KR20020057973A - Enzyme inhibitors - Google Patents

Abstract

Bissulfonamide homologues of Formula (I) can inhibit a) biosynthesis of aromatic amino acids and b) metabolism of quinic acid via the chymate pathway, wherein Ar is an aryl or heteroaryl group; R ₁ and R ₂ are the same or different and each represents hydrogen or alkyl or R ₁ and R ₂ together form a C ₁ -C ₃ alkylene group, -CO- or -CS-; R ₃ and R ₄ are the same or different and each is -alkyl-aryl, -alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl, -alkynyl-heteroaryl, aryl or Heteroaryl.

Formula I

Description

Enzyme inhibitor {ENZYME INHIBITORS}

Dehydroquinate synthetases and dehydroquinase enzymes form an integral part of the chymate pathway in which erythrose-4-phosphate is converted to aromatic amino acids such as tryptophan, tyrosine and phenylalanine. Two types of biosynthetic dehydroquinases, type 1 or AroD variants and type 2 or AroQ variants, have been characterized (Garbe et al, Mol. Gen. Genet., 228, pgs 385-392 (1991), Hawkins et al, J. Gen. Microbiol. 139, pgs 2891-2899 (1993)).

Succimate pathways are essential in bacteria, algae, fungi and higher plants. In addition, recent studies have shown evidence of the presence of enzymes in the schimate pathway in Apicomplexa parasites (Roberts et al, Nature, 393, 1998, pgs 801-805). Thus, compounds that can inhibit the biosynthesis of amino acids via the chymate pathway are variously applied commercially.

In addition to their biosynthetic function, dehydroquinase enzyme type 2 forms an important part of the catabolism pathway in which quinic acid catabolism occurs. This catabolic pathway is found in many fungi and bacteria. Thus inhibitors of dehydroquinase enzyme type 2 are commercially applied as fungicides and antibiotics.

Many diaminobissulfonamides are known. For example, J. Chem. Soc., 1161 (1970) describes the synthesis of many of these compounds as intermediates to tetrahydrodibenzodiazotines, and J. Chem. Soc., 1170 (1962) describes an electrophilic substitution reaction involving diaminobissulfonamides. However, pharmaceutical utility has not been described in these publications. 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)).

It has already been thought that oncolytic activity belongs to some diaminobissulfonamides (J. Med. Che., 599 (1963)). Oncolytic activity has been shown to act through the inhibition of biosynthetic conversion of 1,2-dimethyl-4,5-diaminobenzene to vitamin B ₁₂ by certain types of tumor cells (Biochem. Pharmacol., 1163 (1962). )).

The present invention relates to a series of bissulfonamide analogs that act as inhibitors of dehydroquinate synthetase and dehydroquinase enzyme type 2.

It has now been surprisingly found that certain bissulfonamide homologues of the formula (I) detailed above serve as inhibitors of dehydroquinate synthase and inhibitors of dehydroquinase enzyme type 2. Accordingly, the present invention provides, in a first aspect, the use of a bissulfonamide homologue of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in inhibiting biosynthesis of aromatic amino acids via the chymate pathway.

In the above formula,

Ar is an aryl or heteroaryl group;

R ₁ and R ₂ are the same or different and each represents hydrogen or alkyl or R ₁ and R ₂ together form a C ₁ -C ₃ alkylene group, -CO- or -CS-;

R ₃ and R ₄ are the same or different and each is -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 dehydroquinate synthase, in particular AroB and / or dehydroquinase enzyme type 2, in particular AroQ.

As used herein, an alkyl group or moiety is typically a straight or branched chain alkyl group or moiety having 1 to 6 carbon atoms, such as a C ₁ -C ₄ alkyl group or moiety, for example methyl, ethyl, n-propyl, i -Propyl, n-butyl, i-butyl and t-butyl.

Alkyl groups or moieties may be unsubstituted or substituted at any position. Typically, they are unsubstituted or have one or two substituents. Suitable substituents include halogen, cyano, nitro, amino, hydroxy, oxo and -CO ₂ R, -SOR and -S (O) ₂ R, wherein R is hydrogen or alkyl.

As used herein, alkenyl groups or moieties are typically straight or branched chain alkenyl groups or moieties having 2 to 6 carbon atoms such as C ₂ -C ₄ alkenyl groups or moieties such as ethenyl, propenyl and Butenyl.

Alkenyl groups or residues may be unsubstituted or substituted at any position. Typically, they are unsubstituted or have one or two substituents. Suitable substituents include halogen, amino and hydroxy.

As used herein, an alkynyl group or moiety is a straight or branched chain alkynyl group or moiety having 2 to 6 carbon atoms, such as a C ₂ -C ₄ alkynyl group or moiety, for example ethynyl, propynyl and butynyl to be.

Alkynyl groups or residues may be unsubstituted or substituted at any position. Typically, they are unsubstituted or have one or two substituents. Suitable substituents include halogen, amino and hydroxy.

C ₁ -C ₃ alkylene groups are methylene, ethylene or propylene groups. They may be unsubstituted or substituted at any position. Typically, they are unsubstituted or have one substituent. Suitable substituents include halogen, cyano, nitro, oxo and -CO ₂ R, -SOR and -S (O) ₂ R, wherein R is hydrogen or alkyl.

As used herein, aryl groups are typically C ₆ -C ₁₀ aryl groups such as phenyl or naphthyl. Phenyl is preferred. Aryl groups may be unsubstituted or substituted at any position. Typically, they have 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, -CO ₂ R and -S (O) ₂ R, wherein R is aryl, heteroaryl, hydrogen or alkyl, -CONR'R ", wherein R 'and R" are the same or different and each is aryl, hetero Aryl, 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 represents —CO—L where aryl, heteroaryl, hydrogen, alkyl or L is an alkyl or aryl group) and —OZR ″ ″ ′ ′ where Z is as described above and R ″ ″ ′ is aryl, heteroaryl Or heterocyclyl).

Typically, in the residue -S (O) ₂ R, R is hydrogen or alkyl. Typically, at the residues -Z-NR "'R""and-NR"' R "", R "'and 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, eg methyl. Typically, the residues "OZR""'inR""' are heteroaryl, for example thiazolyl.

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 oxdiazolyl. Other preferred substituents include nitro, hydroxy, halogen such as chlorine, bromine and fluorine, C ₁ -C ₄ haloalkyl such as -CF ₃ and -CCl ₃ , C ₁ -C ₄ alkyl, -CO ₂ R (where R is hydrogen or C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, for example -OCCl ₃ and -OCF ₃ , -S (O) ₂ -C ₁ -C ₄ alkyl, -CONR'R ", wherein R 'and R" are the same or different and are heteroaryl, preferably aryl, hydrogen or C ₁ -C ₄ alkyl, -NR "' R ″ ″ (where R ″ ′ and R ″ ″ are the same or different and each represents hydrogen, alkyl or —CO-alkyl) and —O-alkyl-R ″ ″ ′ ′ where R ″ ″ ′ Is heteroaryl, for example thiazolyl).

The substituents themselves are preferably unsubstituted or substituted by one or more further substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy and hydroxy. do. Typically, such additional substituents themselves are not substituted.

The aryl group can be optionally fused to additional aryl groups or carbocyclic, heterocyclic or heteroaryl groups. For example, they are fused to a pyridine ring to form a quinoline group and fused to a thiadiazole ring such as 1,2,5-thiadiazole ring to isobenzo [1,2,5] -thiadiazole. May form a group or be fused to a 1,4 dioxane or 1,3 dioxolane ring.

As used herein, heteroaryl groups are typically 5- to 10-membered aromatic rings, such as 5- or 6-membered rings containing at least one heteroatom selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadizolyl, isoxazyl, thiadiazolyl, thiazolyl, imidazolyl and pyrazolyl Groups are included. Thienyl groups are preferred. Heteroaryl groups may be unsubstituted or substituted at any position. Typically, it has 1, 2 or 3 substituents. Suitable substituents include aryl, for example phenyl, carbocyclyl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy , -CO ₂ R and S (O) ₂ R, wherein R is aryl, heteroaryl, hydrogen or alkyl, -CONR'R ", where R 'and R" are the same or different and each 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 represents -CO-L wherein aryl, heteroaryl, hydrogen, alkyl or L is an alkyl or aryl group; and -OZR ""'"wherein Z is as described above and R""' is aryl, Heteroaryl or heterocyclyl).

Typically, in the residue -S (O) ₂ R, R is hydrogen or alkyl. Typically, at the residues -Z-NR "'R"",R"' and 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, eg methyl. Typically, R""' at residue -OZR""'is heteroaryl, For example thiazolyl.

Preferred aryl substituent is phenyl. Preferred heteroaryl and heterocyclic substituents are 5 or 6 membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S. Examples include 5 or 6 membered rings containing 1, 2 or 3 heteroatoms, for example isoxazolyl, pyridyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl and thiadiazolyl. Included. Other preferred substituents include nitro, halogen such as chlorine, bromine and fluorine, C ₁ -C ₄ haloalkyl such as -CF ₃ and -CCl ₃ , C ₁ -C ₄ alkyl, -CO ₂ R (here R is hydrogen or C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, -S (O) ₂ -C ₁ -C ₄ alkyl and-(C ₁ -C ₄ alkyl) -NR "'R "" Where R "'and R""are the same or different and each represents hydrogen, alkyl or -CO-aryl, eg -CO-phenyl.

The substituents themselves are preferably unsubstituted or substituted by one or more further substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy and hydroxy. do. Typically, these additional substituents themselves are not substituted.

Heteroaryl groups can be optionally fused to aryl groups, additional heteroaryl groups, or heterocyclic or carbocyclic groups. Examples of such fused heteroaryl groups include, for example, thiophene rings fused to imidazolyl groups.

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

As used herein, an alkoxy group is typically an alkyl group bonded to an oxygen atom. Alkylthio groups are typically alkyl groups bonded with thio groups. Haloalkyl or haloalkoxy groups are typically alkyl or alkoxy groups substituted by one or more halogen atoms. Usually, it is substituted by 1, 2 or 3 halogen atoms. Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX ₃ and -OCX ₃ , where X is a halogen atom. Particularly preferred haloalkyl groups are CF ₃ and CCl ₃ . Particularly preferred haloalkoxy groups are -OCF ₃ and -OCCl ₃ .

As used herein, carbocyclic groups are usually non-aromatic saturated or unsaturated hydrocarbon rings of 3 to 6 carbon atoms. Preferably they are saturated hydrocarbon rings having 3 to 6 carbon atoms (ie cycloalkyl groups). Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferably cyclohexyl. Carbocyclic groups may be unsubstituted or substituted at any position. Suitable substituents include nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO ₂ R and —S (O) ₂ R where R is hydrogen or alkyl, cyano, and —NR′R ″ and —CONR′R ″, where R ′ and R ″ are the same or different and Each represents hydrogen or alkyl) Preferred substituents include halogen such as nitro, chlorine, bromine or fluorine, C ₁ -C ₄ haloalkyl such as -CF ₃ and -CCl ₃ , C ₁ -C ₄ alkyl, -CO ₂ R, wherein R is hydrogen or C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy such as -OCCl ₃ and -OCF ₃ and -S ( O) ₂ -C ₁ -C ₄ alkyl The substituents themselves are usually unsubstituted.

As used herein, a heterocyclic group is typically a non-aromatic saturated or unsaturated C ₅ -wherein one, two or three carbon atoms are replaced by a heteroatom selected from N, O and S. C ₁₀ carbocyclic ring. Saturated heterocyclic groups are preferred. Examples of suitable heterocyclic groups include piperidine, morpholine, 1,4 dioxane and 1,3 dioxolane.

Heterocyclic groups may be unsubstituted or substituted at any position. Suitable substituents include nitro, halogen, alkyl such as haloalkyl, alkylthio, alkoxy such as haloalkoxy, hydroxy, -CO ₂ R and -S (O) ₂ R, wherein R is hydrogen or Alkyl), cyano and -NR'R "and -CONR'R", wherein R 'and R "are the same or different and each represents hydrogen or alkyl. Preferred substituents are nitro, chlorine , Halogen such as bromine or fluorine, C ₁ -C ₄ haloalkyl such as -CF ₃ and -CCl ₃ , C ₁ -C ₄ alkyl, -CO ₂ R (where R is hydrogen or C ₁ -C ₄ alkyl C ₁ -C ₄ alkoxy and —S (O) ₂ —C ₁ -C ₄ -alkyl, wherein the substituents themselves are usually unsubstituted.

Typically, the groups -NR ₁ S (O) ₂ R ₃ and -NR ₂ S (O) ₂ R ₄ combine with an adjacent carbon atom at an Ar residue. If Ar is a heteroaryl group they are usually pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl groups. Preferably, Ar is an aryl group, in particular a phenyl group or a naphthyl group. It is usually unsubstituted or has 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents. Preferred substituents include aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO ₂ R (here, R is aryl, heteroaryl, preferably hydrogen or alkyl) and -NR'R "and -CONR'R", where R 'and R "are the same or different and are aryl, heteroaryl, hydrogen or alkyl Such substituents are preferably unsubstituted or one or more additional selected from nitro, cyano, halogen, alkyl, such as haloalkyl, alkylthio, alkoxy, such as haloalkoxy and hydroxy. Substituents are typically substituted by such additional substituents themselves.

Typically, at least one of R 'and R "at residues -NR'R" and -CONR'R "is hydrogen or alkyl. Preferred aryl substituents are phenyl. Preferred heteroaryl and heterocyclic substituents are N, O and 5- or 6-membered heteroaryl or heterocyclic group containing 1, 2 or 3 heteroatoms selected from S, for example an oxadizolyl group. Further preferred substituents of the group Ar are hydroxyl, Halogen, such as nitro, cyano, chlorine, fluorine and bromine, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkyl, -CO ₂ R (where R is hydrogen or C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy and —CONR′R ″, wherein R ′ and R ″ are the same or different and are aryl, heteroaryl, hydrogen or C ₁ -C ₄ alkyl.

If Ar is an aryl group fused to an aryl, cycloalkyl, heterocyclic or heteroaryl group, they are usually fused to the above heterocyclic group. Preferably, they are fused to saturated heterocyclic groups containing two oxygen atoms as heteroatoms, for example 1,4 dioxane or 1,3 dioxolane.

More preferably, Ar is a group of formula Ar '.

In the above formula,

R ₅ to R ₈ are the same or different and are aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO ₂ R (where R is aryl, heteroaryl, hydrogen or alkyl) or -NR'R "or -CONR'R" (where R 'and R "are the same or different and aryl, heteroaryl, hydrogen Or R ₅ and R ₆ or R ₆ and R ₇ or R ₇ and R ₈ together form an alkylenedioxy group or together with the carbon atom to which they are attached form a phenyl moiety.

Typically, R ₅ to R ₈ are the same or different and are cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO ₂ R (wherein R is aryl, heteroaryl, hydrogen or alkyl), or -NR'R "or -CONR'R" (where R 'and R "are the same or different and are aryl, heteroaryl, hydrogen or alkyl) Or R ₅ and R ₆ or R ₆ and R ₇ or R ₇ and R ₈ together form an alkylenedioxy group or together with the carbon atom to which they are attached form a phenyl moiety.

Typically, in the residue —CO ₂ R, R is hydrogen or alkyl. Typically, R 'and R "at the residues -NR'R" are the same or different and are hydrogen or alkyl. Typically, R 'and R "at the residues -CONR'R" are the same or different and are hydrogen, alkyl or aryl.

Typically, R ₅ and R ₈ are the same or different and are hydrogen, halogen such as bromine, alkyl, hydroxy, alkoxy, or -NR'R ", where R 'and R" are the same or different and hydrogen Or alkyl, wherein R ₆ and R ₇ are the same or different and are hydrogen, halogen, for example bromine, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, heterocyclyl, nitro, cya Furnace, halogen, alkyl, for example haloalkyl, alkoxy, for example haloalkoxy, alkylthio, hydroxy, -CO ₂ R (where R is aryl, heteroaryl, hydrogen or alkyl) or -NR ' R ″ or —CONR′R ″ (where R ′ and R ″ are the same or different and are aryl, heteroaryl, hydrogen or alkyl), or R ₆ and R ₇ together represent methylenedioxy or ethylenedioxy Form an alkylenedioxy group such as a group or together with the carbon atoms to which they are attached It forms a carbonyl moiety.

Typically, R ₅ and R ₈ 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 R ₆ and R ₇ are the same or different and are hydrogen, nitro, cyano, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -CO ₂ R, wherein R is aryl, heteroaryl, hydrogen Or -NR'R "or -CONR'R", wherein R 'and R "are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R ₆ and R ₇ are Together they form alkylene dioxy groups such as methylenedioxy or ethylenedioxy groups, or together with the carbon atoms to which they are attached form a phenyl moiety.

Typically, R ′ and R ″ in the —NR′R ″ residues are the same or different and are hydrogen or alkyl. Typically at the residues -CONR'R ", R 'and R" are the same or different and are hydrogen, alkyl or aryl.

Preferably, at least one of R ₅ and R ₈ is hydrogen. More preferably, at least one of R ₅ and R ₈ is hydrogen and the other is halogen or, preferably hydrogen or hydroxy. More preferably both R ₅ and R ₈ are hydrogen.

Typically, R ₅ to R ₈ are unsubstituted or substituted with one or more additional substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy and hydroxy. It is substituted by. Typically, such additional substituents themselves are not substituted.

Preferably, R ₆ and R ₇ are hydrogen, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, nitro, cyano, alkyl, alkoxy, haloalkyl, halogen, -CO ₂ H, -CO ₂ -alkyl or -CONR'R ", wherein R 'and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R ₆ and R ₇ together are alkylenedioxy group or phenyl To form residues. More preferably, R ₆ and R ₇ are hydrogen, heteroaryl, for example halogen, such as C ₁ -C ₄ alkyl such as oxadiazolyl, nitro, cyano, methyl or ethyl, chlorine, fluorine or bromine,- -CO _2- (C ₁ -C ₄ alkyl), such as CO ₂ -Et and -CO ₂ -Me, C ₁ -C ₄ alkoxy or -CONR'R ", such as -OMe, wherein R 'and R" Represents the same or different and heteroaryl or, preferably aryl, for example phenyl, hydrogen or C ₁ -C ₄ alkyl), or R ₆ and R ₇ together with the carbon atom to which they are attached Form. More preferably, R ₆ and R ₇ are the same or different and are hydrogen, oxadiazolyl, chlorine, fluorine, bromine, nitro, cyano, methyl, methoxy, -CO ₂ H, -CO ₂ Et, -CO ₂ Me, -CONH ₂ , -CONHMe and -CONMe ₂ , -CONH-phenyl, -CONH- (4-trifluoromethoxyphenyl) or -CONH- (3,5-dimethoxyphenyl) or R ₆ and R ₇ together with the carbon atom to which they are attached form an additional phenyl moiety.

If R ₁ and / or R ₂ are alkyl groups they are usually unsubstituted alkyl groups. Preferably, R ₁ and R ₂ are the same or different and are hydrogen or alkyl or R ₁ and R ₂ together form a C ₁ -C ₃ alkylene group. More preferably, both R ₁ and R ₂ are hydrogen.

Typically, R ₃ and R ₄ are not simultaneously -alkynyl-aryl or -alkynyl-heteroaryl groups. Preferred - alkyl-aryl and a-alkyl-heteroaryl group is - (C ₁ -C ₄ -alkyl) -aryl and - (C ₁ -C ₄ alkyl) - heteroaryl group, for example, such as a benzyl group, - (C _1- C ₄ alkyl) -phenyl group. Preferred -alkenyl-aryl and -alkenyl-heteroaryl groups are-(C ₂ -C ₄ alkenyl) -aryl and-(C ₂ -C ₄ alkenyl) -heteroaryl groups such as -ethenyl- -Ethenyl-aryl group such as phenyl group.

Typically, R ₃ and R ₄ are the same or different and each represents 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.

If R ₃ or R ₄ contains an aryl or heteroaryl moiety fused to an aryl, cycloalkyl, heterocyclic or heteroaryl group, they are usually fused to the heterocyclic group or heteroaryl group above. Examples of such fusion groups include (1,2-cyclo (3-thioethyl) -imidazoyl, benzothienyl, indole and quinoline groups, with quinoline groups being preferred.

Typically, R ₃ and R ₄ are unsubstituted or have 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents. Preferred substituents include aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S (O) ₂ -alkyl, haloalkoxy, cyano, -CO ₂ R 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 is aryl, heteroaryl, hydrogen, alkyl or L is alkyl Or an aryl group -CO-L) and -OZR ""'"wherein Z is as described above and R""' is aryl, heteroaryl or heterocyclyl.

Typically, Z in the above residues is alkyl, eg methyl. Typically, in the residues -Z-NR "'R" "and -NR"' R "", R "'and 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, the residues "O-Z-R" "'to R" "' are heteroaryl, for example thiazolyl.

More typically, R ₃ and R ₄ are unsubstituted or substituted with aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S (O) ₂ -alkyl, haloalkoxy, cyano, -CO ₂ R (where R is aryl, heteroaryl, hydrogen or alkyl), alkoxy, hydroxy and -NR'R "and -CONR'R", where R 'and R "are the same or different and aryl, Heteroaryl, hydrogen or alkyl), preferably 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents.

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 such as pyridyl, isoxazolyl, thiadizolyl, thiazolyl, isothiazolyl and pyrazolyl. Other preferred substituents include methyl, ethyl, n- propyl, i- propyl or t- butyl and like C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, halogen, nitro, cyano, C _1, such as methoxy -C ₄ alkoxy, -S (O) ₂ -C ₁ -C ₄ alkyl, -NR "'R"", where R"' and R "" are the same or different and each is hydrogen, C ₁ -C ₄ Alkyl or —CO— (C ₁ -C ₄ alkyl)), — (C ₁ -C ₄ alkyl) —NR ″ ′ R ″ ″, where R ″ ′ and R ″ ″ are the same or different and each Hydrogen, C ₁ -C ₄ alkyl or -CO-aryl, for example -CO-phenyl, and -O- (C ₁ -C ₄ alkyl) -R ""'", wherein R""' Heteroaryl, for example thiazolyl).

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

The substituents themselves are preferably unsubstituted or substituted by one or more further substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy and hydroxy. do. Typically, such additional substituents themselves are not substituted.

Further preferred compounds of the invention are compounds of formula la.

In the above formula,

R ₅ to R ₈ are the same as described above in Formula Ar ',

X and Y are the same or different and represent phenyl or thienyl,

n represents an integer of 0 to 4 if X is phenyl, and an integer of 0 to 3 if X is thienyl,

m represents an integer of 0 to 4 if Y is phenyl, and an integer of 0 to 3 if Y is thienyl,

R ₃ ′ and R ₄ ′ are the same or different and are aryl, heteroaryl and heterocyclic groups, alkyl, for example haloalkyl, halogen, nitro, —S (O) ₂ -alkyl, alkoxy, for example haloalkoxy , Cyano, -CO ₂ R, wherein R is aryl, heteroaryl, hydrogen or alkyl, hydroxy, -CONR'R ", where R 'and R" are the same or different and aryl, hetero Aryl, 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 is aryl , Heteroaryl, hydrogen, alkyl or L represents -CO-L, which is an alkyl or aryl group, or -OZR ""'"wherein Z is as described above and R""' represents aryl, heteroaryl or heterocycle Reel).

Typically, Z in the above residues is alkyl, eg methyl. Typically, at the residues -Z-NR "'R" "and -NR"' R "", R "'and 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, the residues "O-Z-R" "'to R" "' are heteroaryl, for example thiazolyl.

Typically, R ₃ ′ and R ₄ ′ are the same or different and heteroaryl and heterocyclic groups, alkyl, for example haloalkyl, halogen, nitro, —S (O) ₂ -alkyl, alkoxy, for example halo Alkoxy, cyano, -CO ₂ R (where R is aryl, heteroaryl, hydrogen or alkyl), hydroxy and -NR'R "and -CONR'R" (where R 'and R "are The same or different and aryl, heteroaryl, hydrogen or alkyl.

Preferred compounds of formula 1a are those wherein one of R ₅ and R ₈ is hydrogen and the other is hydrogen, halogen or hydroxy, or both R ₅ and R ₈ are hydrogen, and R ₆ and R ₇ are the same or different and are aryl, eg For example phenyl, heteroaryl, for example oxadiazolyl, nitro, cyano, alkyl, for example methyl and ethyl, haloalkyl, halogen, for example chlorine, fluorine and bromine, hydrogen, -CO ₂ H,- CO ₂ -alkyl, for example -CO ₂ -Et and -CO ₂ -Me, alkoxy, for example methoxy and CONR'R ", wherein R 'and R" are the same or different and heteroaryl, or Preferably aryl, hydrogen or alkyl), or R ₆ and R ₇ together form an alkylenedioxy group such as methylenedioxy or ethylenedioxy group, or together with the carbon atom to which they are attached a further phenyl moiety Form, X and Y are the same or different and are phenyl or thi Nyl, n and m are the same or different and are 0, 1 or 2 and R ₃ 'and R ₄ ' are the same or different and are selected from:

(a) when combined with a phenyl moiety, aryl, for example phenyl, C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, i-propyl or t-butyl, C ₁ -C ₄ haloalkyl For example CCl ₃ and CF ₃ , halogen, for example chlorine, fluorine and bromine, nitro, cyano, C ₁ -C ₄ alkoxy, for example methoxy, —CO ₂ R, wherein R is hydrogen Or C ₁ -C ₄ alkyl, -NR'R ", wherein R 'and R" are the same or different and are hydrogen, C ₁ -C ₄ alkyl or -CO- (C ₁ -C ₄ alkyl) , -O- (C ₁ -C ₄ alkyl) -R "'(here,R"' is a heteroaryl, for example, thiazolyl or heterocyclyl) and -S (O) ₂ -C ₁ -C ₄ alkyl; and

(b) when combined with thienyl moieties, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, halogen such as nitro, chlorine, bromine or fluorine, C ₁ -such as CF ₃ and CCl _3; C ₁ -C ₄ alkyl, such as C ₄ haloalkyl, methyl, ethyl, n-propyl, i-propyl or t-butyl, —CO ₂ R, wherein R is hydrogen or C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, such as methoxy,-(C ₁ -C ₄ alkyl) -NH-aryl, for example-(C ₁ -C ₄ alkyl) -NH-phenyl and -S (O) ₂ -C ₁ -C ₄ alkyl.

Typically, in these preferred compounds, R ₆ and R ₇ are the same or different and halogen, such as alkyl, haloalkyl, chlorine, fluorine or bromine, hydrogen, -CO ₂ -Et and -CO ₂ , such as nitro, methyl or ethyl -CO ₂ -alkyl such as -Me, alkoxy such as methoxy and -CONR'R ", wherein R 'and R" are the same or different and are aryl, heteroaryl, or preferably hydrogen or alkyl Or R ₆ and R ₇ together form an alkylenedioxy group, such as methylenedioxy or ethylenedioxy group, or together with the carbon atom to which they are attached form an additional phenyl moiety. Typically, when combined with a phenyl moiety, R ₃ ′ and R ₄ ′ are C ₁ -C ₄ alkyl, for example methyl, ethyl, n-propyl, i-propyl or t-butyl, C ₁ -C ₄ Haloalkyl, for example CCl ₃ and CF ₃ , halogen, for example chlorine, fluorine and bromine, nitro, C ₁ -C ₄ alkoxy, for example methoxy and -S (O) ₂ -C ₁ -C ₄ Selected from alkyl. Typically, when combined with thienyl moieties, R ₃ ′ and R ₄ ′ are isoxazolyl, isothiazolyl, pyrazolyl, nitro, halogen such as chlorine, bromine and fluorine, C ₁ -C ₄ halo Alkyl such as -CF ₃ and -CCl ₃ , C ₁ -C ₄ alkyl such as methyl, ethyl, n-propyl, i-propyl and t-butyl, -CO ₂ R wherein R is hydrogen Or C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy, for example methoxy and -S (O) ₂ -C ₁ -C ₄ alkyl.

Particularly preferred compounds of formula (Ia) are those in which R ₅ and R ₆ are hydrogen, R ₆ and R ₇ are the same or different and are hydrogen, oxadiazolyl, chlorine, fluorine, bromine, nitro, cyano, methyl, methoxy, _{In 2} Et, -CO ₂ Me, -CONH ₂ , -CONHMe, -CONMe ₂ , -CONH-phenyl, -CONH- (4-trifluoromethoxyphenyl) and -CONH- (3,5-dimethoxyphenyl) Or together with the carbon atom 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, R ₃ ′ and R ₄ 'Is the same or different and is methyl, ethyl, i-propyl, chlorine, fluorine, bromine, methoxy, trifluoromethoxy, nitro, cyano, -S (O) ₂ Me, -CO ₂ H, -NH-CO _{-CH 3, -O-CH 2 -} (2- chloro-thiazolyl), and (X and Y is a thienyl) pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, and -CH ₂ -NH- R, wherein R is phenyl or 4-chlorophene A) are those selected from.

More preferred compounds of the present invention are compounds of formula Ib and salts thereof.

In the above formula,

R ₃ and R ₄ are the same or different and (a) halogen, for example chlorine, C ₁ -C ₄ alkyl, for example methyl, C ₁ -C ₄ haloalkyl, for example -CF ₃ or C _1- Phenyl optionally substituted by C ₄ haloalkoxy such as -OCF ₃ and (b) halogen such as chlorine, C ₁ -C ₄ alkyl such as methyl, C ₁ -C ₄ haloalkyl, for example For example -CF ₃ and C ₁ -C ₄ haloalkoxy, for example thienyl optionally substituted by -OCF ₃ ,

R ₆ is halogen such as chlorine and fluorine or C ₁ -C ₄ haloalkoxy such as -CF ₃ and -CCl ₃ .

Compounds of formula (I) containing one or more chiral centers can be used in the form of pure enantiomers or diastereomers or in the form of mixtures of isomers.

Typically, when a compound of the present invention is used as an antimicrobial agent, for example to inhibit a Staphylococcus aureus strain other than MRSA, R ₃ and R ₄ are not phenyl groups substituted by amino groups in the para position. . More typically, R ₃ and R ₄ in these compounds are not 4-aminophenyl or 4-nitrophenyl groups. Preferably, R ₃ and R ₄ in these compounds are not aminophenyl groups.

Preferably, if R ₃ and R ₄ are simultaneously a phenyl group substituted by a C ₁ -C ₄ alkyl group such as a methyl group in the para position, then Ar is R ₅ , R ₇ and R ₈ as described above and R ₆ is -CO _2, such as C ₁ -C ₄ alkyl or -CO ₂ -Et such as methyl- not a group of formula Ar 'is (C ₁ -C ₄ alkyl).

As used herein, pharmaceutically acceptable salts are salts with pharmaceutically acceptable acids or bases. Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid and citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid Organic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metals (eg sodium or potassium) and alkaline earth metals (eg 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-methylphenylsulfonamido) -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) -naphthalene

1,2-bis [2- (3-oxazolyl) -5-thienylsulfonylamino) -naphthalene

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-trifluoromethylphenylsulfonylamino) naphthalene

2,3-bis (2,4-difluorophenylsulfonylamino) 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 (3,5-dimethyl-3-oxazoylsulfonylamino) naphthalene

2,3-bis (2-aza-4,5-benzothiazoylsulfonylamino) naphthalene

2,3bis (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-dimethylbenzene

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

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

1,2-bis (2-methyl-5-nitrophenylsulfonylamino) -4,5-dimethylbenzene

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-thienylsufonylamino) -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-2-methoxyphenylsulfonylamino) -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 (2,6-difluorophenylsulfonylamino) -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) -4,5-dibromobenzene

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

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

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

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

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

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

3,4-bis (4-isopropylphenylsulfonylamino) -benzoic acid methyl ester

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-trifluolmethylphenylsulfonylamino) -benzene

1,2-bis (benzylsulfonylamino) -4,5-difluorobenzene

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 ethyl ester

And salts thereof, especially pharmaceutically acceptable salts thereof.

Particularly effective compounds 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 their pharmaceutically acceptable salts.

Certain bissulfonamide homologues of formula (I) are themselves novel. Such compounds are bissulfonamides of formula Id and salts thereof.

In the above formula,

R ₁ , R ₂ , R ₃ and R ₄ are as described above;

Ar is a group of the formula Ar 'as described above, provided that R ₁ and R ₂ are both hydrogen and Ar is an unsubstituted naphthyl group, a phenanthracene group or 1 or 2 dimethylmethylenedioxy, hydroxy, If it is a phenyl group optionally substituted by methoxy, ethoxy, methyl, chlorine, bromine, fluorine, nitro, CF ₃ or an amino group, then R ₃ and R ₄ are (a) an unsubstituted quinoline group, (b) an unsubstituted phenyl Phenyl group monosubstituted by a group, (c) methyl, methoxy, -CO ₂ H, chlorine, cyano, nitro or amino group or group -O-CO-N (CH ₃ )-or (d) nitro group And phenyl groups which are disubstituted by methyl groups.

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

Preferred novel compounds of the present invention are as described above, wherein R ₁ and R ₂ are both hydrogen and Ar is unsubstituted naphthyl group, phenanthracene group or 1 or 2 C ₁ -C ₄ alkylenedioxy, hydroxy, If C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, halogen, nitro, C ₁ -C ₄ haloalkyl or a phenyl group optionally substituted by an amino group, then R ₃ and R ₄ are unsubstituted quinoline groups or C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, -CO ₂ R (where R is hydrogen or C ₁ -C ₄ alkyl), a group consisting of halogen, cyano, nitro and amino groups and the formula -O- Bissulfonamides of the formula Id and salts thereof, which are not phenyl groups optionally substituted by one or two groups selected from CO-N (C ₁ -C ₄ alkyl) groups.

Compounds of formula (I) may be prepared by a process comprising the step of reacting a compound of formula (II) with a compound of formula (III).

In the above formula,

Ar, R ₁ , R ₂ , R ₃ and R ₄ are as described above,

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 formula (II) and (III) are used.

Compounds of formula (II) can be prepared by reacting compounds of formula (IV) with compounds of formula (V).

In the above formula,

Ar, R ₁ , R ₂ , R ₃ and X are as described 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 the compounds of formulas IV and V are used.

Compounds of formula (I) wherein R ₃ and R ₄ are identical may, of course, be prepared by reacting 2 molar equivalents of compound of formula (IV) with compound of formula (III) under the reaction conditions detailed above.

Preferably the solvent used in the above reaction is acetonitrile or dichloromethane and the reaction takes place in the presence of pyridine or 4-dimethylaminopyridine.

Alternatively, compounds of formula II wherein Ar, R ₁ and R ₃ are as described above and R ₂ is hydrogen can also be prepared by reaction of a compound of formula VI with a suitable reducing agent.

In the above formula,

Ar, R ₁ and R ₃ are as described above.

Typically the reducing agent is palladium on carbon with tin hydrazine hydrate in alkaline solution, tin (II) chloride, platinum on carbon or ferric chloride with hydrogen gas. Preferably the reducing agent is palladium on carbon with tin (II) chloride or 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) may be prepared by reaction of compounds of formula (VII) with compounds of formula (V).

In the above formula,

Ar and R ₁ are as described 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 the compounds of formulas IV and V are used.

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

The bissulfonamide homologue of formula (I) thus obtained can be chlorided by treatment with a suitable acid or base.

Compounds of formula III, IV, V, VI and VII are known compounds or may be prepared analogously to known methods.

Compounds of formula I have been found to be inhibitors of dehydroquinate synthetases, in particular AroB and dehydroquinase enzyme type 2, in particular AroQ.

As mentioned above, dehydroquinate synthetase invariably forms an integral part of the chymate pathway. In addition, dehydroquinase enzyme type 2 is included in the schimate pathway of many organisms. Dehydroquinase enzyme type 2 also forms an important part of the catabolism pathway in which quinic acid catabolism occurs. The compounds of the present invention are particularly active against organisms in which the chymate pathway comprises dehydroquinase enzyme type 2 and organisms using both the chymate and quinic acid catabolic pathways. This is because they have targets of two enzymes in these organisms.

The present invention therefore provides a method of treating a patient in need of an inhibitor of aromatic amino acid biosynthesis via the chymate route comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The succinic acid pathway is essential for the synthesis of aromatic amino acids in fungi and bacteria. Thus, the compounds of the present invention are effective in the treatment or prevention of bacterial or fungal infections. Indeed, the compounds of the present invention are effective against many bacteria that have developed resistance to conventional antibiotics. For example, they are effective against methicillin resistant Staphylococcus aureus (MRSA). Thus, such agents are commonly used for the treatment or prophylaxis of bacterial or fungal infestations, and such patients are typically susceptible to or prone to invading bacteria or fungi. In particular, such patients typically suffer from or are susceptible to MRSA infections, and such agents are commonly used for the prevention or treatment of MRSA infections.

The genes encoding dehydroquinase type 2 are actinobacillus pluronymonia, actinobacillus actinomycete, aeromonas salmonicida, strain salmonicida, amycotopis mediterrani, and Bacillus subtilis. , Corynebacterium glutamisium, Corynebacterium spp. Tuberculosis, Emerisella nidulans, Hemophilus influenza, Helicobacter philoly, Neuroslopa Krasa, Pseudomonas aeruginosa, Streptomyces coelicolor, Streptose Mrs. Lavendula, Cynecosistis Species, Thermomotoga Meritima, Campylobacter jejuni, Clostridium acetobutylicum, Popiromomas ginjivalis, Deinococcus radiodurans, Chlorium tepidium, Vibrio cholera , Yexinia Festis, Shiwanella Putrafaciens, Tiobacilli Peroxidans, Cynecosistis PCC6803, Candida Albicans, Bode La pertussis, Mycobacterium father ium, Mycobacterium tuberculosis Tudor beokyul, Mycobacterium Bovis, Mycobacterium Le Prado, was observed in seven sen bakteo tooth and keulrep when Ella pneumoniae as a cowl.

The compounds of the present invention are particularly active against such organisms. This is because, as mentioned above, the compounds of the present invention act to inhibit both dehydroquinate synthase and dehydroquinase enzyme type 2 in these organisms. Thus, such agents are commonly used to treat or prevent invasion by one of the organisms, and the patient is typically susceptible to or invasion of one of the organisms.

The compounds of the present invention can also be used to generally prevent bacterial growth. For example, they can be added to a solution such as a contact lens solution to prevent bacterial growth. They can also be used in products such as antibiotic coatings of surgical instruments and medicated soaps. Thus, the present invention also provides non-therapeutic use of the compounds of the invention in the inhibition of bacterial growth. Also provided are contact lens solutions or medicated soaps comprising the compounds of the present invention. In addition, the present invention provides a surgical instrument having an antibiotic coating comprising a compound of the present invention.

Shiki acid pathways are also involved in parasite metabolism. For example, it is included in the treatment of apiplex complex parasites. Thus, the compounds of the present invention are effective in the treatment or prevention of infection by parasites where the biosynthesis of aromatic amino acids occurs via the sikimic acid pathway. Such parasites, for example, observe whether (a) in vitro growth is inhibited by well-defined inhibitors of chymate pathways such as glyphosate, and (b) such inhibition is converted by the addition of p-aminobenzoate. It can be identified by observing if it is. Parasites in which growth in vitro is inhibited by glyphosate and this inhibition is converted by the addition of p-aminobenzoate uses the shammate pathway in their metabolism. Thus the compounds of the present invention will be active against these parasites.

In particular, the compounds of the present invention are active against apicomplexa parasites such as toxoplasma gondi, Cryptosporidium parboom and plasmodium fociparum. Plasmodium fociparum is known to cause malaria. Therefore, the above patients usually suffer from or are susceptible to infection by the Apicomplexa parasites, and the medicament is usually used for the treatment or prevention of infections by the Apicomplexa parasites. In particular, such patients are usually susceptible to or susceptible to malaria, and such agents are commonly used for the treatment or prevention of malaria.

When used to treat such disorders, the compounds of the present invention can be administered in a variety of dosage forms. Thus, they can be administered orally, eg as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the present invention can also be administered parenterally by subcutaneous, intravenous, intramuscular, intrasternal, endovascular or infusion techniques. The compound may also be administered as a suppository.

Certain compounds of formula (I) have not yet been published in terms of treatment. Accordingly, the present invention also provides a bissulfonamide analog of formula (I) or a pharmaceutically acceptable salt thereof, as described above, for use in a method of treating a human or animal body, wherein Ar, R ₁ , R ₂ , R ₃ and R ₄ are as described above, provided that when R ₁ and R ₂ are hydrogen and R ₃ and R ₄ are phenyl, 4-methylphenyl or 4-aminophenyl, Ar is And R 'and R "are methyl or chlorine.

The present invention also provides pharmaceutical compositions containing such bissulfonamide analogs or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or diluents.

Compounds of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, oral solid forms include diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch with the active compound; Lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol; Binders such as starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; Separating agents such as starch, alginic acid, alginate or sodium starch glycolate; Foam mixtures; dyes; sweetener; Wetting agents such as lecithin, polysorbate, laurylsulfate; And generally non-toxic and pharmaceutically inert materials used in pharmaceutical formulations. Such pharmaceutical preparations can be prepared by known methods such as mixing, granulating, tableting, sugar coating or film coating.

Dispersions for oral administration may be syrups, emulsions and suspensions. The syrup may contain saccharose as a carrier, for example together with saccharose or glycerin and / or mannitol and / or sorbitol.

Suspensions and emulsions may contain, for example, natural rubber, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol as carriers. Suspensions or solutions for intramuscular injection may contain, in combination with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol and, if necessary, lidocaine hydrochloride. have.

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

A therapeutically effective amount of a compound of the invention is administered to a patient. Typical dosages are about 0.001 to 50 mg / kg body weight, depending on the activity, age, weight of the particular compound and the condition of the patient to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, the daily dosage level is 5 mg to 2 g.

Shiki acid pathways are also essential in higher plants, algae and fungi. In addition, catabolic pathways of quinic acid are also found in fungi. The compounds of the present invention are thus effective in inhibiting higher plants, algae and fungi. These can be used, for example, as selective herbicides and fungicides. The present invention therefore provides the use of a compound of formula (I) or an agriculturally acceptable salt thereof as a herbicide or fungicide. Also provided is a method of inhibiting weeds or fungi in Locus, comprising treating Locus with a compound of Formula I or an agriculturally acceptable salt thereof.

Locus typically includes agricultural or horticultural plants or the environment in which these plants grow.

A preferred method of inhibiting fungus is a method of treating or protecting a plant against which the fungus is infested, comprising applying a compound of formula (I) or an agriculturally acceptable salt thereof to the plant. For example, melanoma and rust of plants can be treated by this method.

Typically, the active compound is applied to the leaves. The number of applications and the speed of application depend on the strength of fungal invasion. However, the active compounds can also be impregnated through the roots (penetration) through the soil by impregnating the plant's locus with a liquid composition comprising the active compound, or by applying a compound in solid form, e. Function) can be applied to plants. The active compounds can also be applied to the seeds by impregnating the seeds with liquid formulations containing the active compounds or by coating them with solid formulations (coating). In special cases, additional types of application are also possible, for example the selective treatment of plant stems or shoots.

The invention also provides herbicide or fungicide compositions comprising the novel bissulfonamide homologs or agriculturally acceptable salts thereof as described above and an agriculturally acceptable carrier or diluent.

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

Said herbicide or fungicide compositions can 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 spraying on plants. Fungicides or herbicide compositions may include additional agricultural chemicals, such as additional fungicides and herbicides or pesticides, tick mites, plant growth regulators, fertilizers, and soil conditioners.

Herbicide or fungicide compositions preferably include additional fungicides or herbicides. This leads to a decrease in dosage and attraction and an expansion of the herbicide or fungicide spectrum. This expansion contributes to cooperative activities.

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

Examples of solid carriers or diluents include clays such as kaolinite, montmorillonite, illite and polygrosite, more particularly pyrophyllite, attapulgite, calculi, kaolinite, bentonite, vermiculite, mica and talc . Other inorganic materials such as gypsum, calcium carbonate, dolomite, diatomaceous earth, magnesium lime, phosphorus lime, zeolite, silicic anhydride and synthetic calcium silicate can also be used. Suitable organic carriers and diluents include soybean powder, tobacco powder, walnut powder, flour, wood powder, starch and crystalline cellulose. Further synthetic or natural polymers are suitable, such as coumarone resins, petroleum resins, alkyd resins, polyvinyl chlorides, polyalkylene glycols, ketone resins, ester rubbers, copal rubbers and dammar rubbers, such as carnauba wax and beeswax. The same applies to wax.

Examples of suitable liquid carriers and diluents include paraffinic or naphthenic hydrocarbons such as kerosene, mineral oil, spindle oil and white oil, aromatic hydrocarbons such as xylene, ethylbenzene, cumene and methylnaphthalene, trichloroethylene, monochlorobenzene and o Chlorinated hydrocarbons such as chlorotoluene, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, acetophenone and isophorone, ethyl acetate, amyl acetate, ethylene glycol Esters such as acetates, diethylene glycol acetate, dibutyl maleate and diethyl succinate, alcohols such as methanol, n-hexanol, ethylene glycol, diethylene glycol, cyclohexanol and benzyl alcohol, ethylene glycol ethyl ether and di Ether alcohols and dimeth, such as ethylene glycol butyl ether It includes polar solvents such as formamide, dimethyl sulfoxide and water.

Typically, herbicide and fungicide compositions are surfactants and / or other adjuvants suitable for various purposes such as emulsifying, dispersing, humidifying, diffusing, diluting, controlling compound breakdown, stabilizing active ingredients, improving fluidity, preventing corrosion and freezing It includes. Preferably, the herbicide and fungicide compositions of the present invention comprise at least one surfactant. The invention also

Bissulfonamides of formula (I) or agriculturally acceptable salts thereof;

At least one surfactant; And

Providing a herbicide or fungicide composition comprising an agriculturally acceptable carrier and diluent.

Suitable surfactants include nonionic, anionic, cationic and amphoteric surfactants. Nonionic and anionic surfactants are preferred.

Suitable anionic surfactants can be water soluble soaps and water soluble synthetic surfactant compounds.

Suitable soaps can be obtained from 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 oleic acid or stearic acid, or for example coconut oil or animal oil. Sodium or potassium salts of natural fatty acid mixtures.

However, so-called synthetic surfactants, in particular aliphatic sulfonates, aliphatic sulfates, sulfonated benzimidazole homologs or alkylarylsulfonates are more often used.

Aliphatic sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and also have C ₈ to C ₂₂ alkyl radicals which contain alkyl groups of alkyl radicals, for example lignonsulfonic acid, Sodium or calcium salt of a fatty alcohol sulfate mixture obtained from dodecyl sulfate or natural fatty acids. Such compounds also include salts of sulfuric acid esters and sulfonic acids of fatty alcohol / ethyl oxide adducts. The sulfonated benzimidazole homologs preferably contain one fatty acid radical containing two sulfonic acid groups and 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid or naphthalenesulfonic acid / formaldehyde condensates. Also suitable are salts of the corresponding phosphates, for example p-nonylphenol and phosphate esters of ethylene oxide 4 to 14 moles of adduct.

Nonionic surfactants are preferably polyglycol ether homologs of aliphatic or cycloaliphatic alcohols or saturated or unsaturated fatty acids and alkylphenols, wherein the homologues are from 3 to 30 glycol ether groups and from (aliphatic) hydrocarbon residues to from 8 to 20 Carbon atoms and alkyl residues of alkylphenols contain 6 to 18 carbon atoms.

Further suitable nonionic surfactants are water soluble adducts of polyethylene oxide and polypropylene glycol, ethylenediamine propylene glycol and alkylpolypropylene glycols containing 1 to 10 carbon atoms in the alkyl chain, which adducts are from 20 to 250 Ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. Such compounds typically contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of nonionic surfactants are nonylphenolpolyethoxyethanol, castor oil polyglycol ether, flopropylene / polyethylene oxide adduct, tributylphenoxypolyethoxyethanol, florethylene glycol and octylphenoxyethoxyethanol. Fatty acid esters of polyoxyethylene sorbitan and polyoxyethylene sorbitan trioleate are also suitable nonionic surfactants.

Cationic surfactants are quaternary ammonium salts, preferably with N-substituents, having at least one C ₈ -C ₂₂ alkyl radical and further substituents as lower unsubstituted or halogenated alkyl, benzyl or lower hydroxyalkyl radicals. . The salt is preferably in the form of halide, methylsulfate or ethylsulfate, for example stearyltrimethylammonium chloride or benzyldi (2-chloroethyl) ethylammonium bromide.

Surfactants commercially available in the formulation field 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.

Such adjuvants include casein, gelatin, albumin, glue, sodium alginate, carboxymethylcellulose, methylcellulose, hydroethylcellulose and polyvinyl alcohol.

The aforementioned carriers or diluents and various auxiliaries may be used alone or in combination.

The content of active compound in the herbicide and fungicide compositions of the present invention can vary widely depending on the form of the formulation. Typically, the amount of active compound is 0.1 to 99% by weight, preferably 1 to 80% by weight of the composition.

In more detail, the wettable powder typically contains from 25 to 90% by weight of the active compound. Granules typically contain from 1 to 35% by weight of active compound, which may be homogeneously mixed with the solid carrier or diluent or may be uniformly mixed or absorbed on the surface of the solid carrier or diluent. It is preferable that the diameter of a granule is 0.2-1.5 mm. Emulsion concentrates typically contain from 5 to 30% by weight of active compound and also from 5 to 20% by weight of emulsifier. Suspension concentrates typically contain from 5 to 50% by weight of active compound, and also from 3 to 10% by weight of dispersing wetting agent.

The compounds of the present invention can be applied in effective amounts to various places to be controlled, for example farmland such as paddy fields and high or non-cropland. When used as herbicides they can be applied to seeds at various stages before germination or after germination to growth. When the compound of the present invention is used as a herbicide, the dosage is generally in the range of 0.1 to 10,000 g / ha, preferably 1 to 5,000 g / ha, more preferably 50 to 3,000 g / ha as the amount of the active ingredient. . Dosages may vary depending on the type of seed desired, their stage of growth, the place of application and the climate. When the compounds of the present invention are used as fungicides, the dosage is usually from 50 g to 5 kg of active ingredient per hectare, preferably from 100 g to 2 kg per hectare, more preferably from 200 g to 500 g per hectare.

The succinic acid pathway is also essential for the synthesis of aromatic amino acids in algae. Thus, the compounds of the present invention are effective in algal inhibition. The present invention therefore provides the use of the compounds of formula (I) or salts thereof in algal inhibition. In particular, the present invention provides a method of treating algae in an aquarium or lake, comprising applying the compound of formula I or a salt thereof to the aquarium or lake.

As mentioned above, dehydroquinase enzyme type 2 forms an important part of the metabolic pathway in which quinic acid metabolism occurs. The present invention therefore also provides the use of bissulfonamide homologs of the formula (I) or salts thereof as described above in the inhibition of quinic acid metabolism. Suitable salts include those listed above as examples of pharmaceutically acceptable salts.

Metabolic pathways are found in many fungi and bacteria. Thus, the compounds of the present invention are commonly used to inhibit the metabolism of quinic acid by fungi or bacteria. They may be formulated for this use as herbicide or fungicide compositions as described above and may be used in 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 (10 mM) in dry pyridine (50 mL) is stirred at room temperature under nitrogen and 3-nitrobenzenesulfonyl chloride (20 mM) is added in fractions over a few minutes. The resulting solution is heated at reflux for 5 hours, then cooled and poured into cold 1 N hydrochloric acid (500 mL). The product is extracted with ethyl acetate (3 x 200 mL) and the combined organic extracts are dried over anhydrous sodium sulfate and washed with water, 1 N sodium hydroxide and then water again before evaporating under reduced pressure. Column chromatography on silica gives the required product (3.1 g, 65%).

Examples 2 to 8

The compounds detailed below are prepared in the same manner as in Example 1 using suitable 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

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

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

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

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

Example 9

1,2-bis (4-toluenesulfonylamino) -benzene

A solution of 1,2-phenylenediamine (10 mM, 1.08 g) in dry acetonitrile (50 mL) is stirred at room temperature under nitrogen. Diisopropylethylamine (5 mL) is added followed by benzenesulfonyl chloride (4.19 g, 22 mM). The resulting solution is heated at reflux for 10 hours and then cooled to evaporate under reduced pressure. The resulting solid is partitioned between water and chloroform to separate the organic layer, washed with 1N sodium hydroxide solution, followed by water and finally dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product is purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane. The product is isolated as white powder (1.8 g, 43%). mpt 203-205 ° C.

Examples 10-21

The compounds detailed below are prepared in the same manner as in Example 9 using suitable starting materials.

Example Compound

10 1,2-bis (3,5-ditrifluoromethylphenylsulfonylamino) -benzene

11 1,2-bis (4-bromophenylsulfonylamino) -benzene

12 1,2-bis (4-tert-butylphenylsulfonylamino) -benzene

13 1,2-bis (4-methylphenylsulfonylamino) -4,5-methylenedioxybenzene

14 1,2-bis (4-methylphenylsulfonylamino) -4,5-dichlorobenzene

15 1,2-bis (4-methylphenylsulfonylamino) -4,5-ethylenedioxybenzene

16 2,3-bis (4-methylphenylsulfonylamino) -naphthalene

17 1,2-bis (4-methylphenylsulfonylamino) -4,5-difluorobenzene

18 1,2-bis (4-bromophenylsulfonylamino) -4,5-dibromobenzene

19 1,2-bis (4-chlorophenylsulfonylamino) -4,5-dibromobenzene

20 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 (10 mM) in dry pyridine (50 mL) was stirred at room temperature under nitrogen and 3- (3-trifluoromethylphenyl) sulfonyl chloride (10 mM) was added in fractions over a few minutes. do. The resulting solution is heated at reflux for 5 hours, then cooled and poured into cold water. The product is extracted with ethyl acetate (3 x 200 mL) and the synthetic organic extracts are dried over anhydrous sodium sulfate and washed with water, 1 N sodium hydroxide and then again with water before evaporating under reduced pressure. The resulting 4- (4-methylphenylsulfonylamino) -3-aminotoluene is added to the same reaction conditions using 3- (trifluoromethylphenyl) sulfonyl chloride (10 mM). Column chromatography on silica provides the required product.

Examples 23 and 24

The compounds detailed below are prepared in the same manner as in Example 22 using the appropriate starting materials.

Example Compound

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

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

yen

Example 25

1,2-bis (4-toluenesulfonylamino) -4,5-dibromobenzene

A solution of 1,2-bis (4-toluenesulfonylamino) -benzene (500 mg, 1.2 mM) in glacial acetic acid (10 mL) is stirred and sodium acetate (200 mg) is added. Bromine (385 mg, 0.13 mL, 2.4 mM) is added dropwise and the resulting concentrated solution is heated at 80 ° C. for 3 hours. Water (50 mL) is added and the resulting precipitate is separated by filtration and purified by recrystallization with acetic acid to give the required product as a white needle, mpt 213-215 ° C. (650 mg, 94%).

Example 26

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

4,5-dibromo-1,2-bis (4-methylphenylsulfonylamino) benzene (176 mg, 3 x 10 ^-4 mol) and dibromoethane (57 mg, 3 x 10 ^-4 mol) Reflux under nitrogen for 4 hours with potassium carbonate (1.0 g, 7.25 x 10 ^-4 mol) in dry acetonitrile (250 mL) and stir overnight in RTP. The solution is filtered and evaporated to dryness to yield the product as a pale brown glass (0.16 g, 89%).

Example 27

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

4-chloro-5-methylphenylene-1,2-diamine (10 mM, 1.56) is dissolved in dry pyridine (100 mL) and stirred at room temperature under nitrogen. To this solution is added a solution of 5-chloro-2-thienylsulfonyl chloride (21 mM, 4.55 g) in pyridine (15 mL) and the resulting solution is stirred at 85 ° C. under nitrogen for 18 hours. The solution is then poured into 0.5 M cold dilute hydrochloric acid (125 mL) and the product is extracted with chloroform. The solution is then dried over anhydrous sodium hydrogen carbonate and evaporated under reduced pressure. The crude product is purified by column chromatography on silica eluting with a mixture of chloroform and methanol, the product is further purified by recrystallization with ethanol / water and the product is dried under vacuum overnight. The product is obtained in the form of an off-white crystalline solid (2.18 g, 42%).

Examples 28-58

The compounds detailed below are prepared in the same manner as in Example 27 using suitable 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-dibromoben

Jen

44 1,2-bis (2-trifluoromethoxyphenylsulfonylamino) -3,5-dibromo

benzene

45 1,2-bis (4-trifluoromethoxyphenylsulfonylamino) -4,5-dibromo

benzene

46 1,2-bis (2- (3-oxazoyl) -5-thienylsulfonylamino) -4,5-dimethylbenzene

47 1,2-bis (2- (3-oxazoyl) -5-thienylsulfonylamino) -4,5-dibromoben

Jen

48 1,2-bis (3-chloro, 4-acetamidophenylsulfonylamino) -4,5-dibro

Mobenzene

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-chloro

Robenzene

53 1,2-bis (2- (2-methyl-4-thiazoyl) -5-thienylsulfonylamino) -4-chloro

Robenzene

54 1,2-bis (2- (2-methyl-4-thiazoyl) -5-thienylsulfonylamino) -4-flu

Orobenzene

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

Pyridine (0.05 mL, 0.66 mmol, 3 equiv) is added to a solution of 1,2 phenylenediamine (24 mg, 0.22 mmol) in acetonitrile (2 mL). To this solution is added a solution of (4-trifluoromethoxy) phenylsulfonyl chloride (84 mg, 0.44 mmol) in acetonitrile (2 mL). The reaction mixture is allowed to stand at ambient temperature for 24 hours. Upon completion the reaction mixture is concentrated in vacuo to give a heavy syrup. The syrup is dissolved in dichloromethane (1 mL) and water (1 mL). The phases are separated and the organic phase is washed with water (1 mL), citric acid (10%, 1 mL) and saturated brine (1 mL). The organic solution is dried in vacuo to give the final product which is analyzed by liquid chromatography with mass spectroscopy.

Examples 60-64

The compounds detailed below are prepared in the same manner as in Example 59 using suitable starting materials.

Example Compound

60 1,2-bis (4-isopropylphenylsulfonylamino) -benzene

61 1,2-bis (4-fluorophenylsulfonylamino) -4,5-dimethylbenzene

62 1,2-bis (4-methylphenylsulfonylamino) -4,5-dimethylbenzene

63 1,2-bis (3-trifluoromethoxyphenylsulfonylamino) -4,5-dimethylbene

Jen

64 1,2-bis (4-isopropylphenylsulfonylamino) -4,5-dimethylbenzene

The compound is analyzed by liquid chromatography with a mass spectrometer as a detector. The equipment used is the Waters 2700 Sample Manager, the Waters 2690 Alliance Solvent Delivery System, and the Waters 996 Photodiode Array Detector. The mass spectrometer used is the Micromass Platform LCZ mass spectrometer running Micromass MassLynx Software, v3.2 build 004. Chromatography was 0.5 ml / min over 3 minutes with an elution gradient of 5% 10 mM formic acid in acetonitrile and 95% 10 mM formic acid in water to 95% 10 mM formic acid in acetonitrile and 5% 10 mM formic acid in water. Waters Symmetry is performed on a 3.5 μm C18 50 × 2.0 mm (WAT200650) column at a flow rate of. UV detection is performed at 200-300 nm and mass spectra are collected by positive and negative electrosprays. All reaction products appear to be the desired compound with satisfactory purity.

Example 65

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

Pyridine (0.05 mL, 0.66 mmol, 3 equiv) is added to a solution of 4,5-dimethyl-1,2-phenylenediamine (30 mg, 0.22 mmol) in acetonitrile (2 mL). To this solution is added a solution of 3-trifluoromethylphenylsulfonylchloride (108 mg, 0.44 mmol) in dimethylformamide (2 mL). The reaction mixture is allowed to stand at ambient temperature for 24 hours. Upon completion the reaction mixture is concentrated in vacuo to give a heavy syrup. The syrup is dissolved in dichloromethane (1 mL) and water (1 mL). The phases are separated and the organic phase is washed with water (1 mL), citric acid (10%, 1 mL) and saturated brine (1 mL). The organic solution is dried in vacuo to give the final product which is analyzed by liquid chromatography with mass spectroscopy.

Examples 66-256

The compounds detailed below are prepared in the same manner as in Example 65 using the 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) -ethyl benzoate

Ster

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) -ethyl benzoate

Ster

103 1,2-bis (2-thienylsulfonylamino) -benzene

104 2,3-bis (2-thienylsulfonylamino) -phenol

105 1,2-bis (2-chloro-5-thienylsulfonylamino) -naphthalene

106 1,2-bis [2- (3-oxazolyl) -5-thienylsulfonylamino) -naphthalene

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-Difluoro-4,5-bis (2-thienylsulfonylamino) -benzene

117 1,2-Dibromo-4,5-bis (2,3-dichloro-5-thienylsulfonylamino) -ben

Jen

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) -bene

Jen

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-tet

Lamethylbenzene

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-trifluoromethylphenylsulfonylamino) -naphthalene

137 2,3-bis (2,4difluorophenylsulfonylamino) -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 (3,5-dimethyl-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-imidazoylsul

Phonyamino) -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) -methyl benzoate

Ster

151 3,4-bis (2-chloro-5-thienylsulfonylamino) -benzoic acid methyl ester

152 3,4-bis (2-methoxy, 2-chlorophenylsulfonylamino) -benzoic acid methyl s

Ter

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

Porn

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-difluorobenzene

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

Porn

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

Porn

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-tetramethylbene

Jen

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 s

Ter

208 1,2-bis (2- (1,2-cyclo (3-thioethyl) -4-chloro-5-imidazoylsulfo

Nylamino) -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-methylbene

Jen

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

Porn

224 3,4-bis (4-isopropylphenylsulfonylamino) -benzoic acid methyl ester

225 1,2-bis (4-methylphenylsulfonylamino) -4-chlorobenzene

226 3,4-bis (3,5-dimethyl-4-oxazoylsulfonylamino) -4,5-difluorobenzo

Eight

227 1,2-bis (2- (3-oxazoyl) -5-thienylsulfonylamino) -4-methoxybenzene

228 1,2-bis (2- (1,2-cyclo (3-thioethyl) -4-chloro, 5-imidazoylsulfo

Nylamino) -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-difluorobene

Jen

239 1,2-bis (4-trifluoromethoxyphenylsulfonylamino) -4-chloro-5-methyl

benzene

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-methylbene

Jen

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-methylbene

Jen

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-dimethyl

benzene

The compound is analyzed by liquid chromatography with a mass spectrometer as a detector. The equipment used is the Waters 2700 Sample Manager, the Waters 2690 Alliance Solvent Delivery System, and the Waters 996 Photodiode Array Detector. The mass spectrometer used is a MicromassPlatform LCZ mass spectrometer running Micromass MassLynx Software v3.2 build 004. Chromatography was followed by elution gradient of 5% 10 mM formic acid in acetonitrile and 95% 10 mM formic acid in water to 95% 10 mM formic acid in acetonitrile and 5% 10 mM formic acid in water over 0.5 ml / min. Waters Symmetry is performed on a 3.5 μm C18 50 × 2.0 mm (WAT200650) column at a flow rate of. UV detection is performed at 200-300 nm and mass spectra are collected with positive and negative electrosprays. All reaction products appear to be 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, 3.5 g, 7.38 x 10 ^-4 mol) was added to a 1 N sodium hydroxide solution (250 mL) for 5 hours at 60 ° C. Stir while. After this time the solution is cooled and the precipitate is filtered off, washed with water and then recrystallized with acetic acid and water to give 2.0 g (59%) of the title compound.

Example 258

1,2-bis (3-trifluoromethylphenylsulfonylamino) -4- (3-methyloxadiazol-5-yl) benzene

N-hydroxyacetamidine (0.028 g, 0.39 mmol) in THF (dry, 15 mL) is added to a stirred solution of dry THF (5 mL) containing sodium hydride (0.015 g, 0.39 mmol). The mixture is heated to 60 ° C. under nitrogen. A solution of 3,4-bis (3-trifluoromethylphenylsulfonylamino) -benzoic acid methyl ester (Example 207, 76 mg, 0.13 mM) in dry THF (15 mL) was added dropwise over 15 minutes. The reaction is refluxed overnight. Methanol (5 mL), then water (5 mL) is added continuously and the mixture is concentrated to dryness. The crude mixture is added to column chromatography on silica with methanol / dichloromethane to afford the product (21 mg, 27%).

Example 259

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

3,4-bis (4-methylphenylsulfonylamino) -benzoic acid (Example 257, 0.092 g, 0.2 mmol), aniline (0.0186 g, 0.2 mmol), N, N- (diisopropyl) amino-methylpolystyrene resin (PSDIEA) (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) is stirred in anhydrous acetonitrile (8 mL) under nitrogen and heated to 50 ° C. for 40 h. After this time the reaction mixture is cooled to room temperature. The separable reactant-tetrafluorophthalic anhydride (0.132 g, 0.6 mmol) is then added and the reaction mixture is stirred under nitrogen for 18 hours. Macroporous triethylammonium methylpolystyrene carbonate resin (MP-carbonate, 0.630 g, 2.0 mM, loading 3.18 mM / g) is then added and the reaction mixture is stirred for an additional 48 hours under nitrogen. The reaction mixture is then filtered through a filter syringe into a vial and the precipitate is washed with methanol. The combined solvents are removed with a vacuum concentrator to yield 0.051 g (48%). The product was analyzed by LC-MS and had a purity of 85.0%.

Examples 260 and 261

The compounds detailed below are prepared in the same manner as in Example 259 using suitable starting materials.

Example Compound

260 3,4-bis (4-methylphenylsulfonylamino) -N- (4-fluoromethoxyphenyl)

Benzamide

261 3,4-bis (4-methylphenylsulfonylamino) -N- (3,5-dimethoxyphenyl) benzia

Maid

Example 262

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

4- (3-Trifluoromethylsulfonylamino) -3-nitro-benzoic acid ethyl ester (prepared as in Example 22 with suitable starting material; 1.00 g, 2.66 mmol) is dissolved in ethanol (50 mL). The solution is stirred and slowly added palladium on carbon (5%), followed by ethanol addition to wash the vessel side, followed by the addition of excess hydrazine hydrate (2 mL). The solution is refluxed for 18 hours, filtered and then evaporated to dryness. The product was then purified on silica using methanol / chloroform as eluent to afford 3-amino-4- (3-trifluoromethylbenzenesulfonylamino) -benzoic acid ethyl ester as a dry white solid (0.81 g, 89%). To obtain. This material is then reacted with 2-phenylethenesulfonyl chloride as in Example 22 to afford the title product.

Examples 263 to 271

The compounds detailed below are prepared in the same manner as in Example 262 using a suitable starting material.

Example Compound

263 1- (4-methoxyphenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonyl

Amino) -4-chlorobenzene

264 1- (3-chlorophenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonyl

Amino) -4-chlorobenzene

265 1- (2-chlorophenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonyl

Amino) -4-chlorobenzene

266 1- (3-methylphenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonyla

Mino) -4-chlorobenzene

267 1- (4-methylamidomethylphenylsulfonylamino) -2- (3-trifluoromethylfe

Nylsulfonylamino) -4-chlorobenzene

268 1- (2- (phenylamidomethyl) -5-thienylsulfonylamino) -2- (3-trifluoro

Methylphenylsulfonylamino) -4-chlorobenzene

269 1- (4- (2-chloro-5-thiazoylmethoxyphenylsulfonylamino) -2- (3-triple

Fluoromethylphenylsulfonylamino) -4-chlorobenzene

270 3- (2,5-dichloro-3-thienylsulfonylamino) -4- (3-trifluoromethylsulfur

Ponylamino) -Methylbenzoate

271 3- (4-methylphenylsulfonylamino) -4- (3-trifluoromethylphenylsulfonyl

Mino) -Methylbenzoate

Example 272

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

1-nitro-2- (3-trifluoromethylphenylsulfonylamino) -4-fluorobenzene (prepared as in Example 22 using an appropriate starting material; 0.13 g, 0.32 mmol) was dissolved in tin (II) chloride ( Stir in dimethylformamide (5 mL) containing 0.28 g, 1.25 mmol). The reaction is stirred overnight at room temperature under nitrogen. The mixture is diluted with water (15 mL) and the pH adjusted to 7 with 1 M sodium hydroxide solution. The aqueous solution is extracted with chloroform and the chloroform is removed in vacuo to give an orange oil. It is purified by flash chromatography on silica using methanol / chloroform to give 1-amino-2- (3-trifluoromethylphenylsulfonylamino) -4-fluorobenzene (0.07 g, 58%). This material is then reacted with 4-methylphenylsulfonyl chloride in the same manner as in Example 22 to afford the title compound.

Examples 273 to 285

The compounds detailed below are prepared in the same manner as in Example 272 using suitable starting materials.

Example Compound

273 1- (4-methylphenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonyl

Amino) -4-fluorobenzene

274 1- (3-trifluoromethylsulfonylamino) -2- (2-phenylethenylsulfonylami

No) -4-fluorobenzene

275 1- (3-trifluoromethylsulfonylamino) -2- (2-phenylethenylsulfonylamimi

Furnace) -benzene

276 1- (3-trifluoromethylsulfonylamino) -2- (benzylsulfonylamino) -4-ple

Luorobenzene

277 1- (2,5-dichloro-3-thienylsulfonylamino) -2- (3-trifluoromethyl

Sulfonylamino) -benzene

278 1- (2- (phenylamidomethyl) -5-thienylsulfonylamino) -2- (3-trifluoro

Romethylphenylsulfonylamino) -benzene

279 1- (2- (phenylamidomethyl) -5-thienylsulfonylamino) -2- (3-trifluoro

Romethylmethylsulfonylamino) -4-fluorobenzene

280 1- (4- (2-chloro-5-thiazoylmethoxyphenylsulfonylamino) -2- (3-tri

Fluoromethylphenylsulfonylamino) -benzene

281 1- (4- (2-chloro-5-thiazoylmethoxyphenylsulfonylamino) -2- (3-t

Rifluoromethylphenylsulfonylamino) -4-fluorobenzene

282 1- (2-chlorophenylsulfonylamino) -2- (3-trifluoromethylphenylsulfo

Nylamino) -benzene

283 1- (2-chlorophenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonyl

Amino) -4-fluorobenzene

284 1- (2-methylphenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonyla

Mino) -benzene

285 1- (3-methylphenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonyla

Mino) -4-fluorobenzene

Example 286

Analytical Data of Representative Compounds of Examples 1 to 285

Example 287

Inhibition rate of purified dehydroquinate synthase (AroB) is measured in 96-well plates at a single concentration (50 μM). Briefly, a 3-enzyme binding assay using dehydroquinate synthetase (AroB), dehydroquinase (type 1) and dehydroscimate dehydratase (DHSD) is performed. In the presence of this enzyme mixture, the substrate 3-deoxy-D-arabinoheptulosonic acid-7-phosphate (DAHP) is converted to protocatechuic acid, which can be quantified using a set of spectrophotometer plate readers at 290 nm. have. A second incubation after addition of 0.1% ferric chloride showed a protocatechuic acid-iron complex at 570 nm. In the absence of inhibitors, DAHP concentrations in the assay are adjusted to provide 1 unit of absorbance at 290 nm after the initial stages of the assay. Compounds were tested at 50 μM for reducing the absorbance at 290 nm and 570 nm at each assay step, indicating a reduction in the conversion of DAHP to protocatechuic acid by the enzyme mixture. The assay medium also contains buffer (morpholino propanesulfonic acid, pH 7.0), cobalt chloride (40 μM final concentration), zinc sulfate (40 μM) and magnesium sulfate (2.5 mM). NAD is added at 20 μΜ as co-factor.

The following dehydroquinase assay is used to confirm that the active compound inhibits dehydroquinate synthase. This assay is performed similarly to the above, but uses dehydroquinate as the substrate and omits dehydroquinate synthetase from the assay medium. None of the test compounds showed activity in the modified assays, so all compounds appear to inhibit only dehydroquinate synthase.

Example 288

Inhibition rate of purified dehydroquinate synthetase (AroB) is measured in 96-well plates using the method described above in Example 287. The experiment is repeated at different concentrations to calculate IC ₅₀ values. IC ₅₀ values are calculated at 290 nm.

Example 289

Inhibition of purified M. tuberculosis dehydroquinase type 2 (AroQ) is measured in 96-well plates at a single concentration (50 μM). Briefly, a two-enzyme binding assay using AroQ and dehydroscimate dehydratase (DHSD) is performed. In the presence of this enzyme mixture, the substrate quinate is converted to protocatechuic acid, which is quantified (using a set of spectrophotometer readers at 570 nm) after 2 min incubation with 0.1% ferric chloride. Compounds were tested for their ability to reduce absorbance at 570 nm at 50 μM, indicating a decrease in the conversion of quinate to protocatechuic acid by the enzyme mixture. The assay medium also contains buffer (morpholino propanesulfonic acid, pH 7.0), cobalt chloride (40 μM final concentration), zinc sulfate (40 μM) and magnesium sulfate (2.5 mM).

The following assay is used to confirm that the active compound inhibits dehydroquinase. Briefly, compounds are incubated in the presence of AroQ in conventional buffer mixtures and the ability to reduce the conversion of quinate to dehydrosuccinic acid is measured at 240 nm with a spectrophotometer. All test compounds appear to be active in the modified assay and therefore appear to be inhibitors of dehydroquinase.

Example 290

Inhibition of purified Mycobacterium tuberculosis dehydroquinase type 2 (AroQ) is measured in 96 well plates using the method described in Example 289. The experiment is repeated at different concentrations to calculate CI ₅₀ values. IC ₅₀ values are calculated using the results at 570 nm.

Example 291

Antimicrobial Activity of the Compound Against Staphylococcus aureus

The method detailed below is used to determine the minimum inhibitory concentration (MIC) of a compound for Staphylococcus aureus, a methicillin sensitive and resistant strain. This is a variation of the method used in clinical laboratories to measure antimicrobial susceptibility (NCCLS M7-A4 method for dilution antimicrobial susceptibility testing of aerobic quaternary growing bacteria).

The broth medium used for the analysis is 9 parts of M9 minimum salt to 1 part of Lennox medium (9: 1 M9: LB).

M9 minimal salt Lennox Badge NaCl 1.00 g / ℓNa ₂ HPO ₄ 6.78 g / ℓKH ₂ PO ₄ 3.00 g / ℓNH ₄ Cl 1.00 g / ℓ NaCl 5.00 g / ℓ Yeast extract 5.00 g / ℓ Casein enzyme digestion 10.00 g / ℓ

For agar plates this medium is solidified by the addition of 1.5% (w / v) noble agar.

3 ml of 9: 1 M9: LB liquid medium is inoculated with a single colony from a fresh culture of methicillin sensitive or methicillin resistant lineage Staphylococcus aureus grown in 9: 1 M9: LB agar. It is incubated for 4-5 hours with shaking at 37 ° C. (about 250 rpm). The optical density of the liquid medium is measured at 600 nm and the culture is diluted to give an A600 of about 0.1 in 0.85% sterile saline. The method of Miles and Misra is performed with diluted inoculum as follows:

a) 90 μl 0.85% sterile saline is added to the remaining wells of the microtiter plate (columns B to H);

b) 10 μl of the culture is taken from rows A to B and mixed well. Continue diluting the plate continuously and replace the tip for each transfer;

c) In triplicate, deliver a volume of 5 μl of each dilution to the surface of the dry agar plate. The plate is allowed to stand for about 1 hour to allow the liquid droplets to dry with agar;

d) Incubate plates overnight at 37 ° C. and count colony numbers in dilutions with 10-50 isolated colonies per spot. A suitable calculation method (see below) is then used.

200 μl of 9: 1 M9: LB broth is added to the top row of sterile microtiter plate wells, and 10 μl of the compound of Example 25 in dimethyl sulfoxide (DMSO) is added to the wells in duplicate. To either one add 2 μl of 10 mg / ml phenylalanine, 2 μl of 10 mg / ml tryptophan, 40 μl of 0.5 mg / ml tyrosine and 2 μl of 5 μg / ml p-aminobenzoic acid. The wells are then inoculated with 5 μl of diluted bacterial culture (see above). Microtiter plates are incubated for 16-20 hours with shaking at 37 ° C. (about 150 rpm) and A600 is recorded and then Miles and Misra's method is performed with the culture (see above).

The criterion used to measure> MIC = (bacterial concentration) is the concentration at which sub-culture broth from drug treated batches do not grow in antimicrobial media. It is calculated by testing the compound at a narrow range of molar concentrations where bacterial growth inhibition concentration is slightly greater than MIC. The curve is then plotted for the total number of bacteria in the microplate well as a percentage of the number of bacteria inoculated into the wells.

The calculation used for the conclusion is c.f.u./ml = (colonial number x dilution coefficient) x 200. Number of bacteria in the inoculum = c.f.u./ml/200. Total number of bacteria in wells = c.f.u./ml/5.

Activity against Staphylococcus aureus of the Smith family (methicillin susceptibility)

Activity against methicillin-resistant Staphylococcus aureus

Example 292

Toxicity to VERO Cell Lines

Cells are routinely incubated with L-alanyl-L-glutamine (Gibco 21885-025) in Dulbecco's Modified Eagle Medium (DMEM) containing 10% Fetal Bovine Serum (FBS) (Gibco 16000-044). The method includes:

1. On the first day, seed 100 μl of cells into 96 × well plates at 5 × 10 ⁴ cells / ml.

2. On the second day of cell attachment, dilute the compound from 20 mM stocks in DMSO to twice the final concentration required in growth medium (DMEM) and add 100 μl per well. 0.5% DMSO in growth medium is added to the control wells.

3. Incubate cells at 37 ° C., 5% CO ² for 72-96 hours.

4. Remove the medium by aspiration and stain the cells by adding 100 μl of methylene blue (0.5% in 50% EtOH) per well and incubate for 1 hour at room temperature. The dye is then washed with running water and air dried.

5. Signs of morphological changes in cells can be tested.

6. Release the dye from the cells by adding 100 μl of solubilization solution (1% N-lauryl sarcosine in distilled water, Sigma L-5125) and shake gently for 1 hour. The plate is then read to measure the OD at 620 nm. Percent cell growth inhibition is calculated by comparison with non-pharmaceutical treated control wells.

Claims (35)

Use of a bissulfonamide homologue of formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in inhibiting biosynthesis of aromatic amino acids via a succimate pathway. Formula I In the above formula, Ar is an aryl or heteroaryl group; R ₁ and R ₂ are the same or different and each represents hydrogen or alkyl or R ₁ and R ₂ together form a C ₁ -C ₃ alkylene group, —CO or —CS; R ₃ and R ₄ are the same or different and each is -alkyl-aryl, -alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl, -alkynyl-heteroaryl, aryl Or heteroaryl. 2. Use according to claim 1, wherein R ₃ and R ₄ are the same or different and each represents an aryl or heteroaryl group. 2. Use according to claim 1, wherein Ar is a group Ar '. Formula Ar ' In the above formula, R ₅ to R ₈ are the same or different and are aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -CO ₂ R (wherein R is aryl, heteroaryl, hydrogen or alkyl) or -NR'R "or -CONR'R", where R 'and R "are the same or different and are aryl, heteroaryl, hydrogen or alkyl , R ₅ and R ₆ or R ₆ and R ₇ or R ₇ and R ₈ together form an alkylenedioxy group or together with the carbon atom to which they are attached form a phenyl moiety. 4. The compound of claim 3, wherein R ₅ and R ₈ are the same or different and are hydrogen, halogen, alkyl, hydroxy, alkoxy or —NR′R ″, wherein R ′ and R ″ are the same or different and are hydrogen or alkyl. ) R ₆ and R ₇ are the same or different and are hydrogen, aryl, heteroaryl, heterocyclyl, nitro, cyano, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -CO ₂ R (herein R is aryl, heteroaryl, hydrogen or alkyl) or -NR'R "or -CONR'R" (wherein R 'and R "are the same or different and aryl, heteroaryl, hydrogen or Alkyl), or R ₆ and R ₇ together form an alkylenedioxy group or a phenyl moiety together with the carbon atom to which they are attached. The compound of claim 4, wherein one of R ₅ and R ₈ is hydrogen, the other is hydrogen, halogen or hydroxy and R ₆ and R ₇ are hydrogen, aryl, heteroaryl, nitro, cyano, alkyl, alkoxy, halo Alkyl, halogen, -CO ₂ H, -CO ₂ -alkyl or -CONR'R ", wherein R 'and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R ₆ And R ₇ together form an alkylenedioxy group or phenyl moiety. The use according to any one of claims 1 to 5, wherein R ₁ and R ₂ are the same or different and represent hydrogen or alkyl or R ₁ and R ₂ together form a C ₁ -C ₃ alkylene group. The compound according to any one of claims 1 to 6, wherein R ₃ and / or R ₄ is phenyl, naphthyl, pyridyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, isoxazolyl, pyrrolyl, (1,2-cyclo (3-thioethyl) -imidazolyl, benzothienyl, indolyl or quinolinyl. 8. The compound of claim 1, wherein R ₃ and / or R ₄ are unsubstituted or aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, —S (O) ₂ —. Alkyl, haloalkoxy, cyano, -CO ₂ R (where R is aryl, heteroaryl, hydrogen or alkyl), alkoxy, hydroxy, -CONR'R "where R 'and R" are the same Or different and is aryl, heteroaryl, hydrogen or alkyl), -Z-NR "'R""and-NR"' R "", wherein Z is alkyl or alkenyl and R "'and R""are Are the same or different and each represents -CO-L wherein aryl, heteroaryl, hydrogen, alkyl or L is an alkyl or aryl group; and -OZR ""'"wherein Z is as described above and R""' is aryl , Heteroaryl or heterocyclyl). 2. Use according to claim 1, wherein the bissulfonamide analog of formula (I) is the bissulfonamide homolog of formula (Ia). Formula Ia In the above formula, R ₅ to R ₈ are as defined in claim 3, X and Y are the same or different and represent phenyl or thienyl. n represents an integer of 0 to 4 if X is phenyl, and an integer of 0 to 3 if X is thienyl, m represents an integer of 0 to 4 if Y is phenyl, and an integer of 0 to 3 if Y is thienyl, R ₃ ′ and R ₄ ′ are the same or different and are aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, —S (O) ₂ —, alkyl, alkoxy, haloalkoxy, cyano, − CO ₂ R (where R is aryl, heteroaryl, hydrogen or alkyl), hydroxy, -CONR'R ", where R 'and R" are the same or different and 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 is aryl, heteroaryl, hydrogen , Represents alkyl-or -CO-L, wherein L is an alkyl or aryl group, and -OZR ""'(where Z is as described above and R ""' is aryl, heteroaryl or heterocyclyl) do. The compound of claim 9, wherein in formula (Ia) R ₅ and R ₈ are hydrogen, R ₆ and R ₇ are the same or different and aryl, heteroaryl, nitro, cyano, alkyl, haloalkyl, halogen, hydrogen, —CO ₂ H, -CO _2- , alkyl, alkoxy and -CONR'R ", wherein R 'and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R ₆ and R ₇ are Together form an alkylenedioxy group or together with the carbon atoms to which they are attached form an additional phenyl moiety wherein 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 R ₃ ′ and R ₄ ′ are the same or different and are selected from: (a) when combined with a phenyl moiety, aryl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, halogen, nitro, cyano, C ₁ -C ₄ alkoxy, —CO ₂ R wherein R is Is hydrogen or C ₁ -C ₄ alkyl, -NR'R ", wherein R 'and R" are the same or different and are hydrogen, C ₁ -C ₄ alkyl or -CO- (C ₁ -C ₄ alkyl ), -O- (C ₁ -C ₄ alkyl) -R ″, wherein R ″ is heteroaryl or heterocyclyl, and -S (O) ₂ -C ₁ -C ₄ alkyl; And (b) when combined with a thienyl moiety, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, nitro, halogen, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkyl, —CO ₂ R wherein R is hydrogen or C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy,-(C ₁ -C ₄ alkyl) -NH-aryl and -S (O) ₂ -C ₁ -C ₄ alkyl. The use according to any one of claims 1 to 10, wherein the medicament is for use in the inhibition of dehydroquinate synthetase. Use according to claim 11, wherein the dehydroquinate synthetase is AroB. Use according to any one of claims 1 to 12, wherein the medicament is for use in the inhibition of dehydroquinase enzyme type 2. 14. Use according to claim 13, wherein the dehydroquinase enzyme type 2 is AroQ. Use according to any one of claims 1 to 14, wherein the medicament is for use in treating or preventing a bacterial or fungal infection. Use according to claim 15, wherein the medicament is for use in the treatment or prophylaxis of methicillin resistant Staphylococcus aureus infection. The use according to any one of claims 1 to 12, wherein the medicament is for use in the treatment or prevention of infection by parasites in which the biosynthesis of aromatic amino acids occurs via the schimate pathway. 18. The use of claim 17, wherein the medicament is for use in the treatment or prevention of malaria. -Bissulfonamide homologs of formula (I) or agriculturally acceptable salts thereof as defined in any of claims 1 to 10; At least one surfactant; And Herbicide or fungicide compositions comprising an agriculturally acceptable carrier or diluent. Use of a bissulfonamide analog of formula (I) or an agriculturally acceptable salt thereof as defined in any of claims 1 to 10 as herbicide or fungicide. In Rocus comprising administering a bissulfonamide analog of formula (I) or an agriculturally acceptable salt thereof, or a composition according to claim 19 or 32 as defined in any one of claims 1 to 10. Inhibition of weeds or fungi. 22. The method of claim 21 wherein the rocus comprises agricultural or horticultural plants or the environment in which these plants grow. Use of the bissulfonamide homologue of formula (I) or a salt thereof as defined in any one of claims 1 to 10 in algal inhibition. A method of treating algae in an aquarium or a lake comprising applying to an aquarium or a lake the bissulfonamide homologue of formula (I) as defined in any one of claims 1 to 10 or a salt thereof. Non-therapeutic use in inhibiting bacterial growth of a bissulfonamide homologue of formula (I) or a salt thereof as defined in any one of claims 1 to 10. A surgical instrument having an antibiotic coating comprising a bissulfonamide analog of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 10. Bissulfonamide homologue of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a human or animal body. Formula I In the above formula, Ar is an aryl or heteroaryl group; R ₁ and R ₂ are the same or different and each represents hydrogen or alkyl or R ₁ and R ₂ together form a C ₁ -C ₃ alkylene group, —CO or —CS; R ₃ and R ₄ are the same or different and each represents an aryl or heteroaryl group; Provided that when R ₁ and R ₂ are hydrogen and R ₃ and R ₄ are phenyl, 4-methylphenyl or 4-aminophenyl, Ar is In which R ′ and R ″ are methyl or chlorine. A pharmaceutical composition comprising the bissulfonamide homolog according to claim 27 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. Bissulfonamide homologue of formula (Id) or salt thereof. Chemical Formula Id In the above formula, R ₁ and R ₂ are as defined in any of claims 1 to 6; R ₃ and R ₄ are as defined in any of claims 1, 7 and 8; Ar is as defined in any of claims 3 to 5; Provided that R ₁ and R ₂ are both hydrogen and Ar is unsubstituted naphthyl group, phenanthracene group or 1 or 2 dimethylmethylenedioxy, hydroxy, methoxy, ethoxy, methyl, chlorine, bromine, fluorine, If it is a phenyl group optionally substituted by nitro, CF ₃ or an amino group, then R ₃ and R ₄ represent (a) an unsubstituted quinoline group, (b) an unsubstituted phenyl group, (c) methyl, methoxy, -CO ₂ H , Chlorine, cyano, nitro or amino group, or a phenyl group monosubstituted by the group -O-CO-N (CH ₃ )-or (d) a phenyl group disubstituted by the nitro group and methyl group. 30. The compound of claim 29, wherein the bissulfonamide analog of formula (Id) is the bissulfonamide analog of formula (Ia) as defined in claims 9 or 10. The method of claim 30 wherein Ar is Group wherein R ₅ to R ₈ are as defined in any one of claims 3 to 5, provided that R ₅ and R ₆ or R ₇ and R ₈ together do not form a phenyl moiety. The method of claim 29, 1,2-bis (4-trifluoromethyloxyphenylsulfonylamino) -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. A herbicide or fungicide composition comprising a bissulfonamide analog of formula (I) or an agriculturally acceptable salt thereof and an agriculturally acceptable carrier or diluent as defined in any one of claims 29 to 32. Use in the inhibition of quinic acid metabolism of bissulfonamide analogs of formula (I), or salts thereof, as defined in any one of claims 1 to 10. 35. The use of claim 34, wherein bissulfonamide or a salt thereof is used to inhibit the metabolism of quinic acid by fungi or bacteria.