioxanthone and its 10,10-dioxide; Prep. (9) 3-carboxythioxanthone-10,10-dioxide from 3-carboxy-thioxanthone-10,10-dioxide; Prep. (10) 2,6-dicarboxythioxanthone - 10,10 - dioxide from diphenylsulphone 2,4<SP>1</SP>,5- tricarboxylic acid; Prep. (11) 2,7 - dicarboxythioxanthone - 10,10 - dioxide by a route analogous to prep. (4); Prep. (12) 3- methoxycarbonylthioxanthone - 10,10 - dioxide from the corresponding free acid; Example (1) 7 - ethylthioxanthone - 3 - carboxylic acid from ethylbenzene via p-ethylthiophenol, and 2-(pethylphenylthio) terephthalic acid; Example (2) 7 - t - butylthioxanthone - 3 - carboxylic acid from p - t - butylthiophenol and nitroterephthalonitrile via 2 - (p - t - butylphenylthio) terephthalic acid; Example (3) 2,8 - dimethylphenoxathiin - 10,10 - dioxide from p - bromotoluene and p-cresol via 4,4<SP>1</SP>-dimethyldiphenyl ether and 2,8-dimethylphenoxathiin; Example (4) p - chlorophenylsulphonyl terephthalic acid from p-chlorothiophenol and nitroterephthalonitrile via p-chlorophenylthioterephthalonitrile and the corresponding free acid; Example (5) 7 - methoxythioxanthone - 3 - carboxylic acid by a route analogous to Example (2); Prep. (15) 3- carboxydibenzothiophene - 5,5 - dioxide from dibenzothiophene - 5,5 - dioxide via 3 - nitro- and 3 - amino - dibenzothiophene - 5,5 - dioxide; Prep. (16) 3-carboxythioxanthene-10,10-dioxide from 3 - carboxythioxanthone - 10,10 - dioxide; Example (6) 7-methylthioxanthone-3-carboxylic acid by a route analogous to Example (2); Example (10) 7-Nitrothioxanthone- 3-carboxylic acid from sodium 4-nitrothiophenoxide and 2,5- dicyanonitrobenzene via 2,5-dicyano- 4<SP>1</SP>-nitrodiphenylsulphide and p - nitrothiophenoxy terephthalic acid; Prep. (17) 2,5-dicarboxythioxanthone-10,10-dioxide from thioxanthone-2,5-dicarboxylic acid which is itself obtained by a route analogous to Example (10); Prep. (18) 1-carboxythioxanthone-10,10-dioxide by a route analogous to Prep. (17); Prep. (19) 3-carboxythianthrene-5,5,10-trioxide from 3-carboxythianthrene-5,5-dioxide; and Prep. (20) 4,5-dicarboxythioxanthone-10,10-dioxide by a route analogous to Prep. (17). Other intermediates are described in Specification 1,447,031.