CA2387593A1 - 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 an d 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 sa me or different and each represent -alkyl-aryl, -alkyl-heteroaryl, -alkenyl-ary l, -alkenyl-heteroaryl, -alkynyl-aryl-alkynyl-heterorayl, aryl or heteroaryl.</ SDOAB>

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-(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 1,2-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. Cryst., 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 1,2-dimethyl-4,5-diaminobenzene to vitamin Biz 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, O= S=O
/~1 Ar (I) \NR

O= S=O

wherein:
- Ar is an aryl or heteroaryl group;
- R, and Rz are the same or different and each represent hydrogen or alkyl or R, and RZ together form a C~-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 -COzR, -SOR
and -S(O)ZR 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 CZ-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 CZ-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 C,-C3 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 -COzR, -SOR and -S(O)ZR wherein R is hydrogen or alkyl.
As used herein, an aryl group is typically a C6-Clo 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, -COzR and -S(O)zR 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~~~~ 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 -O-Z-R~~~~~
wherein Z
is as defined above and R~~~~~is aryl, heteroaryl or heterocyclyl.
Typically, R in the moiety -S (O) zR is hydrogen or alkyl. Typically, R~~~ 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~~~~~ in the moiety -O-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 pyridyl, isoxazolyl, isothiazolyl, pyrazolyl, thiadiazolyl and oxadiazolyl. Other preferred substituents include nitro, hydroxy, halogen, for example chlorine, bromine and fluorine, C,-C4 haloalkyl such as -CF3 and -CC13, C,-C4 alkyl, -COZR wherein R is hydrogen or C,-C4 alkyl, C,-C4 alkoxy, C,-C4 haloalkoxy, for example -OCC13 and -OCF3, -S(O)z-C,-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 R~~~ and R~~~~
are the same or different and each represent hydrogen, alkyl or -CO-alkyl, and -O-alkyl-R~"'~, wherein R'~"~ 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 ftom 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 l, 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, -COzR and -S (O) 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~~~~
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 -O-Z-R~~~~~ wherein Z is as defined above and R~~~~~ is aryl, heteroaryl or heterocyclyl.
Typically, R in the moiety -S(O)zR is hydrogen or alkyl. Typically, R~~~
and R~~~~ in the moieties -Z-NR~~~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~~~~ is hydrogen or alkyl. Typically, Z is alkyl, for example methyl. Typically, R~~~~~ in the moiety -O-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 l, 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, Cl-haloalkyl such as -CF3 and -CC13, C,-C4 alkyl, -COZR wherein R is hydrogen or C,-C4 alkyl, C,-C4 alkoxy, -S(O)z-C1-C4 alkyl and -(Cl-C4 alkyl)-NR~~~R~~~~ wherein R~~~ 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 thin 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 -OCC13.
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, -COZR and -S(O)ZR
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, C,-C4 haloalkyl such as -CF3 and -CCl3, C,-C4 alkyl, -COzR wherein R is hydrogen or C,-C4 alkyl, Cl-C4 alkoxy, C,-C4 haloalkoxy, for example -OCC13 and -OCF3, and -S(O)Z-C,-C4 alkyl. The above substituents are typically themselves unsubstituted.
As used herein, a heterocyclic group is typically a non-aromatic, saturated or unsaturated CS-C,o carbocyclic ring in which one or more, for example l, 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 vitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -COzR and -S(O)zR 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 vitro, halogen such as chlorine, bromine or fluorine, C1-C4 haloalkyl such as -CF3 and -CC13, C1-C4 alkyl, -COZR wherein R is hydrogen or C,-C4 alkyl, C1-C4 alkoxy and -S(O)2-C1-C4 alkyl. The above substituents are typically themselves unsubstituted.
Typically, the groups -NR1S(O)zR3 and -NRzS(O)zR4 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 l, 2, 3 or 4 substituents, preferably 1 or 2 substituents.
Preferred substituents include aryl, heteroaryl, heterocyclyl, cyano, vitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -COzR
wherein R is aryl, heteroaryl, or, preferably, hydrogen or alkyl, and -NR' R~~and -CONR~R" 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 vitro, 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~R~~ 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, C,-C4 haloalkyl, Cl-C4 alkyl, -COzR wherein R is hydrogen or Cl-C4 alkyl, C,-C4 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' Rs R, wherein R5 to R8 are the same or different and represent aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -COZR 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 RS and R6 or R6 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, RS to R$ are the same or different and represent cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -COzR 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 RS and R6 or R6 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 -COZR 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, RS and R8 are the same or different and represent hydrogen, halogen, for example bromine, alkyl, hydroxy, alkoxy or -NR'R~~ 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, halogen, for example, bromine, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, heterocyclyl, vitro, cyano, halogen, alkyl, for example haloalkyl, alkoxy, for example haloalkoxy, alkylthio, hydroxy, -COZR
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 R6 and R~ 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, RS and R8 are the same or different and represent hydrogen, alkyl, hydroxy, alkoxy or -NR~R° 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, vitro, cyano, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -COZR 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 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, 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~R~~ are the same or different and are hydrogen, alkyl or aryl.
Preferably, at least one of RS and R8 is hydrogen. More preferably, one of RS and R8 is hydrogen and the other is halogen or, preferably, hydrogen or hydroxy. More preferably still, both RS and R8 are hydrogen.
Typically, RS to R8 are unsubstituted or substituted by one or more further substituent selected from vitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, and hydroxy. Typically, these further substituents are themselves unsubstituted.
Preferably, R6 and R7 represent hydrogen, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, vitro, cyano, alkyl, alkoxy, haloalkyl, halogen, COzH, -COZ-alkyl 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 a said alkylenedioxy group or a phenyl moiety. More preferably, R6 and R7 represent hydrogen, heteroaryl, for example oxadiazolyl, vitro, cyano, C,-C4 alkyl such as methyl or ethyl, halogen such as chlorine, fluorine or bromine, -COz-(C,-C4 alkyl) such as -COZ-Et and -COz-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 R6 and R7, together with the carbon atoms to which they are attached, form a further phenyl moiety. More preferably still, R6 and R~ are the same or different and are selected from hydrogen, oxadiazolyl, chlorine, fluorine, bromine, vitro, cyano, methyl, methoxy, -COZH, -COzEt, -COZMe, -CONH2, -CONHMe and -CONMe2, -CONH-phenyl, -CONH-(4-trifluoromethoxyphenyl) or -CONH-(3,5-dimethoxyphenyl), or R6 and R7, together with the carbon atoms to which they are attached, form a further phenyl moiety.
When R, and/or RZ is an alkyl group it is typically an unsubstituted alkyl group. Preferably, R, and Rz are the same or different and are hydrogen or alkyl or Rl and RZ together from a C,-C3 alkylene group. More preferably, R, and RZ
are both hydrogen.
Typically, R3 and R4 are not simultaneously -alkynyl-aryl or -alkynyl-heteroaryl groups. Preferred -alkyl-aryl and -alkyl-heteroaryl groups are -(C,-alkyl)-aryl and -(C,-C4 alkyl)-heteroaryl groups, for example -(C,-C4 alkyl)-phenyl groups such as benzyl groups. Preferred -alkenyl-aryl and -alkenyl-heteroaryl groups are -(CZ-C4 alkenyl)-aryl and -(CZ-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 R4 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 (1,2-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, vitro, -S (O) Z-alkyl, haloalkoxy, cyano, -COZR wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy, -CONR~R~~ 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~~~ 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-R~~~~~
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~~~ 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, R~~~~~ in the moiety -O-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, vitro, -S(O)z-alkyl, haloalkoxy, cyano, -COZR wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy and -NR~R~~
and -CONR~R~~ wherein R~ 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 l, 2 or 3 heteroatoms, for example pyridyl, isoxazolyl, thiadiazolyl, thiazolyl, isothiazolyl and pyrazolyl. Other preferred substituents include C,-C4 alkyl such as methyl, ethyl, n-propyl, i-propyl or t-butyl, C,-C4 haloalkyl, halogen, vitro, cyano, C,-C4 alkoxy such as methoxy, -S(O)z-C,-C4 alkyl, -NR~~~R~~~~
wherein R~~~ and R~~~~ are the same or different and each represent hydrogen, C,-C4 alkyl, or -CO-(C,-C4 alkyl), -(C,-C4 alkyl)-NR~~~R~~~~ wherein R~~~ and R~~~~
are the same or different and each represent hydrogen, C~-C4 alkyl or -CO-aryl, for example -CO-phenyl, and -O-(C~-C4 alkyl)-R~~~~~, wherein R~~~~~ is heteroaryl, for example thiazolyl.
Most preferred substituents are phenyl, methyl, trifluoromethyl, chlorine, fluorine, bromine, methoxy, trifluoromethoxy, vitro, cyano, -S(O)z-Me, isoxazolyl, isothiazolyl, pyrazolyl, thiadiazolyl, pyridyl, thiazolyl, -NH-CO-Me, -O-CHz-thiazolyl, -CHz-NH-phenyl and -CH2-NH-(4-chlorophenyl).
The above substituents are themselves preferably unsubstituted or substituted by one or more further substituents selected from vitro, 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 (Ia) ~(R3 )n X
I
O=S=O
(Ia) Rs O=~=O
Y~(Ra~)m wherein RS to R$ are as defined above in the formula Ar', 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 R3~
and R4~ are the same or different and are selected from aryl, heteroaryl and heterocyclic groups, alkyl, for example haloalkyl, halogen, nitro, -S (O) z-alkyl, alkoxy, for example haloalkoxy, cyano, -COZR 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~~~R~~~~ and -NR~~~R~~~~ 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, or -O-Z-R~~~~~
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~~~ 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, R~~~~~ in the moiety -O-Z-R~~~~~ is heteroaryl, for example thiazolyl.

Typically R3~ and R4 are the same or different and are selected from heteroaryl and heterocyclic groups, alkyl, for example haloalkyl, halogen, vitro, -S(O)Z-alkyl, alkoxy, for example haloalkoxy, cyano, -COzR wherein R is aryl, heteroaryl, hydrogen or alkyl, hydroxy and -NR~R~~ and -CONR~R~~ wherein R~
and R~~
are the same or different and are aryl, heteroaryl, hydrogen or alkyl.
Preferred compounds of formula (Ia) are those in which one of RS and R8 is hydrogen and the other is hydrogen, halogen or hydroxy, or in which RS
and R8 are both hydrogen, R6 and R~ are the same or different and are selected from aryl, for example phenyl, heteroaryl, for example oxadiazolyl, vitro, cyano, alkyl for example methyl and ethyl, haloalkyl, halogen, for example chlorine, fluorine and bromine, hydrogen, -COzH, -COz-alkyl for example -COZ-Et and -COZ-Me, alkoxy, for example methoxy and CONR~R~~ wherein R' and R" are the same or different and are heteroaryl, or, preferably, aryl, 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 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 R4 are the same or different and are selected from:
(a) when attached to a phenyl moiety, aryl, for example phenyl, C,-C4 alkyl, for example methyl, ethyl, n-propyl, i-propyl or t-butyl, C,-C4 haloalkyl, for example CCl3 and CF3, halogen, for example chlorine, fluorine and bromine, vitro, cyano, C,-C4 alkoxy, for example methoxy, -COZR wherein R is hydrogen or C,-C4 alkyl, -NR~R~~ wherein R~ and R~~ are the same or different and are hydrogen, C,-C4 alkyl or -CO-(C,-C4 alkyl), -O-(C,-C4 alkyl)-R~~~ wherein R~~~ is heteroaryl, for example thiazolyl, or heterocyclyl, and -S(O)Z-C,-C4 alkyl; and (b) when attached to a thienyl moiety, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, vitro, halogen such as chlorine, bromine or fluorine, C,-C4 haloalkyl such as -CF3 and -CCl3, C,-C4 alkyl such as methyl, ethyl, n-propyl, i-propyl or t-butyl, -COZR wherein R is hydrogen or C,-C4 alkyl, C,-C4 alkoxy such as methoxy, -(C,-C4 alkyl)-NH-aryl, for example -(C,-C4 alkyl)-NH-phenyl, and -S(O)z-C,-C4 alkyl.

Typically, in these preferred compounds, R6 and R7 are the same or different and are selected from vitro, alkyl such as methyl or ethyl, haloalkyl, halogen such as chlorine, fluorine or bromine, hydrogen, -COz-alkyl such as -COz-Et and -COz-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 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 further phenyl moiety. Typically, when attached to a phenyl moiety, R3~ and R4~ are selected from Cl-C4 alkyl, for example methyl, ethyl, n-propyl, i-propyl or t-butyl, C,-haloalkyl, for example CC13 and CF3, halogen, for example chlorine, fluorine and bromine, vitro, C,-C4 alkoxy, for example methoxy, and -S(O)Z-C1-C4 alkyl.
Typically, when attached to a thienyl moiety, R3~ and R4~ are selected from isoxazolyl, isothiazolyl, pyrazolyl, vitro, halogen, for example chlorine, bromine and fluorine, Cl-C4 haloalkyl, for example -CF3 and -CC13, C,-C4 alkyl, for example methyl, ethyl, n-propyl, i-propyl and t-butyl, -COzR wherein R is hydrogen or C1-C4 alkyl, Ci-alkoxy, for example methoxy, and -S (O) Z-C,-C4 alkyl.
Particularly preferred compounds of the formula (Ia) are those in which RS and R8 are hydrogen, R6 and R~ are the same or different and are selected from hydrogen, oxadiazolyl, chlorine, fluorine, bromine, vitro, cyano, methyl, methoxy, -COZEt, -COZMe, -CONH2, -CONHMe, -CONMeZ, -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 R3~ and R4 are the same or different and are selected from methyl, ethyl, i-propyl, chlorine, fluorine, bromine, methoxy, trifluoromethoxy, vitro, cyano, -S(O)zMe, -COzH, -NH-CO-CH3, -O-CHZ-(2-chlorothiazolyl) and, when X
and Y are thienyl, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl and -CHz-NH-R
wherein R is phenyl or 4-chlorophenyl.
Compounds of the invention which are more preferred are compounds of formula (Ib) and salts thereof.

~3 ) wherein R3 and R4 are the same or different and are selected from (a) phenyl optionally substituted by halogen, for example chlorine, C~-C4 alkyl, for example methyl, C,-C4 haloalkyl, for example -CF3 or C,-C4 haloalkoxy, for example -and (b) thienyl, optionally substituted by halogen, for example chlorine, C~-C4 alkyl, for example methyl, C,-C4 haloalkyl, for example -CF3 and Cl-C4 haloalkoxy, for example -OCF3, and R6 is halogen, for example chlorine and fluorine, or C1-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 R4 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 Cl-C4 alkyl group such as a methyl group, Ar is not a group of formula Ar', as defined above, wherein RS, R? and R8 are hydrogen and R6 is C,-C4 alkyl such as methyl or -COZ-(C,-C4 alkyl) such as -COz-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, malefic, 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 1,2-Bis(4-methylphenylsulfonylamino)-4,5-dibromobenzene 3,4-Bis (4-methylphenylsulfonylamino) -6-bromotoluene 1,2-Bis(4-methylphenylsulfonylamino)-4-fluorobenzene 3-(3-trifluoromethylphenylsulfonylamino)-4-(4-iodophenylsulfonylamino) toluene 1,2-Bis(4-methylphenylsulfonylamino)-4-nitrobenzene 3-(4-methylphenylsulfonylamino)-4-(4-chlorophenylsulfonylamino) toluene 1,2-Bis (4-methylphenylsulfonylamino) -benzene 1,2-Bis(4-methylphenylsulfonylamino)-4-fluoro-5-nitrobenzene 3,4-Bis(4-methylphenylsulfonylamino)-benzoic acid methyl ester 1,2-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 1,2-Bis(4-bromophenylsulfonylamino)-4,5-dibromobenzene 1,2-Bis(4-fluorophenylsulfonylamino)-4,5-dibromobenzene 1,2-Bis(3-bromophenylsulfonylamino)-4,5-dibromobenzene 1,2-Bis (4-trifluoromethoxyphenylsulfonylamino) -benzene 1,2-Bis (4-isopropylphenylsulfonylamino) -benzene 1,2-Bis (4-fluorophenylsulfonylamino) -4,5-dimethylbenzene 1,2-Bis(4-methylphenylsulfonylamino)-4,5-dimethylbenzene 1,2-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 1,2-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 1,2-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 1,2-Bis(2,4-difluorophenylsulfonylamino) benzene 1,2-Bis (phenylsulfonylamino) -4,5-dimethylbenzene 1,2-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 1,2-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 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-phenol 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-anisole 1,2-Dibromo-4,5-bis (2,5-dichloro-3-thienylsulfonylamino) -benzene 3,4-Bis(2,5-dichloro-3-thienylsulfonylamino)chlorobenzene 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-3,4,5,6-tetramethylbenzene 2,3-Bis(phenylsulfonylamino)naphthalene 2,3-Bis (3-trifluoromethylphenylsulfonylamino) naphthalene 2,3-Bis(4-trifluoromethoxyphenylsulfonylamino)naphthalene 2,3-Bis(3,4-dichlorophenylsulfonylamino)naphthalene 2,3-Bis (4-isopropylphenylsulfonylamino) naphthalene 2,3-Bis(4-trifluoromethyphenylsulfonylamino)naphthalene 2,3-Bis(2,4diflurophenylsulfonylamino)naphthalene 2,3-Bis(2-chloro-5-thienylsulfonylamino)naphthalene 2,3-Bis(2-methyl-4-nitrophenylsulfonylamino)naphthalene 2,3-Bis (2-methyl-3-chlorophenylsulfonylamino) naphthalene 2,3-Bis (4-cyanophenylsulfonylamino) naphthalene 2,3-Bis(3,5dimethyl-3-oxazoylsulfonylamino)naphthalene 2,3-Bis (2-aza-4,5-benzothiazoylsulfonylamino) naphthalene 2,3-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)naphthalene 2,3-Bis(2,6-difluorophenylsulfonylamino)naphthalene 2,3-Bis (3-nitro-4-methylphenylsulfonylamino) naphthalene 3,4-Bis (2- ( 1,2-cyclo (3-thioethyl) -4-chloro-5-imidazoylsulfonylamino) naphthalene 2,3-Bis(4-methylsulfonophenylsulfonylamino)naphthalene 1,2-Bis(4-fluorophenylsulfonylamino)-4-nitrobenzene 3,4-Bis(4-fluorophenylsulfonylamino)-benzoic acid methyl ester 3,4-Bis(4-trifluoromethylphenylsulfonylamino)-benzoic acid methyl ester 3,4-Bis(2-chloro-5-thienylsulfonylamino)-benzoic acid methyl ester 3,4-Bis(2-methoxy-2-chlorophenylsulfonylamino)-benzoic acid methyl ester 3,4-Bis(4-methyl-2-nitrophenylsulfonylamino)-benzoic acid methyl ester 1,2-Bis (3-trifluoromethylphenylsulfonylamino) -4-fluorobenzene 1,2-Bis (2-thienylsulfonylamino) -4-fluorobenzene 1,2-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 -dime thylbenzene 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 1,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4,5-dimethylbenzene 1,2-Bis(4-methylsulfonophenylsulfonylamino)-4,5-dimethylbenzene 1,2-Bis(1-naphthylsulfonylamino)-4,5-dibromobenzene 1,2-Bis (2,3-dichloro-5-thienylsulfonylamino) -4,5-dibromobenzene 1,2-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 1,2-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 1,2-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 1,2-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 1,2-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(2,6difluorophenylsulfonylamino)-benzoic acid methyl ester 1,2-Bis(2-chloro-5-thienylsulfonylamino)-4-fluorobenzene 1,2-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-trifluoromethylphenylsulfonylamino) -4,5-difluorobenzene 1,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4,5-difluorobenzene 1,2-Bis (4-methyl-3-nitrophenylsulfonylamino) -4>5-difluorobenzene 1,2-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 1,2-Bis(4-cyanophenylsulfonylamino)-4-fluorobenzene 1,2-Bis(4-methylphenylsulfonylamino)-4-cyanobenzene 1,2-Bis (3-trifluoromethylphenylsulfonylamino) -4,5dibromobenzene 1,2-Bis(2-trifluoromethoxyphenylsulfonylamino)-3,5dibromobenzene 1,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4,5dibromobenzene 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 1,2-Bis(4-methylphenylsulfonylamino)-4-chlorobenzene 1,2-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 1,2-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 1,2-Bis (4-trifluoromethoxyphenylsulfonylamino) -4-chloro-5-methylbenzene 1,2-Bis(2-thienylsulfonylamino)-4-chloro-5-methylbenzene 1,2-Bis(3,4-dichlorophenylsulfonylamino)-4-chloro-5-methylbenzene 1,2-Bis(4-trifluoromethylphenylsulfonylamino)-4-chloro-5-methylbenzene 1,2-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 1,2-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 1,2-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 1,2-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-methyl-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 1,2-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 1,2-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 1,2-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 1-(3-trifluoromethylsulfonylamino)-2-(benzylsulfonylamino)-4-fluorobenzene 4-(3-trifluoromethylsulfonylamino)-3-(2-phenylethenylsulfonylamino)-benzoic acid ethylester 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 (1d), and salts thereof, O= S=O
/fit Ar (Id) ~2 O= S=O

wherein:
- Rl and Rz 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 RZ 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 R4 are not (a) unsubstituted quinoline groups, (b) unsubstituted phenyl groups, (c) phenyl groups monosubstituted by a methyl, methoxy, -COzH, chlorine, cyano, nitro or amino group, or by a group -O-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 Rl and RZ 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, C,-alkoxy, C,-C4 alkyl, halogen, nitro, C~-C4 haloalkyl or amino groups, R3 and R4 are not unsubstituted quinoline groups or phenyl groups optionally substituted by 1 or 2 groups selected from C,-C4 alkyl, C,-C4 alkoxy, -COzR wherein R is hydrogen or C,-C4 alkyl, halogen, cyano, nitro and amino groups, and from groups of the formula -O-CO-N(Cl-C4 alkyl)-.
The compounds of formula (I) may be prepared by a process comprising reacting a compound of formula (II) , p=S=O
Ar/
~2 wherein Ar, Ri, Rz and R3 are as defined above, with a compound of formula (III) X
O=S=O
~a 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).
W
~~2 wherein Ar, R, and RZ are as defined above, with a compound of formula (V) X
O=S =O

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 Rz is hydrogen, can also be prepared by reaction of a compound of formula (VI) with a suitable reducing agent.

O= S=O
(VI) Ar wherein Ar, Rl 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
NRl Ar/ (VII) 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, Actinobacillus actinomycetes, Aeromonas salmonicida subsp. Salmonicida, Amycolatopsis mediterranei, Bacillus subtilis, Corynebacterium glutamicum, Corynebacterium pseudotuberculosis, Emericella nidulans, Haemophilus inf luenzae, Helicobacter pylori, Neurospora crassa, Pseudomonas aeruginosa, Streptomyces coelicolor, Streptomyces lavendulae, Synechocystis sp, Thermotoga meritima, Campylobacter jejuni, Clostridium acetobutylicum, Porphyromonas gingivalis, Deinococcus radiodurans, Chlorobium tepidum, Vibrio cholerae, Yersinia pesos, Sheavanella 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,, Rz, R3 and R4 are as defined above, provided that, when R, and RZ are hydrogen and R3 and R4 are phenyl, 4-methylphenyl or 4-aminophenyl, Ar is not R~
R// ~ s 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-chlorotoluene, 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 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, triburylphenoxypolyethoxyethanol, 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-CzZ 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 l.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 100g to 2kg per hectare, more preferably from 200g to 5008 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 invention 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 (IOmM) in dry pyridine (50m1) 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 1N
hydrochloric acid (500m1). The product was extracted into ethyl acetate (3x200m1) and the combined organic extracts washed with water, 1N 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%).
Exambles 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 1,2-Bis (4-methylphenylsulfonylamino) -4-fluorobenzene 4 3,4-Bis-(phenylsulfonylamino)toluene 1,2-Bis- (methylphenylsulfonylamino) -4-nitrobenzene 6 3,4-Bis(4-methylphenylsulfonylamino)toluene ? 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 (IOmM, 1.08g) in dry acetonitrile (50m1) was stirred under nitrogen at room temperature. Diisopropylethylamine (5m1) was added, followed by benzenesulfonyl chloride (4.198, 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 1N 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 1,2-Bis(3,5-ditrifluoromethylphenylsulfonylamino)-benzene 11 1,2-Bis(4-bromophenylsulfonylamino)-benzene 12 1,2-Bis(4-tent-butylphenylsulfonylamino)-benzene 13 1,2-Bis(4-methylphenylsulfonylamino)-4,5-methylenedioxybenzene 14 1,2-Bis(4-methylphenylsulfonylamino)-4,5-dichlorobenzene 1,2-Bis(4-methylphenylsulfonylamino)-4,5-ethylenedioxybenzene 16 2,3-Bis(4-methylphenylsulfonylamino)-naphthalene 17 1,2-Bis (4-me thylphenylsulfonylamino) -4,5-difluorobenzene 18 1,2-Bis(4-bromophenylsulfonylamino)-4,5-dibromobenzene 19 1,2-Bis (4-chlorophenylsulfonylamino) -4,5-dibromobenzene 1,2-Bis(4-fluorophenylsulfonylamino)-4,5-dibromobenzene 21 1,2-Bis (3-bromophenylsulfonylamino) -4,5-dibromobenzene Example 22 3-(3-trifluoromethylphenylsulfonylamino)-4-(4-methylphenylsulfonylamino) toluene A solution of 3,4-diaminotoluene (IOmM) in dry pyridine (50m1) 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 (3x200m1) and the combined organic extracts washed with water, 1N 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, l.2mM) in glacial acetic acid (lOml) was stirred and sodium acetate (200mg) added.
Bromine (385mg, 0.13m1, 2.4mM) was added dropwise and the resulting dark solution then heated at 80°C for 3hr. Water (50m1) 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-1,2-bis(4-methylphenylsulfonylamino) benzene (176mg, 3x10'4mo1) and dibromoethane (57mg, 3x10'4mo1) were refluxed with potassium carbonate (1.0g, 7.25 x 10'4mo1) in dry acetonitrile (250m1) 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 1,2-Bis(2-chloro,5-thienylsulfonylamino)-4-chloro-5-methylbenzene 4-chloro-5-methylphenylene-1,2-diamine (IOmM, 1.56) was dissolved in dry pyridine (100m1) and stirred at room temperature under nitrogen. To this solution a solution of 5-chloro-2-thienylsulfonyl chloride (2lmM, 4.55g) in pyridine (15 ml) is added and the resultant solution stirred at 85°C for 18 hr under nitrogen.
The solution was then poured into 0.5M cold dilute hydrochloric acid (125m1) 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 (2.188, 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 1,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-benzene 30 1,2-Bis( 1-naphthylsulfonylamino)-4,5-dibromobenzene 31 1,2-Bis(2,3-dichloro-5-thienylsulfonylamino)-4,5-dibromobenzene 32 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4,5-dibromobenzene 33 1,2-Bis(4-nitrophenylsulfonylamino)-4,5-dibromobenzene 34 1,2-Bis(4-biphenylsulfonylamino)-4,5-dibromobenzene 35 1,2-Bis(4-bromophenylsulfonylamino)-4,5-dibromobenzene 36 1,2-Bis(4-carboxyphenylsulfonylamino)-4,5-dibromobenzene 37 1,2-Bis(3,4-dimethoxyphenylsulfonylamino)-4,5-dibromobenzene 38 1,2-Bis(3-methylphenylsulfonylamino)-4,5-dibromobenzene 39 1,2-Bis(2-fluorophenylsulfonylamino)-4,5-dibromobenzene 40 1,2-Bis(2-methoxyphenylsulfonylamino)-4,5-dibromobenzene 41 2,3-Bis(4-fluorophenylsulfonylamino)naphthalene 42 1,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4-fluorobenzene 43 1,2-Bis(3-trifluoromethylphenylsulfonylamino)-4,5-dibromobenzene 44 1,2-Bis(2-trifluoromethoxyphenylsulfonylamino)-3,5-dibromobenzene 45 1,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4,5-dibromobenzene 46 1,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4,5-dimethylbenzene 47 1,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4,5-dibromobenzene 48 1,2-Bis(3-chloro,4-acetamidophenylsulfonylamino)-4,5-dibromobenzene 49 1,2-Bis(4-acetamidophenylsulfonylamino)-4,5-dibromobenzene 50 1,2-Bis(5-(2-pyridyl)-2-thienylsulfonylamino)-4-chlorobenzene 51 1,2-Bis(5-(4-chloroacetamidomethyl)-2-thienylsulfonylamino)-4-chlorobenzene 52 1,2-Bis(2-(2-aza-4-thiazoyl)-5-thienylsulfonylamino)-4-chlorobenzene 53 1,2-Bis(2-(2-methyl-4-thiazoyl)-5-thienylsulfonylamino)-4-chlorobenzene 54 1,2-Bis(2-(2-methyl-4-thiazoyl)-5-thienylsulfonylamino)-4-fluorobenzene 55 1,2-Bis(4-methoxyphenylsulfonylamino),4,5-dibromobenzene 56 1,2-Bis(4-methoxyphenylsulfonylamino),4,5-dichlorobenzene.
57 1,2-Bis(2-(N-phenylamidomethyl)-5-thienylsulfonylamino)-benzene 58 1,2-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 6 The compounds set out below were prepared in the same way as in Example 59, using appropriate starting materials.
Example I Compound 60 I 1,2-Bis(4-isopropylphenylsulfonylamino)-benzene 61 1,2-Bis(4-fluorophenylsulfonylamino)-4,5-dimethylbenzene 62 I 1,2-Bis(4-methylphenylsulfonylamino)-4,5-dimethylbenzene 63 1,2-Bis(3-trifluoromethoxyphenylsulfonylamino)-4,5-dimethylbenzene 64 1,2-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.Omm (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% IOmM formic acid in water over 3 minutes at 0.5m1/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-1,2-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.

Exameles 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-methylphenylsulfonylamino)-anisole 72 3,4-Bis(4-trifluoromethoxyphenylsulfonylamino)-anisole 73 3,4-Bis(4-isopropylphenylsulfonylamino)-anisole 74 3,4-Bis[(4-methylsulfonyl)phenylsulfonylamino]anisole 75 1,2-Bis(3-trifluoromethylphenylsulfonylamino)-benzene 76 1,2-Bis(4-trifluoromethylphenylsulfonylamino)-benzene 77 1,2-Bis(3-chloro-2-methylphenylsulfonylamino)-benzene 78 1,2-Bis(2,6-difluorophenylsulfonylamino)-benzene 79 1,2-Bis(phenylsulfonylamino)-benzene 80 1,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4,5-dimethylbenzene 81 1,2-Bis(2,6-difluorophenylsulfonylamino)-4,5-dimethylbenzene 82 1,2-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-difluorophenylsulfonylamino)-phenol 86 1,2-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 1,2-Bis(4-fluorophenylsulfonylamino)-benzene 92 1,2-Bis(2,4-difluorophenylsulfonylamino)-benzene 93 1,2-Bis(phenylsulfonylamino)-4,5-dimethylbenzene 94 1,2-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 1,2-Bis(5-chloro,2-methoxyphenylsulfonylamino)-benzene 99 2,3-Bis(4-trifluoromethylphenylsulfonylamino)-phenol 100 3,4-Bis(4-trifluoromethylphenylsulfonylamino)-anisole 101 1,2-Bis(4-trifluoromethylphenylsulfonylamino)-4-fluorobenzene 102 3,4-Bis(3-trifluoromethylphenylsulfonylamino)-benzoic acid ethyl ester 103 1,2-Bis(2-thienylsulfonylamino)-benzene 104 2,3-Bis(2-thienylsulfonylamino)-phenol 105 1,2-Bis(2-chloro-5-thienylsulfonylamino)-napthalene 106 1,2-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 1,2-Bis[2-(3-oxazolyl)-5-thienylsulfonylamino)-benzene 114 1,2-Dimethyl-4,5-bis(2-thienylsulfonylamino)-benzene 115 1,2-Dimethyl-4,5-bis(2-chloro-5-thienylsulfonylamino)-benzene 116 1,2-Diftuoro-4,5-bis (2-thienylsulfonylamino) -benzene 117 1,2-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 1,2-Bis(2-thienylsulfonylamino)-3,4,5,6-tetramethylbenzene 123 3,4-bis(2-thienylsulfonylamino)-benzoic acid ethyl ester 124 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4,5-dimethylbenzene 125 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-anisole 126 1,2-Dibromo-4,5-bis (2,5-dichloro-3-thienylsulfonylamino)-benzene 127 2,3-Bis(4-isopropylphenylsulfonylamino)-phenol 128 1,2-Bis(2,5-dichlorothienyl-3-sulfonylamino)-4,5-dimethylbenzene 129 1,2-Bis(2,5-dichlorothienyl-3-sulfonylamino)-4-methoxybenzene 130 1,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-3,4,5,6-tetramethylbenzene 131 2,3-Bis(phenylsulfonylamino)-naphthalene 132 2,3-Bis(3-trifluoromethylphenylsulfonylamino)-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-(1,2-cyclo(3-thioethyl)-4-chloro,5-imidazoylsulfonylamino)-naphthalene 147 2,3-Bis(4-methylsulfonophenylsulfonylamino)-naphthalene 148 1,2-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-Bis(2-chloro-5-thienylsulfonylamino)-benzoic acid methyl ester 152 3,4-Bis(2-methoxy,2-chlorophenylsulfonylamino)-benzoic acid methyl ester 153 3,4-Bis(4-methyl,2-nitrophenylsulfonylamino)-benzoic acid methyl ester 154 1,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-fluorobenzene 155 1,2-Bis(2-thienylsulfonylamino)-4-fluorobenzene 156 1,2-Bis(3,4-dichlorophenylsulfonylamino)-4-fluorobenzene 157 1,2-Bis(2-methyl-5-nitrophenylsulfonylamino)-4-fluorobenzene 158 1,2-Bis(phenylsulfonylamino)-4,5-difluorobenzene 159 1,2-Bis(benzylsulfonylamino)-4,5-diflurobenzene 160 3,4-Bis(2,4-dichlorophenylsulfonylamino)-benzoic acid ethyl ester 161 3,4-Bis(2-chloro-5-thienylsulfonylamino)-benzoic acid ethyl ester 162 3,4-Bis(2-methyl-5-nitrophenylsulfonylamino)-benzoic acid ethyl ester 163 3,4-Bis(2,6-difluorophenylsulfonylamino)-benzoic acid ethyl ester 164 1,2-Bis(2-methyl-5-nitrophenylsulfonylamino)-4-methoxybenzene 165 1,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4-methoxybenzene 166 1,2-Bis(benzylsulfonylamino)-benzene 167 1,2-Bis(3,4-dichlorophenylsulfonylamino)-benzene 168 1,2-Bis(2-chloro-5-thienylsulfonylamino)-benzene 169 1,2-Bis(2-methyl-5-nitrophenylsulfonylamino)-benzene 170 1,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-benzene 171 1,2-Bis(4-isopropylphenylsulfonylamino)-4-nitrobenzene 172 1,2-Bis(2-thienylsulfonylamino)-4,5-dimethylbenzene 173 1,2-Bis(3,4-dichlorophenylsulfonylamino)-4,5-dimethylbenzene 174 1,2-Bis(2-chloro-5-thienylsulfonylamino)-4,5-dimethylbenzene 175 1,2-Bis(2-methyl-5-nitrophenylsulfonylamino)-4,5-dimethylbenzene 176 1,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4,5-dimethylbenzene 177 1,2-Bis(4-methylsulfonophenylsulfonylamino)-4,5-dimethylbenzene 178 1,2-Bis(4-methylphenylsulfonylamino)-4-cyanobenzene 179 1,2-Bis(phenylsulfonylamino)-4-chlorobenzene 180 1,2-Bis(4-fluorophenylsulfonylamino)-4-chlorobenzene 181 1,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 182 1,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4-chlorobenzene 183 1,2-Bis(2-thienylsulfonylamino)-4-chlorobenzene 184 1,2-Bis(3,4-dichlorophenylsulfonylamino)-4-chlorobenzene 185 1,2-Bis(4-isopropylphenylsulfonylamino)-4-chlorobenzene 186 1,2-Bis(2,4-difluorophenylsulfonylamino)-4-chlorobenzene 187 3,4-Bis(4-chloro-2-methoxyphenylsulfonylamino)-benzoic acid ethyl ester 188 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4-chlorobenzene 189 1,2-Bis(2-chloro-5-thienylsulfonylamino)-4-chlorobenzene 190 1,2-Bis(2-methyl-5-nitrophenylsulfonylamino)-4-chlorobenzene 191 1,2-Bis(2-methyl-3-chlorophenylsulfonylamino)-4-chlorobenzene 192 1,2-Bis(4-cyanophenylsulfonylamino)-4-chlorobenzene 193 1,2-Bis(3,5-dimethyl-4-oxazoylsulfonylamino)-4-chlorobenzene 194 1,2-Bis(2,6-difluorophenylsulfonylamino)-4-chlorobenzene 195 1,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4-chlorobenzene 196 3,4-Bis(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 1,2-Bis(2-chloro-5-thienylsulfonylamino)-4-fluorobenzene 201 1,2-Bis(2-methyl-3-chlorophenylsulfonylamino)-4-fluorobenzene 202 1,2-Bis(2-methoxy-5-chlorophenylsulfonylamino)-4-fluorobenzene 203 1,2-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 1,2-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 1,2-Bis(3-trifluoromethylphenylsulfonylamino)-4,5-difluorobenzene 210 1,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4,5-difluorobenzene 211 1,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4,5-difluorobenzene 212 1,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-chloro-5-methylbenzene 213 2,3-Bis(2-thienylsulfonylamino) naphthalene 214 1,2-Bis(4-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 215 1,2-Bis(4-fluorophenylsulfonylamino)-4,5-difluorobenzene 216 1,2-Bis(4-methylsulfonophenylsulfonylamino)-3,4,5,6-tetramethylbenzene 217 1,2-Bis(4-isopropylphenylsulfonylamino)-4-fluorobenzene 218 1,2-Bis(4-cyanophenylsulfonylamino)-4-fluorobenzene 219 1,2-Bis(4-methylphenylsulfonylamino)-4-cyanobenzene 220 3,4-Bis(8-quinolylsulfonylamino)-benzoic acid ethyl ester 221 1,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4-fluorobenzene 222 1,2-Bis(phenylsulfonylamino)-4-fluorobenzene 223 3,4-Bis(3,5-dimethyl-4-oxazoylsulfonylamino)-benzoic acid methyl ester 224 3,4-Bis(4-isopropylphenylsulfonylaxnino)-benzoic acid methyl ester 225 1,2-Bis(4-methylphenylsulfonylamino)-4-chlorobenzene 226 3,4-Bis(3,5-dimethyl-4-oxazoylsulfonylamino)-4,5-difluorobenzoate 227 1,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4-methoxybenzene 228 1,2-Bis(2-( 1,2-cyclo(3-thioethyl)-4-chloro,5-imidazoylsulfonylamino)-4-methoxybenzene 229 1,2-Bis(phenylsulfonylamino)-4-cyanobenzene 230 1,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-cyanobenzene 231 1,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4-cyanobenzene 232 1,2-Bis(2-thienylsulfonylamino)-4-cyanobenzene 233 1,2-Bis(4-isopropylphenylsulfonylamino)-4-cyanobenzene 234 1,2-Bis(2,4-difluorophenylsulfonylamino)-4-cyanobenzene 235 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino)-4-cyanobenzene 236 1,2-Bis(3-chloro-2-methylphenylsulfonylamino)-4-cyanobenzene 237 1,2-Bis(2,6-difluorophenylsulfonylamino)-4-cyanobenzene 238 1,2-Bis(2-(3-oxazoyl)-5-thienylsulfonylamino)-4,5-difluorobenzene 239 1,2-Bis(4-trifluoromethoxyphenylsulfonylamino)-4-chloro-5-methylbenzene 240 1,2-Bis(benzylsulfonylamino)-4-chloro-5-methylbenzene 241 1,2-Bis(2-thienylsulfonylamino)-4-chloro-5-methylbenzene 242 1,2-Bis(3,4-dichlorophenylsulfonylamino)-4-chloro-5-methylbenzene 243 1,2-Bis(4-trifluoromethylphenylsulfonylamino)-4-chloro-5-methylbenzene 244 1,2-Bis(2,4-difluorophenylsulfonylamino)-4-chloro-5-methylbenzene 245 1,2-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 1,2-Bis(2-aza-4,5-benzothiazoylsulfonylamino)-4-chloro-5-methylbenzene 248 1,2-Bis(2-(5-oxa-2-thiazoyl)-5-thienylsulfonylamino)-4-chloro-5-methylbenzene 249 1,2-Bis(2,4-difluorophenylsulfonylamino)-4-chloro-5-methylbenzene 250 1,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4-chloro-5-methylbenzene 251 1,2-Bis(4-methyl-3-nitrophenylsulfonylamino)-4-cyanobenzene 252 1,2-Bis(phenylsulfonylamino)-4-chloro-5-methylbenzene 253 2,3-Bis(2,4-dichlorophenylsulfonylamino)naphthalene 254 1,2-Bis(2,4-dichlorophenylsulfonylamino)-benzene 255 1,2-Bis(2-(2-methyl-4-thiazoyl)-5-thienylsulfonylamino)-benzene 256 1,2-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 3.5~m C18 50x2.Omm (WAT200650) column with a gradient elution from 5% lOmM formic acid in acetonitrile and 95% IOmM formic acid in water to 95% lOmM formic acid in acetonitrile and 5% IOmM formic acid in water over 3 minutes at 0.5m1/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 l0~mo1) was stirred in 1N 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, 15m1) was added to a stirred solution of dry THF (5m1) containing sodium hydride (0.0158, 0.39mmol). The mixture was heated to 60°C under nitrogen. A solution of 3,4-Bis(3-trifluoromethylphenylsulfonylamino)-benzoic acid methyl ester (Example 207, 76m8, 0.13mM) in dry THF (15m1) was added dropwise over l5mins. The reaction was left to reflux overnight. Methanol (5m1) then Water (5m1) 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 (21m8, 27%) Example 259 3,4-Bis (4-methylphenylsulfonylamino) -IV-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 O-(7-azabenzotriazol-1-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 ~C
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 mM, 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)-N (4-fluoromethoxyphenyl) benzamide 261 3,4-Bis(4-methylphenylsulfonylamino)-N (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, 2.66mmo1) was dissolved in ethanol (50m1). 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 (2m1). 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 (0.81g, 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 1-(4-methoxyphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-chlorobenzene 264 1-(3-chlorophenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 265 1-(2-chlorophenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 266 1-(3-methylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 267 1-(4-methylamidomethylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 268 1-(2-(phenylamidomethyl)-5-thienylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 269 1-(4-(2-chloro-5-thiazoylmethoxyphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene 270 3-(2,S-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.
1-Nitro-2-(3-trifluoromethylphenylsulfonylamino)-4-fluorobenzene (prepared as per example 22 using appropriate starting materials; 0.138, 0.32mmol) was stirred in dimethylformamide (5m1) containing tin (II) chloride (0.28g, 1.25mmo1). The reaction was left to stir overnight at room temperature under nitrogen. The mixture was diluted with water (15m1) and the pH adjusted to 7 with 1M 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 1-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 I-(4-methylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-fluorobenzene 274 I-(3-trifluoromethylsulfonylamino)-2-(2-phenylethenylsulfonylamino)-4-fluorobenzene 275 I -(3-trifluoromethylsulfonylamino)-2-(2-phenylethenylsulfonylamino)-benzene 276 1-(3-trifluoromethylsulfonylamino)-2-(benzylsulfonylamino)-4-fluorobenzene 277 I-(2,5-dichloro-3-thienylsulfonylamino)-2-(3-trifluoromethylsulfonylamino)-benzene 278 I-(2-(phenylamidomethyl)-5-thienylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-benzene 279 1-(2-(phenylamidomethyl)-5-thienylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-fluorobenzene 280 1-(4-(2-chloro-5-thiazoylmethoxyphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-benzene 281 1-(4-(2-chloro-5-thiazoyhnethoxyphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-fluorobenzene 282 I-(2-chlorophenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-benzene 283 1-(2-chlorophenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-fluorobenzene 284 1-(2-methylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-benzene 285 I-(3-methylphenylsulfonylamino)-2-(3-trifluoromethylphenylsulfonylamino)-4-fluorobenzene Example 286 Analytical Data for compounds representative of Examples 1 to 285 ExampleNMR Data Mass Micro Analysis Spectrum, Calc.d (found) technique 1 8H(CD3COCD3, 400MHz) 6.95 478 (Mt) (2H, dd, J EI

8,2Hz); 7.85 (2H, t, J 8Hz,);
8.10 (2H, dd, J

8,2 Hz); 8.45 (4H, m), 25 SH(CD3COCD3, 400MHz) 2.35 574 (M~) (6H, s); EI

6.65 (2H, bs); 7.10 (2H, s);
7.20 (4H, d, J

8Hz); 7.50 (4H, d, J 8Hz), 11 ( SH(CD3COCD3, 400MHz) 6.96 546 (M~), (2H, m); ~ EI

7.05 (4H, AB d, J 8.lHz);
7.07 (2H, m);

7.5 8 (4H, AB d, J 8.1 Hz).

12 gH(CD3COCD3, 400MHz) 1.26 500 (Mt), (18H, s); EI

6.73, 4H, m); 7.36 (4H, AB
d, J 8.9Hz);

7.57 (4H, AB d, J 8.9Hz).

15 8H(CD3COCD3, 400MHz) 2.35 452 (Mt), (6H, s); EI

3.53 (4H, s); 6.51 (2H, s);
7.31 (4H, AB d, J 8.OHz); 7.58 (4H, AB d, J 8.OHz).

16 8H(CD3COCD3) 2.33 (6H, s);
7.28 (4H, AB d, J 8.3Hz); 7.40 (2H, m); 7.53 (2H, s);

7.64 (4H, AB d, J 8.3Hz);
7.68 (2H, m).

1~ 8H(CD3COCD3 400MHz) 2.39 (6H, s);

6.99 (2H, t, JF_H 9.8Hz);
7.35 (4H, AB d, J

7.9Hz); 7.60 (4H, AB d, J
7.9Hz).

59 bH(CDC13, 300MHz) 6.95 (2H, C: 43.17 (43.00), m); 7.05 (2H, m); 7.15 (2H, bs); 7.25 H: 2.54 (2.19), (4H, m); 7.75 (4H, m) N: 5.03 (4.91) 140 $H(CD3COCD3, 400MHz) 2.75 534 (M-H)-,C: 53.83 (54.19) (6H, s);

7.2-7.3 (2H, t, J 8Hz); 7.4-7.5F~ H: 3.96 (3.69) (2H, m); 7.55 (2H, s); 7.6-7.7 (4H, m); N: 5.23 (5.08) 7.75-7.80 (2H, d, J

8 Hz); 9.0 (2H, bs) 181 8H(CD3COCD3~ 400Hz) 6.75 (1H,559 (M-H)-,C: 42.98 (43.05) d, J

8.6Hz); 6.90 (1H, d, J2.3Hz);F~ H: 2.34 (2.06 6.98 (1H, dd, J 8.6, 2.3Hz); 7.65 (2H, t, N: 5.01 (4.86 J 7.9Hz); 7.77-7.88 (6H, m) 182 sH(CD3COCD3, 400MHz) 6.81 590 (M-H)-,C: 40.61 (40.65) (1H, d, J

9Hz); 6.92 ( 1 H, d, J 2.4Hz);ES -ve, H: 2.22 ( 6.97 ( 1 H, dd, J 1.93) 9, 2.4Hz); 7.43 (4H, m); 7.68 N: 4.74 (4.56) (4H, m) 188 8H(CDC13, 300MHz) 7.0-7.6 571 (M-H)-,C: 29.36 (29.19) (5H, m) Es -ve H: 1.23 (0.97) N: 4.89 (4.49) 189 8H(CD3COCD3, 400MHz) 7.6-8.1 502 (M-H)-,C: 33.57 (33.37) (7H, Es m); 9.4 (2H, bs) -ve H: 1.62 (1.80) N: 5.51 (5.56) 200 SH(CD30D, 300MHz) 6.85-6.95 485 (M-H)-,C: 34.50 (34.71) (1H, m); Es 6.95-7.0 (1H, m); 7.0-7.05 -ve H: 1.86 (1.61) (2H, m); 7.08 (1H, dd, J 10, 3Hz); 7.25 (1H, d, J 3Hz); N: 5.75 (5.67) 7.38 (1H, d, J3Hz) 201 8H(CDC13, 300MHz) 2.55 (3H, 503 (Mt)-, C: 47.72 (47.52) s); 2.63 (3H, s); 6.43-6.47 (2H, m); F~ H: 3.40 (3.19) 6.74 (1H, dd, J

10, 3Hz); 7.11-7.44 (2H, m); N: 5.56 (5.45) 7.45-7.6 (3H, m); 7.71 ( 1 H, d, J 1 OHz) 242 sH(CD3COCD3, 400MHz) 2.2 (3H,573 (M-H)-,C: 39.71 (39.90) s); 7.1 Es (2H, d, J IOHz); 7.6-7.7 (2H,-ve H: 2.28 (2.11) m); 7.75-7.80 (2H, m); 7.85 (2H, m); 8.6-8.7 (2H, bs) N: 4.87 (4.72) 268 8H(CDC13, 400MHz) 4.8 (2H, 628 (M-H)-,C: 47.66 (47.68) d, J SHz); Es 6.3 ( 1 H, d, J 9Hz); 6.8 -ve H: 3.04 (3.04) ( 1 H, dd, J 8, 4Hz);

6.9 (1H, d, J4Hz); 7.2 (1H, N: 6.67 (6.57) m); 7.3 (1H, d, J 6Hz); 7.35-7.45 (3H, m);
7.5-7.6 (2H, m);

7.65-7.8 (4H, m) 269 8H(CD3COCD3, 400MHz) 5.2 (2H,636 (M-H)-,C: 43.27 (43.84) s); Es 6.85 (1H, d, J 8Hz); 6.9-7.0 -ve H: 2.53 (2.47) (3H, m); 7.3 ( 1 H, m); 7.5 ( 1 H, s);
7.6 ( 1 H, t, J 1 OHz); N: 6.58 (6.64) 7.6-7.7 (2H, m); 7.8 (1H, d, J 8Hz); 7.85 ( 1 H, d, J 8Hz); 7.9 ( 1 H, s); 8.5 (2H, bs) 27'1 8H(CDC13, 300MHz) 6.92 (1H, C: 38.43 (38.36) s); 7.03-7.21 (4H, m); 7.65 (1H, t, H: 2.09 (1.86) J9Hz); 7.86 (1H, d, J 9Hz); 8.0 (2H, s) N: 5.27 (5.15) Example 287 Inhibition of purified dehydroquinate synthetase (AroB) measured in 96-well plates at single concentrations (50~M). 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 50pm 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 (40pM
final conc.n), zinc sulfate (40pM) and magnesium sulfate (2.5mM). NAD was added as co-factor at 20~M.
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 absorbance at 290nm 570nm _ 32 36 58 50 S.OOE+01 262 8.00E+01 275 68 9.20E+01 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 ICSO values to be calculated.
The ICSo values were calculated at 290 nm.

Example ICso (wM) Example ICso (w~

135 100+ 208 >100 143 20 216 >100 146 10 220 100+

234 300+ 274 >300 246 18 37 100+

247 20 38 100+

254 >100 46 7 256 >100 48 60 260 58 50 6.5 263 30 53 5.5 ExamQle 289 Inhibition of purified M. tuberculosis Type II dehydroquinase (AroQ) was measured in 96-well plates at single concentrations (50pM). 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 50~M 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 (40~M final conc.n), zinc sulfate (40~M) and magnesium sulfate (2.SmM).
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 Example 290 Inhibition of purified mycobacterium tuberculosis type II
dehydroquinase (AroQ) was measured in 96 well plates using the method set out in Example 289. Experiments were repeated at different concentrations to allow ICso values to be calculated. The ICSO values were calculated using results at 570nm.
Example IC m Example IC

Example 291 Antibacterial activity of compounds against Staphyloccocus 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'" edition).
The broth media used for the assay was 9 parts M9 Minimal Salts to 1 part Luria (Lennox) Media (9:1 M9:LB).
M9 Minimal Luria (Lennox) Media Salts NaCI 1.00 g/1 NaCI 5.00 g/1 NazHP04 6.78 g/1 Yeast extract 5.00 g/1 KHZP04 3.00 g/1 Enzymatic casein digest 10.00 g/1 NH4C1 1.00 g/1 For agar plates this media was solidified by addition of 1.5% (w/v) Noble Agar.
3m19:1 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 Aboo of ---0.1 in sterile 0.85% saline. Miles and Misra's were carried out on the diluted inoculum as follows:
a) 90p.1 of sterile 0.85% saline was added to the remaining wells of the microtitre plate (rows B to H) ;

b) lOpl 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, 5~1 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.
200p1 of 9:1 M9:LB Broth was added to the top row of wells in a sterile microtitre plate, to this 101 of the compound of Example 25 in dimethyl sulphoxide (DMSO) was added to the wells in duplicate. To one of the duplicates 2p1 of lOmg/ml Phenylalanine, 2p1 of lOmg/ml Tryptophan, 401 of 0.5mg/ml Tyrosine and 2~1 of 5~g/ml p-Aminobenzoic acid were added. The wells were then inoculated with 5p1 of the diluted bacterial culture (see above). The microtitre plates were incubated at 37°C with shaking (---150rpm) for 16-20 hrs and the Aboo 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.~u./ml / 5 Activit,~against Smith Strain (Methicillin sensitive) Staphwloccocus aureus Example MIC (~,M) Example ~ MIC (~M) 1 1 178 100+

300 181 1.2 18 15 184 2.2 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 46 >30 201 0.4 59 4.2 205 5 102 30 212 7.5 127 0.4 215 30+

132 14 217 30+

133 12 219 6.5 135 30+ 224 30+

136 3 225 30+

137 100+ 230 30 138 100+ 233 25 139 30+ 236 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. aureusMIC M
strain 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 20 201 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:
1. On day 1 1001 of cells ate seeded at 5 x 104 cell/ ml in a 96 well plate.
2. 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 1001 per well. 0.5% DMSO made up in growth medium is added to the control wells.
3. Cells are incubated at 37°C, 5% COZ for 72-96 hours.
4. Medium is removed by aspiration and cells are stained by adding 100.1 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 1001 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 MICIuMI Example MICf uM

28 >100 219 38 132 25 237 >100 136 >100 240 40 156 60 247 >100 171 85 249 >100

Claims (35)

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;
- 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-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 Ar' wherein R5 to R6 are the same or different and represent aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -CO2R 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 R6 or R6 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" 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, -CO2R 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 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 R6 and R7 represent hydrogen, aryl, heteroaryl, nitro, cyano, alkyl, alkoxy, haloalkyl, halogen, -CO2H, -CO2-alkyl 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 a phenyl moiety.

6. Use according to any one of the preceding claims wherein R1 and R2 are the same or different and represent hydrogen or alkyl or R1 and R2 together form a C1-C3 alkylene group.

7. Use according to any one of the preceding claims wherein R3 and/or R4 is phenyl, naphthyl, pyridyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, isoxazolyl, pyrrolyl, (1,2-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(O)2-alkyl, haloalkoxy, cyano, -CO2R wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy, -CONR'R" 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'" 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-R"" wherein Z is as defined above and R"" is aryl, heteroaryl or heterocyclyl.

9. Use according to claim 1, wherein the bissulfonamide derivative of formula (I) is a bissulfonamide derivative of formula (Ia) wherein R5 to R6 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 R3' and R4' are the same or different and are selected from aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S (O)2-alkyl, alkoxy, haloalkoxy, cyano, -CO2R 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"'R"" and -NR"'R""
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 -O-Z-R""' wherein Z is as defined above and R'"" is aryl, heteroaryl or heterocyclyl.

10. Use according to claim 9, wherein, in the formula (Ia), R5 and R6 are hydrogen, R6 and R7 are the same or different and are selected from aryl, heteroaryl, nitro, cyano, alkyl, haloalkyl, halogen, hydrogen, -CO2H, -CO2-alkyl, alkoxy and -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 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 R4' are the same or different and are selected from:
(a) when attached to a phenyl moiety, aryl, C1-C4 alkyl, C1-C4 haloalkyl, halogen, nitro, cyano, C1-C4 alkoxy, -CO2R wherein R is hydrogen or C1-C4 alkyl, -NR'R" wherein R' and R" are the same or different and are hydrogen, C1-C4 alkyl or -CO-(C1-C4 alkyl), -O-(C1-C4 alkyl)-R" wherein R" is heteroaryl or heterocyclyl, and -S(O)2-C1-C4 alkyl; and (b) when attached to a thienyl moiety, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, nitro, halogen, C1-C4 haloalkyl, C1-C4 alkyl, -CO2R
wherein R is hydrogen or C1-C4 alkyl, C1-C4 alkoxy, -(C1-C4 alkyl)-NH-aryl and -S(O)2-C1-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, 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 an aryl or heteroaryl group, for use in a method of treating the human or animal body, provided that, when R1 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:
- R1 and R2 are as defined in any one of claims 1 and 6;
- R3 and R4 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 R1 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 R4 are not (a) unsubstituted quinoline groups, (b) unsubstituted phenyl groups, (c) phenyl groups monosubstituted by a methyl, methoxy, -CO2H, chlorine, cyano, nitro or amino group, or by a group -O-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 (1d) is a bissulfonamide derviate of formula (1a), as defined in claim 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 R8 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;
1,2-Bis(2-chloro-5-thienylsulfonylamino)-4-chlorobenzene;
1,2-Bis(2-methyl-3-chlorophenylsulfonylamino)-4-fluorobenzene;
1,2-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.