WO2001028537A2 - Bissulfonamide derivatives as enzyme inhibitors - Google Patents

Abstract

Bissulfonamide derivatives of formula (I) are capable of inhibiting: a) the biosynthesis of aromatic amino acids via the shikimate pathway and b) the catabolism of quinic acid, wherein: Ar is an aryl or heteroaryl group; R1 and R2 are the same or different and each represent hydrogen or alkyl or R1 and R2 together form a C1-C3 alkylene group, -CO- or -CS-; and R3 and R4 are the same or different and each represent -alkyl-aryl, -alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl-alkynyl-heterorayl, aryl or heteroaryl.

Description

ENZYME INHIBITORS

The present invention relates to a series of bissulfonamide derivatives which act as inhibitors of dehydroquinate synthetase and type II dehydroquinase enzymes.

Dehydroquinate synthetase and dehydroquinase enzymes form an essential part of the shikimate pathway by which erythrose-4-phosphate is converted to aromatic amino acids such as tryptophan, tyrosine and phenylalanine. Two types of biosynthetic dehydroquinase have been characterised, a Type I, or AroD, variety and a Type II, or AroQ, variety (Garbe et al, Mol. Gen. Genet., 228, pgs 385-392 (1991), Hawkins et al, J. Gen. Microbiol. 139, pgs 2891-2899 (1993)).

The shikimate pathway is essential in bacteria, algae, fungi and higher plants. Further, recent work shows evidence for the presence of enzymes of the shikimate pathway in apicomplexan parasites (Roberts et al, Nature, 393, 1998, pgs 801-805). Compounds which can inhibit the biosynthesis of amino acids via the shikimate pathway therefore have a variety of commercial applications.

In addition to their biosynthetic function, type II dehydroquinase enzymes form an important part of the catabolic pathway by which quinic acid catabolism is effected. This catabolic pathway is found in many fungi and bacteria. Inhibitors of type II dehydroquinase enzymes therefore have commercial applications as fungicides and antibiotics.

Numerous diaminobissulfonamides are known. For example J. Chem. Soc, 1161 (1970) describes the synthesis of many of these compounds as intermediates to tetrahydrodibenzodiazocines, and J. Chem. Soc, 1170 (1962) describes electrophillic substitution reactions involving diaminobissulfonamides. No pharmaceutical utility is described in these publications, however. The synthesis and use of l,2-bis(4-methylphenylsulfonylamino)-4,5-dibromobenzene as an intermediate to substituted phthalocyanines has been reported (Acta. Chemica. Scand., 658 (1995)). Some diaminobissulfonamides are of interest as candidates for non-linear optical studies (Acta. Crys , 2395 (1995)). Oncolytic activity has previously been ascribed to some diaminobissulfonamides (J- Med. Chem., 599 (1963)). The oncolytic activity was found to operate via inhibition of the biosynthetic conversion of l,2-dimethyl-4,5- diaminobenzene to vitamin B₁₂ by certain types of tumour cells (Biochem. Pharmacol., 1163 (1962)).

It has now surprisingly been found that particular bissulfonamide derivatives of the general formula (I) set out below act as inhibitors of dehydroquinate synthetase enzymes and as inhibitors of type II dehydroquinase enzymes. Accordingly, the present invention provides, in a first embodiment, the use of a bissulfonamide derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in inhibiting the biosynthesis of aromatic amino acids via the shikimate pathway,

R₃

O=S=O

wherein:

Ar is an aryl or heteroaryl group;

R_[ and R₂ are the same or different and each represent hydrogen or alkyl or R_j and R₂ together form a -C₃ alkylene group, -CO- or -CS-; and

R₃ and R₄ are the same or different and each represent -alkyl-aryl,

-alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl,

-alkynyl-heteroaryl, aryl or heteroaryl. Typically, the medicament is for use in the inhibition of a dehydroquinate synthetase enzyme, in particular AroB, and/or a type II dehydroquinase enzyme, in particular AroQ.

As used herein, an alkyl group or moiety is typically a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a - alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.

An alkyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, cyano, nitro, amino, hydroxy, oxo and -C0₂R, -SOR and -S(0)₂R wherein R is hydrogen or alkyl.

As used herein, an alkenyl group or moiety is typically a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, such as a C₂- C₄ alkenyl group or moiety, for example ethenyl, propenyl and butenyl.

An alkenyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, amino and hydroxy.

As used herein, an alkynyl group or moiety is typically a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, such as a C₂- C₄ alkynyl group or moiety, for example ethynyl, propynyl and butynyl.

An alkynyl group or moiety may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, amino and hydroxy.

A -Cj alkylene group is a methylene, ethylene or propylene group. It may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one substituent. Suitable substituents include halogen, cyano, nitro, oxo and -C0₂R, -SOR and -S(0)₂R wherein R is hydrogen or alkyl.

As used herein, an aryl group is typically a C₆-C₁₀ aryl group such as phenyl or naphthyl. Phenyl is preferred. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2, 3 or 4 substituents. Suitable substituents include aryl, carbocyclyl, heteroaryl and heterocyclic groups, nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -C0₂R and -S(0)₂R wherein R is aryl, heteroaryl, hydrogen or alkyl,

-CONR'R^ wherein R' and R^/ are the same or different and each represent aryl, heteroaryl, hydrogen or alkyl, -Z-NR^R^and -NR ^/ R^/y wherein Z is alkyl or alkenyl and R^and R are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, and -0-Z-R^//;/ wherein Z is as defined above and R ^/is aryl, heteroaryl or heterocyclyl.

Typically, R in the moiety -S(0)₂R is hydrogen or alkyl. Typically, R^fl/ and R^/; in the moieties -Z-NR^R^ and -NR^R^are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably, at least one of R and R^//; is hydrogen or alkyl. Typically, Z is alkyl, for example methyl. Typically, R^/7// in the moiety -O-Z- R^m is heteroaryl, for example thiazolyl.

A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocyclic substituents are 5- or 6- membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S. Examples include 5- or 6- membered rings containing 1, 2 or 3 heteroatoms, for example pyridyl, isoxazolyl, isothiazolyl, pyrazolyl, thiadiazolyl and oxadiazolyl. Other preferred substituents include nitro, hydroxy, halogen, for example chlorine, bromine and fluorine, C_t-C₄ haloalkyl such as -CF₃ and -CC1₃, -C₄ alkyl, -C0₂R wherein R is hydrogen or C,-C₄ alkyl, Cι-C₄ alkoxy, - haloalkoxy, for example -OCCl₃ and -OCF₃, -S(0)₂-C_!-C₄ alkyl, -CONR'R' wherein R' and R" are the same or different and are heteroaryl or, preferably, aryl, hydrogen or C,-C₄ alkyl, -NR^R*' wherein R⁷ and R ^7/ are the same or different and each represent hydrogen, alkyl or -CO-alkyl, and -O-alkyl-R^⁷, wherein R^m is heteroaryl, for example thiazolyl.

The above substituents are themselves preferably unsubstituted or substituted by one or more further substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkythio, alkoxy, for example haloalkoxy, and hydroxy. Typically, these further substituents are themselves unsubstituted.

An aryl group may optionally be fused to a further said aryl group or to a carbocyclic, heterocyclic or heteroaryl group. For example, it may be fused to a pyridine ring to form a quinoline group, to a thiadiazole ring, for example a 1,2,5- thiadiazole ring to form an isobenzo[ 1,2,5] -thiadiazole group, or to a 1,4 dioxane or 1,3 dioxolane ring.

As used herein, a heteroaryl group is typically a 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazyl, thiadiazolyl, thiazolyl, imidazolyl and pyrazolyl groups. Thienyl groups are preferred. A heteroaryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2 or 3 substituents. Suitable substituents include aryl, for example phenyl, carbocyclyl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -C0₂R and -S(0)₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, -CONR ⁷ wherein R⁷ and R" are the same or different and each represent aryl, heteroaryl, hydrogen or alkyl, -Z-NR^R^ and -NR^R*' wherein Z is alkyl or alkenyl and R⁷ and R^;/// are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, and -0-Z-R ^; wherein Z is as defined above and R¹"" is aryl, heteroaryl or heterocyclyl.

Typically, R in the moiety -S(0)₂R is hydrogen or alkyl. Typically, R⁷ and R in the moieties -Z- R^R'^ and -Z-NR^R^are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably at least one of R'" and R^/7/ is hydrogen or alkyl. Typically, Z is alkyl, for example methyl. Typically, R""¹ in the moiety -0-Z-R ^; is heteroaryl, for example thiazolyl.

A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocyclic substituents are 5- or 6- membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S. Examples include 5- or 6- membered rings containing 1, 2 or 3 heteroatoms, for example isoxazolyl, pyridyl imidazolyl, thiazolyl, isothiazolyl, pyrazolyl and thiadiazolyl. Other preferred substituents include nitro, halogen such as chlorine, bromine or fluorine, - haloalkyl such as -CF₃ and -CC1₃, - alkyl, -C0₂R wherein R is hydrogen or - alkyl, C,-C₄ alkoxy, -S(0)₂-C,-C₄ alkyl and -(C C₄ alkyl) -NR^R^ wherein R¹¹¹ and R^; are the same or different and each represent hydrogen, alkyl or -CO-aryl, for example -CO-phenyl.

The above substituents are themselves preferably unsubstitued or substituted by one or more further substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, and hydroxy. Typically, these further substituents are themselves unsubstituted.

A heteroaryl group may optionally be fused to a said aryl group, to a further heteroaryl group or to a heterocyclic or carbocyclic group. Examples of such fused heteroaryl groups include, for example, a thiophene ring fused to an imidazolyl group.

As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, fluorine or bromine.

As used herein, a said alkoxy group is typically a said alkyl group attached to an oxygen atom. An alkylthio group is typically a said alkyl group attached to a thio group. A haloalkyl or haloalkoxy group is typically a said alkyl or alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX₃ and -OCX₃ wherein X is a said halogen atom. Particularly preferred haloalkyl groups are CF₃ and CC1₃. Particularly preferred haloalkoxy groups are -OCF₃ and -OCCl₃.

As used herein, a carbocyclic group is a non-aromatic saturated or unsaturated hydrocarbon ring, typically having from 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl group) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It is preferably cyclohexyl. A carbocyclic group may be unsubstituted or substituted at any position. Suitable substituents include nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -C0₂R and -S(0)₂R wherein R is hydrogen or alkyl, cyano, and -NR'R⁷' and -CONR'R⁷ wherein R and R^/; are the same or different and each represent hydrogen or alkyl. Preferred substituents are nitro, halogen such as chlorine, bromine or fluorine, - haloalkyl such as -CF₃ and -CC1₃, - alkyl, -C0₂R wherein R is hydrogen or - alkyl, -C₄ alkoxy, - haloalkoxy, for example -OCCl₃ and -OCF₃, and -S(0)₂- -C₄ alkyl. The above substituents are typically themselves unsubstituted.

As used herein, a heterocyclic group is typically a non-aromatic, saturated or unsaturated C₅-C₁₀ carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S. Saturated heterocyclic groups are preferred. Examples of suitable heterocyclic groups include piperidine, morpholine, 1,4 dioxane and 1,3 dioxolane.

A heterocyclic group may be unsubstituted or substituted at any position. Suitable substituents include nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -C0₂R and -S(0)₂R wherein R is hydrogen or alkyl, cyano, and -NR^;R^/; and -CONR'R^ wherein R' and R are the same or different and each represent hydrogen or alkyl. Preferred substituents are nitro, halogen such as chlorine, bromine or fluorine, - haloalkyl such as -CF₃ and -CC1₃, - alkyl, -C0₂R wherein R is hydrogen or -G, alkyl, - alkoxy and -S(0)₂-C_!-C₄ alkyl. The above substituents are typically themselves unsubstituted.

Typically, the groups -NR^O)^ and -NR₂S(0)₂R₄ are attached to adjacent carbon atoms on the Ar moiety. When Ar is a heteroaryl group it is typically a pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl group. Preferably, Ar is an aryl group, in particular a phenyl group or a naphthyl group. Typically, it is unsubstituted or carries 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents. Preferred substituents include aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -C0₂R wherein R is aryl, heteroaryl, or, preferably, hydrogen or alkyl, and -NR R^and -CONR'R'⁷ wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl. These substituents are preferably unsubstituted or substituted by one or more further substituent selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy and hydroxy. Typically, these further substituents are themselves unsubstituted.

Typically, at least one of R' and R" in the moieties -NR " and -CONR'R is hydrogen or alkyl. A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocyclic substituents are 5- or 6- membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, for example oxadiazolyl groups. Further preferred substituents on the group Ar include hydroxyl nitro, cyano, halogen such as chlorine, fluorine and bromine, -C₄ haloalkyl, -Q, alkyl, -C0₂R wherein R is hydrogen or - alkyl, - alkoxy and -CONR'R' wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or C,-C₄ alkyl.

When Ar is an aryl group fused to an aryl, cycloalkyl, heterocyclic or heteroaryl group, it is typically fused to a said heterocyclic group. Preferably, it is fused to a saturated heterocyclic group containing, as heteroatoms, 2 oxygen atoms, for example 1,4 dioxane or 1,3 dioxolane.

More preferably, Ar is a group of formula Ar

wherein R₅ to Rg are the same or different and represent aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R' or -CONR^/R wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R₅ and R^ or R^ and R₇ or R₇ and R₈ together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.

Typically, R₅ to R₈ are the same or different and represent cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R^ or -CONR'R^ wherein R^; and R are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R₅ and R^ or R^ and R₇ or R₇ and R₈ together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.

Typically, R in the moiety -C0₂R is hydrogen or alkyl. Typically, R' and R" in the moiety -NR'R'' are the same or different and are hydrogen or alkyl. Typically, R and R in the moiety -CONR'R' are the same or different and are hydrogen, alkyl or aryl.

Typically, R₅ and Rg are the same or different and represent hydrogen, halogen, for example bromine, alkyl, hydroxy, alkoxy or -NR'R'⁷ wherein R^; and R'¹ are the same or different and are hydrogen or alkyl, and 1^ and R₇ are the same or different and represent hydrogen, halogen, for example, bromine, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, heterocyclyl, nitro, cyano, halogen, alkyl, for example haloalkyl, alkoxy, for example haloalkoxy, alkylthio, hydroxy, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR⁷R^/y or -CONR ⁷' wherein R and R^/; are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R₆ and R₇ together form an alkylenedioxy group such as a methylenedioxy or ethylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.

Typically, R₅ and R₈ are the same or different and represent hydrogen, alkyl, hydroxy, alkoxy or -NR'R⁷ wherein R^f and R^;/ are the same or different and are hydrogen or alkyl, and R^ and R₇ are the same or different and represent hydrogen, nitro, cyano, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R or -CONR'R wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R^ and R₇ together form an alkylenedioxy group such as a methylenedioxy or ethylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.

Typically, R! and R" in the -NR'R'' moiety are the same or different and are hydrogen or alkyl. Typically R' and R^/; in the moiety -CONR '⁷ are the same or different and are hydrogen, alkyl or aryl.

Preferably, at least one of R₅ and R₈ is hydrogen. More preferably, one of R₅ and R₈ is hydrogen and the other is halogen or, preferably, hydrogen or hydroxy. More preferably still, both R₅ and R₈ are hydrogen.

Typically, R₅ to R₈ are unsubstituted or substituted by one or more further substituent selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, and hydroxy. Typically, these further substituents are themselves unsubstituted.

Preferably, R^ and R₇ represent hydrogen, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, nitro, cyano, alkyl, alkoxy, haloalkyl, halogen, - C0₂H, -C0₂-alkyl or -CONR'R" wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R^ and R₇ together form a said alkylenedioxy group or a phenyl moiety. More preferably, Rg and R₇ represent hydrogen, heteroaryl, for example oxadiazolyl, nitro, cyano, -C₄ alkyl such as methyl or ethyl, halogen such as chlorine, fluorine or bromine, -C0₂-(C₁-C₄ alkyl) such as -C0₂-Et and -C0₂- Me, C[-C₄ alkoxy such as -OMe, or -CONR'R' wherein R and R are the same or different and are heteroaryl, or, preferably, aryl, for example phenyl, hydrogen or C,- C₄ alkyl, or R_$ and R₇, together with the carbon atoms to which they are attached, form a further phenyl moiety. More preferably still, ^ and R₇ are the same or different and are selected from hydrogen, oxadiazolyl, chlorine, fluorine, bromine, nitro, cyano, methyl, methoxy, -C0₂H, -C0₂Et, -C0₂Me, -CONH₂, -CONHMe and -CONMe₂, -CONH-phenyl, -CONH-(4-trifluoromethoxyphenyl) or -CONH-(3,5- dimethoxyphenyl), or 1^ and R₇, together with the carbon atoms to which they are attached, form a further phenyl moiety.

When R_j and/or R₂ is an alkyl group it is typically an unsubstituted alkyl group. Preferably, R[ and R₂ are the same or different and are hydrogen or alkyl or R_t and R₂ together from a -C₃ alkylene group. More preferably, R_x and R₂ are both hydrogen.

Typically, R₃ and R,, are not simultaneously -alkynyl-aryl or -alkynyl- heteroaryl groups. Preferred -alkyl-aryl and -alkyl-heteroaryl groups are -(C,-C₄- alkyl)-aryl and -( -C₄ alkyl) -heteroaryl groups, for example -( -G, alkyl) -phenyl groups such as benzyl groups. Preferred -alkenyl-aryl and -alkenyl-heteroaryl groups are -(C₂-C₄ alkenyl) -aryl and -(C₂-C₄ alkenyl) -heteroaryl groups, for example -ethenyl-aryl groups such as -ethenyl-phenyl groups.

Typically, R₃ and R₄ are the same or different and each represent an aryl or heteroaryl group. Preferred aryl and heteroaryl groups include phenyl, naphthyl, pyridyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, isoxazolyl and pyrrolyl groups. More preferred aryl and heteroaryl groups are phenyl, naphthyl, furanyl, thienyl and isoxazolyl groups.

When R₃ or R^ contains an aryl or heteroaryl moiety which is fused to an aryl, cycloalkyl, heterocyclic or heteroaryl group, it is typically fused to a said heterocyclic group or to a said heteroaryl group. Examples of such fused groups include (l,2-cyclo(3-thioethyl)-imidazoyl, benzothienyl, indole and quinoline groups. Quinoline groups are preferred.

Typically, R₃ and R₄ are unsubstituted or carry 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents. Preferred substituents include aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S(0)₂-alkyl, haloalkoxy, cyano, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy, -CONR'R'⁷ wherein R^; and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, -Z-NR^R*' and -NR^R^ wherein Z is alkyl or alkenyl and R¹" and R are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, and -O-Z-R¹¹¹¹¹ wherein Z is as defined above and R^m is aryl, heteroaryl or heterocyclyl.

Typically, Z is alkyl, for example methyl, in the above moieties. Typically, R^/7 and R¹¹" in the moieties -Z-NRV and -NRV are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably, at least one of R^/; and R ^; is hydrogen or alkyl. Typically, R^m in the moiety -0-Z-R^;// is heteroaryl, for example thiazolyl.

More typically, R₃ and R₄ are unsubstituted or carry 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents selected from aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S(0)₂-alkyl, haloalkoxy, cyano, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy and -NR'R⁷ and -CONR'R'' wherein R¹ and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl. A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocyclic substituents are 5- or 6- membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S. Examples include 5- or 6- membered rings containing 1, 2 or 3 heteroatoms, for example pyridyl, isoxazolyl, thiadiazolyl, thiazolyl, isothiazolyl and pyrazolyl. Other preferred substituents include Cι-C₄ alkyl such as methyl, ethyl, n-propyl, i-propyl or t-butyl, -C₄ haloalkyl, halogen, nitro, cyano, 0,-0₄ alkoxy such as methoxy, -SfO^- - alkyl, 'NR^/I/R"" wherein R^;/ and R^7/ are the same or different and each represent hydrogen, - alkyl, or -CO-(C,-C₄ alkyl), -(C,-C₄ alkyl) -NR ^;R^//7 wherein R^//f and R^m are the same or different and each represent hydrogen, C_t-C₄ alkyl or -CO-aryl, for example -CO-phenyl, and -0-(C_t-C₄ alkyl) -R^m, wherein R^m is heteroaryl, for example thiazolyl.

Most preferred substituents are phenyl, methyl, trifluoromethyl, chlorine, fluorine, bromine, methoxy, trifluoromethoxy, nitro, cyano, -S(0)₂-Me, isoxazolyl, isothiazolyl, pyrazolyl, thiadiazolyl, pyridyl, thiazolyl, -NH-CO-Me, -O- CH₂-thiazolyl, -CH₂-NH-phenyl and -CH₂-NH-(4-chlorophenyl).

The above substituents are themselves preferably unsubstituted or substituted by one or more further substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy and hydroxy. Typically, these further substituents are themselves unsubstituted.

Further preferred compounds of the invention are compounds of formula (la)

(R₃')n

/

X

wherein R₅ to R₈ are as defined above in the formula Ar⁷, X and Y are the same or different and represent phenyl or thienyl, n represents an integer of from 0 to 4 when X is phenyl and an integer of from 0 to 3 when X is thienyl, m represents an integer of from 0 to 4 when Y is phenyl and an integer of from 0 to 3 when Y is thienyl, and R and R are the same or different and are selected from aryl, heteroaryl and heterocyclic groups, alkyl, for example haloalkyl, halogen, nitro, -S(0)₂-alkyl, alkoxy, for example haloalkoxy, cyano, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, hydroxy, -CONR^ wherein R^f and R^7/ are the same or different and are aryl, heteroaryl, hydrogen or alkyl, -Z-NR^R^⁷ and -NR^/;/R^/7/ wherein Z is alkyl or alkenyl and R ^/ and R^7// are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, or -0-Z-R ^/7 wherein Z is as defined above and R is aryl, heteroaryl or heterocyclyl.

Typically, Z is alkyl, for example methyl, in the above moieties. Typically, R^/7/ and R"" in the moieties -Z-NRV and -NR^R*⁷ are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably, at least one of R^/; and R^; is hydrogen or alkyl. Typically, R¹"" in the moiety -0-Z-R^;// is heteroaryl, for example thiazolyl. Typically R and R are the same or different and are selected from heteroaryl and heterocyclic groups, alkyl, for example haloalkyl, halogen, nitro, -S(0)₂-alkyl, alkoxy, for example haloalkoxy, cyano, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, hydroxy and -NR⁷R^/; and -CONRR^ wherein R' and R⁷ are the same or different and are aryl, heteroaryl, hydrogen or alkyl.

Preferred compounds of formula (la) are those in which one of R₅ and R₈ is hydrogen and the other is hydrogen, halogen or hydroxy, or in which R₅ and R₈ are both hydrogen, R^ and R₇ are the same or different and are selected from aryl, for example phenyl, heteroaryl, for example oxadiazolyl, nitro, cyano, alkyl for example methyl and ethyl, haloalkyl, halogen, for example chlorine, fluorine and bromine, hydrogen, -C0₂H, -C0₂-alkyl for example -C0₂-Et and -C0₂-Me, alkoxy, for example methoxy and CONR'R⁷ wherein R' and R" are the same or different and are heteroaryl, or, preferably, aryl, hydrogen or alkyl, or Rg and R₇ together form an alkylenedioxy group such as a methylenedioxy or ethylenedioxy group or, together with the carbon atoms to which they are attached, form a further phenyl moiety, X and Y are the same or different and are phenyl or thienyl, n and m are the same or different and are 0, 1 or 2 and R and R are the same or different and are selected from:

(a) when attached to a phenyl moiety, aryl, for example phenyl, - alkyl, for example methyl, ethyl, n-propyl, i-propyl or t-butyl, C C₄ haloalkyl, for example CC1₃ and CF₃, halogen, for example chlorine, fluorine and bromine, nitro, cyano, -C₄ alkoxy, for example methoxy, -C0₂R wherein R is hydrogen or C[-C₄ alkyl, -NR'R⁷ wherein R and R^7/ are the same or different and are hydrogen, C_t- C₄ alkyl or -CO-(C C₄ alkyl), -0-(C,-C₄ alkyl)-^ wherein R^;/ is heteroaryl, for example thiazolyl, or heterocyclyl, and -S(0)₂-C_!-C₄ alkyl; and

(b) when attached to a thienyl moiety, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, nitro, halogen such as chlorine, bromine or fluorine, C C₄ haloalkyl such as -CF₃ and -CC1₃, C,-C₄ alkyl such as methyl, ethyl, n-propyl, i-propyl or t-butyl, -C0₂R wherein R is hydrogen or C,-C₄ alkyl, C,-C₄ alkoxy such as methoxy, -(C,-C₄ alkyl) -NH-aryl, for example -(C_t-C₄ alkyl) -NH-phenyl, and -S(0)₂- C,-C₄ alkyl. Typically, in these preferred compounds, R^ and R₇ are the same or different and are selected from nitro, alkyl such as methyl or ethyl, haloalkyl, halogen such as chlorine, fluorine or bromine, hydrogen, -C0₂-alkyl such as -C0₂-Et and -C0₂-Me, alkoxy such as methoxy and -CONR'R* wherein R' and R" are the same or different and are aryl, heteroaryl, or, preferably, hydrogen or alkyl, or R^ and R₇ together form an alkylenedioxy group such as a methylenedioxy or ethylenedioxy group or, together with the carbon atoms to which they are attached, form a further phenyl moiety. Typically, when attached to a phenyl moiety, R and R are selected from - alkyl, for example methyl, ethyl, n-propyl, i-propyl or t-butyl, C[-C₄ haloalkyl, for example CC1₃ and CF₃ halogen, for example chlorine, fluorine and bromine, nitro, C,-C₄ alkoxy, for example methoxy, and -S(0)₂-Cj-C₄ alkyl. Typically, when attached to a thienyl moiety, R and R are selected from isoxazolyl, isothiazolyl, pyrazolyl, nitro, halogen, for example chlorine, bromine and fluorine, - C₄ haloalkyl, for example -CF₃ and -CC1₃, C)-C₄ alkyl, for example methyl, ethyl, n- propyl, i-propyl and t-butyl, -C0₂R wherein R is hydrogen or -Q, alkyl, C,-C₄ alkoxy, for example methoxy, and -S(0)₂-C_!-C₄ alkyl.

Particularly preferred compounds of the formula (la) are those in which R₅ and R₈ are hydrogen, R^ and R₇ are the same or different and are selected from hydrogen, oxadiazolyl, chlorine, fluorine, bromine, nitro, cyano, methyl, methoxy, -C0₂Et, -C0₂Me, -CONH₂, -CONHMe, -CONMe₂, -CONH-phenyl, -CONH-(4-trifluromethoxyphenyl) and -CONH-(3,5-dimethoxyphenyl) or, together with the carbon atoms to which they are attached, form a phenyl moiety, n and m are the same or different and are 0, 1 or 2, X and Y are the same or different and are phenyl or thienyl and R and R are the same or different and are selected from methyl, ethyl, i-propyl, chlorine, fluorine, bromine, methoxy, trifluoromethoxy, nitro, cyano, -S(0)₂Me, -C0₂H, -NH-CO-CH₃, -0-CH₂-(2-chlorothiazolyl) and, when X and Y are thienyl, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl and -CH₂-NH-R wherein R is phenyl or 4-chlorophenyl.

Compounds of the invention which are more preferred are compounds of formula (lb) and salts thereof.

wherein R₃ and R^ are the same or different and are selected from (a) phenyl optionally substituted by halogen, for example chlorine, C[-C₄ alkyl, for example methyl, -C₄ haloalkyl, for example -CF₃ or C[-C₄ haloalkoxy, for example -OCF₃ and (b) thienyl, optionally substituted by halogen, for example chlorine, C,-C₄ alkyl, for example methyl, -C₄ haloalkyl, for example -CF₃ and - haloalkoxy, for example -OCF₃, and Rή is halogen, for example chlorine and fluorine, or C,-C₄ haloalkoxy, for example -CF₃ and -CC1₃.

Compounds of the formula (I) containing one or more chiral centre may be used in enantiomerically or diasteroisomerically pure form, or in the form of a mixture of isomers.

Typically, when the compounds of the invention are used as antibacterial agents, for example to inhibit a strain of staphylococcus aureus other than MRSA, R₃ and R^ are not phenyl groups substituted at the para position by an amino group. More typically, in such compounds R₃ and R₄ are not 4-aminophenyl or 4- nitrophenyl groups. Preferably, R₃ and R₄ are not aminophenyl groups in such compounds.

Preferably, when R₃ and R₄ are simultaneously phenyl groups substituted at the para position with a -C., alkyl group such as a methyl group, Ar is not a group of formula At⁷, as defined above, wherein R₅, R₇ and R₈ are hydrogen and Rg is -C₄ alkyl such as methyl or -00₂-(C₁-C₄ alkyl) such as -C0₂-Et. As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutical acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.

Particularly preferred compounds of formula (I) include: 1 ,2-Bis(4-nitrophenylsulfonylamino) -benzene l,2-Bis(4-methylphenylsulfonylamino)-4,5-dibromobenzene 3,4-Bis(4-methylphenylsulfonylamino)-6-bromotoluene l,2-Bis(4-methylphenylsulfonylamino)-4-fluorobenzene

3- (3-trifluoromethylphenylsulfonylamino) -4- (4-iodophenylsulfonylamino) toluene l,2-Bis(4-methylphenylsulfonylamino)-4-nitrobenzene 3 - (4-methylphenylsulfonylamino) -4- (4-chlorophenylsulfonylamino) toluene l,2-Bis(4-methylphenylsulfonylamino) -benzene l,2-Bis(4-methylphenylsulfonylamino)-4-fluoro-5-nitrobenzene 3, 4-Bis(4-methylphenylsulfonylamino) -benzoic acid methyl ester l,2-Bis(4-bromophenylsulfonylamino)-benzene N,N- 1 ,4-bis(4-methylphenylsulfonamdio) -7,8-dibromoquinazoline

1.2 -Bis (4-methylphenylsulfonylamino) -4,5-dichlorobenzene

2.3 -Bis (4-methylphenylsulfonylamino) naphthalene

1 ,2 -Bis (4-methylphenylsulfonylamino) -4,5 -difluorobenzene l,2-Bis(4-bromophenylsulfonylamino)-4,5-dibromobenzene l,2-Bis(4-fluorophenylsulfonylamino)-4,5-dibromobenzene 1 ,2 -Bis (3 -bromophenylsulfonylamino) -4,5 -dibromobenzene l,2-Bis(4-trifluoromethoxyphenylsulfonylamino) -benzene 1 ,2 -Bis (4-isopropylphenylsulfonylamino) -benzene l,2-Bis(4-fluorophenylsulfonylamino)-4,5-dimethylbenzene l,2-Bis(4-methylphenylsulfonylamino)-4,5-dimethylbenzene l,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4,5-dimethylbenzene

1.2 -Bis (4-isopropylphenylsulfonylamino) -4,5 -dimethylbenzene

2.3 -Bis (4-fluorophenylsulfonylamino) phenol 2, 3 -Bis (4-methylphenylsulfonylamino) phenol 2,3-Bis(4-trifluoromethoxyphenylsulfonylamino) phenol 2,3-Bis(4-isopropylphenylsulfonylamino) phenol

3 ,4-Bis (4-fluorophenylsulfonylamino) anisole

3 ,4-Bis (4-methylphenylsulfonylamino) anisole

3 ,4-Bis (4-fluoromethoxyphenylsulfonylamino) anisole

3 ,4-Bis (4-isopropylphenylsulfonylamino) anisole

3,4-Bis(4-methylsulfonphenylsulfonylamino) anisole

1 ,2 -Bis (phenylsulfonylamino) benzene

1 ,2 -Bis (3 -trifluoromethylphenylsulfonylamino) benzene

1 ,2 -Bis (4-trifluoromethylphenylsulfonylamino) benzene

1 ,2 -Bis (3 -chloro-2 -methylphenylsulfonylamino) benzene

1 ,2 -Bis (2 ,6-difluorophenylsulfonylamino) benzene

1.2 -Bis (3 -trifluoromethylphenylsulfonylamino) -4,5 -dimethylbenzene l,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4,5-dimethylbenzene 1 ,2-Bis (2 ,6-difluorophenylsulfonylamino) -4,5 -dimethylbenzene

1 ,2-Bis (2 ,6-difluorophenylsulfonylamino) -4-fluorobenzene

2.3 -Bis (3 ,4-dichlorophenylsulfonylamino) -phenol 2 ,3 -Bis (2 ,4-difluorophenylsulfonylamino) -phenol l,2-Bis(4-trifluoromethylphenylsulfonylamino)-4,5-dimethylbenzene 2,3-Bis(5-chloro,2-methoxyphenylsulfonylamino) -phenol

3, 4-Bis(4-trifluoromethylphenylsulfonylamino) -benzoic acid ethyl ester

3 ,4-Bis (3 ,4-dichlorophenylsulfonylamino) anisole

3 ,4-Bis (5 -chloro,2 -methoxyphenylsulfonylamino) anisole

1 ,2 -Bis (4-fluorophenylsulfonylamino) benzene l,2-Bis(2,4-difluorophenylsulfonylamino) benzene

1 , 2 -Bis (phenylsulfonylamino) -4,5 -dimethylbenzene l,2-Bis(5-chloro-2-methoxyphenylsulfonylamino)-4,5-dimethylbenzene

2 ,3 -Bis (phenylsulfonylamino) -phenol

2 ,3 -Bis (2 -methyl-5 -nitrophenylsulfonylamino) phenol

3,4-Bis(3-trifluoromethylphenylsulfonylamino) anisole

1 ,2 -Bis (5 -chloro-2 -methoxyphenylsulfonylamino) benzene

2,3-Bis(4-trifluoromethylphenylsulfonylamino) phenol

3 ,4-Bis (4-trifluoromethylphenylsulfonylamino) anisole

1 ,2-Bis (4-trifluoromethylphenylsulfonylamino) -4-fluorobenzene

3,4-Bis(3-trifluoromethylphenylsulfonylamino)-benzoic acid ethyl ester

1.2 -Bis (2 - thienylsulfonylamino) -benzene

2.3 -Bis (2 -thienylsulfonylamino) -phenol

1.2 -Bis (2 -chloro-5 -thienylsulfonylamino) -napthalene

1 ,2-Bis [2 - (3-oxazolyl) -5-thienylsulfonylamino) -napthalene

3, 4-Bis(2-chloro-5-thienylsulfonylamino) -benzoic acid methyl ester

3.4 -Bis (2 - thienylsulfonylamino) fluorobenzene

2 ,3 -Bis (2 -chloro-5 -thienylsulfonylamino) phenol

3, 4-Bis (2 -chloro-5 -thienylsulfonylamino) -benzoic acid ethyl ester

3 ,4-Bis (2 -thienylsulfonylamino) -anisole

2.3 -Bis (2 -chloro-5 -thienylsulfonylamino) -benzene

1 ,2-Bis [2 - (3 -oxazolyl) -5-thienylsulfonylamino) -benzene

1 ,2 -Dimethyl-4,5 -bis (2 -thienylsulfonylamino) -benzene

1 ,2 -Dimethyl-4,5 -bis (2 -chloro-5 -thienylsulfonylamino) -benzene

1,2- Difluoro-4 ,5 -bis (2 - thienylsulfonylamino) -benzene l,2-Dibromo-4,5-bis(2,3-dichloro-5-thienylsulfonylamino) -benzene

3 ,4-Bis (2 -thienylsulfonylamino) chlorobenzene

3 ,4-Bis (5 -chloro-2 -thienylsulfonylamino) chlorobenzene

3, 4-bis (2 -thienylsulfonylamino) -benzoic acid methyl ester

3, 4-Bis (2 -chloro-5 -thienylsulfonylamino) fluorobenzene

1,2 -Bis (2 -thienylsulfonylamino) -3,4,5, 6-tetramethylbenzene

3,4-bis(2-thienylsulfonylamino) -benzoic acid ethyl ester

1 ,2-Bis (2 ,5 -dichloro-3 -thienylsulfonylamino) -4,5 -dimethylbenzene l,2-Bis(2,5-dichloro-3-thienylsulfonylamino) -phenol

1 ,2-Bis (2 ,5-dichloro-3 -thienylsulfonylamino) -anisole l,2-Dibromo-4,5-bis(2,5-dichloro-3-thienylsulfonylamino) -benzene ,4-Bis (2 ,5 -dichloro-3 -thienylsulfonylamino) chlorobenzene l,2-Bis(2,5-dichloro-3-thienylsulfonylamino) -3, 4,5, 6-tetramethylbenzene ,3 -Bis (phenylsulfonylamino) naphthalene ,3 -Bis (3 -trifluoromethylphenylsulfonylamino) naphthalene ,3 -Bis (4-trifluoromethoxyphenylsulfonylamino) naphthalene ,3-Bis(3,4-dichlorophenylsulfonylamino)naphthalene ,3 -Bis (4-isopropylphenylsulfonylamino) naphthalene ,3 -Bis (4-trifluoromethyphenylsulfonylamino) naphthalene ,3 -Bis (2 ,4diflurophenylsulfonylamino) naphthalene ,3 -Bis (2 -chloro-5 -thienylsulfonylamino) naphthalene ,3 -Bis (2 -methyl-4-nitrophenylsulfonylamino) naphthalene ,3 -Bis (2 -methyl-3 -chlorophenylsulfonylamino) naphthalene ,3 -Bis (4-cyanophenylsulfonylamino) naphthalene ,3-Bis (3 ,5dimethyl-3 -oxazoylsulfonylamino) naphthalene ,3-Bis(2-aza-4,5-benzothiazoylsulfonylamino)naphthalene ,3-Bis (2 - (3 -oxazoyl) -5-thienylsulfonylamino) naphthalene ,3 -Bis (2 ,6-difluorophenylsulfonylamino) naphthalene ,3 -Bis (3 -nitro-4-methylphenylsulfonylamino) naphthalene ,4-Bis (2 - ( 1 ,2 -cyclo (3 -thioethyl) -4-chloro-5 -imidazoylsulfonylamino) naphthalene ,3 -Bis (4-methylsulfonophenylsulfonylamino) naphthalene

1 ,2-Bis (4-fluorophenylsulfonylamino) -4-nitrobenzene ,4-Bis(4-fluorophenylsulfonylamino)-benzoic acid methyl ester ,4-Bis(4-trifluoromethylphenylsulfonylamino)-benzoic acid methyl ester ,4-Bis(2-chloro-5-thienylsulfonylamino)-benzoic acid methyl ester , 4-Bis (2 -methoxy-2 -chlorophenylsulfonylamino) -benzoic acid methyl ester ,4-Bis(4-methyl-2-nitrophenylsulfonylamino) -benzoic acid methyl ester

1 ,2 -Bis (3 -trifluoromethylphenylsulfonylamino) -4-fluorobenzene

1 ,2-Bis (2 -thienylsulfonylamino) -4-fluorobenzene l,2-Bis(3,4-dichlorophenylsulfonylamino) -4-fluorobenzene

1 ,2-Bis (2 -methyl-5 -nitrophenylsulfonylamino) -4-fluorobenzene

1 ,2-Bis (phenylsulfonylamino) -4,5-difluorobenzene

3, 4-Bis (3, 4-dichlorophenylsulfonylamino) -benzoic acid ethyl ester

3, 4-Bis (2, 4-dichlorophenylsulfonylamino) -benzoic acid ethyl ester

3, 4-Bis (2 -chloro-5 -thienylsulfonylamino) -benzoic acid ethyl ester

3, 4-Bis (2 -methyl,5 -nitrophenylsulfonylamino) -benzoic acid ethyl ester

3, 4-Bis (2 ,6-difluorophenylsulfonylamino) -benzoic acid ethyl ester

1 ,2-Bis (2 -methyl,5 -nitrophenylsulfonylamino) -4-methoxybenzene

1, 2 -Bis (4-methyl,3 -nitrophenylsulfonylamino) -4-methoxybenzene

1 ,2-Bis (3 ,4-dichlorophenylsulfonylamino) -benzene

1,2 -Bis (2 -chloro-5 -thienylsulfonylamino) -benzene

1 ,2 -Bis (2 -methyl-5 -nitrophenylsulfonylamino) -benzene

1 ,2 -Bis (2 - (3 -oxazoyl) -5-thienylsulfonylamino) -benzene

1 , 2 -Bis (4 -methyl-3 -nitrophenylsulfonylamino) -benzene

1 ,2-Bis (4-isopropylphenylsulfonylamino) -4-nitrobenzene

1 , 2 -Bis (2 - thienylsulfonylamino) -4,5 -dimethylbenzene

1 ,2-Bis (3 ,4-dichlorophenylsulfonylamino) -4,5-dimethylbenzene

1 ,2-Bis (2 -chloro-5 -thienylsulfonylamino) -4,5-dimethylbenzene

1 ,2-Bis (2 -methyl-5 -nitrophenylsulfonylamino) -4,5-dimethylbenzene l,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4,5-dimethylbenzene l,2-Bis(4-methylsulfonophenylsulfonylamino)-4,5-dimethylbenzene

1 ,2 -Bis ( 1 -naphthylsulfonylamino) -4,5 -dibromobenzene l,2-Bis(2,3-dichloro-5-thienylsulfonylamino)-4,5-dibromobenzene l,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4,5-dibromobenzene

1 ,2 -Bis (4-nitrophenylsulfonylamino) -4,5 -dibromobenzene

1 ,2 -Bis (4-biphenylsulfonylamino) -4, 5 -dibromobenzene l,2-Bis(4-bromophenylsulfonylamino)-4,5-dibromobenzene

1 ,2 -Bis (4-carboxyphenylsulfonylamino) -4, 5 -dibromobenzene

1 ,2-Bis (3 ,4-dimethoxyphenylsulfonylamino) -4,5-dibromobenzene

1 , 2 -Bis (3 -methylphenylsulfonylamino) -4,5 -dibromobenzene l,2-Bis(2-fluorophenylsulfonylamino) -4,5-dibromobenzene

1 , 2 -Bis (2 -methoxyphenylsulfonylamino) -4,5 -dibromobenzene

1 ,2-Bis (4-methylphenylsulfonylamino) -4-cyanobenzene

1 ,2-Bis(phenylsulfonylamino) -4 -chlorobenzene

1 ,2-Bis (4-fluorophenylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (3 -trifluoromethylphenylsulfonylamino) -4-chlorobenzene

1 ,2 -Bis (3 -trifluoromethoxyphenylsulfonylamino) -4-chlorobenzene l,2-Bis(2-thienylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (3 ,4-dichlorophenylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (4-isopropylphenylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (2 ,4-difluorophenylsulfonylamino) -4-chlorobenzene

3, 4-Bis (4-chloro-2methoxyphenylsulfonylamino) -benzoic acid ethyl ester l,2-Bis(2,5-dichloro-3-thienylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (2 -chloro-5-thienylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (2 -methyl-5-nitrophenylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (2 -methyl-3-chlorophenylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (4-cyanophenylsulfonylamino) -4-chlorobenzene

1 ,2 -Bis (3 ,5 -dimethyl-4-oxazoylsulfonylamino) -4-chlorobenzene

1 ,2 -Bis (2 ,6-difluorophenylsulfonylamino) -4-chlorobenzene

1 ,2 -Bis (4-methyl-3 -nitrophenylsulfonylamino) -4-chlorobenzene

3, 4-Bis (2, 4-difluorophenylsulfonylamino) -benzoic acid methyl ester

3,4-Bis(2-methyl-5-nitrophenylsulfonylamino)-benzoic acid methyl ester

3,4-Bis(2-methyl-3-chlorophenylsulfonylamino) -benzoic acid methyl ester

3, 4-Bis (2, όdifluorophenylsulfonylamino) -benzoic acid methyl ester l,2-Bis(2-chloro-5-thienylsulfonylamino) -4-fluorobenzene l,2-Bis(2-methyl-3-chlorophenylsulfonylamino) -4-fluorobenzene

1.2 -Bis (2 -methoxy-5 -chlorophenylsulfonylamino) -4-fluorobenzene

1 ,2-Bis (2 -methyl-3 -chlorophenylsulfonylamino) -3,4,5 , 6-tetramethylbenzene 3, 4-Bis (2 -thienylsulfonylamino) -benzoic acid ethyl ester 3,4-Bis(3-chloro-2-methylphenylsulfonylamino)-benzoic acid ethyl ester

2.3 -Bis (4-fluorophenylsulfonylamino) naphthalene 1 ,2 -Bis (2 ,5 -dichloro-3 -thienylsulfonylamino) -benzene

3, 4-Bis (3 -trifluoromethylphenylsulfonylamino) -benzoic acid methyl ester

1 ,2 -Bis (2 - (3 -oxazoyl) -5 -thienylsulfonylamino) -4-fluorobenzene

1 ,2-Bis (2 - ( 1 ,2 -cyclo (3 -thioethyl) -4-chloro-5 -imidazoylsulfonylamino) -4- fluorobenzene

1.2 -Bis (3 - trifluorome thylphenylsulfonylamino) -4,5 -difluorobenzene l,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4,5-difluorobenzene 1 ,2-Bis (4-methyl-3 -nitrophenylsulfonylamino) -4,5 -difluorobenzene l,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-chloro-5-methylbenzene

2.3 -Bis (2 -thienylsulfonylamino) naphthalene

1 ,2-Bis (4-trifluoromethylphenylsulfonylamino) -4-chlorobenzene

1 ,2-Bis (4-fluorophenylsulfonylamino) -4,5 -difluorobenzene

1 ,2-Bis (4-methylsulfonophenylsulfonylamino) -3,4,5 , 6-tetramethylbenzene

1 ,2-Bis(4-isopropylphenylsulfonylamino) -4-fluorobenzene l,2-Bis(4-cyanophenylsulfonylamino) -4-fluorobenzene

1 ,2-Bis (4-methylphenylsulfonylamino) -4-cyanobenzene

1 ,2-Bis (3 -trifluoromethylphenylsulfonylamino) -4, 5 dibromobenzene

1 ,2-Bis (2 -trifluoromethoxyphenylsulfonylamino) -3 ,5 dibromobenzene

1 ,2-Bis (4-trifluoromethoxyphenylsulfonylamino) -4, 5 dibromobenzene

3, 4-Bis (8 -quinolylsulfonylamino) -benzoic acid ethyl ester

1 ,2 -Bis (4-trifluoromethoxyphenylsulfonylamino) -4-fluorobenzene

1 ,2 -Bis (phenylsulfonylamino) -4-fluorobenzene

3,4-Bis (3, 5-dimethyl-4-oxazoylsulfonylamino) -benzoic acid methyl ester

3 ,4-Bis (4-isopropylphenylsulfonylamino) -benzoic acid methyl ester l,2-Bis(4-methylphenylsulfonylamino)-4-chlorobenzene l,2-Bis(2-(3-oxazoyl) -5-thienylsulfonylamino) -4,5-dimethylbenzene

3 ,4-Bis (3 ,5 -dimethyl-4-oxazoylsulfonylamino) -4,5-difluorobenzoate

1 ,2-Bis (2 - (3 -oxazoyl) -5 -thienylsulfonylamino) -4-methoxybenzene

1 ,2 -Bis (2 - ( 1 ,2 -cyclo(3 -thioethyl) -4-chloro-5-imidazoylsulfonylamino) -4- methoxybenzene

1 ,2-Bis (phenylsulfonylamino) -4-cyanobenzene l,2-Bis(3-trifluoromethylphenylsulfonylamino) -4-cyanobenzene

1 ,2-Bis (4-trifluoromethoxyphenylsulfonylamino) -4-cyanobenzene

1 , 2 -Bis (2 -thienylsulfonylamino) -4-cyanobenzene

1 ,2-Bis (4-isopropylphenylsulfonylamino) -4-cyanobenzene

1 ,2-Bis (2 ,4-difluorophenylsulfonylamino) -4-cyanobenzene

1 ,2 -Bis (2 ,5-dichloro-3 -thienylsulfonylamino) -4-cyanobenzene

1 ,2-Bis (3 -chloro,2 -methylphenylsulfonylamino) -4-cyanobenzene

1 ,2-Bis (2 ,6-difluorophenylsulfonylamino) -4-cyanobenzene

1 ,2-Bis (2 - (3-oxazoyl) -5-thienylsulfonylamino) -4,5-difluorobenzene l,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4-chloro-5-methylbenzene l,2-Bis(2-thienylsulfonylamino)-4-chloro-5-methylbenzene l,2-Bis(3,4-dichlorophenylsulfonylamino)-4-chloro-5-methylbenzene l,2-Bis(4-trifluoromethylphenylsulfonylamino)-4-chloro-5-methylbenzene l,2-Bis(2,4-difluorophenylsulfonylamino)-4-chloro-5-methylbenzene

1 ,2-Bis (2 ,5 -dichloro,3 -thienylsulfonylamino) -4-chloro-5 -methylbenzene

1 ,2-Bis (2 -chloro,5-thienylsulfonylamino) -4-chloro-5 -methylbenzene

3,4-Bis(2,4-dimethyl,5-oxa-3-thiazoylsulfonylamino)-4-chloro-5-methylbenzene

1 ,2 -Bis (2 -aza-4,5 -benzothiazoylsulfonylamino) 4-chloro-5 -methylbenzene

1 ,2 -Bis (2 - (5 -oxa-2 -thiazoyl) -5 -thienylsulfonylamino) -4-chloro-5 -methylbenzene l,2-Bis(2,4-difluorophenylsulfonylamino)-4-chloro-5-methylbenzene

1 ,2 -Bis (4-methyl,3-nitrophenylsulfonylamino) -4-chloro-5 -methylbenzene

1 ,2-Bis (4-methyl,3-nitrophenylsulfonylamino) -4-cyanobenzene

1 ,2 -Bis (phenylsulfonylamino) -4-chloro-5 -methylbenzene

1 ,2 -Bis (2 - (3-oxazoyl) -5-thienylsulfonylamino) -4,5-dibromobenzene l,2-Bis(3-chloro,4-acetamidophenylsulfonylamino) -4,5-dibromobenzene

1 ,2-Bis (4-acetamidophenylsulfonylamino) -4,5-dibromobenzene

1 ,2 -Bis (5 - (2 -pyridyl) -2 -thienylsulfonylamino) -4-chlorobenzene l,2-Bis(5-(4-chloroacetamidomethyl)-2-thienylsulfonylamino) -4-chlorobenzene

1 ,2 -Bis (2 - (2 -aza-4-thiazoyl) -5-thienylsulfonylamino) -4-chlorobenzene

1 ,2 -Bis (2 - (2 -methyl-4-thiazoyl) -5 -thienylsulfonylamino) -4-chlorobenzene

3,4-Bis(4-methylphenylsulfonylamino) -benzoic acid 2 ,3 -Bis (2 ,4-dichlorophenylsulfonylamino) naphthalene

1 ,2-Bis (2 ,4-dichlorophenylsulfonylamino) -benzene

1 , 2 -Bis (2 - (2 -me thyl-4 - thiazoyl) -5 -thienylsulfonylamino) -benzene

1 ,2-Bis (2 - (2 -methyl-4-thiazoyl) -5 -thienylsulfonylamino) -4,5-dimethylbenzene

1 ,2-Bis (2 - (2 -methyl-4-thiazoyl) -5-thienylsulfonylamino) -4-fluorobenzene l,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-(3-methyl-5-oxadiazole) benzene

1 - (4-methylphenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonylamino) -4- fluorobenzene

1 - (2 ,5 -dichloro-3 -thienylsulfonylamino) -2 - (3 -trifluoromethylsulfonylamino) -benzene

3 ,4-Bis (4-methylphenylsulfonylamino) -N-phenyl-benzamide

3 ,4-Bis (4-methylphenylsulfonylamino) -N- (4-fluoromethoxyphenyl) benzamide

3 ,4-Bis (4-methylphenylsulfonylamino) -N- (3 ,5-dimethoxyphenyl) benzamide

3- (4-methylphenylsulfonylamino) -4- (3-trifluoromethylphenylsulfonylamino) -benzoic acid methyl ester

3- (2 ,5 -dichloro-3 -thienylsulfonylamino) -4- (3 -trifluoromethylsulfonylamino) -benzoic acid methyl ester

1 ,2 -Bis (4-methoxyphenylsulfonylamino) -4,5 -dibromobenzene

1 ,2-Bis (4-methoxyphenylsulfonylamino) -4,5-dichlorobenzene

1 - (4-methoxyphenylsulfonylamino) -2 - (3 -trifluoromethylphenylsulfonylamino) -4- chlorobenzene

1 - (3 -chlorophenylsulfonylamino) -2 - (3 - trifluoromethylphenylsulfonylamino) -4- chlorobenzene

1 - (2 -chlorophenylsulfonylamino) -2 - (3 -trifluoromethylphenylsulfonylamino) -4- chlorobenzene

1 - (3 -methylphenylsulfonylamino) -2 - (3 - trifluoromethylphenylsulfonylamino) -4- chlorobenzene

1 - (4-methylamidomethylphenylsulfonylamino) -2 - (3 - trifluoromethylphenylsulfonylamino)-4-chlorobenzene

1 - (2 - (phenylamidomethyl) -5-thienylsulfonylamino) -2 - (3 - trifluoromethylphenylsulfonylamino) -4-chlorobenzene 1 - (4- (2 -chloro-5 -thiazoylmethoxyphenylsulfonylamino) -2 - (3 - trifluoromethylphenylsulfonylamino) -4-chlorobenzene

1 - (2 - (phenylamidomethyl) -5-thienylsulfonylamino) -2 - (3 - trifluoromethylphenylsulfonylamino)-benzene

1 - (2 - (phenylamidomethyl) -5 -thienylsulfonylamino) -2 - (3 - trifluoromethylphenylsulfonylamino)-4-fluorobenzene l,2-Bis(2-(N-phenyl)amidomethyl-5-thienylsulfonylamino) -benzene

1 - (4- (2 -chloro-5-thiazoylmethoxyphenylsulfonylamino) -2 - (3 - trifluoromethylphenylsulfonylamino) -benzene

1 - (4- (2 -chloro-5 -thiazoylmethoxyphenylsulfonylamino) -2 - (3- trifluoromethylphenylsulfonylamino) -4-fluorobenzene

1 - (2 -chlorophenylsulfonylamino) -2 - (3 -trifluoromethylphenylsulfonylamino) -benzene

1 - (2 -chlorophenylsulfonylamino) -2 - (3 -trifluoromethylphenylsulfonylamino) -4- fluorobenzene

1 - (2 -methylphenylsulfonylamino) -2 - (3 -trifluoromethylphenylsulfonylamino) -benzene

1 - (3 -methylphenylsulfonylamino) -2 - (3 -trifluoromethylphenylsulfonylamino) -4- fluorobenzene

1 - (4-trifluoromethylphenylsulfonylamino) -2 - (3 -trifluoromethylphenylsulfonylamino) - benzene

1 ,2 -Bis (benzylsulfonylamino) -4,5 -diflurobenzene

1 ,2-Bis (benzylsulfonylamino) -benzene l,2-Bis(benzylsulfonylamino)-4-chloro-5-methylbenzene

1 ,2-Bis(phenylstyrylsulfonylamino) -4-chlorobenzene

1 - (3 -trifluoromethylsulfonylamino) -2- (phenylstyrylsulfonylamino) -4-fluorobenzene

1 - (3 -trifluoromethylsulfonylamino) -2 - (phenylstyrylsulfonylamino) -benzene l-(3-trifluoromethylsulfonylamino) -2- (benzylsulfonylamino) -4-fluorobenzene

4- (3 -trifluoromethylsulfonylamino) -3 - (2 -phenylethenylsulfonylamino) -benzoic acid ethyl ester and salts thereof, in particular pharmaceutically acceptable salts thereof.

Compounds which are particularly effective are 1,2-Bis (2,5-dichloro-3-thienylsulfonylamino)-4-chlorobenzene, 1 ,2-Bis (4-trifluoromethoxyphenylsulfonylamino) -4-chlorobenzene,

1 ,2-Bis (3-trifluoromethylphenylsulfonylamino) -4-chlorobenzene,

1 ,2-Bis (2 -chloro-5 -thienylsulfonylamino) -4-chlorobenzene,

1,2-Bis (2-chloro-5-thienylsulfonylamino)-4-fluorobenzene,

1 ,2-Bis (2 -methyl-3 -chlorophenylsulfonylamino) -4-fluorobenzene, and salts thereof, in particular pharmaceutically acceptable salts thereof.

Certain bissulfonamide derivatives of the formula (I) are novel per se. These compounds are bissulfonamides of the formula (Id), and salts thereof,

R₃ o=s=o

wherein:

R_t and R₂ are as defined above; R₃ and R₄ are as defined above and Ar is a group of formula Ar, as defined above, provided that when R_{ and R₂ are both hydrogen, and Ar is an unsubstituted napthyl group, a phenanthracene group or a phenyl group optionally substituted by 1 or 2 dimethylmethylenedioxy, hydroxy, methoxy, ethoxy, methyl, chlorine, bromine, fluorine, nitro, CF₃ or amino groups, R₃ and R_^, are not (a) unsubstituted quinoline groups, (b) unsubstituted phenyl groups, (c) phenyl groups monosubstituted by a methyl, methoxy, -C0₂H, chlorine, cyano, nitro or amino group, or by a group -0-CO-N(CH₃)- or (d) phenyl groups disubstituted by a nitro group and a methyl group. Suitable salts include these mentioned above as examples of pharmaceutically acceptable salts.

Preferred novel compounds of the invention are bissulfonamides of the formula (Id), as defined above, and salts thereof, wherein, when R_t and R₂ are both hydrogen and Ar is an unsubstituted napthyl group, a phenanthracene group or a phenyl group optionally substituted by 1 or 2 C,-C₄ alkylenedioxy, hydroxy, -G, alkoxy, -G, alkyl, halogen, nitro, -Q, haloalkyl or amino groups, R₃ and R^ are not unsubstituted quinoline groups or phenyl groups optionally substituted by 1 or 2 groups selected from -C₄ alkyl, C,-C₄ alkoxy, -C0₂R wherein R is hydrogen or C_{- C₄ alkyl, halogen, cyano, nitro and amino groups, and from groups of the formula -O- CO-N( -C₄ alkyl)-.

The compounds of formula (I) may be prepared by a process comprising reacting a compound of formula (II)

R₃ O=S=O

NR, (D)

Ar

\

NHR₂

wherein Ar, R_t, R₂ and R₃ are as^' defined above, with a compound of formula (III)

X o=s=o (m)

R4

wherein R₄ is as defined above and X is a leaving group such as a chlorine atom. Typically, the reaction takes place in the presence of an organic solvent and a base. Typically, the base is pyridine, triethylamine or 4-dimethylaminopyridine. Typically, the solvent is acetonitrile, dichloromethane, toluene or dimethylformamide. Typically, molar equivalents of the compounds of formulae (II) and (III) are used.

A compound of formula II may be prepared by reacting a compound of formula (IV).

wherein Ar, R, and R₂ are as defined above, with a compound of formula (V)

X O=S =O (V)

R₃

wherein R₃ and X are as defined above.

Typically, the reaction takes place in the presence of an organic solvent and a base. Typically the solvent is acetonitrile, dichloromethane, toluene or dimethylformamide. Typically the base is pyridine, triethylamine or 4-dimethylaminopyridine. Typically, molar equivalents of compounds of formulae (IV) and (V) are used.

Compounds of formula I wherein R₃ and R₄ are the same may, of course, be prepared by reacting a compound of formula (IV) with two molar equivalents of a compound of formula (III) under the reaction conditions set out above.

Preferably the solvent used in the above reactions is acetonitrile or dichloromethane and the reactions take place in the presence of pyridine or 4-dimethylaminopyridine. Alternatively, compounds of formula (II), in which Ar, R„ and R₃ are as defined above and R₂ is hydrogen, can also be prepared by reaction of a compound of formula (VI) with a suitable reducing agent.

₃ O=S=O

NRi (VI)

Ar^'

\

NO₂

wherein Ar, R_[ and R₃ are as defined above.

Typically the reducing agent is palladium on carbon with hydrazine hydrate, tin (II) chloride, platinum on carbon with hydrogen gas or ferric chloride in alkaline solution. Preferably the reducing agent is tin (II) chloride or palladium on carbon with hydrazine hydrate. The reaction can be carried out in an organic solvent such as ethanol, dimethylformamide, chloroform, ethyl acetate or tetrahydrofuran. Preferably the solvent is dimethylformamide or ethanol.

Compounds of formula (VI) can be prepared by reaction of a compound of formula (VII) ,

H

I NRi

/

Ar (VII)

\

NO₂

wherein Ar and R are as defined above, with a compound of formula (V) . Typically, the reaction takes place in the presence of an organic solvent and a base. Typically the solvent is acetonitrile, dichloromethane, toluene or dimethylformamide. Typically the base is pyridine, triethylamine or 4- dimethylaminopyridine. Typically, molar equivalents of compounds of formulae (IV) and (V) are used

Further synthetic manipulation of the thus obtained compounds of formula (I) , such as bromination, nitration and acylation may be carried out by conventional methods to achieve further compounds of formula I.

The thus obtained bissulfonamide derivatives of formula (I) may be salified by treatment with an appropriate acid or base.

Compounds of formulae (III), (IV), (V), (VI) and (VII) are known compounds, or may be prepared by analogy with known methods.

The compounds of formula (I) are found to be inhibitors of dehydroquinate synthetase enzymes, in particular AroB, and type II dehydroquinase enzymes, in particular AroQ.

As explained above, dehydroquinate synthetase enzymes invariably form an essential part of the shikimate pathway. Further, type II dehydroquinase enzymes have been implicated in the shikimate pathway in many organisms. Type II dehydroquinase enzymes also form an important part of the catabolic pathway by which quinic acid catabolism is effected. The compounds of the invention are particularly highly active against organisms in which the shikimate pathway involves a type II dehydroquinase enzyme and organisms using both the shikimate pathway and the quinic acid catabolic pathway. That is because they have two enzyme targets in such organisms.

The present invention thus provides a method for treating a patient in need of an inhibitor of the biosynthesis of aromatic amino acids via the shikimate pathway which method comprises administering to said patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The shikimic acid pathway is essential for the synthesis of aromatic amino acids in fungi and bacteria. Accordingly, the compounds of the invention are effective in treating or preventing bacterial or fungal infection. Indeed, the compounds of the invention are effective against many bacteria which have developed resistance to conventional antibiotics. For example, they are effective against Methicillin Resistant Staphylococcus Aureus (MRSA) . Accordingly, the said medicament is typically for use in treating or preventing, and the said patient is typically suffering from or susceptible to, a bacterial or fungal attack. In particular, the said patient is typically suffering from or susceptible to, and the said medicament is typically for use in the prevention or treatment of, a MRSA infection.

The gene encoding type II dehydroquinase has been observed in Actinobacillus pleuropneumoniae, Actinobacϊllus actinomycetes, Aeromonas salmonicida subsp. Salmonicida, Amycolatopsis mediterranei, Bacillus subtilis, Corynebacterium glutamicum, Corynebacterium pseudotuberculosis, Emericeϊla nidulans, Haemophilus influenzae, Helicobacter pylori, Neurospora crassa, Pseudomonas aeruginosa, Streptomyces coelicolor, Streptomyces lavendulae, Synechocystis sp, Thermotoga meritima, Campylobacter jejuni, Clostndium acetobutylicum, Porphyromonas gingivalis, Deinococcus radiodurans, Chlorobium tepidum, Vibrio cholerae, Yersinia pestis, Shewanella putrafaciens, Thiobacillus ferroxidans, Synechocystis PCC6803, Candida albicans, Bordetella pertussis, Mycobacterium avium, Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Caulobacter eresentus and Klebsiella pneumoniae.

The compounds of the present invention are particularly active against the above organisms. This is because, as explained above, the compounds of the invention act to inhibit both dehydroquinate synthetase and Type II dehydroquinase enzymes in these organisms. Accordingly, the said medicament is typically for use in the treatment or prevention of, or the said patient is typically suffering from or susceptible to, attack by one of the above organisms.

The compounds of the invention can also be used generally to prevent bacterial growth. For example, they may be added to solutions, such as solutions for contact lenses, to prevent bacterial growth. They may also be used in antibiotic coatings on surgical instruments and in products such as medicated soaps. Accordingly, the present invention also provides the non- therapeutic use of a compound of the invention in inhibiting bacterial growth. Also provided is a contact lens solution or a medicated soap comprising a compound of the invention. Further, the present invention provides a surgical instrument having thereon an antibiotic coating comprising a compound of the invention.

The shikimic acid pathway is also implicated in the metabolism of parasites. For example, it is implicated in the treatment of apicomplexan parasites. Accordingly, the compounds of the invention are effective in the treatment or prevention of infection by a parasite in which the biosynthesis of aromatic amino acids is effected via the shikimic pathway. Such parasites can be identified, for example, by (a) determining whether in vitro growth is inhibited by well characterised inhibitors of the shikimate pathway such as glyphosphate, and (b) determining whether such inhibition is reversed by addition of p-aminobenzoate. Parasites whose in vitro growth is inhibited by glyphosphate and in which such inhibition is reversed by addition of p-aminobenzote use the shikimate pathway in their metabolic processes. The compounds of the invention will therefore be active against such parasites.

In particular, the compounds of the invention are active against apicomplexan parasites, for example Toxoplasma gondii, Cryptosporidium parvum and Plasmodium falciparum. Plasmodium falciparum is known to cause malaria. Thus, the said patient is typically suffering from or susceptible to, and the said medicament is typically for use in the treatment or prevention of, infection by an apicomplexan parasite. In particular, the said patient is typically suffering from or susceptible to, and the said medicament is typically for use in the treatment or prevention of, malaria.

When used for treating the above disorders, the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.

Certain compounds of the formula (I) have not previously been disclosed in a therapeutic context. Accordingly, the present invention also provides a bissulfonamide derivative of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body, wherein Ar, R„ R₂, R₃ and R^ are as defined above, provided that, when R_[ and R₂ are hydrogen and R₃ and R₄ are phenyl, 4-methylphenyl or 4-aminophenyl, Ar is not

wherein R' and R" are methyl or chlorine.

The present invention also provides a pharmaceutical composition containing such a bissulfonamide derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.001 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.

The shikimic acid pathway is also essential in higher plants, algae and fungi. Further, the pathway for the catabolism of quinic acid is also found in fungi. The compounds of the invention are therefore effective in controlling higher plants, algae and fungi. They can be used as selective herbicides and fungicides, for example. Accordingly, the present invention provides the use of a compound of formula (I) , or an agriculturally acceptable salt thereof, as a herbicide or a fungicide. Also provided is a method of controlling weeds or fungi at a locus, which method comprises treating the locus with a compound of formula (I) or an agriculturally acceptable salt thereof.

Typically the locus comprises agricultural or horticultural plants or a medium in which such plants grow.

A preferred method of controlling fungi is a method of treating a plant for, or protecting a plant against, fungal attack, which method comprises applying to the plant a compound of formula (I) or an agriculturally acceptable salt thereof. Smuts and rusts on a plant can, for example, be treated by this method.

Typically, the active compound is applied to the leaves. The number of applications and the rate of application depend on the intensity of the fungal attack. However, an active compound can also be applied to a plant through the roots via the soil (systemic action) by impregnating the locus of the plant with a liquid composition comprising the active compound, or by applying the compound in solid form to the soil, e.g. in granular form (soil application). The active compound may also be applied to seeds (coating) by impregnating the seeds either with a liquid formulation containing the active compound, or coating them with a solid formulation. In special cases, further types of application are also possible, for example, selective treatment of the plant stems or buds.

The present invention also provides a herbicidal or fungicidal composition comprising a novel bissulfonamide derivative, as defined above, or an agriculturally acceptable salt thereof and an agriculturally acceptable carrier or diluent.

Suitable agriculturally acceptable salts include those salts mentioned above as examples of pharmaceutically acceptable salts.

The said herbicidal or fungicidal composition may be prepared by mixing a compound of formula (I), or an agriculturally acceptable salt thereof, with an agriculturally acceptable carrier or diluent. Suitable such compositions include wettable powders, granules, water-dispersible granules, emulsion concentrates, suspension concentrates, and powders suitable for dusting plants. The fungicidal or herbicidal compositions may comprise further agricultural chemicals, for example further fungicides and herbicides or insecticides, miticides, plant growth regulators, fertilizers and soil conditioners.

The herbicidal or fungicidal composition preferably comprises a further fungicide or herbicide. This leads not only to a reduction in dose and manpower, but also to broadening of the herbicidal or fungicidal spectrum. This broadening is attributable to cooperative activities.

Suitable agriculturally acceptable carriers and diluents include solid or liquid carriers and diluents.

Examples of the solid carriers or diluents include clays such as kaolinites, montmorillonites, illites and polygroskites, more specifically pyrophyllite, attapulgite, sepiolite, kaolinite, bentonite, vermiculite, mica and talc. Other inorganic substances such as gypsum, calcium carbonate, dolomite, diatomaceous earth, magnesium lime, phosphorus lime, zeolite, silicic anhydride and synthetic calcium silicate may also be used. Suitable organic carriers and diluents include soybean flour, tobacco flour, walnut flour, wheat flour, wood flour, starch and crystalline cellulose. Further synthetic or natural polymers such as coumarone resin, petroleum resin, alkyd resin, polyvinyl chloride, polyalkylene glycol, ketone resin, ester gum, copal gum and dammar gum are suitable, as are waxes such as carnauba wax and bee wax.

Examples of suitable liquid carriers and diluents include paraffin or naphthene hydrocarbons such as kerosene, mineral oil, spindle oil and white oil, aromatic hydrocarbons such as xylene, ethylbenzene, cumene and methylnaph- thalene, chlorinated hydrocarbons such as trichloroethylene, monochlorobenzene and o-chloro toluene, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, acetophenone and isophorone, esters such as ethyl acetate, amyl acetate, ethylene glycol acetate, diethylene glycol acetate, dibutyl maleate and diethyl succinate, alcohols such as methanol, n-hexanol, ethylene glycol, diethylene glycol, cyclohexanol and benzyl alcohol, ether alcohols such as ethylene glycol ethyl ether and diethylene glycol butyl ether and polar solvents such as dimethylformamide, dimethyl sulfoxide and water.

Typically the herbicidal and fungicidal compositions comprise a surfactant and/or another auxiliary agent suitable for various purposes such as emulsification, dispersion, humidification, spreading, dilution, combination destruction control, stabilization of active ingredients, improvement of flowability, prevention of corrosion and prevention of freezing. Preferably, the herbicidal and fungicidal compositions of the invention comprise at least one surfactant. The present invention also provides a herbicidal or fungicidal composition comprising:

- a bissulfonamide of formula (I) or an agriculturally acceptable salt thereof;

- at least one surfactant; and

- an agriculturally acceptable carrier or diluent.

Suitable surfactants include nonionic, anionic, cationic and amphoteric surfactants. Nonionic and anionic surfactants are preferred. Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic surface-active compounds.

Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (chains of 10 to 22 carbon atoms), for example the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained for example from coconut oil or tallow oil. The fatty acid methyltaurin salts may also be used.

More frequently, however, so-called synthetic surfactants are used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.

The fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and have a C₈ to C₂₂ alkyl radical which also includes the alkyl moiety of alkyl radicals, for example, the sodium or calcium salt of lignonsulfonic acid, of dodecylsulfate or of a mixture of fatty alcohol sulfates obtained from natural fatty acids. These compounds also comprise the salts of sulfuric acid esters and sulfonic acids of fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one fatty acid radical containing 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnapthalenesulfonic acid, or of a naphthalenesulfonic acid/formaldehyde condensation product. Also suitable are corresponding phosphates, e.g. salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4 to 14 moles of ethylene oxide.

Non-ionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, or saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols.

Further suitable non-ionic surfactants are the water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediamine propylene glycol and alkylpolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of non-ionic surfactants are nonylphenolpolyethoxyethanols, castor oil polyglycol ethers, polypropylene /polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxyethoxyethanol. Fatty acid esters of polyoxyethylene sorbitan and polyoxyethylene sorbitan trioleate are also suitable non-ionic surfactants.

Cationic surfactants are preferably quaternary ammonium salts which have, as N-substituents, at least one C₈-C₂₂ alkyl radical and, as further substituents, lower unsubstituted or halogenated alkyl, benzyl or lower hydroxyalkyl radicals. The salts are preferably in the form of halides, methylsulfates or ethylsulfates, e.g. stearyltrimethylammonium chloride or benzyldi(2-chloroethyl)ethylammomium bromide.

The surfactants customarily employed in the art of formulation are described, for example, in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp. Ringwood, New Jersey, 1979, and Sisely and Wood, Encyclopaedia of Surface Active Agents, Chemical Publishing Co., Inc. New York, 1980.

The said auxiliary agent includes casein, gelatin, albumin, glue, sodium alginate, carboxymethylcellulose, methylcellulose, hydroyethylcellulose and polyvinyl alcohol.

The above-described carriers or diluents and various auxiliary agents may be used alone or in combination.

The content of active compound in the herbicidal and fungicidal composition of the invention may vary widely depending on the form of formulation. Typically, the amount of active compound is 0.1 to 99%, preferably 1 to 80% by weight of the composition.

More specifically, wettable powders typically contain 25 to 90% by weight of active compound. Granules typically contain 1 to 35% by weight of active compound, which may be mixed with the solid carrier or diluent uniformly, or mixed to or absorbed on the surface of the solid carrier or diluent uniformly. It is preferred that the diameter of the granules is from 0.2 to 1.5mm. Emulsion concentrates typically contain 5 to 30% by weight of active compound, and in additional 5 to 20% by weight of an emulsifier. Suspension concentrates typically contain 5 to 50% by weight of active compound, and in addition 3 to 10% by weight of a dispersion wetting agent.

The compounds of the invention may be applied in effective amounts to various places to be protected, for example farm-lands such as paddy fields and upland, or non-crop lands. When used as herbicides they may be applied prior to germination of weeds or to weeds of various stages from after germination to growth period. When the compounds of the invention are used as herbicides, the dose is generally, as amount of active ingredients, on the order of 0.1 to 10,000 g/ha, preferably 1 to 5,000 g/ha, more preferably from 50 to 3,000 g/ha. The dose may be varied depending on the kind of objective weeds, their growth stages, places of application and weather. When the compounds of the invention are used as fungicides, the dose is typically from 50g to 5kg of active ingredient per hectare, preferably from lOOg to 2kg per hectare, more preferably from 200g to 500g per hectare.

The shikimic acid pathway is also essential for the synthesis of aromatic amino acids in algae. Accordingly, the compounds of the present invention are effective in controlling algae. The present invention therefore provides the use of a compound of formula (I), or a salt thereof, in controlling algae. In particular, the mvention provides a method of treating algae in a fish tank or pond, which method comprises applying to the fish tank or pond a compound of formula (I) or a salt thereof.

As explained above, type II dehydroquinase enzymes form an important part of the catabolic pathway by which quinic acid catabolism is effected. The present invention therefore also provides the use of a bissulfonamide derivative of the formula (I), as defined above, or a salt thereof, in the inhibition of quinic acid catabolism. Suitable salts include those given above as examples of pharmaceutically acceptable salts. The catabolic pathway is found in many fungi and bacteria. The compounds of the invention are therefore typically used to inhibit the catabolism of quinic acid by a fungus or a bacterium. They may be formulated for such use as a herbicidal or fungicidal composition, as defined above, and used at the dosage ranges given above.

The following Examples illustrate the invention.

Example 1

1 ,2-Bis (3 -nitrophenylsulfonylamino) -benzene

A solution of 1,2-phenylenediamine (lOmM) in dry pyridine (50ml) was stirred under nitrogen at room temperature and 3-nitrobenzenesulfonyl chloride (20mM) was added portion- wise over a few minutes. The resulting solution was heated at reflux for 5hr then allowed to cool and poured onto cold IN hydrochloric acid (500ml). The product was extracted into ethyl acetate (3x200ml) and the combined organic extracts washed with water, IN sodium hydroxide, then water again before drying over anhydrous sodium sulfate and evaporating under reduced pressure. Column chromatography on silica provided the required product (3.1g, 65%).

Examples 2 to 8

The compounds set out below were prepared in the same way as in Example 1, using appropriate starting materials.

Example Compound

2 3,4-Bis(4-methylphenylsulfonylamino)-6-bromotoluene

3 l,2-Bis(4-methylphenylsulfonylamino) -4-fluorobenzene

4 3,4-Bis- (phenylsulfonylamino) toluene

5 1 ,2-Bis- (methylphenylsulfonylamino) -4-nitrobenzene

6 3, 4-Bis(4-methylphenylsulfonylamino) toluene

7 1 ,2-Bis (4-methylphenylsulfonylamino-4-fluoro-5 -nitrobenzene

8 3,4-Bis(4-methylphenylsulfonylamino) -benzoic acid methyl ester

Example 9 1,2 -Bis (4-toluenesulfonylamino) -benzene

A solution of 1,2 -phenylenediamine (lOmM, l.Oδg) in dry acetonitrile (50ml) was stirred under nitrogen at room temperature. Diisopropylethylamine (5ml) was added, followed by benzenesulfonyl chloride (4.19g, 22mM). The resulting solution was heated at reflux for lOhr then cooled and evaporated under reduced pressure. The resulting solid was partitioned between water and chloroform and the organic layer separated, washed with IN sodium hydroxide solution, then water, and finally dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane. The product was isolated as a white powder (1.8g, 43%) mpt 203-205°C.

Examples 10 to 21

The compounds set out below were prepared in the same way as in Example 9 using appropriate starting materials.

Example Compound

10 l,2-Bis(3,5-ditrifluoromethylphenylsulfonylamino)-benzene

11 l,2-Bis(4-bromophenylsulfonylamino)-benzene 12 l,2-Bis(4-tert-butylphenylsulfonylamino)-benzene 13 l,2-Bis(4-methylphenylsulfonylamino)-4,5-methylenedioxybenzene 14 l,2-Bis(4-methylphenylsulfonylamino)-4,5-dichlorobenzene 15 l,2-Bis(4-methylphenylsulfonylamino)-4,5-ethylenedioxybenzene 16 2,3-Bis(4-methylphenylsulfonylamino)-naphthalene 17 l,2-Bis(4-methylphenylsulfonylamino)-4,5-difluorobenzene 18 l,2-Bis(4-bromophenylsulfonylamino)-4,5-dibromobenzene 19 l,2-Bis(4-chlorophenylsulfonylamino) -4,5-dibromobenzene 20 l,2-Bis(4-fluorophenylsulfonylamino)-4,5-dibromobenzene 21 l,2-Bis(3-bromophenylsulfonylamino) -4,5-dibromobenzene Example 22

3 - (3-trifluoromethylphenylsulfonylamino) -4- (4-methylphenylsulfonylamino) toluene

A solution of 3,4-diaminotoluene (lOmM) in dry pyridine (50ml) was stirred under nitrogen at room temperature and 3-(3-trifluoromethylphenyl)sulfonyl chloride (lOmM) was added portion-wise over a few minutes. The resulting solution was heated at reflux for 5hr then allowed to cool and poured onto cold water. The product was extracted into ethyl acetate (3x200ml) and the combined organic extracts washed with water, IN sodium hydroxide, then water again before drying over anhydrous sodium sulfate and evaporating under reduced pressure. The resulting 4- (4-methylphenylsulfonylamino) -3 -aminotoluene was subjected to the same reaction conditions, employing 3 -(trifluoromethylphenyl)sulfonyl chloride (lOmM). Column chromatography on silica provided the required product.

Examples 23 and 24

The compounds set out below were prepared in the same way as in Example 22, using appropriate starting materials.

Example Compound

23 3-(4-chlorophenylsulfonylamino) -4- (4-methylphenylsulfonylamino) toluene

24 3-(4-fluorophenylsulfonylamino) -4- (4-methylphenylsulfonylamino) toluene

Example 25

1 ,2-Bis (4-toluenesulfonylamino) -4,5 -dibromobenzene A solution of 1,2 -Bis (4-toluenesulfonylamino) -benzene (500mg, 1.2mM) in glacial acetic acid (10ml) was stirred and sodium acetate (200mg) added. Bromine (385mg, 0.13ml, 2.4mM) was added dropwise and the resulting dark solution then heated at 80°C for 3hr. Water (50ml) was added and the resulting precipitate isolated by filtration and purified by recrystallisation from acetic acid to give the required product as white needles, m.pt 213-215°C (650mg, 94%).

Example 26

N,N- 1 ,4-Bis (4-methylphenylsulfonylamino) quinazoline

4,5-Dibromo-l,2-bis(4-methylphenylsulfonylamino) benzene (176mg, 3xl0^'4mol) and dibromoethane (57mg, 3xl0^'4mol) were refluxed with potassium carbonate (l.Og, 7.25 x 10^'4mol) in dry acetonitrile (250ml) for 4 hours under nitrogen and then stirred at RTP overnight. The solution was filtered and evacuated to dryness to yield the product as a light brown glass (0.16g, 89%).

Example 27

l,2-Bis(2-chloro,5-thienylsulfonylamino)-4-chloro-5-methylbenzene

4-chloro-5-methylphenylene-l,2-diamine (lOmM, 1.56) was dissolved in dry pyridine (lOOml) and stirred at room temperature under nitrogen. To this solution a solution of 5-chloro-2-thienylsulfonyl chloride (21mM, 4.55g) in pyridine (15 ml) is added and the resultant solution stirred at 85^SC for 18 hr under nitrogen. The solution was then poured into 0.5M cold dilute hydrochloric acid (125ml) and the product extracted into chloroform. The solution was then dried over anhydrous sodium hydrogen carbonate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica eluting with a mixture of chloroform and methanol. the product was further purified by recrystallisation from ethanol/water and the product dried overnight under vacuum. The product was obtained as an off white crystalline solid (2.18g, 42%).

Examples 28 to 58

The compounds set out below were prepared in the same way as in Example 27, using appropriate starting materials.

Example Compound

28 2,3-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)naphthalene 29 l,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-benzene 30 1 ,2-Bis( 1 -naphthylsulfonylamino)-4,5-dibromobenzene 31 l,2-Bis(2,3-dichloro-5-thienylsulfonylamino)-4,5-dibromobenzene 32 l,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4,5-dibromobenzene 33 l,2-Bis(4-nitrophenylsulfonylamino)-4,5-dibromobenzene 34 l,2-Bis(4-biphenylsulfonylamino)-4,5-dibromobenzene 35 l,2-Bis(4-bromophenylsulfonylamino)-4,5-dibromobenzene 36 l,2-Bis(4-carboxyphenylsulfonylamino)-4,5-dibromobenzene 37 l,2-Bis(3,4-dimethoxyphenylsulfonylamino)-4,5-dibromobenzene 38 l,2-Bis(3-methylphenylsulfonylamino)-4,5-dibromobenzene 39 l,2-Bis(2-fluorophenylsulfonylamino)-4,5-dibromobenzene 40 l,2-Bis(2-methoxyρhenylsulfonylamino)-4,5-dibromobenzene 41 2,3-Bis(4-fluorophenylsulfonylamino)naphthalene 42 l,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4-fluorobenzene 43 l,2-Bis(3-trifluoromethylphenylsulfonylamino)-4,5-dibromobenzene 44 l,2-Bis(2-trifluoromethoxyphenylsulfonylamino)-3,5-dibromobenzene 45 l,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4,5-dibromobenzene 46 l,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4,5-dimethylbenzene 47 l,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4,5-dibromobenzene 48 l,2-Bis(3-chloro,4-acetamidophenylsulfonylamino)-4,5-dibromobenzene 49 l,2-Bis(4-acetamidophenylsulfonylamino)-4,5-dibromobenzene 50 l,2-Bis(5-(2-pyridyl)-2-thienylsulfonylamino)-4-chlorobenzene 51 l,2-Bis(5-(4-chloroacetamidomethyl)-2-thienylsulfonylamino)-4-chlorobenzene 52 l,2-Bis(2-(2-aza-4-thiazoyl)-5-thienylsulfonylamino)-4-chlorobenzene 53 l,2-Bis(2-(2-methyl-4-thiazoyl)-5-thienylsulfonylamino)-4-chlorobenzene 54 l,2-Bis(2-(2-methyl-4-thiazoyl)-5-thienylsulfonylamino)-4-fluorobenzene 55 l,2-Bis(4-methoxyphenylsulfonylamino),4,5-dibromobenzene 56 l,2-Bis(4-methoxyphenylsulfonylamino),4,5-dichlorobenzene. 57 l,2-Bis(2-( V-phenylamidomethyl)-5-thienylsulfonylamino)-benzene 58 l,2-Bis(2-phenylethenylsulfonylamino)-4-chlorobenzene

Example 59

1 ,2 -Bis (4-trifluoromethoxyphenylsulfonylamino) -benzene

To a solution of 1,2 phenylenediamine (24 mg, 0.22 mmol) in acetonitrile (2 ml) was added pyridine (0.05 ml, 0.66 mmol, 3 equivalents). To this solution was added a solution of (4-trifluoromethoxy)phenylsulfonyl chloride (84 mg, 0.44 mmol) in acetonitrile (2 ml). The reaction mixture was left to stand at ambient temperature for twenty four hours. On completion the reaction mixture was concentrated in vacuo to afford a heavy syrup. The syrup was dissolved in dichloromethane (1 ml) and water (1 ml). The phases were separated and the organic phase was washed with water (1 ml), citric acid (10%, 1 ml) and saturated brine

(1 ml). The organic solution was dried in vacuo to afford the final product which was analysed by liquid chromatography in conjunction with mass spectrometry.

Examples 60 to 64

The compounds set out below were prepared in the same way as in Example 59, using appropriate starting materials.

Example Compound

60 l,2-Bis(4-isopropylphenylsulfonylamino)-benzene

61 l,2-Bis(4-fluorophenylsulfonylamino)-4,5-dimethylbenzene 62 l,2-Bis(4-methylphenylsulfonylami_no)-4,5-dimethylbenzene 63 l,2-Bis(3-trifluoromethoxyphenylsulfonylamino)-4,5-dimethylbenzene 64 l,2-Bis(4-isopropylphenylsulfonylamino)-4,5-dimethylbenzene

The above compounds were analysed by liquid chromatography, in conjunction with a mass spectrometer as detector. The equipment used was a Waters 2700 Sample Manager, with Waters 2690 Alliance Solvent Delivery System and Waters 996 Photodiode Array Detector. The mass spectrometer used was a Micromass Platform LCZ Mass Spectrometer running Micromass MassLynx Software, v3.2 build 004. Chromatography was carried out on a Waters Symmetry 3.5[]m C18 50x2.0mm (WAT200650) column with a gradient elution from 5% lOmM formic acid in acetonitrile and 95% lOmM formic acid in water to 95% lOmM formic acid in acetonitrile and 5% lOmM formic acid in water over 3 minutes at 0.5ml/minute flow rate. UV detection was at 200-300nm and mass spectra were collected by positive and negative electrospray. All reaction products showed the desired compound with satisfactory purity.

Example 65

1 ,2-Bis (3 -trifluoromethylphenylsulfonylamino) -4,5-dimethylbenzene

To a solution of 4,5-dimethyl-l,2-phenylenediamine (30 mg, 0.22 mmol) in acetonitrile (2 ml) was added pyridine (0.05 ml, 0.66 mmol, 3 equivalents). To this solution was added a solution of 3-trifluoromethylphenylsulphonylchloride (108 mg, 0.44 mmol) in dimethylformamide (2 ml). The reaction mixture was left to stand at ambient temperature for twenty four hours. On completion the reaction mixture was concentrated in vacuo to afford a heavy syrup. The syrup was dissolved in dichloromethane (1 ml) and water (1 ml). The phases were separated and the organic phase was washed with water (1 ml), citric acid (10%, 1 ml) and saturated brine (1 ml). The organic solution was dried in vacuo to afford the final product which was analysed by liquid chromatography in conjunction with mass spectrometry. Examples 66 to 256

The compounds set out below were prepared in the same way as Example 65, using appropriate starting materials.

Example Compound

66 2,3-Bis(4-methylphenylsulfonylamino)-phenol

67 2,3-Bis(4-trifluoromethoxyphenylsulfonylamino)-phenol

68 2,3-Bis(4-isopropylphenylsulfonylamino)-phenol

69 2,3-Bis(4-methylsulfonphenylsulfonylamino)-phenol

70 3,4-Bis(4-fluorophenylsulfonylamino)-anisole

71 3,4-Bis(4-methylρhenylsulfonylamino)-anisole

72 3,4-Bis(4-trifluoromethoxyphenylsulfonylamino)-anisole

73 3,4-Bis(4-isopropylphenylsulfonylamino)-anisole

74 3 ,4-Bis [(4-methylsulfonyl)phenylsulfonylamino] anisole

75 l,2-Bis(3-trifluoromethylphenylsulfonylamino)-benzene

76 l,2-Bis(4-trifluoromethylphenylsulfonylamino)-benzene

77 l,2-Bis(3-chloro-2-methylphenylsulfonylamino)-benzene

78 l,2-Bis(2,6-difluorophenylsulfonylamino)-benzene

79 l,2-Bis(phenylsulfonylamino)-benzene

80 l,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4,5-dimethylbenzene

81 l,2-Bis(2,6-difluorophenylsulfonylamino)-4,5-dimethylbenzene

82 l,2-Bis(2,6-difluorophenylsulfonylamino)-4-fluorobenzene

83 2,3-Bis(3-trifluoromethylphenylsulfonylamino)-phenol

84 2,3-Bis(3,4-dichlorophenylsulfonylamino)-phenol

85 2,3-Bis(2,4-difluorophenylsulfonylam__no)-phenol

86 l,2-Bis(4-trifluoromethylphenylsulfonylamino)-4,5-dimethylbenzene

87 2,3-Bis(5-chloro,2-methoxyphenylsulfonylamino)-phenol

88 3,4-bis(4-trifluoromethylphenylsulfonylamino)-benzoic acid ethyl ester

89 3,4-Bis(3,4-dichlorophenylsulfonylamino)-anisole

90 3,4-Bis(5-chloro,2-methoxyphenylsulfonylamino)-anisole

91 l,2-Bis(4-fluorophenylsulfonylamino)-benzene

92 l,2-Bis(2,4-difluorophenylsulfonylamino)-benzene

93 l,2-Bis(phenylsulfonylamino)-4,5-dimethylbenzene

94 l,2-Bis(5-chloro,2-methoxyphenylsulfonylamino)-4,5-dimethylbenzene

95 2,3-Bis(phenylsulfonylamino)-phenol

96 2,3-Bis(2-methyl,5-nitrophenylsulfonylamino)-phenol

97 3,4-Bis(3-trifluoromethylphenylsulfonylamino)-anisole

98 l,2-Bis(5-chloro,2-methoxyphenylsulfonylamino)-benzene

99 2,3-Bis(4-trifluoromethylphenylsulfonylamino)-phenol

100 3,4-Bis(4-trifluoromethylphenylsulfonylamino)-anisole

101 l,2-Bis(4-trifluoromethylphenylsulfonylamino)-4-fluorobenzene

102 3,4-Bis(3-trifluoromethylphenylsulfonylam__no)-benzoic acid ethyl ester

103 l,2-Bis(2-thienylsulfonylamino)-benzene

104 2,3-Bis(2-thienylsulfonylamino)-phenol 105 l,2-Bis(2-chloro-5-thienylsulfonylamino)-napthalene 106 l,2-Bis[2-(3-oxazolyl)-5-thienylsulfonylamino)-napthalene 107 3,4-Bis(2-chloro-5-thienylsulfonylamino)-benzoic acid methyl ester 108 3,4-Bis(2-thienylsulfonylamino)-fluorobenzene 109 2,3-Bis(2-chloro-5-thienylsulfonylamino)-phenol 110 3,4-Bis(2-chloro-5-thienylsulfonylamino)-benzoic acid methyl ester 111 3,4-Bis(2-thienylsulfonylamino)-anisole 112 2,3-Bis(2-chloro-5-thienylsulfonylamino)-benzene 113 l,2-Bis[2-(3-oxazolyl)-5-thienylsulfonylamino)-benzene 114 l,2-Dimethyl-4,5-bis(2-thienylsulfonylamino)-benzene 115 l,2-Dimethyl-4,5-bis(2-chloro-5-thienylsulfonylamino)-benzene 116 l,2-Difluoro-4,5-bis(2-thienylsulfonylamino) -benzene 117 l,2-Dibromo-4,5-Bis(2,3-dichloro-5-thienylsulfonylamino)-benzene 118 3,4-Bis(2-thienylsulfonylamino)-chlorobenzene 119 3,4-Bis(5-chloro-2-thienylsulfonylamino)-chlorobenzene 120 3,4-bis(2-thienylsulfonylamino)-benzoic acid methyl ester 121 3,4-Bis(2-chloro-5-thienylsulfonylamino)-fluorobenzene 122 l,2-Bis(2-thienylsulfonylamino)-3,4, 5, 6-tetramethylbenzene 123 3,4-bis(2-thienylsulfonylamino)-benzoic acid ethyl ester 124 l,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4,5-dimethylbenzene 125 l,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-anisole 126 l,2-Dibromo-4,5-bis (2,5-dichloro-3-thienylsulfonylamino)-benzene 127 2,3-Bis(4-isopropylphenylsulfonylamino)-phenol 128 l,2-Bis(2,5-dichlorothienyl-3-sulfonylamino)-4,5-dimethylbenzene 129 l,2-Bis(2,5-dichlorothienyl-3-sulfonylamino)-4-methoxybenzene 130 l,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-3,4, 5, 6-tetramethylbenzene 131 2,3-Bis(phenylsulfonylamino)-naphthalene 132 2 ,3 -Bis(3 -trifluoromethylphenylsulfony lamino)-naphthalene 133 2,3-Bis(4-trifluoromethoxyphenylsulfonylamino)-naphthalene 134 2,3-Bis(3,4-dichlorophenylsulfonylamino)-naphthalene 135 2,3-Bis(4-isopropylphenylsulfonylamino)-naphthalene 136 2,3-Bis(4-trifluoromethyphenylsulfonylamino)-naphthalene 137 2,3-Bis(2,4diflurophenylsulfonylamino)-naphthalene 138 2,3-Bis(2-chloro-5-thienylsulfonylamino)-naphthalene 139 2,3-Bis(2-methyl-4-nitrophenylsulfonylamino)-naphthalene 140 2,3-Bis(2-methyl-3-chlorophenylsulfonylamino)-naphthalene 141 2,3-Bis(4-cyanophenylsulfonylamino)-naphthalene 142 2,3-Bis(3,5dimethyl-3-oxazoylsulfonylamino)-naphthalene 143 2,3-Bis(2-aza-4,5-benzothiazoylsulfonylamino)-naphthalene 144 2,3-Bis(2,6-difluorophenylsulfonylamino)-naphthalene 145 2,3-Bis(3-nitro-4-methylphenylsulfonylamino)-naphthalene 146 3,4-Bis(2-(l,2-cyclo(3-thioethyl)-4-chloro,5-imidazoylsulfonylamino)-naphthalene 147 2,3-Bis(4-methylsulfonophenylsulfonylamino)-naphthalene 148 l,2-Bis(4-fluorophenylsulfonylamino)-4-nitrobenzene 149 3,4-Bis(4-fluorophenylsulfonylamino)-benzoic acid methyl ester 150 3,4-Bis(4-trifluoromethylphenylsulfonylamino)-benzoic acid methyl ester 151 3,4-Biss((2-chloro-5-thienylsulfonylamino)-benzoic acid methyl ester

152 3,4-Biss((2-methoxy,2-chlorophenylsulfonylamino)-benzoic acid methyl ester

153 3,4-Biss((4-methyl,2-nitrophenylsulfonylamino)-benzoic acid methyl ester

154 1,2-Biss((3-trifluoromethylphenylsulfonylamino)-4-fluorobenzene

155 1,2-Biss((2-thienylsulfonylamino)-4-fluorobenzene

156 1,2-Biss((3,4-dichlorophenylsulfonylamino)-4-fluorobenzene

157 1,2-Biss((2-methyl-5-nitrophenylsulfonylamino)-4-fluorobenzene

158 1,2-Biss((]phenylsulfonylamino)-4,5-difluorobenzene

159 1,2-Biss((1benzylsulfonylamino)-4,5-diflurobenzene

160 3,4-Biss((2,4-dichlorophenylsulfonylamino)-benzoic acid ethyl ester

161 3,4-Biss((2-chloro-5-thienylsulfonylamino)-benzoic acid ethyl ester

162 3,4-Biss((2-methyl-5-nitrophenylsulfonylamino)-benzoic acid ethyl ester

163 3,4-Bis s((2,6-difluorophenylsulfonylamino)-benzoic acid ethyl ester

164 1,2-Bis s((2-methyl-5-nitrophenylsulfonylamino)-4-methoxybenzene

165 1,2-Bis s((<4-methyl-3-nitrophenylsulfonylamino)-4-methoxybenzene

166 1,2-Bis s((lbenzylsulfonylamino)-benzene

167 1,2-Bis s((3,4-dichlorophenylsulfonylamino)-benzene

168 1,2-Bis s((2-chloro-5-thienylsulfonylamino)-benzene

169 1,2-Biss((2-methyl-5-nitrophenylsulfonylamino)-benzene

170 1,2-Biss(('4-methyl-3-nitrophenylsulfonylamino)-benzene

171 1,2-Bis s(('4-isopropylphenylsulfonylamino)-4-nitrobenzene

172 1,2-Bis s((2-thienylsulfonylamino)-4,5-dimethylbenzene

173 1,2-Bis s((3,4-dichlorophenylsulfonylamino)-4,5-dimethylbenzene

174 1,2-Bis s((2-chloro-5-thienylsulfonylamino)-4,5-dimethylbenzene

175 1,2-Bis s((2-methyl-5-nitrophenylsulfonylamino)-4,5-dimethylbenzene

176 1,2-Bis s(4-methyl-3-nitrophenylsulfonylamino)-4,5-dimethylbenzene

177 1,2-Bis s((<4-methylsulfonophenylsulfonylamino)-4,5-dimethylbenzene

178 1,2-Bis s((<4-methylphenylsulfonylamino)-4-cyanobenzene

179 1,2-Bis s((]phenylsulfonylamino)-4-chlorobenzene

180 1,2-Bis s(('4-fluorophenylsulfonylamino)-4-chlorobenzene

181 1,2-Bis s((3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene

182 1,2-Bis s((4'-trifluoromethoxyphenylsulfonylamino)-4-chlorobenzene

183 1,2-Biss((:2-thienylsulfonylamino)-4-chlorobenzene

184 1,2-Biss((.3,4-dichlorophenylsulfonylamino)-4-chlorobenzene

185 1,2-Biss(4-isopropylphenylsulfonylamino)-4-chlorobenzene

186 1,2-Biss((:2,4-difluorophenylsulfonylamino)-4-chlorobenzene

187 3,4-Biss(('4-chloro-2-methoxyphenylsulfonylamino)-benzoic acid ethyl ester

188 1,2-Biss((.2,5-dichloro-3-thienylsulfonylamino)-4-chlorobenzene

189 1,2-Biss((.2-chloro-5-thienylsulfonylamino)-4-chlorobenzene

190 1,2-Biss((:2-methyl-5-nitrophenylsulfonylamino)-4-chlorobenzene

191 1,2-Biss((:2-methyl-3-chlorophenylsulfonylamino)-4-chlorobenzene

192 1,2-Biss(('4-cyanophenylsulfonylamino)-4-chlorobenzene

193 1,2-Biss((.3,5-dimethyl-4-oxazoylsulfonylamino)-4-chlorobenzene

194 1,2-Biss((:2,6-difluorophenylsulfonylamino)-4-chlorobenzene

195 1,2-Biss(4-methyl-3-nitrophenylsulfonylamino)-4-chlorobenzene

196 3,4-Biss((:2,4-difluorophenylsulfonylamino)-benzoic acid methyl ester 197 3,4-Bis(2-methyl,5-nitrophenylsulfonylamino)- benzoic acid methyl ester 198 3,4-Bis(2-methyl,3-chlorophenylsulfonylamino)- benzoic acid methyl ester 199 3,4-Bis(2,6difluorophenylsulfonylamino)- benzoic acid methyl ester 200 l,2-Bis(2-chloro-5-thienylsulfonylamino)-4-fluorobenzene 201 l,2-Bis(2-methyl-3-chlorophenylsulfonylamino)-4-fluorobenzene 202 l,2-Bis(2-methoxy-5-chlorophenylsulfonylamino)-4-fluorobenzene 203 l,2-Bis(2-methyl-3-chlorophenylsulfonylamino)-3,4,5,6-tetramethylbenzene 204 3,4-Bis(2-thienylsulfonylamino)-benzoic acid ethyl ester 205 3,4-Bis(3-chloro-2-methylphenylsulfonylamino)-benzoic acid ethyl ester 206 l,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-benzene 207 3,4-Bis(3-trifluoromethylphenylsulfonylamino)-benzoic acid methyl ester 208 1 ,2-Bis(2-( 1 ,2-cyclo(3-thioethyl)-4-chloro-5-imidazoylsulfonylamino)-4-fluorobenzene 209 l,2-Bis(3-trifluoromethylphenylsulfonylamino)-4,5-difluorobenzene 210 l,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4,5-difluorobenzene 211 l,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4,5-difluorobenzene 212 l,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-chloro-5-methylbenzene 213 2,3-Bis(2-thienylsulfonylamino) naphthalene 214 l,2-Bis(4-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 215 l,2-Bis(4-fluorophenylsulfonylamino)-4,5-difluorobenzene 216 l,2-Bis(4-methylsulfonophenylsulfonylamino)-3,4,5, 6-tetramethylbenzene 217 l,2-Bis(4-isopropylphenylsulfonylamino)-4-fluorobenzene 218 l,2-Bis(4-cyanophenylsulfonylamino)-4-fluorobenzene 219 l,2-Bis(4-methylphenylsulfonylamino)-4-cyanobenzene 220 3,4-Bis(8-quinolylsulfonylamino)-benzoic acid ethyl ester 221 l,2-Bis(4-trifluoromethoxyphenylsulfonylami_no)-4-fluorobenzene 222 l,2-Bis(phenylsulfonylamino)-4-fluorobenzene 223 3,4-Bis(3,5-dimethyl-4-oxazoylsulfonylamino)-benzoic acid methyl ester 224 3,4-Bis(4-isopropylphenylsulfonylamino)-benzoic acid methyl ester 225 l,2-Bis(4-methylphenylsulfonylamino)-4-chlorobenzene 226 3,4-Bis(3,5-dimethyl-4-oxazoylsulfonylamino)-4,5-difluorobenzoate 227 l,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4-methoxybenzene 228 l,2-Bis(2-(l,2-cyclo(3-thioethyl)-4-chloro,5-imidazoylsulfonylamino)-4- methoxybenzene

229 l,2-Bis(phenylsulfonylamino)-4-cyanobenzene 230 l,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-cyanobenzene 231 l,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4-cyanobenzene 232 l,2-Bis(2-thienylsulfonylamino)-4-cyanobenzene 233 l,2-Bis(4-isopropylphenylsulfonylamino)-4-cyanobenzene 234 l,2-Bis(2,4-difluorophenylsulfonylamino)-4-cyanobenzene 235 l,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4-cyanobenzene 236 l,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4-cyanobenzene 237 l,2-Bis(2,6-difluorophenylsulfonylamino)-4-cyanobenzene 238 l,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4,5-difluorobenzene 239 l,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4-chloro-5-methylbenzene 240 l,2-Bis(benzylsulfonylamino)-4-chloro-5-methylbenzene 241 l,2-Bis(2-thienylsulfonylamino)-4-chloro-5-methylbenzene 242 l,2-Bis(3,4-dichlorophenylsulfonylamino)-4-chloro-5-methylbenzene 243 l,2-Bis(4-trifluoromethylphenylsulfonylamino)-4-chloro-5-methylbenzene 244 l,2-Bis(2,4-difluorophenylsulfonylamino)-4-chloro-5-methylbenzene 245 l,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4-chloro-5-methylbenzene 246 3,4-Bis(2,4-dimethyl-5-oxa-3-thiazoylsulfonylamino)-4-chloro-5-methylbenzene 247 l,2-Bis(2-aza-4,5-benzothiazoylsulfonylamino)-4-chloro-5-methylbenzene 248 l,2-Bis(2-(5-oxa-2-thiazoyl)-5-thienylsulfonylamino)-4-chloro-5-methylbenzene 249 l,2-Bis(2,4-difluorophenylsulfonylamino)-4-chloro-5-methylbenzene 250 l,2-Bis(4-methyl-3-nitroρhenylsulfonylamino)-4-chloro-5-methylbenzene 251 l,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4-cyanobenzene 252 l,2-Bis(phenylsulfonylamino)-4-chloro-5-methylbenzene 253 2,3-Bis(2,4-dichlorophenylsulfonylamino)naphthalene 254 l,2-Bis(2,4-dichlorophenylsulfonylamino)-benzene 255 l,2-Bis(2-(2-methyl-4-thiazoyl)-5-thienylsulfonylamino)-benzene 256 l,2-Bis(2-(2-methyl-4-thiazoyl)-5-thienylsulfonylamino)-4,5-dimethylbenzene

The above compounds were analysed by liquid chromatography, in conjunction with a mass spectrometer as detector. The equipment used was a Waters 2700 Sample Manager, with Waters 2690 Alliance Solvent Delivery System and Waters 996 Photodiode Array Detector. The mass spectrometer used was a Micromass Platform LCZ Mass Spectrometer running Micromass MassLynx Software, v3.2 build 004. Chromatography was carried out on a Waters Symmetry 3.5μm C18 50x2.0mm (WAT200650) column with a gradient elution from 5% lOmM formic acid in acetonitrile and 95% lOmM formic acid in water to 95% lOmM formic acid in acetonitrile and 5% lOmM formic acid in water over 3 minutes at 0.5ml/minute flow rate. UV detection was at 200-300nm and mass spectra were collected by positive and negative electrospray. All reaction products showed the desired compound with satisfactory purity.

Example 257

3 ,4-Bis (4-methylphenylsulfonylamino) -benzoic acid

3, 4-Bis (4-methylphenylsulfonylamino) -benzoic acid methyl ester (Example 8, 3.5g, 7.38 x 10 mol) was stirred in IN sodium hydroxide solution (250 mL) at 60 °C for 5 hr. After this time the solution was cooled and the precipitate filtered, washed with water and recrystallised from acetic acid and water to yield 2.0g, 59 % of the title compound. Example 258

1 ,2-Bis (3 -trifluoromethylphenylsulfonylamino) -4- (3 -methyloxadiazole-5-yl) benzene

N-hydroxy-acetamidine (0.028g,0.39mmol) in THF (dry, 15ml) was added to a stirred solution of dry THF (5ml) containing sodium hydride (0.015g, 0.39mmol). The mixture was heated to 60^QC under nitrogen. A solution of 3,4-Bis(3- trifluoromethylphenylsulfonylamino)-benzoic acid methyl ester (Example 207, 76mg, 0.13mM) in dry THF (15ml) was added dropwise over 15mins. The reaction was left to reflux overnight. Methanol (5ml) then Water (5ml) were added sequentially and the mixture concentrated to dryness. The crude micture was subjected to column chromatography on silica with methanol / dichloromethane to yield the product (2 lmg, 27%)

Example 259

3,4-Bis(4-methylphenylsulfonylamino)-N-phenyl-benzamide

3, 4-Bis (4-methylphenylsulfonylamino) -benzoic acid (Example 257, 0.092 g, 0.2 mmol), aniline (0.0186 g, 0.2 mmol), N, N-(diisopropyl)amino-methylpolystyrene resin (PS- DIEA), (0.172 g, 0.6 mmol, loading 3.5 mmol/g) and 0-(7-azabenzotriazol-l-yl)-N, N, N, N-tetramethyluronium hexafluorophosphate (HATU) (0.076 g, 0.2 mmol) was stirred under nitrogen in anhydrous acetonitrile (8 mL) and heated to 50 ^DC for 40 hr. After this time the reaction mixture was cooled to room temperature. A sequestration enabling reagent - tetrafluorophthalic anhydride (0.132 g, 0.6 mmol) was then added and the reaction mixture was stirred under nitrogen for 18 hours. Macroporous triethylammonium methylpolystyrene carbonate resin (MP-carbonate, 0.630 g, 2.0 M, loading 3.18 mM/g) was then added and the reaction mixture was stirred under nitrogen for a further 48 hours. The reaction mixture was then filtered through a filter syringe into a vial and the precipitate washed with methanol. The combined solvent was removed on a vacuum concentrator to yield 0.051 g, 48 %. The product was analysed by LC-MS and had 85.0 % purity.

Examples 260 and 261.

The compounds set out below were prepared in the same way as Example 259, using appropriate starting materials.

Example Compound

260 3,4-Bis(4-methylphenylsulfonylamino)-./V-(4-fluoromethoxyphenyl) benzamide 261 3,4-Bis(4-methylphenylsulfonylamino)-Λ^-(3,5-dimethoxyphenyl) benzamide

Example 262

3 - (2 -Phenyl-ethenesulfonylamino) -4- (3 -trifluoromethylbenzenesulfonylamino) - benzoic acid ethyl ester

4- (3 -trifluoromethylsulfonylamino) -3 -nitro-benzoic acid ethyl ester (prepared as per Example 22 from appropriate starting materials; l.OOg, 2.66mmol) was dissolved in ethanol (50ml). This solution was stirred and palladium on carbon (5%) added slowly followed by ethanol to wash vessel sides and then an excess of hydrazine hydrate (2ml). This solution was refluxed for 18 hr filtered and evacuated to dryness. The product was then purified on silica using methanol/chloroform as the eluent to yield 3-amino-4- (3 -trifluoromethylbenzenesulfonylamino) -benzoic acid ethyl ester as a dry white solid (0.8 lg, 89%). This material was then reacted with 2-phenylethenesulfonyl chloride as per example 22 to provide the title product.

Examples 263 to 271

The compounds set out below were prepared in the same way as Example 262, using appropriate starting materials. Example Compound

263 l-(4-methoxyphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4- chlorobenzene 264 l-(3-chlorophenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4- chlorobenzene 265 l-(2-chlorophenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4- chlorobenzene 266 l-(3-methylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4- chlorobenzene

267 l-(4-methylamidomethylphenylsulfonylamino)-2-(3- trifluoromethylphenylsulfonylamino)-4-chlorobenzene 268 l-(2-(phenylamidomethyl)-5-thienylsulfonylamino)-2-(3- trifluoromethylphenylsulfonylamino)-4-chlorobenzene 269 l-(4-(2-chloro-5-thiazoylmethoxyphenylsulfonylamino)-2-(3- trifluoromethylphenylsulfonylamino)-4-chlorobenzene

270 3-(2,5-dichloro-3-thienylsulfonylamino),4-(3-trifluoromethylsulfonylamino)- methylbenzoate

271 3-(4-methylphenylsulfonylamino),4-(3-trifluoromethylphenylsulfonylamino)- methylbenzoate

Example 272

1 - (4-methylphenylsulfonylamino) -2 - (3 -trifluoromethylphenylsulfonylamino) -4- fluorobenzene.

l-Nitro-2-(3-trifluoromethylphenylsulfonylamino) -4-fluorobenzene (prepared as per example 22 using appropriate starting materials; 0.13g, 0.32mmol) was stirred in dimethylformamide (5ml) containing tin (II) chloride (0.28g, 1.25mmol). The reaction was left to stir overnight at room temperature under nitrogen. The mixture was diluted with water (15ml) and the pH adjusted to 7 with IM sodium hydroxide solution. The aqueous solution was extracted with chloroform and the chloroform removed under vacuum to yield an orange oil. This was purified by flash chromatography on silica using methanol/chloroform to yield l-amino-2-(3- trifluoromethylphenylsulfonylamino) -4-fluorobenzene (0.07g, 58%). This material was then reacted with 4-methylphenylsulfonyl chloride in the same way as Example 22 to provide the title compound.

Examples 273 to 285 The compounds set out below were prepared in the same way as Example 272, using appropriate starting materials.

Example Compound

273 l-(4-methylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4- fluorobenzene

274 l-(3-trifluoromethylsulfonylamino)-2-(2-phenylethenylsulfonylamino)-4-fluorobenzene 275 l-(3-trifluoromethylsulfonylamino)-2-(2-phenylethenylsulfonylamino)-benzene 276 l-(3-trifluoromethylsulfonylamino)-2-(benzylsulfonylamino)-4-fluorobenzene 277 l-(2,5-dichloro-3-thienylsulfonylamino)-2-(3-trifluoromethylsulfonylamino)-benzene 278 1 -(2-(phenylamidomethyl)-5 -thienylsulfonylamino)-2-(3 - trifluoromethylphenylsulfonylamino)-benzene

279 l-(2-(ρhenylamidomethyl)-5-thienylsulfonylamino)-2-(3- trifluoromethylphenylsulfonylamino)-4-fluorobenzene

280 l-(4-(2-chloro-5-thiazoylmethoxyphenylsulfonylamino)-2-(3- trifluoromethylphenylsulfonylamino)-benzene

281 l-(4-(2-chloro-5-thiazoylmethoxyρhenylsulfonylamino)-2-(3- trifluoromethylρhenylsulfonylamino)-4-fluorobenzene

282 l-(2-chlorophenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-benzene 283 l-(2-chlorophenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4- fluorobenzene

284 l-(2-methylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-benzene 285 l-(3-methylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4- fluorobenzene

Example 286

Analytical Data for compounds representative of Examples 1 to 285

Example 287

Inhibition of purified dehydroquinate synthetase (AroB) measured in 96-well plates at single concentrations (50μM). Briefly, a three-enzyme linked assay employing dehydroquinate synthase (AroB), dehydroquinase (Type I) and dehydroshikimate dehydratase (DHSD) was constructed. In the presence of this enzyme mixture the substrate, 3-Deoxy-D-arabino heptulosonic acid-7-phosphate (DAHP), is converted into protocatechuic acid, which can be quantified using a spectrophotometric plate reader set at 290nm. A second incubation, after addition of 0.1% ferric chloride, allows measurement of a protocatechuic acid-iron complex at 570nm. In the absence of inhibitors, the DAHP concentration in the assay is adjusted to give an absorbance of 1 unit at 290nm after the initial stage of the assay. Compounds were tested at 50μm for their ability to reduce the absorbance at 290nm and 570nm at the respective stages of the assay, representing reduced conversion of DAHP to protocatechuic acid by the enzyme mixture. The assay medium also contained buffer (morpholino propanesulfonic acid at pH 7.0), cobalt chloride (40μM final conc.n), zinc sulfate (40μM) and magnesium sulfate (2.5mM). NAD was added as co-factor at 20μM.

A follow-up dehydroquinase assay was used to confirm that active compounds were inhibiting dehydroquinate synthase. This assay was carried out similarly to above, but employing dehydroquinate as the substrate and omitting dehydroquinate synthase from the assay medium. None of the tested compounds showed any activity in the modified assay, hence all actives were shown to be inhibiting dehydroquinate synthase only.

Example Reduction in Reduction in absorbance at 290nm absorbance at 570nm

1 50 40

25 79 84

2 88 99

3 51 68

22 76 100

5 88 100

23 21 44

9 50 61

7 87 100

8 10 15

11 89 96

26 18 36

14 90 98

16 81 100

17 88 99

18 77 92

20 79 91

21 75 88

59 73 76

60 29 33

61 29 33

62 30 30

63 21 34

64 22 24

66 20 24

67 36 41

68 18 28 70 18 17

71 32 36

72 35 31

73 12 38

74 17 34

75 27 88

76 39 76

77 41 92

78 9 23

79 23 50

80 8 20

81 5 18

82 5 21

84 7 18

85 8 22

86 5 17

87 8 19

88 48 93

89 3 20

90 3 15

91 8 23

92 7 19

93 5 24

94 8 17

95 10 26

96 6 22

97 8 13

98 10 17

99 12 7

100 11 14

101 44 82

102 48 95

103 9 26

104 11 26

105 84 98

106 68 97

107 80 94

110 82 94

112 55 76

113 5 62

115 39 58

118 21 35

119 90 95

121 90 103

124 40 90

125 54 87 126 59 66

27 100 100

28 68 97

29 5 62

30 70 97

31 69 99

32 59 66

33 82 100

34 25 88

35 80 100

36 49 61

37 68 88

38 71 101

39 98 103

40 83 100

41 42 95

42 0 97

43 68 97

45 70 93

46 80 80

47 60 60

48 40 40

49 40 40

50 50 50

52 20 50

53 50 50

54 80 84

55 100 100

56 100 100

57 79

58 50 5.00E+01

128 40 90

129 20 30

131 51 65

132 83 94

133 79 96

134 73 95

135 0 20

136 85 96

137 50 70

138 84 98

139 47 68

140 85 94

141 45 68

142 66 75

143 59 80 144 76 88

145 86 96

146 73 85

148 20 33

149 84 101

150 89

151 80 94

153 73 86

154 86 94

156 72 91

157 2 36

158 24 39

160 23

161 82 94

162 29 60

163 4 32

165 80 93

167 68 70

168 55 76

169 37

171 69 84

173 10 33

174 39 58

176 31 45

178 34

179 49 70

180 8 43

181 88 100

182 85 98

183 21 35

184 89 103

185 84 94

186 80 98

187 23 51

188 88 101

189 90 95

190 62 89

191 93 103

192 32 55

193 20 32

194 18 31

195 83 35

196 82

197 79

198 79 96

199 32 200 90 103

201 92 96

202 23 51

205 72 99

206 64 92

207 20 100

208 39 50

209 63 62

210 72 64

211 63 84

212 68 99

213 34 42

214 43 50

215 49 77

216 10 39

217 50 60

218 40

219 90 75

220 70

221 80 80

222 37

223 40

224 50 80

225 80 74

226 44 44

227 70 70

228 40 40

229 50 50

230 30 30

231 80 75

232 20 50

233 90 90

234 50

235 80 50

236 90 90

237 50 50

238 90 85

239 20 56

240 98 100

241 50 50

242 99 98

243 80 75

244 85 90

245 100 100

246 80 80

247 70 60 248 90 95

249 50 65

250 90 85

251 89 90

252 50 50

253 80 70

254 40

255 30 50

256 65 47

258 40 89

259 34 73

260 64 89

261 59 73

262 8.00E+01

263 60 60

264 95 98

265 100 100

266 80 85

267 50 50

268 100 100

269 95 97

270 47

271 47

272 71 80

273 53 87

274 37 64

275 68 9.20E+01

276 73 88

277 74

278 68

279 45

280 73

282 63

283 74

284 38

Example 288

Inhibition of purified dehydroquinate synthetase (AroB) was measured in 96-well plates using the method set out in Example 287. Experiments were repeated at different concentrations to allow IC₅₀ values to be calculated. The IC₅₀ values were calculated at 290 nm. Example IC₅₀(μM) Example IC_S0(μM)

154 8

16 5 156 5

18 7 158 40

25 8 160 50

2 10 161 10

21 12 162 20

128 12 163 60

102 15 165 17

8 15 167 6

17 20 168 10

59 20 171 7

129 20 174 11

77 20 176 11

88 20 179 94

22 20 180 62

5 20 181 3

7 30 182 5

3 60 185 18

20 30 186 24

76 30 188 11

75 40 189 3

101 50 190 44

105 10 191 18

106 15 192 50

112 10 195 9

103 11 196 30

197 40

105 11

198 7

127 11 199 64

130 5 200 6

131 90 201 6

132 10 205 6

133 10 206 8

134 10 207 20

135 100+ 208 >100

136 7 209 80

137 50 210 60

138 10 211 25

139 32 212 15

140 12 213 80

141 13 214 8

142 15 215 15

143 20 216 >100

144 30 217 12

145 15 219 7

146 10 220 100+

148 25 221 5

149 60 224 12

151 25 225 18

153 30

Example 289

Inhibition of purified M. tuberculosis Type II dehydroquinase (AroQ) was measured in 96-well plates at single concentrations (50μM). Briefly, a two- enzyme linked assay employing AroQ and dehydroshikimate dehydratase (DHSD) was constructed. In the presence of this enzyme mixture the substrate, quinate, is converted into protocatechuic acid, which can be quantified (using a spectrophotometric plate reader set at 570nm) after 2 minutes incubation with 0.1% ferric chloride. Compounds were tested at 50μM for their ability to reduce the absorbance at 570nm, representing reduced conversion of quinate to protocatechuic acid by the enzyme mixture. The assay medium also contained buffer (morpholino propanesulfonic acid at pH 7.0), cobalt chloride (40μM final conc.n), zinc sulfate (40μM) and magnesium sulfate (2.5mM).

A follow-up assay was used to confirm that active compounds were inhibiting the dehydroquinase. Briefly, compounds were incubated in the presence of AroQ in the usual buffer mix and their ability to reduce conversion of quinate to dehydroshikimic acid measured in a spectrophotometer at 240nm. All of the tested compounds showed activity in the modified assay, and are thus shown to be inhibitors of the dehydroquinase.

Example Reduction in Example Reduction in absorbance at 570nm absorbance at 570nm

25 40 122 22

5 40 123 44

14 65 126 72

18 50 27 50

21 60 28 100

76 74 29 100

77 80 30 100

84 20 31 49

102 75 32 72

105 76 33 100

106 100 34 46

107 63 35 40

108 41 36 60

109 18 37 50

110 67 38 99

111 24 39 63

112 76 40 50

113 100 44 100

114 34 45 82

115 64 46 100

116 25 47 60

117 49 49 40

118 35 51 80

119 76 52 62

120 27 58 50

121 80 131 48

132 42

Example 290

Inhibition of purified mycobacterium tuberculosis type II dehydroquinase (AroQ) was measured in 96 well plates using the method set out in

Example 291

Antibacterial activity of compounds against Staph loccocus aureus.

The method set out below was used to determine the Minimum Inhibitory Concentration (MIC) of compounds against methicillin sensitive and resistant strains of Staphylococcus aureus. It is a modification of the method used in clinical laboratories to determine anti-microbial susceptibility (NCCLS M7-A4 Methods for dilution anti-microbial susceptibility tests for bacteria that grow aerobically 4^th edition).

The broth media used for the assay was 9 parts M9 Minimal Salts to 1 part Luria (Lennox) Media (9:1 M9:LB).

For agar plates this media was solidified by addition of 1.5% (w/v) Noble Agar.

3ml 9:1 M9:LB broth was inoculated with a single colony from a fresh culture of methicillin sensitive or methicillin resistant strain of Staphylococcus aureus grown on 9:1 M9:LB agar. This was incubated at 37°C with shaking (~250rpm) for 4-5 hrs. Optical density of the broth was measured at 600nm and the culture diluted to give an A₆₀₀of —0.1 in sterile 0.85% saline. Miles and Misra's were carried out on the diluted inoculum as follows:

a) 90μl of sterile 0.85% saline was added to the remaining wells of the microtitre plate (rows B to H) ; b) lOμl of culture was taken from row A to row B and mixed well. The serial dilution was continued down the plate, changing tips with each transfer; c) in triplicate, 5μl volumes of each dilution were transferred to the surface of a dry agar plate. The plates were left for around lhr to allow the drops of liquid to dry into the agar; and d) the plates were incubated at 37°C overnight and the number of colonies at a dilution where there are between 10 & 50 discrete colonies per spot were counted. The appropriate calculation (see below) was then used.

200μl of 9:1 M9:LB Broth was added to the top row of wells in a sterile microtitre plate, to this lOμl of the compound of Example 25 in dimethyl sulphoxide (DMSO) was added to the wells in duplicate. To one of the duplicates 2μl of lOmg/ml Phenylalanine, 2μl of lOmg/ml Tryptophan, 40μl of 0.5mg/ml Tyrosine and 2μl of 5 μg/ml p- Aminobenzoic acid were added. The wells were then inoculated with 5μl of the diluted bacterial culture (see above). The microtitre plates were incubated at 37°C with shaking (~150rpm) for 16-20 hrs and the A^ recorded, Miles and Misra's were then performed on the cultures (see above).

The criteria used for determining the >MIC= (bactericidal concentration) was the concentration at which a sub-cultured broth from the drug- treated batch shows no growth on media free of anti-microbial agent. The bacteriostatic concentration was calculated by testing the compound at a narrow range of molarities just above the MIC. A curve was then plotted of the total number of bacteria in the well of the microplate as a percentage of the number of bacteria that the wells were inoculated with.

The used calculations for the results were c.f.u./ml = (number of colonies X dilution factor) X 200. Number of bacteria in inoculum = c.f.u./ml / 200. Total number of bacteria in well = c.f.u./ml / 5 Activity against Smith Strain (Methicillin sensitive) Stab h loccocus aureus

Example MIC (μM)

Example MIC (μM)

1 1 178 100+

5 300 181 1.2

7 1 182 1

18 15 184 2.2

25 1 185 20

27 4 186 >30

28 30+ 188 0.5

30 30+ 189 2

32 30+ 191 2.7

33 30+ 195 30+

39 30+ 198 30

43 10 200 30

46 >30 201 0.4

59 4.2 205 5

72 9 206 6

102 30 212 7.5

127 0.4 215 30+

132 14 217 30+

133 12 219 6.5

134 8 221 7

135 30+ 224 30+

136 3 225 30+

137 100+ 230 30

138 100+ 233 25

139 30+ 236 30

140 30 238 30

141 30+ 239 3

142 100+ 240 30+

143 30+ 241 3

145 30+ 243 3

146 30+ 244 30

148 100+ 245 2

149 30 246 30+

150 10 247 30+

151 100+ 248 30+

153 100+ 249 30+

154 8 250 30+

156 6 251 30+

161 30+ 258 >30

162 30+ 260 >30

165 30 272 >30

167 13 273 >30

171 3.4 274 >30

275 >30

276 1.5 Activity against Methicillin Resistant Staphyloccocus aureus

Example Methicillin resistant S. aureus strain MIC (uM)

25 MecA+ 10196/7 5

25 MecA+ 320/97 5

25 MecA+ 1789/97 5

25 MecA+ 4099/98 5

25 MecA+ 7623/98 5

25 MecA+ 8038/97 10

25 MecA+ 7449 20

25 MecA+ 2298 20

25 MecA+ 5033/98 20

25 MecA+ 1905/98 20

182 NCTC 12493 5

188 NCTC 12493 2

201 NCTC 12493 5

Example 292

Toxicity against the VERO cell line.

Cells are routinely cultured in Dulbecco's Modified Eagle Medium (DMEM), with L-Alanyl-L-Glutamine (Gibco 21885-025), containing 10% Foetal Bovine Serum (FBS) (Gibco 16000-044). The process followed comprises:

On day 1 lOOμl of cells ate seeded at 5 x IO⁴ cell/ ml in a 96 well plate.

On day 2 having allowed cells to attach, compounds are diluted in growth medium (DMEM) to 2X final required concentration, from a 20mM stock made up in DMSO, and add lOOμl per well. 0.5% DMSO made up in growth medium is added to the control wells.

3. Cells are incubated at 37^SC, 5% CO² for 72-96 hours.

4. Medium is removed by aspiration and cells are stained by adding lOOμl methylene blue (0.5% in 50% EtOH) per well, and incubated at room temperature for 1 hour. The stain was then washed off under running water and left to air dry.

5. Cells can be examined for signs of changes in morphology. 6. Stain is released from the cells by addition of lOOμl of solubilisation solution (1%

N-lauryl sarcosine, Sigma L-5125, in distilled water), and gently shook for 1 hour. Plates are then read measuring the OD at 620nm. The percentage inhibition of cell growth was calculated relative to non-drug treated control wells. Toxicity Toxicity

Example Example MIC(μM) MIC(μM)

1 30 184 64

18 70 185 32

20 45 188 65

21 60 189 40

27 28 201 22

28 >100 219 38

43 75 221 23

53 62 224 42

59 15 225 61

72 25 233 75

132 25 237 >100

133 40 238 100

134 23 239 16

136 >100 240 40

140 10 241 36

141 2 243 28

142 2 244 22

150 23 245 31

154 21 246 34

156 60 247 >100

167 35 248 100

171 85 249 >100

181 50 250 76

182 33 252 81

Claims

1. Use of a bissulfonamide derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in inhibiting the biosynthesis of aromatic amino acids via the shikimate pathway,

wherein:

Ar is an aryl or heteroaryl group;

R[ and R₂ are the same or different and each represent hydrogen or alkyl or R_x and R₂ together form a -G, alkylene group,

-CO- or -CS-; and

R₃ and R₄ are the same or different and each represent -alkyl-aryl,

-alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl

-alkynyl-heteroaryl, aryl or heteroaryl.

2. Use according to claim 1 wherein R₃ and R₄ are the same or different and each represent an aryl or heteroaryl group.

3. Use according to claim 1 wherein Ar is a group At'

wherein R₅ to R₈ are the same or different and represent aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R⁷' or -CONR'R^ wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R₅ and R^ or R^ and R₇ or R₇ and R₈ together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.

4- Use according to claim 3, wherein R₅ and R₈ are the same or different and represent hydrogen, halogen, alkyl, hydroxy, alkoxy or -NR'R'⁷ wherein R' and R^; are the same or different and are hydrogen or alkyl and R₆ and R₇ are the same or different and represent hydrogen, aryl, heteroaryl, heterocyclyl, nitro, cyano, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -N ^ or -CONR'R^ wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R₆ and R₇ together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.

5. Use according to claim 4 wherein one of R₅ and R₈ is hydrogen, and the other is hydrogen, halogen or hydroxy and R and R₇ represent hydrogen, aryl, heteroaryl, nitro, cyano, alkyl, alkoxy, haloalkyl, halogen, -C0₂H, -C0₂-alkyl or -CONR^' wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or Rg and R₇ together form an alkylenedioxy group or a phenyl moiety.

6. Use according to any one of the preceding claims wherein R_! and R₂ are the same or different and represent hydrogen or alkyl or R_{ and R₂ together form a -C₃ alkylene group.

7. Use according to any one of the preceding claims wherein R₃ and/or R^ is phenyl, naphthyl, pyridyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, isoxazolyl, pyrrolyl, (l,2-cyclo(3-thioethyl)-imidazolyl, benzothienyl, indolyl or quinolinyl.

8. Use according to any one of the preceding claims, wherein R₃ and/or R₄ are unsubstituted or are substituted by one or two substituents selected from aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S(0)₂-alkyl, haloalkoxy, cyano, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy, -CONR'R'⁷ wherein R^; and R^/; are the same or different and are aryl, heteroaryl, hydrogen or alkyl, -Z-NR^R^ and -NR^R*' wherein Z is alkyl or alkenyl and R^7/ and R^/7// are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, and O-Z-R wherein Z is as defined above and R^m is aryl, heteroaryl or heterocyclyl.

9. Use according to claim 1, wherein the bissulfonamide derivative of formula (I) is a bissulfonamide derivative of formula (la) (R₃ ⁷)n

/

X

wherein R₅ to R₈ are as defined in claim 3, X and Y are the same or different and represent phenyl or thienyl, n represents an integer of from 0 to 4 when X is phenyl and an integer of from 0 to 3 when X is thienyl, m represents an integer of from 0 to 4 when Y is phenyl and an integer of from 0 to 3 when Y is thienyl, and R and R are the same or different and are selected from aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S(0)₂- alkyl, alkoxy, haloalkoxy, cyano, -C0₂R wherein R is aryl, heteroaryl, hydrogen or alkyl, hydroxy, -CONR'R* wherein R' and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, -Z-NR^R⁷⁷⁷⁷ and -NR.V wherein Z is alkyl or alkenyl and R^/;/ and R^{/ /} are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group and -0-Z-R^/y// wherein Z is as defined above and R is aryl, heteroaryl or heterocyclyl.

10. Use according to claim 9, wherein, in the formula (la), R₅ and R₈ are hydrogen, R_ό and R₇ are the same or different and are selected from aryl, heteroaryl, nitro, cyano, alkyl, haloalkyl, halogen, hydrogen, -C0₂H, -C0₂- alkyl, alkoxy and -CONRT^ wherein R^f and R^; are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R^ and R₇ together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a further phenyl moiety, X and Y are the same or different and are phenyl or thienyl, n and m are the same or different and are 0, 1 or 2 and R₃ ^; and R are the same or different and are selected from:

(a) when attached to a phenyl moiety, aryl, - alkyl, -C, haloalkyl, halogen, nitro, cyano, - alkoxy, -C0₂R wherein R is hydrogen or - alkyl, -NR'R^ wherein R^f and R⁷ are the same or different and are hydrogen, C,-C₄ alkyl or -CO-(C,-C₄ alkyl), -0-(C,-C₄ alkyl) -R wherein R" is heteroaryl or heterocyclyl, and -S(0)₂-C,-C₄ alkyl; and

(b) when attached to a thienyl moiety, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, nitro, halogen, - haloalkyl, - alkyl, -C0₂R wherein R is hydrogen or C,-C₄ alkyl, C,-C₄ alkoxy, -( - alkyl) -NH-aryl and -S(0)₂-C[-C₄ alkyl.

11. Use according to any one of the preceding claims, wherein the medicament is for use in the inhibition of a dehydroquinate synthetase enzyme.

12. Use according to claim 11, wherein the dehydroquinate synthetase enzyme is AroB.

13. Use according to any one of the preceding claims, wherein the medicament is for use in the inhibition of a type II dehydroquinase enzyme.

14. Use according to claim 13, wherein the type II dehydroquinase enzyme is AroQ.

15. Use accordingly to any one of the preceding claims, wherein the medicament is for use in treating or preventing a bacterial or fungal infection.

16. Use according to claim 15 wherein the medicament is for use in the treatment or prevention of a Methicillin Resistant Staphylococcus Aureus infection.

17. Use accordingly to any one of claims 1 to 12, wherein the medicament is for use in the treatment or prevention of an infection by a parasite in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway.

18. Use according to claim 17 wherein the medicament is for use in the treatment or prevention of malaria.

19. A herbicidal or fungicidal composition, comprising: a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or an agriculturally acceptable salt thereof; at least one surfactant; and an agriculturally acceptable carrier or diluent;

20. Use of a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or an agriculturally acceptable salt thereof, as a herbicide or a fungicide.

21. A method of controlling weeds or fungi at a locus, which method comprises administering thereto a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or an agriculturally acceptable salt thereof, or a composition according to claim 19 or 32.

22. A method according to claim 21, wherein the locus comprises agricultural or horticultural plants or a medium in which such plants grow.

23. Use of a bissulfonamide derivative of formula (I) as defined in any one of claims 1 to 10, or a salt thereof, in controlling algae.

24. A method of treating algae in a fish tank or pond, which method comprises applying to the fish tank or pond a bissulfonamide derivative of formula (I) , as defined in any one of claims 1 to 10, or a salt thereof.

25. Non-therapeutic use of a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or a salt thereof, in inhibiting bacterial growth.

26. A surgical instrument having thereon an antibiotic coating comprising a bissulfonamide derivative of formula (I) , as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

27. A bissulfonamide derivative of formula (I), or a pharmaceutically acceptable salt thereof,

P>3

O=S=O

wherein:

Ar is an aryl or heteroaryl group;

R_[ and R₂ are the same or different and each represent hydrogen or alkyl or R_x and R₂ together form a C,-C₃ alkylene group,

-CO- or -CS-; and

R₃ and R,, are the same or different and each represent an aryl or heteroaryl group, for use in a method of treating the human or animal body, provided that, when R_t and R₂ are hydrogen and R₃ and R₄ are phenyl, 4-methylphenyl, or 4- aminophenyl Ar is not

wherein R' and R are methyl or chlorine.

28. A pharmaceutical composition comprising a bissulfonamide derivative according to claim 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

29. A bissulfonamide derivative of formula (Id) , or a salt thereof,

wherein:

R_l and R₂ are as defined in any one of claims 1 and 6;

R₃ and R^ are as defined in any one of claims 1, 7 and 8, and

Ar is as defined in any one of claims 3 to 5 provided that when R_j and R₂ are both hydrogen and Ar is an unsubstituted napthyl group, a phenanthracene group or a phenyl group optionally substituted by 1 or 2 dimethylmethylenedioxy, hydroxy, methoxy, ethoxy, methyl, chlorine, bromine, fluorine, nitro, CF₃ or amino groups, R₃ and R_₄ are not (a) unsubstituted quinoline groups, (b) unsubstituted phenyl groups, (c) phenyl groups monosubstituted by a methyl, methoxy, -C0₂H, chlorine, cyano, nitro or amino group, or by a group -0-CO-N(CH₃)- or (d) phenyl groups disubstituted by a nitro group and a methyl group.

30. A compound according to claim 29, wherein the bissulfonamide derivative of formula (Id) is a bissulfonamide derviate of formula (la), as defined in claim 9 or 10.

31. A compound according to claim 30 wherein Ar represents a group

wherein R₅ to R₈ are as defined in any one of claims 3 to 5, provided that neither R₅ and R₆ nor R₇ and Rg together form a phenyl moiety.

32. A compound according to claim 29, which is

1 ,2-Bis (4-trifluoromethyoxyphenylsulfonylamino) -4-chlorobenzene,

1 ,2-Bis (3 -trifluoromethylphenylsulfonylamino) -4-chlorobenzene,

1 ,2-Bis (2 ,5 -dichloro-3-thienylsulfonylamino) -4-chlorobenzene; l,2-Bis(2-chloro-5-thienylsulfonylamino) -4-chlorobenzene;

1 ,2-Bis (2 -methyl-3 -chlorophenylsulfonylamino) -4-fluorobenzene; l,2-Bis(2-chloro-5-thienylsulfonylamino)-4-fluorobenzene; or a salt thereof.

33. A herbicidal or fungicidal composition comprising a bissulfonamide derivative of the formula (I), as defined in any one of claims 29 to 32, or an agriculturally acceptable salt thereof, and an agriculturally acceptable carrier or diluent.

34. Use of a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or a salt thereof, in the inhibition of quinic acid catabolism.

35. Use according to claim 34, wherein the bissulfonamide or salt thereof is used to inhibit the catabolism of quinic acid by a fungus or a bacterium.