Patent GB-1447031-A (GB)
Title: Tricyclic sulphones and pharmaceutical compositions containing them
IPC: C07D257/04
Filed: 1973-05-04
Abstract: 1447031 Tricyclic sulphones WELLCOME FOUNDATION Ltd 17 Aug 1973 [19 May 1972 6 Sept 1972 4 May 1973] 23805/72 and 414291/72 Heading C2C The invention comprises compounds of the formula wherein Z<SP>1</SP> is 5-tetrazolyl or 5-(1- or 2-C 1 -C 6  alkyl)-tetrazolyl where the alkyl groups may be substituted by OH, NH 2  optionally substituted by one or two CH 3  groups or COOH, Z<SP>2</SP> is H, a group such as Z<SP>1</SP>, COOH, (C 1 -C 6 )-alkylsulphonyl, alkylsulphinyl, alkylthio, alkyl or alkoxy, (C 2 -C 7 )-alkanoyl or alkanoylamino, amino, NO 2 , CN or halogen, Z<SP>3</SP> is a bond, -CO-, -O-, -S-, -SO-, or -CH 2 -; or a salt thereof, or when Z<SP>2</SP> is COOH, an ester or amide thereof. They may be obtained by (a) when one or both of Z<SP>1</SP> and Z<SP>2</SP> are tetrazolyl or (l-alkyl)-tetrazolyl, reacting hydrazoic acid or a salt thereof, or nitrous acid with a compound of formula wherein at least one of Y<SP>8</SP> and Y<SP>7</SP> is a tetrazolyl group precursor and the other is a group as defined for Z<SP>1</SP> or Z<SP>2</SP>; (b) when Z<SP>2</SP> is COOH, hydrolysing a compound of the formula wherein Y<SP>1</SP> is the same as Z<SP>1</SP> and Y<SP>2</SP> is carbonyl group precursor, with a base or with a dilute aqueous mineral acid optionally in the presence of an organic acid; (c) oxidizing a compound of the formula wherein Y<SP>5</SP> and Y<SP>3</SP> are the same as Z<SP>1</SP> and Z<SP>3</SP> respectively, 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>6</SP> is the same as Z<SP>2</SP> then at least Y<SP>4</SP> is -S-or -SO- or Y<SP>3</SP> is -CH 2 - or -S-, with an appropriate oxidizing agent; (d) 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; (e) cyclizing a compound of the formula using a Lewis acid; (f) cyclizing a compound of the formula with ClSO 3 H; (g) 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; (h) 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 (i) 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 ester, or an alkyl tetrazolyl compound is required converting the products obtained above by appropriate reactions. Pharmaceutical compositions comprise the compounds of Formula I 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 is described: Prep. (1) 3-carboxythioxanthone - 10,10 - dioxide from nitroterephthalonitrile via phenylthioterephthalonitrile, phenylthioterephthalic acid and thioxanthone-3- carboxylic acid; Example (1) 3-cyanothioxanthone-10,10-dioxide from the corresponding carboxylic acid via its carbamoyl derivative; Example (2) 7 - ethyl - 3 - (5 - tetrazolyl) - thioxanthone from 7 - ethylthioxanthone - 3 - carboxylic via 3-cyano-7-ethylthioxanthone; Example (3) 7 - t - butyl - 3 - (5 - tetrazolyl)thioxanthone from 7 - t - butylthioxanthone - 3 - carboxylic acid via its amide and nitrile; Prep. (4) 4- carboxythioxanthone-10,10-dioxide from o-chlorobenzoic acid via its cupric salt, a cupric complex of thiosalicylic acid, diphenyl sulphide - 2,21- dicarboxylic acid and thioxanthone-4-carboxylic acid; Example (4) 4-cyanothioxanthone-10,10- dioxide from the corresponding carboxylic acid via its amide; Prep. (5) 3-carboxythianthrene-5,5- dioxide from 3 - amino - 4 - chlorobenzoic acid via 4 - chloro - 3 - mercaptobenzoic acid, 4- chloro - 3 - (o - nitrophenylthio) benzoic acid and 3 - (o - nitro - and - aminophenylsulphonyl) - 4- chlorobenzoic acids; Example (9) 3-cyanothianthene-5,5-dioxide from the corresponding carboxylic acid via its acid chloride and amide Example (10) 2-cyano-8-methylphenoxathin-10, 10-dioxide from the corresponding carboxylic acid via its acid chloride and amide; Example (12) 7 - chloro - 3 - (5 - tetrazolyl) thioxanthone from p - chlorophenylthioterephthalonitrile via 2 - (p - chlorophenylthio) - 4 - (5 - tetrazolyl) benzonitrile, the corresponding free carboxylic acid and 7 - chloro - 3 - (5 - tetrazolyl) thioxanthone; Example (13) 3-cyanothioxanthone-10,10-dioxide from the corresponding carboxylic acid via its acid chloride and amide; Example (16) 3-(5- tetrazolyl) thioxanthone from the corresponding carboxylic acid via its acid chloride, amide and nitrile; Example (17) 3-cyano-7-methylthioxanthone-10,10-dioxide from the corresponding 3- carbamoyl derivative; Example (18) 2-(5- tetrazolyl) phenoxathiin from phenoxathiin via phenoxathiin-2-aldehyde and 2-cyanophenoxathiin; Example (19) 2-phenylsulphonyl-4-(5- tetrazolyl) benzoic acid from phenylthioterephthalonitrile via 2-phenylthio-4- (5-tetrazolyl)- benzonitrile, the corresponding free carboxylic acid and 2 - phenylsulphonyl - 4 - (5 - tetrazolyl)- benzoic acid; and Example (20) 7-methoxy-3-(5- tetrazolyl) thioxanthone from 7-methoxythioxanthone-3-carboxylic via its acid chloride, amide and nitrile. Other intermediates are described in Specification 1,447,032.