JP2003512319A - Enzyme inhibitors - Google Patents

Abstract

(57) Abstract: Formula (I) wherein Ar is an aryl or heteroaryl group, and R ₁ and R ₂ are the same or different and each represents hydrogen or alkyl; ₁ and R ₂ together form a C ₁ -C ₃ alkylene group, —CO— or —CS—, and R ₃ and R ₄ are the same or different and are each -alkyl-aryl, -alkyl- Bissulfonamide derivatives of heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl, -alkynyl-heteroaryl, aryl or heteroaryl) are described by a) aromatic amino acids via the shikimate route And (b) the catabolism of quinic acid. Embedded image

Description

Detailed Description of the Invention

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

Dehydroquinate synthetase and dehydrokinase enzymes are erythrose-
It forms an integral part of the shikimate pathway that converts 4-phosphate to aromatic amino acids such as tryptophan, tyrosine and phenylalanine. Two types of biosynthetic dehydrokinases, type I (or AroD) species, and type II (or Ar
oQ) species have been characterized (Garbe et al, Mol. Gen. Genet., 228, pgs 38).
5-392 (1991), Hawkins et al, J. Gen. Microbiol. 139, pgs 2891-2899 (1993
).

The shikimate pathway is essential in bacteria, algae, fungi and higher plants. Furthermore, recent studies have shown evidence of the presence of enzymes of the shikimate pathway in Apicomplexan parasites (Roberts et al, Nature, 393, 1998, pgs 801-805). Therefore, compounds capable of inhibiting the biosynthesis of amino acids via the shikimate pathway have various commercial applications.

Besides their biosynthetic function, type II dehydrokinase enzymes form an important part of the catabolic pathway in which quinic acid catabolism occurs. This catabolic pathway is found in many fungi and bacteria. Therefore inhibitors of the type II dehydrokinase enzyme have commercial use as fungicides and antibiotics.

A large number of diaminobissulfonamides are known. For example, J. Chem.
Soc., 1161 (1970) describes the synthesis of many of these compounds as intermediates to tetrahydrodibenzodiazocines, and J. Chem. The electron substitution reaction is described. However, the pharmaceutical utility is not mentioned in these publications. The synthesis and use of 1,2-bis (4-methylphenylsulfonylamino) -4,5-dibromobenzene as an intermediate to substituted phthalocyanines has been reported (Ac
Ta. Chemica. Scand., 658 (1995)). Some diaminobissulfonamides are interesting as candidates for nonlinear optical studies (Acta. Cryst., 2395 (1995)).
.

Oncolytic activity has previously been attributed to several diaminobissulfonamides (J. Med. Chem., 599 (1963)). Oncolytic activity was found to act by inhibition of biosynthesis conversion 1,2-dimethyl-4,5-diaminobenzene to the vitamin B ₁₂ by tumor cells of a certain type (Biochem. Pharmacol., 1163 ( 1962))
.

[0007]   Surprisingly, the following general formula (I):

[0008]

[Chemical 8]

Wherein Ar is an aryl or heteroaryl group, R ₁ and R ₂ are the same or different and each represent hydrogen or alkyl, or R ₁ and R ₂ together C ₁ -C ₃ alkylene group, -CO- or -
Forming 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) is a specific bissulfonamide derivative which inhibits dehydroquinate synthetase enzyme It has been found to act as an agent and as an inhibitor of the type II dehydrokinase enzyme. Therefore, the present invention provides, in a first embodiment, a bissulfonamide derivative of formula (I), or a pharmaceutical thereof, in the manufacture of a medicament for use in inhibiting the biosynthesis of aromatic amino acids via the shikimate pathway. The use of a pharmaceutically acceptable salt.

Typically, the agent is for use in inhibiting a dehydroquinate synthetase enzyme, especially AroB, and / or a type II dehydrokinase enzyme, especially AroQ.

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

The alkyl group or moiety may be unsubstituted or substituted at any position. Typically it is unsubstituted or has 1 or 2 substituents. Suitable substituents include halogen, cyano, nitro, amino, hydroxy,
Oxo and -CO ₂ R, -SOR and -S (O) ₂ R (where, R is hydrogen or alkyl) and the like.

Alkenyl groups or moieties as used herein are typically straight or branched chain alkenyl groups containing 2 to 6 carbon atoms, such as C ₂ -C ₄ alkenyl groups or moieties. Or moieties such as ethenyl, propenyl and butenyl.

The alkenyl group or moiety may be unsubstituted or substituted at any position. Typically it is unsubstituted or has 1 or 2 substituents. Suitable substituents include halogen, amino and hydroxy.

An alkynyl group or moiety as used herein is typically a straight or branched chain alkynyl group containing 2 to 6 carbon atoms, such as a C ₂ -C ₄ alkynyl group or moiety, For example, ethynyl, propynyl and butynyl.

The alkynyl group or moiety may be substituted or unsubstituted at any position. Typically it is unsubstituted or has 1 or 2 substituents. Suitable substituents include halogen, amino and hydroxy.

A C ₁ -C ₃ alkylene group is a methylene, ethylene or propylene group. It may be unsubstituted or substituted at any position. Typically it is unsubstituted or has one substituent. Suitable substituents include halogen, cyano, nitro, oxo and -CO ₂ R, -SOR and -S (O) ₂ R (
Where R is hydrogen or alkyl).

Aryl groups as used herein are typically C ₆ -C ₁₀ aryl groups such as phenyl or naphthyl. Phenyl is preferred. The aryl group may be unsubstituted or substituted at any position. Typically it has 1, 2, 3 or 4 substituents. Suitable substituents include aryl, carbocyclyl, heteroaryl and heterocyclic groups, nitro, cyano, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg haloalkoxy),
Hydroxy, -CO ₂ R and -S (O) ₂ R (where, R represents aryl, heteroaryl, is hydrogen or alkyl), - CONR'R "(where, R 'and R" are the same Or different, each representing aryl, heteroaryl, hydrogen or alkyl), -Z-NR '"R""and-NR'" R "", where Z is alkyl or alkenyl, R '"and R""are the same or different and are each aryl, heteroaryl, hydrogen, alkyl or-.
CO-L, where L is an alkyl or aryl group, as well as -O-Z-R '"", where Z is as defined above and R'"". Is aryl, heteroaryl or heterocyclyl).

Typically, R in the —S (O) ₂ R moiety is hydrogen or alkyl. Typically, R '"and R in the -Z-NR'" R "" and -NR '"R""moieties
"" Are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably, at least one of R '"and R""is hydrogen or alkyl. Typically Z is alkyl, for example methyl. Typically -O-Z-R'"". R '"" in the section is heteroaryl,
For example, thiazolyl.

A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocycle substituents are 5- or 6-membered heteroaryl or heterocycle groups containing 1, 2 or 3 heteroatoms selected from N, O and S.
Examples include 5- or 6-membered rings containing 1, 2 or 3 heteroatoms, for example pyridyl, isoxazolyl, isothiazolyl, pyrazolyl, thiadiazolyl and oxadiazolyl. Other preferred substituents include nitro, hydroxy, halogen (e.g., 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 (e.g., -OCCl ₃ and _{-OCF 3), - S (O} ) 2 -
C ₁ -C ₄ alkyl, -CONR'R "(where, R 'and R" are the same or different, heteroaryl or is preferably aryl, hydrogen or C ₁ -C ₄ alkyl ), -NR '"R""(whereR'" and R "" are the same or different and are each hydrogen, alkyl or -CO-alkyl), and -O-alkyl-R. """(Where R '""is heteroaryl, eg thiazolyl).

The substituents themselves are preferably unsubstituted or one or selected from nitro, cyano, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg haloalkoxy) and hydroxy. It is substituted with further further substituents. Typically, these additional substituents themselves are unsubstituted.

The aryl group may be optionally fused to a further aryl group or carbocycle, heterocycle or heteroaryl group as described above. For example, it may be fused to a pyridine ring to form a quinoline group, fused to a thiadiazole ring (eg, 1,2,5-thiadiazole ring) to form an isobenzo [1,2,5] -thiadiazole group. Or fused to a 1,4 dioxane or 1,3 dioxolane ring.

A heteroaryl group, as used herein, typically contains from 5 to 10 members such as a 5 or 6 membered ring containing at least one heteroatom selected from O, S and N.
It is a membered aromatic ring. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazyl, thiadiazolyl, thiazolyl, imidazolyl and pyrazolyl groups. A thienyl group is preferred. The heteroaryl group may be unsubstituted or substituted at any position. Typically it is 1, 2 or 3
Has one substituent. Suitable substituents include aryl (eg phenyl),
Carbocyclyl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl (e.g., haloalkyl), alkylthio, alkoxy (e.g., haloalkoxy), hydroxy, -CO ₂ R and -S (O) ₂ R (where, R represents ,
Aryl, heteroaryl, hydrogen or alkyl), -CONR'R "(
Wherein R'and R "are the same or different and each represents aryl, heteroaryl, hydrogen or alkyl), -Z-NR '" R "" and -NR
'"R""(where Z is alkyl or alkenyl, R'" and R "
"" Are the same or different and are each aryl, heteroaryl, hydrogen,
Alkyl or -CO-L (where L is an alkyl or aryl group)
Represents) and as well as —O—Z—R ′ ″ ″, where Z is as defined above and R ′ ″ ″ is aryl, heteroaryl or heterocyclyl.

Typically, R in the —S (O) ₂ R moiety is hydrogen or alkyl. Typically, R '"and R""in the -Z-NR'" R "" and -Z-NR '"R""moieties are the same or different and are hydrogen, alkyl, -CO-alkyl. Or —CO-phenyl, preferably at least one of R ′ ″ and R ″ ″ is hydrogen or alkyl. Typically Z is alkyl, for example methyl. Typically, R '"" in the -O-Z-R'"" moiety is heteroaryl, such as thiazolyl.

A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocycle substituents are 5- or 6-membered heteroaryl or heterocycle 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 isoxazolyl, pyridyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl and thiadiazolyl. Other preferred substituents include nitro, chlorine, halogens such as bromine or fluorine, -CF ₃ and -CC
C ₁ -C ₄ haloalkyl such as l ₃ , C ₁ -C ₄ alkyl, —CO ₂ R (where 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""(wherein,
R ′ ″ and R ″ ″ are the same or different and each is hydrogen, alkyl or —CO-aryl, such as —CO-phenyl).

The substituents themselves are preferably unsubstituted or one or selected from nitro, cyano, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg haloalkoxy) and hydroxy. It is substituted with further further substituents. Typically, these additional substituents themselves are unsubstituted.

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

Halogen as used herein is typically chlorine, fluorine, bromine or iodine, preferably chlorine, fluorine or bromine.

The alkoxy group used herein is typically the above alkyl group bonded to an oxygen atom. The alkylthio group is typically the above alkyl group attached to a thio group. Haloalkyl or haloalkoxy groups are typically the above alkyl or alkoxy groups substituted with one or more of the above halogen atoms. Typically it is substituted with 1, 2 or 3 of the above halogen atoms.
Preferred haloalkyl and haloalkoxy groups, -CX ₃ and -OC
And perhaloalkyl and perhaloalkoxy groups such as X ₃ (where X is a halogen atom as described above). A particularly preferred haloalkyl group is CF ₃
And CCl ₃ . Particularly preferred haloalkoxy groups, -OCF ₃ and -O
It is CCl ₃ .

Carbocyclic groups, as used herein, are non-aromatic saturated or unsaturated hydrocarbon rings typically having 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring having 3 to 6 carbon atoms (ie a cycloalkyl group). Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It is preferably cyclohexyl. The carbocyclic group may be unsubstituted or substituted at any position. Suitable substituents include nitro, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg haloalkoxy), hydroxy, —CO ₂ R and —S (O) ₂ R, where
R is hydrogen or alkyl), cyano, and -NR'R "and -C
ONR'R "(wherein R'and R" are the same or different and each represents hydrogen or alkyl). Preferred substituents are nitro, chlorine,
Halogens 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 represents hydrogen or C ₁ ~
C ₄ alkyl), C _{1 ~C 4} alkoxy, C ₁ -C ₄ haloalkoxy (e.g., -OCCl ₃ and -OCF _3), and a _{-S (O) 2 -C 1 ~C} 4 alkyl. The substituents themselves are typically unsubstituted.

Heterocyclic groups, as used herein, typically have one or more, for example 1, 2 or 3 carbon atoms replaced by a heteroatom selected from N, O and S. a C ₅ -C ₁₀ carbocyclic non-aromatic saturated or unsaturated. A saturated heterocyclic group is preferred. Examples of suitable heterocyclic groups include piperidine, morpholine,
Included are 1,4 dioxane and 1,3 dioxolane.

The heterocyclic group may be unsubstituted or substituted at any position. Suitable substituents include nitro, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg 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 represent hydrogen or alkyl. Preferred substituents are halogens 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 (where R is Is hydrogen or C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy and-
It is _{S (O) 2 -C 1 ~C} 4 alkyl. The substituents themselves are typically unsubstituted.

Typically —NR ₁ S (O) ₂ R ₃ and —NR ₂ S (O) ₂ R ₄ groups are attached to adjacent carbon atoms on the Ar moiety. When Ar is a heteroaryl group, it is typically a pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl group. Preferably Ar is an aryl group, especially a phenyl group or a naphthyl group. Typically it is unsubstituted or has 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents. Preferred substituents are aryl,
Heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl (eg, haloalkyl), alkylthio, alkoxy (eg, haloalkoxy),
Hydroxy, —CO ₂ R, where R is aryl, heteroaryl, or preferably hydrogen or alkyl, and —NR′R ″ and —CO.
NR′R ″, where R ′ and R ″ are the same or different and are aryl, heteroaryl, hydrogen or alkyl. These substituents are preferably unsubstituted or one or more further substituents selected from nitro, cyano, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg haloalkoxy) and hydroxy. It is substituted with a substituent. Typically, these additional substituents themselves are unsubstituted.

Typically, R ′ and R ″ in the —NR′R ″ and —CONR′R ″ moieties
At least one of is hydrogen or alkyl. Preferred aryl substituents are
It is phenyl. Preferred heteroaryl and heterocycle substituents are 5- or 6-membered heteroaryl or heterocycle groups containing 1, 2 or 3 heteroatoms selected from N, O and S, eg oxadiazolyl groups. . Ar
Further preferred substituents on the group are hydroxyl, nitro, cyano, chlorine,
Halogens such as 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 ″, where R ′ and R ″ are the same or different and are aryl, heteroaryl, hydrogen or C ₁ -C ₄ alkyl.

When Ar is an aryl group fused to an aryl, cycloalkyl, heterocycle or heteroaryl group, it is typically fused to the above heterocycle group. Preferably it is a saturated heterocyclic group containing two oxygen atoms as heteroatoms, eg
Fuse to 1,4 dioxane or 1,3 dioxolane.

[0036]   More preferably, Ar has the formula Ar ':

[0037]

[Chemical 9]

[0038] (In the formula, R_Five~ R₈Are the same or different and are aryl, heteroaryl
, Heterocyclyl, cyano, nitro, halogen, alkyl (eg haloalkyl
), Alkylthio, alkoxy (eg, haloalkoxy), hydroxy,-
CO₂R (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 ar
Represents a kill) or R_FiveAnd R₆Or R₆And R₇Or R ₇ And R₈Form together an alkylenedioxy group or they bind
Form a phenyl moiety with a carbon atom) Is a group having

Typically R _{5 to} R ₈ are the same or different and are cyano, nitro, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg haloalkoxy), hydroxy, —CO ₂ R, where R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R "or -CO.
NR'R ", wherein 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 Alternatively, 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 in the —CO ₂ R moiety is hydrogen or alkyl. Typically, R'and R "in the -NR'R" moiety are the same or different,
Hydrogen or alkyl. Typically, R'and R "in the -CONR'R" moiety 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 (
Bromine), 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 , Same or different, hydrogen, halogen (
For example, bromine), aryl (eg, phenyl), heteroaryl (eg, oxadiazolyl), heterocyclyl, nitro, cyano, halogen, alkyl (eg, haloalkyl), alkoxy (eg, 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 , Aryl, heteroaryl, hydrogen or alkyl) or R ₆ and R ₇ together form an alkylenedioxy group, such as a methylenedioxy or ethylenedioxy group, or they are attached. Forms a phenyl moiety with a carbon atom.

Typically R ₅ and R ₈ are the same or different and are 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, hydrogen, nitro, cyano, halogen, alkyl,
Haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -C
O ₂ R (where R is aryl, heteroaryl, hydrogen or alkyl), or —NR′R ″ or —CONR′R ″ (where R ′ and R ″ are the same, or Or, differently, is aryl, heteroaryl, hydrogen or alkyl), or R ₆ and R ₇ together form an alkylenedioxy group such as a methylenedioxy or ethylenedioxy group, or they are It forms a phenyl moiety with the carbon atom to which it is attached.

Typically, R ′ and R ″ in the —NR′R ″ moiety are the same or different and are hydrogen or alkyl. Typically, R in the -CONR'R "part
'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,
One of R ₅ and R ₈ is hydrogen and the other is halogen, or more preferably hydrogen or hydroxy. More preferably, both R ₅ and R ₈ are hydrogen.

Typically R _{5 to} R ₈ are unsubstituted or selected from nitro, cyano, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg haloalkoxy), and hydroxy 1. It is substituted with one or more further substituents. Typically, these additional substituents themselves are unsubstituted.

[0046]   Preferably R₆And R₇Is hydrogen, aryl (eg, phenyl), hetero
Aryl (eg, oxadiazolyl), nitro, cyano, alkyl, alkoxy
Ci, haloalkyl, halogen, -CO₂H, -CO₂-Alkyl or -CONR
'R ", wherein R'and R" are the same or different and are aryl,
Heteroaryl, hydrogen or alkyl) or R₆And R₇ Together form the above alkylenedioxy group or phenyl moiety. More preferred
Actually, R₆And R₇Is hydrogen, heteroaryl (eg, oxadiazolyl)
C, such as, nitro, cyano, methyl or ethyl₁~ C_FourAlkyl, chlorine, fluorine
Elemental or halogen such as bromine, -CO₂-Et and -CO₂-Like Me-
CO₂-(C₁~ C_FourAlkyl), C such as -OMe₁~ C_FourAlkoxy, or
-CONR'R "(where R'and R" are the same or different,
Heteroaryl, or, preferably, aryl (eg, phenyl), hydrogen if
Kuha C₁~ C_FourIs alkyl) or R₆And R₇Joins it
Forming a further phenyl moiety with the carbon atom which carries More preferably, R ₆ And R₇Are the same or different and are hydrogen, oxadiazolyl, chlorine,
Fluorine, bromine, nitro, cyano, methyl, methoxy, -CO₂H, -CO₂Et,
-CO₂Me, -CONH₂, -CONHMe, and -CONMe₂, -CON
H-phenyl, -CONH- (4-trifluoromethoxyphenyl) or -C
Selected from ONH- (3,5-dimethoxyphenyl) or R₆And
And R₇Form an additional phenyl moiety with the carbon atom to which they are attached
.

When R ₁ and / or R ₂ is an alkyl group it is typically an unsubstituted alkyl group. 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, R ₁ and R ₂ are both hydrogen.

Typically R ₃ and R ₄ are not simultaneously -alkynyl-aryl or -alkynylheteroaryl groups. Preferred -alkyl-aryl and-
Alkyl - heteroaryl group, - (C ₁ ~C ₄ - alkyl) Ariru and -
(C ₁ -C ₄ alkyl) - heteroaryl group, e.g., - (C ₁ -C ₄ Arukiru)
A phenyl (such as benzyl) group. Preferred - alkenyl - aryl and - alkenyl - heteroaryl group, - (C ₂ -C ₄ alkenyl) - aryl and - (C ₂ -C ₄ alkenyl) - heteroaryl group, for example - ethenyl - such as phenyl - It is an ethenylaryl 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.

When R ₃ and R ₄ contain an aryl or heteroaryl moiety fused to an aryl, cycloalkyl, heterocycle or heteroaryl group, it is typically fused to the above heterocycle group or above heteroaryl group. It Examples of such fused groups include (1,2-cyclo (3-thioethyl) -imidazoyl, benzothienyl,
Indole and quinoline groups. Quinoline groups are preferred.

Typically R ₃ and R ₄ are unsubstituted or carry 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents. Preferred substituents are aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl,
Halogen, nitro, -S (O) ₂ - alkyl, haloalkoxy, cyano, -CO ₂ R (where, R represents aryl, heteroaryl, hydrogen or alkyl),
Alkoxy, hydroxy, -CONR'R "(where R'and R" are the same or different and are aryl, heteroaryl, hydrogen or alkyl), -Z-NR '"R""and -NR '"R""(where Z is alkyl or alkenyl and R'" and R "" are the same or different and are each aryl, heteroaryl, hydrogen, alkyl or -CO-. L (where
L represents an alkyl or aryl group), and —O—Z—R ′ ″.
"Where Z is as defined above and R '""is aryl, heteroaryl or heterocyclyl.

Typically Z is alkyl in the above moieties, for example methyl. -Z
R '"and R""in the NR'" R "" and -NR '"R""moieties are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Is at least one of R ′ ″ and R ″ ″ is hydrogen or alkyl. Typically, R '"" in the -O-Z-R'"" moiety is heteroaryl, such as thiazolyl.

More typically, R ₃ and R ₄ are unsubstituted or have 1, 2, 3 or 4 substituents, preferably aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl. , halogen, nitro, -S (O) ₂ - alkyl, haloalkoxy, cyano, -CO ₂ R (where, R represents aryl, heteroaryl, hydrogen or alkyl), alkoxy, hydroxy and -NR'R "And -CONR'R", where R'and R "are the same or different,
It has one or two substituents selected from aryl, heteroaryl, hydrogen or alkyl).

A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocycle substituents are 5- or 6-membered heteroaryl or heterocycle groups containing 1, 2 or 3 heteroatoms selected from N, O and S. Examples are 5- or 6-membered rings containing 1, 2 or 3 heteroatoms,
Examples include pyridyl, isoxazolyl, thiadiazolyl, thiazolyl, isothiazolyl and pyrazolyl. Other preferred substituents include methyl,
Ethyl, n- propyl, i- propyl or t-C ₁ -C ₄ alkyl, such as butyl, 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""(wherein,R'" and R "" are the same or different and are each hydrogen, C ₁ -C represents a ₄ alkyl or -CO-, (C ₁ ~C _{4 alkyl)), - (C 1 ~C} 4 alkyl) -NR '"R""(wherein,R'" and R "" Are the same or different and are each hydrogen, C ₁ -C ₄ alkyl or —CO-aryl (eg, —CO—
Phenyl)), and -O- (C ₁ ~C ₄ alkyl) -R '"" (wherein,
R '"" is heteroaryl, for example thiazolyl).

Most preferred substituents are phenyl, methyl, trifluoromethyl, chlorine, fluorine, bromine, methoxy, trifluoromethoxy, nitro, cyano, —S (O) ₂ —.
Me, isoxazolyl, isothiazolyl, pyrazolyl, 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 one or their selected from nitro, cyano, halogen, alkyl (eg haloalkyl), alkylthio, alkoxy (eg haloalkoxy) and hydroxy. It is substituted with the above further substituents. Typically, these additional substituents themselves are unsubstituted.

[0057]   More preferred compounds of the present invention have the formula (Ia):

[0058]

[Chemical 10]

(Wherein R _{5 to} R ₈ are as defined above in formula Ar ′, and X and Y are
The same or different, represents phenyl or thienyl, n represents an integer of 0 to 4 when X is phenyl, represents an integer of 0 to 3 when X is thienyl, and m is Y Represents an integer of 0 to 4 when phenyl, and 0 when Y represents thienyl.
Represents an integer of ₃ and R ₃ ′ and R ₄ ′ are the same or different and are aryl, heteroaryl and heterocyclic groups, alkyl (eg haloalkyl), halogen, nitro, —S (O) ₂ - alkyl, alkoxy (e.g., haloalkoxy), cyano, -CO ₂ R (where, R represents aryl, heteroaryl, hydrogen or alkyl), hydroxy, -CONR'R "(where, R 'and R ”
Are the same or different and are aryl, heteroaryl, hydrogen or alkyl), -Z-NR '"R""and-NR'" R "", where Z is
Alkyl or alkenyl, R ′ ″ and R ″ ″ are the same or different and are each aryl, heteroaryl, hydrogen, alkyl or —CO—L (
Here, L represents an alkyl or aryl group), or -O-Z-
R '"" (where Z is as defined above, R'"" is aryl,
Heteroaryl or heterocyclyl))).

Typically Z is alkyl in the above moieties, for example methyl. Typically, R '"and R in the -Z-NR'" R "" and -NR '"R""moieties
"" Are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably, at least one of R ′ ″ and R ″ ″ is hydrogen or alkyl. Typically, R ′ in the —O—Z—R ′ ″ ″ part.
"" Is heteroaryl, for example thiazolyl.

Typically R ₃ ′ and R ₄ ′ are the same or different and are heteroaryl and heterocycle groups, alkyl (eg haloalkyl), halogen, nitro, —
S (O) ₂ -alkyl, alkoxy (for example, haloalkoxy), cyano, -C
O ₂ R (where, R represents aryl, heteroaryl, hydrogen or alkyl), hydroxy, and -NR'R "and -CONR'R" (where, R '
And R ″ are the same or different and are selected from aryl, heteroaryl, hydrogen, or alkyl).

[0062]   Preferred compounds of formula (Ia) are R_FiveAnd R₈One is hydrogen,
The other is hydrogen, halogen or hydroxy, or R_FiveAnd R₈With
Is hydrogen and R₆And R₇Are the same or different and are aryl (eg
Phenyl), heteroaryl (eg oxadiazolyl), nitro, sia
No, alkyl (eg methyl and ethyl), haloalkyl, halogen (eg
Chlorine, fluorine and bromine), hydrogen, -CO₂H, -CO₂-Alkyl (eg
, -CO₂-Et and -CO₂-Me), alkoxy (eg methoxy),
And CONR'R ", where R'and R" are the same or different.
, Heteroaryl, or, preferably, aryl, hydrogen or alkyl.
R) or R₆And R₇Together with methylenedioxy
Forms an alkylenedioxy group, such as an ethylenedioxy group, or it
Together with the carbon atom to which they are attached form a further phenyl moiety, X and Y are
The same or different, phenyl or thienyl, n and m are
The same or different, 0, 1 or 2, R₃'And R_Four’Is the same
The same or different, below:   (A) when attached to a phenyl moiety, aryl (eg, phenyl), C₁~
C_FourAlkyl (eg methyl, ethyl, n-propyl, i-propyl or t
-Butyl), C₁~ C_FourHaloalkyl (eg CCl₃And CF₃),halogen
(Eg chlorine, fluorine and bromine), nitro, cyano, C₁~ C_FourAlkoxy (
For example, methoxy), -CO₂R (where R is hydrogen or C₁~ C_FourAlkyl
, -NR'R ", where R'and R" are the same or different.
Becomes, hydrogen, C₁~ C_FourAlkyl or -CO- (C₁~ C_Four) Is alkyl),
-O- (C₁~ C_FourAlkyl) -R '"(where R'" is heteroaryl (eg,
, Thiazolyl), or heterocyclyl), and -S (O).₂−
C₁~ C_FourAlkyl; and   (B) When bonded to a thienyl moiety, pyridyl, thiazolyl, isoxazoli
Groups such as hydrogen, isothiazolyl, pyrazolyl, nitro, chlorine, bromine or fluorine.
Rogen, -CF₃And -CCl₃C like₁~ C_FourHaloalkyl, methyl, ethi
C such as le, n-propyl, i-propyl or t-butyl₁~ C_FourAlkyl,
-CO₂R (where R is hydrogen or C₁~ C_FourAlkyl), methoxy
Like C₁~ C_FourAlkoxy,-(C₁~ C_FourAlkyl) -NH-aryl (eg,
,-(C₁~ C_FourAlkyl) -NH-phenyl), as well as -S (O).₂-C₁~ C _Four Alkyl, Is a compound selected from.

Typically, in these preferred compounds, R ₆ and R ₇ are the same or different and are alkyl such as nitro, methyl or ethyl, haloalkyl, halogen such as chlorine, fluorine or bromine, hydrogen, -CO ₂ -Et and -CO ₂ -
Me as -CO ₂ - alkyl, alkoxy such as methoxy, and -CO
NR'R ", where R'and R" are the same or different and are selected from aryl, heteroaryl, or preferably hydrogen or alkyl, or R ₆ and R ₇ Together form an alkylenedioxy group such as a methylenedioxy or ethylenedioxy group, or together with the carbon atom to which they are attached form a further phenyl moiety. Typically, when bound to the phenyl moiety, R ₃ 'and R _4' is, C ₁ -C ₄ alkyl (e.g., methyl, ethyl, n- propyl, i- propyl or t- butyl), C ₁ -C ₄ haloalkyl (e.g., CCl ₃ and CF _3), halogen (e.g., chlorine, fluorine and bromine), nitro, C ₁ -C ₄ alkoxy (e.g., methoxy), and -S (O) ₂
It is selected from -C ₁ -C ₄ alkyl. Typically, when attached to a thienyl moiety,
R ₃ ′ and R ₄ ′ are isoxazolyl, isothiazolyl, pyrazolyl, nitro, halogen (eg chlorine, bromine and fluorine), C ₁ -C ₄ haloalkyl (eg —CF ₃ and —CCl ₃ ), C ₁ -C. ₄ alkyl (eg, methyl, ethyl,
n- propyl, i- propyl, and t- butyl), - CO ₂ R (where, R represents
Hydrogen or C ₁ -C ₄ alkyl), C ₁ -C ₄ alkoxy (eg methoxy), and —S (O) ₂ —C ₁ -C ₄ alkyl.

Particularly preferred compounds of formula (Ia) are those in which R ₅ and R ₈ are hydrogen and R ₆ and R ₇ are the same or different and are hydrogen, oxadiazolyl, chlorine, fluorine, bromine, nitro, cyano, methyl, _{methoxy, -CO 2 Et, -CO 2 Me} , -C
_{ONH 2, -CONHMe, -CONMe 2,} -CONH- phenyl, -CONH
Selected from-(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 being the same With or different, 0, 1 or 2, X and Y are the same or different, phenyl or thienyl, and R ₃ 'and R ₄ ' are the same or different, 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-Kurorochiazoriru) and, if X and Y are thienyl, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl and -CH ₂ -NH-R (where, R represents phenyl or 4-chlorophenyl There is a compound selected from.

[0065]   More preferred compounds of the present invention have the formula (Ib):

[0066]

[Chemical 11]

Wherein R ₃ and R ₄ are the same or different and (a) halogen (eg chlorine), C ₁ -C ₄ alkyl (eg methyl), C ₁ -C ₄ haloalkyl (e.g., -CF _3), or C ₁ -C ₄ haloalkoxy (e.g., -OCF ₃₎ phenyl optionally substituted with, and (b) halogen (e.g., chlorine), C ₁ -C ₄ alkyl (e.g. , Methyl), C ₁ -C ₄ haloalkyl (eg, —CF ₃ ) and C ₁ -C ₄ haloalkoxy (eg, —OCF ₃ ) optionally substituted thienyl, and R ₆ is halogen (eg, , Chlorine and fluorine), or C ₁ -C ₄ haloalkoxy (for example, —CF ₃ and —CCl ₃ )), or a salt thereof.

The compounds of formula (I) containing one or more chiral centers are used in enantiomerically or diastereomerically pure form, or in the form of a mixture of isomers. Good.

[0069]   Typically, compounds of the invention inhibit, for example, Staphylococcus aureus strains other than MRSA.
When used as an antibacterial agent to harm, R₃And R_FourIs the para position at the amino group
It is not a phenyl group substituted by. More typically, in such compounds R ₃ And R_FourIs not a 4-aminophenyl or 4-nitrophenyl group. Preferred
Actually, R₃And R_FourIs not an aminophenyl group in such compounds.

Preferably, when R ₃ and R ₄ are phenyl groups which are simultaneously substituted in the para position with a C ₁ -C ₄ alkyl group such as a methyl group, Ar is of the formula Ar ′ (as defined above.
Wherein, R _5, R _7, and R ₈ are hydrogen, R ₆ is, -CO ₂ as C ₁ -C ₄ alkyl or -CO ₂ -Et such as methyl - (C ₁ ~C ₄ alkyl A) is not a group having

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. 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. Both acids, organic acids such as tartaric acid, benzoic acid, acetic acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid are mentioned. Pharmaceutically acceptable bases include alkali metal hydroxides (eg sodium or potassium) and alkaline earth metal hydroxides (eg calcium or magnesium), and alkylamines, aralkylamines or heterocyclic amines. An organic base is mentioned.

Particularly preferred compounds of formula (I) include 1,2-bis (4-nitrophenylsulfonylamino) -benzene 1,2-bis (4-methylphenylsulfonylamino) -4,5-dibromobenzene
Benzene 3,4-bis (4-methylphenylsulfonylamino) -6-bromotoluene 1,2-bis (4-methylphenylsulfonylamino) -4-fluorobenze
3- (3-trifluoromethylphenylsulfonylamino) -4- (4-ioo
Dephenylsulfonylamino) toluene 1,2-bis (4-methylphenylsulfonylamino) -4-nitrobenzene 3- (4-methylphenylsulfonylamino) -4- (4-chlorophenyls
Rufonylamino) toluene 1,2-bis (4-methylphenylsulfonylamino) -benzene 1,2-bis (4-methylphenylsulfonylamino) -4-fluoro-5-
Nitrobenzene 3,4-bis (4-methylphenylsulfonylamino) -methyl benzoate
Tell 1,2-bis (4-bromophenylsulfonylamino) -benzene N, N-1,4-bis (4-methylphenylsulfonamide) -7,8-dib
Lomoquinazoline 1,2-bis (4-methylphenylsulfonylamino) -4,5-dichlorobe
Benzene 2,3-bis (4-methylphenylsulfonylamino) naphthalene 1,2-bis (4-methylphenylsulfonylamino) -4,5-difluoro
Benzene 1,2-bis (4-bromophenylsulfonylamino) -4,5-dibromobe
Benzene 1,2-bis (4-fluorophenylsulfonylamino) -4,5-dibromo
Benzene 1,2-bis (3-bromophenylsulfonylamino) -4,5-dibromobe
Benzene 1,2-bis (4-trifluoromethoxyphenylsulfonylamino) -ben
Zen 1,2-bis (4-isopropylphenylsulfonylamino) -benzene 1,2-bis (4-fluorophenylsulfonylamino) -4,5-dimethyl
Benzene 1,2-bis (4-methylphenylsulfonylamino) -4,5-dimethylbenzene
Benzene 1,2-bis (4-trifluoromethoxyphenylsulfonylamino) -4,
5-Dimethylbenzene 1,2-bis (4-isopropylphenylsulfonylamino) -4,5-dime
Cylbenzene 2,3-bis (4-fluorophenylsulfonylamino) phenol 2,3-bis (4-methylphenylsulfonylamino) phenol 2,3-bis (4-trifluoromethoxyphenylsulfonylamino) pheno
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-methylsulfonophenylsulfonylamino) 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, - bis (2,6-difluorophenyl sulfonylamino) benzene 1,2-bis (3-trifluoromethylphenyl sulfonylamino) -4,5
-Dimethylbenzene 1,2-bis (3-chloro-2-methylphenylsulfonylamino) -4,5
-Dimethylbenzene 1,2-bis (2,6-difluorophenylsulfonylamino) -4,5-di
Methylbenzene 1,2-bis (2,6-difluorophenylsulfonylamino) -4-fluor
Robenzene 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) -phen
Nole 3,4-bis (4-trifluoromethylphenylsulfonylamino) -benzoyl
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) pheno
Le 3,4-bis (3-trifluoromethylphenylsulfonylamino) aniso
Ru 1,2-bis (5-chloro-2-methoxyphenylsulfonylamino) benze
2,3-bis (4-trifluoromethylphenylsulfonylamino) phenone
Le 3,4-bis (4-trifluoromethylphenylsulfonylamino) aniso
Ru 1,2-bis (4-trifluoromethylphenylsulfonylamino) -4-ph
Luorobenzene 3,4-bis (3-trifluoromethylphenylsulfonylamino) -benzoic acid
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) -methyl benzoate
Luster 3,4-bis (2-thienylsulfonylamino) fluorobenzene 2,3-bis (2-chloro-5-thienylsulfonylamino) phenol 3,4-bis (2-chloro-5-thienylsulfonylamino) -benzoic acid Acid ethi
Luster 3,4-bis (2-thienylsulfonylamino) -anisole 2,3-bis (2-chloro-5-thienylsulfonylamino) -benzene 1,2-bis [2- (3-oxazolyl) -5-thienyl Sulfonylamino]
-Benzene 1,2-dimethyl-4,5-bis (2-thienylsulfonylamino) -benze
1,2-dimethyl-4,5-bis (2-chloro-5-thienylsulfonylamido)
No) -benzene 1,2-difluoro-4,5-bis (2-thienylsulfonylamino) -ben
Zen 1,2-dibromo-4,5-bis (2,3dichloro-5-thienylsulfonyl)
Amino) -benzene 3,4-bis (2-thienylsulfonylamino) chlorobenzene 3,4-bis (5-chloro-2-thienylsulfonylamino) chlorobenzene 3,4-bis (2-thienylsulfonylamino) -methyl benzoate Ester 3,4-bis (2-chloro-5-thienylsulfonylamino) fluorobenzene
1,2-bis (2-thienylsulfonylamino) -3,4,5,6-tetrame
Cylbenzene 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) -pheno
1,2-bis (2,5-dichloro-3-thienylsulfonylamino) -anisole
1,2-dibromo-4,5-bis (2,5-dichloro-3-thienylsulfonyl)
Lumino) -benzene 3,4-bis (2,5-dichloro-3-thienylsulfonylamino) chlorobe
Benzene 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) naphtha
Len 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) ) Naphthale
2,3-bis (2-methyl-3-chlorophenylsulfonylamino) naphthalene
2,3-bis (4-cyanophenylsulfonylamino) naphthalene 2,3-bis (3,5-dimethyl-3-oxazoylsulfonylamino) naphth
Thallene 2,3-bis (2-aza-4,5-benzothiazoylsulfonylamino) naphth
Thallene 2,3-bis (2- (3-oxazoyl) -5-thienylsulfonylamino)
Naphthalene 2,3-bis (2,6-difluorophenylsulfonylamino) naphthalene 2,3-bis (3-nitro-4-methylphenylsulfonylamino) naphthalene
3,4-bis (2- (1,2-cyclo (3-thioethyl) -4-chloro-5-
Imidazolylsulfonylamino) naphthalene 2,3-bis (4-methylsulfonophenylsulfonylamino) naphthalene 1,2-bis (4-fluorophenylsulfonylamino) -4-nitrobenze
3,4-Bis (4-fluorophenylsulfonylamino) -methyl benzoate
Steal 3,4-bis (4-trifluoromethylphenylsulfonylamino) -benzoyl
Acid methyl ester 3,4-bis (2-chloro-5-thienylsulfonylamino) -benzoic acid methyl ester
Luster 3,4-bis (2-methoxy-2-chlorophenylsulfonylamino) -benzo
Aromatic acid methyl ester 3,4-bis (4-methyl-2-nitrophenylsulfonylamino) -benzoic acid
Acid methyl ester 1,2-bis (3-trifluoromethylphenylsulfonylamino) -4-fluoro
Luorobenzene 1,2-bis (2-thienylsulfonylamino) -4-fluorobenzene 1,2-bis (3,4-dichlorophenylsulfonylamino) -4-fluoro
Benzene 1,2-bis (2-methyl-5-nitrophenylsulfonylamino) -4-ph
Luorobenzene 1,2-bis (phenylsulfonylamino) -4,5-difluorobenzene 3,4-bis (3,4-dichlorophenylsulfonylamino) -ethyl benzoate
Luster 3,4-bis (2,4-dichlorophenylsulfonylamino) -benzoic acid ethi
Luster 3,4-bis (2-chloro-5-thienylsulfonylamino) -benzoic acid ethi
Luster 3,4-bis (2-methyl, 5-nitrophenylsulfonylamino) -benzoic acid
Acid ethyl ester 3,4-bis (2,6-difluorophenylsulfonylamino) -benzoic acid
Tyl ester 1,2-bis (2-methyl, 5-nitrophenylsulfonylamino) -4-me
Toxybenzene 1,2-bis (4-methyl, 3-nitrophenylsulfonylamino) -4-me
Toxibenzene 1,2-bis (3,4-dichlorophenylsulfonylamino) -benzene 1,2-bis (2-chloro-5-thienylsulfonylamino) -benzene 1,2-bis (2-methyl-5-nitrophenyl) Sulfonylamino) -benze
1,2-bis (2- (3-oxazoyl) -5-thienylsulfonylamino)
-Benzene 1,2-bis (4-methyl-3-nitrophenylsulfonylamino) -benze
1,2-bis (4-isopropylphenylsulfonylamino) -4-nitrobe
Benzene 1,2-bis (2-thienylsulfonylamino) -4,5-dimethylbenzene 1,2-bis (3,4-dichlorophenylsulfonylamino) -4,5-dimethyl
Cylbenzene 1,2-bis (2-chloro-5-thienylsulfonylamino) -4,5-dime
Cylbenzene 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-di
Methylbenzene 1,2-bis (1-naphthylsulfonylamino) -4,5-dibromobenzene 1,2-bis (2,3-dichloro-5-thienylsulfonylamino) -4,5
-Dibromobenzene 1,2-bis (2,5-dichloro-3-thienylsulfonylamino) -4,5
-Dibromobenzene 1,2-bis (4-nitrophenylsulfonylamino) -4,5-dibromobenzene
Benzene 1,2-bis (4-biphenylsulfonylamino) -4,5-dibromobenze
1,2-bis (4-bromophenylsulfonylamino) -4,5-dibromobenzene
Benzene 1,2-bis (4-carboxyphenylsulfonylamino) -4,5-dibroth
Mobenzene 1,2-bis (3,4-dimethoxyphenylsulfonylamino) -4,5-di
Bromobenzene 1,2-bis (3-methylphenylsulfonylamino) -4,5-dibromobe
Benzene 1,2-bis (2-fluorophenylsulfonylamino) -4,5-dibromo
Benzene 1,2-bis (2-methoxyphenylsulfonylamino) -4,5-dibromo
Benzene 1,2-bis (4-methylphenylsulfonylamino) -4-cyanobenzene 1,2-bis (phenylsulfonylamino) -4-chlorobenzene 1,2-bis (4-fluorophenylsulfonylamino) -4-chlorobenze
1,2-bis (3-trifluoromethylphenylsulfonylamino) -4-ku
Lorobenzene 1,2-bis (3-trifluoromethoxyphenylsulfonylamino) -4-
Chlorobenzene 1,2-bis (2-thienylsulfonylamino) -4-chlorobenzene 1,2-bis (3,4-dichlorophenylsulfonylamino) -4-chlorobe
Benzene 1,2-bis (4-isopropylphenylsulfonylamino) -4-chlorobe
Benzene 1,2-bis (2,4-difluorophenylsulfonylamino) -4-chloro
Benzene 3,4-bis (4-chloro-2-methoxyphenylsulfonylamino) benzoic
Acid ethyl ester 1,2-bis (2,5-dichloro-3-thienylsulfonylamino) -4-quat
Lolobenzene 1,2-bis (2-chloro-5-thienylsulfonylamino) -4-chlorobe
Benzene 1,2-bis (2-methyl-5-nitrophenylsulfonylamino) -4-quan
Lolobenzene 1,2-bis (2-methyl-3-chlorophenylsulfonylamino) -4-ku
Lorobenzene 1,2-bis (4-cyanophenylsulfonylamino) -4-chlorobenzene 1,2-bis (3,5-dimethyl-4-oxazoylsulfonylamino) -4
-Chlorobenzene 1,2-bis (2,6-difluorophenylsulfonylamino) -4-chloro
Benzene 1,2-bis (4-methyl-3-nitrophenylsulfonylamino) -4-ku
Lolobenzene 3,4-bis (2,4-difluorophenylsulfonylamino) -benzoic acid
Tyl ester 3,4-bis (2-methyl-5-nitrophenylsulfonylamino) -benzoic acid
Acid methyl ester 3,4-bis (2-methyl-3-chlorophenylsulfonylamino) -benzoic acid
Acid methyl ester 3,4-bis (2,6-difluorophenylsulfonylamino) -benzoic acid
Tyl ester 1,2-bis (2-chloro-5-thienylsulfonylamino) -4-fluoro
Benzene 1,2-bis (2-methyl-3-chlorophenylsulfonylamino) -4-ph
Luorobenzene 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
Acid ethyl ester 2,3-bis (4-fluorophenylsulfonylamino) naphthalene 1,2-bis (2,5-dichloro-3-thienylsulfonylamino) -benze
3,4-bis (3-trifluoromethylphenylsulfonylamino) -benzoic acid
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-ku
Lolo-5-methylbenzene 2,3-bis (2-thienylsulfonylamino) naphthalene 1,2-bis (4-trifluoromethylphenylsulfonylamino) -4-ku
Lolobenzene 1,2-bis (4-fluorophenylsulfonylamino) -4,5-difluor
Robenzene 1,2-bis (4-methylsulfonophenylsulfonylamino) -3,4,5
, 6-Tetramethylbenzene 1,2-bis (4-isopropylphenylsulfonylamino) -4-fluoro
Benzene 1,2-bis (4-cyanophenylsulfonylamino) -4-fluorobenze
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) -ammonium
Benzoic acid methyl ester 3,4-bis (4-isopropylphenylsulfonylamino) -benzoic acid methyl ester
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-si
Anobenzene 1,2-bis (4-trifluoromethoxyphenylsulfonylamino) -4-
Cyanobenzene 1,2-bis (2-thienylsulfonylamino) -4-cyanobenzene 1,2-bis (4-isopropylphenylsulfonylamino) -4-cyanobe
Benzene 1,2-bis (2,4-difluorophenylsulfonylamino) -4-cyano
Benzene 1,2-bis (2,5-dichloro-3-thienylsulfonylamino) -4-si
Anobenzene 1,2-bis (3-chloro, 2-methylphenylsulfonylamino) -4-si
Anobenzene 1,2-bis (2,6-difluorophenylsulfonylamino) -4-cyano
Benzene 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
Benzene 1,2-bis (3,4-dichlorophenylsulfonylamino) -4-chloro-
5-methylbenzene 1,2-bis (4-trifluoromethylphenylsulfonylamino) -4-quat
Lolo-5-methylbenzene 1,2-bis (2,4-difluorophenylsulfonylamino) -4-chloro
-5-Methylbenzene 1,2-bis (2,5-dichloro, 3-thienylsulfonylamino) -4-ku
Lolo-5-methylbenzene 1,2-bis (2-chloro, 5-thienylsulfonylamino) -4-chloro-
5-methylbenzene 3,4-bis (2,4-dimethyl, 5-oxa-3-thiazoylsulfonyla
Mino) -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-thienylsulfoni
Luamino) -4-chloro-5-methylbenzene 1,2-bis (2,4-difluorophenylsulfonylamino) -4-chloro
-5-Methylbenzene 1,2-bis (4-methyl, 3-nitrophenylsulfonylamino) -4-ku
Lolo-5-methylbenzene 1,2-bis (4-methyl, 3-nitrophenylsulfonylamino) -4-si
Anobenzene 1,2-bis (phenylsulfonylamino) -4-chloro-5-methylbenze
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-dib
Lomobenzene 1,2-bis (5- (2-pyridyl) -2-thienylsulfonylamino) -4
-Chlorobenzene 1,2-bis (5- (4-chloroacetamidomethyl) -2-thienylsulfo
Nylamino) -4-chlorobenzene 1,2-bis (2- (2-aza-4-thiazoyl) -5-thienylsulfonyl
Amino) -4-chlorobenzene 1,2-bis (2- (2-methyl-4-thiazoyl) -5-thienylsulfoni
Lumino) -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-thienylsulfoni
Lumino) -benzene 1,2-bis (2- (2-methyl-4-thiazoyl) -5-thienylsulfoni
Lumino) -4,5-dimethylbenzene 1,2-bis (2- (2-methyl-4-thiazoyl) -5-thienylsulfoni
Ruamino) -4-fluorobenzene 1,2-bis (3-trifluoromethylphenylsulfonylamino) -4- (
3-Methyl-5-oxadiazole) benzene 1- (4-methylphenylsulfonylamino) -2- (3-trifluoromethyl)
Luphenylsulfonylamino) -4-fluorobenzene 1- (2,5-dichloro-3-thienylsulfonylamino) -2- (3-tri
Fluoromethylsulfonylamino) -benzene 3,4-bis (4-methylphenylsulfonylamino) -N-phenyl-ben
Zamido 3,4-bis (4-methylphenylsulfonylamino) -N- (4-fluoro
Methoxyphenyl) benzamide 3,4-bis (4-methylphenylsulfonylamino) -N- (3,5-dime
Toxyphenyl) benzamide 3- (4-methylphenylsulfonylamino) -4- (3-trifluoromethyl)
Luphenylsulfonylamino) -benzoic acid methyl ester 3- (2,5-dichloro-3-thienylsulfonylamino) -4- (3-tri
Fluoromethylsulfonylamino) -benzoic acid methyl ester 1,2-bis (4-methoxyphenylsulfonylamino) -4,5-dibromo
Benzene 1,2-bis (4-methoxyphenylsulfonylamino) -4,5-dichloro
Benzene 1- (4-methoxyphenylsulfonylamino) -2- (3-trifluorome
Tylphenylsulfonylamino) -4-chlorobenzene 1- (3-chlorophenylsulfonylamino) -2- (3-trifluoromethyl)
Luphenylsulfonylamino) -4-chlorobenzene 1- (2-chlorophenylsulfonylamino) -2- (3-trifluoromethyl)
Luphenylsulfonylamino) -4-chlorobenzene 1- (3-methylphenylsulfonylamino) -2- (3-trifluoromethyl)
Luphenylsulfonylamino) -4-chlorobenzene 1- (4-methylamidomethylphenylsulfonylamino) -2- (3-tri
Fluoromethylphenylsulfonylamino) -4-chlorobenzene 1- (2- (phenylamidomethyl) -5-thienylsulfonylamino) -2
-(3-Trifluoromethylphenylsulfonylamino) -4-chlorobenzene 1- (4- (2-chloro-5-thiazoylmethoxyphenylsulfonylamino)
) -2- (3-Trifluoromethylphenylsulfonylamino) -4-chlorobe
Benzene 1- (2- (phenylamidomethyl) -5-thienylsulfonylamino) -2
-(3-Trifluoromethylphenylsulfonylamino) -benzene 1- (2- (phenylamidomethyl) -5-thienylsulfonylamino) -2
-(3-Trifluoromethylphenylsulfonylamino) -4-fluorobenze
1,2-bis (2- (N-phenyl) amidomethyl-5-thienylsulfonyl)
Amino) -benzene 1- (4- (2-chloro-5-thiazoylmethoxyphenylsulfonylamino
) -2- (3-Trifluoromethylphenylsulfonylamino) -benzene 1- (4- (2-chloro-5-thiazoylmethoxyphenylsulfonylamino)
) -2- (3-Trifluoromethylphenylsulfonylamino) -4-fluoro
Benzene 1- (2-chlorophenylsulfonylamino) -2- (3-trifluoromethyl)
Luphenylsulfonylamino) -benzene 1- (2-chlorophenylsulfonylamino) -2- (3-trifluoromethyl)
Luphenylsulfonylamino) -4-fluorobenzene 1- (2-methylphenylsulfonylamino) -2- (3-trifluoromethyl)
Luphenylsulfonylamino) -benzene 1- (3-methylphenylsulfonylamino) -2- (3-trifluoromethyl)
Luphenylsulfonylamino) -4-fluorobenzene 1- (4-trifluoromethylphenylsulfonylamino) -2- (3-tri
Fluoromethylphenylsulfonylamino) -benzene 1,2-bis (benzylsulfonylamino) -4,5-difluorobenzene 1,2-bis (benzylsulfonylamino) -benzene 1,2-bis (benzylsulfonylamino) -4- Chloro-5-methylbenze
1,2-bis (phenylstyrylsulfonylamino) -4-chlorobenzene 1- (3-trifluoromethylsulfonylamino) -2- (phenylstyryl
Sulfonylamino) -4-fluorobenzene 1- (3-trifluoromethylsulfonylamino) -2- (phenylstyryl)
Sulfonylamino) -benzene 1- (3-trifluoromethylsulfonylamino) -2- (benzylsulfoni
Ruamino) -4-fluorobenzene 4- (3-trifluoromethylsulfonylamino) -3- (2-phenylethene)
Nylsulfonylamino) -benzoic acid ethyl ester and salts thereof, especially their pharmaceutically acceptable salts.

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, particularly pharmaceutically acceptable thereof It is a salt.

Certain bissulfonamide derivatives of formula (Ia) are novel per se. These compounds have the following formula (Id):

[0075]

[Chemical 12]

Where R ₁ and R ₂ are as defined above, R ₃ and R ₄ are as defined above, and Ar is a group of Ar ′ as defined above. Where R ₁ and R ₂ are both hydrogen and Ar is an unsubstituted naphthyl group, 1 or 2 dimethylmethylenedioxy, hydroxy, methoxy, ethoxy, methyl, chlorine, bromine, fluorine, nitro, When it is a phenanthracene group optionally substituted with CF ₃ or an amino group or a phenyl group, R ₃ and R ₄ are (a) an unsubstituted quinoline group, (b) an unsubstituted phenyl group, and (c) Methyl, methoxy, -C
In an O ₂ H, chlorine, cyano, nitro or amino group, or a phenyl group monosubstituted by an —O—CO—N (CH ₃ ) — group, (d) a phenyl group disubstituted by a nitro group and a methyl group, No) bissulfonamide, and salts thereof.

[0077]   Suitable salts include those mentioned above for pharmaceutically acceptable salts.

[0078]   The preferred novel compounds of the present invention are bis-sulfurs of formula (Id) as defined above.
Honamide, and salts thereof, wherein R₁And R₂Are both hydrogen,
Ar is an unsubstituted naphthyl group, one or two C₁~ C_FourAlkylenedioxy
, Hydroxy, C₁~ C_FourAlkoxy, C₁~ C_FourAlkyl, halogen, nitro, C ₁ ~ C_FourA phenanthracene group optionally substituted with a haloalkyl or amino group
Is a phenyl group, R₃And R_FourIs an unsubstituted quinoline group or C₁
~ C_FourAlkyl, C₁~ C_FourAlkoxy, -CO₂R (where R is hydrogen or C₁
~ C_FourAlkyl), halogen, cyano, nitro and amino groups,
And formula-O-CO-N (C₁~ C_FourOne or two selected from alkyl)-
Not a phenyl group optionally substituted with a group.

[0079]   The compound of formula (I) has the following formula (II):

[0080]

[Chemical 13]

Wherein Ar, R ₁ , R ₂ and R ₃ are as defined above, the compound of formula (III):

[0082]

[Chemical 14]

May be prepared by a process comprising reacting a compound of the formula: wherein R4 is as defined above and X is a leaving group such as a chlorine atom.

The reaction is typically carried out 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 compounds of formulas (II) and (III) are used.

[0085]   The compound of formula II has the formula (IV):

[0086]

[Chemical 15]

(Wherein Ar, R ₁ and R ₂ are as defined above), a compound of formula (V):

[0088]

[Chemical 16]

May be prepared by reacting with a compound of the formula: wherein R ₃ and X are as defined above.

The reaction is typically carried out in the presence of organic solvent and base. Typically the solvent is acetonitrile, dichloromethane, toluene or dimethylformamide. Typically the base is pyridine, triethylamine or 4-dimethylaminopyridine. Typically, molar equivalents of compounds of formulas (IV) and (V) are used.

The compound of formula I, wherein R ₃ and R ₄ are the same, is, of course, the compound of formula (IV), under the above reaction conditions, with 2 molar equivalents of the compound of formula (III) You may prepare by making it react.

Preferably, the solvent used in the above reaction is acetonitrile or dichloromethane and the reaction is carried out in the presence of pyridine or 4-dimethylaminopyridine.

Alternatively, the compound of formula (II), wherein Ar, R ₁ and R ₃ are as defined above, and R ₃ is hydrogen, is represented by the following formula (VI):

[0094]

[Chemical 17]

It can also be prepared by reacting a compound of the formula: wherein Ar, R ₁ and R ₃ are as defined above with a suitable reducing agent.

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

[0097]   The compound of formula (VI) has the following formula (VII):

[0098]

[Chemical 18]

It can be prepared by reacting a compound of formula (V) in which Ar and R ₁ are as defined above with a compound of formula (V). Typically the reaction is carried out in the presence of organic solvent and base. Typically the solvent is acetonitrile, dichloromethane, toluene or dimethylformamide. Typically the base is pyridine, triethylamine or 4-dimethylaminopyridine. Typically, molar equivalents of compounds of formulas (IV) and (V) are used.

Further synthetic manipulations (eg bromination, nitration and acylation) of the thus obtained compounds of formula (I) may be carried out by conventional methods for obtaining further compounds of formula I.

The bissulfonamide derivative of formula (I) thus obtained may be salified by treatment with a suitable acid and base.

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

The compounds of formula (I) have been found to be inhibitors of dehydroquinate synthetase enzymes, especially AroB, and type II dehydrokinase enzymes, especially AroQ.

As explained above, the dehydroquinate synthetase enzyme invariably becomes an integral part of the shikimate pathway. Moreover, type II dehydrokinase enzymes are involved in the shikimate pathway in many organisms. The type II dehydrokinase enzyme also becomes an important part of the catabolic pathway in which quinic acid catabolism occurs. The compounds of the present invention are particularly highly active against organisms where the shikimate pathway comprises a type II dehydrokinase enzyme and those that use both the shikimate pathway and the quinic acid catabolic pathway. It has two enzymatic targets for such organisms.

Accordingly, the present invention provides a method of treating a patient in need of an inhibitor of aromatic amino acid biosynthesis via the shikimate pathway, which comprises an effective amount of a compound of formula (I) Is administered to said patient.

The shikimate pathway is essential for the synthesis of aromatic amino acids in fungi and bacteria. Accordingly, the compounds of the present invention are effective in treating or preventing bacterial or fungal infections. In fact, the compounds of this 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, the agents are for use in treating or preventing a bacterial or fungal attack, and the patient is typically vulnerable to or susceptible to a bacterial or fungal attack. In particular, the patient is typically afflicted with or susceptible to MRSA infection, and the agent is typically for use in the prevention or treatment of MRSA infection.

Genes encoding type II dehydrokinases include Actinobacillus pleuropneumoniae, Actinobacillus actinomycetes, and Aeromonas salmonicida.
omonas salmonicida) subspecies, Salmonicida, Amycolatopsis
Mediterranei (Amycolatopsis mediterranei), Bacillus subtilis (Bacillu
s subtilis), Corynebacterium glutamicum
), Corynebacterium pseudotubercosis
rculosis), Emericella nidulans, Haemophilus
Haemopnilus influenzae, Helicob
acter pylori), Neurospora crassa, Pseudomonas aeruginosa, Streptomyces coelicolor (S
treptomyces coelicolor), Streptomyces lavendrae (Streptomyces l
avendulae), Synechocystis sp, Thermotoga melitima (Th
ermotoga meritima), Campylobacter jejuni,
Clostridium acetobutylicum, Porphyromonas gingivalis, Deinococcus radiodurans, Chlorobium tepdom
idum), Vibrio cholerae, Yersini pestis (Yersini)
a pestis), Shewanella putrafaciens, Thiobacillus ferroxidans, Synechocystis
echocystis PCC6803, Candida albicans, Bordetella pertussis, Mycobacterium aviumu, Mycobacterium tuberculosis (Mycobacteri)
um tuberculosis), Mycobacterium bovis, Mycobacterium leprae, Caulobacter eresentus, and Klebsiella pneumoniae.
pneumoniae).

The compounds of the invention are particularly active against the organisms mentioned above. This is because, as mentioned above, the compounds of the invention act to inhibit both dehydroquinate synthetase and type II dehydrokinase enzymes in these organisms. Thus, the agent is typically for use in the treatment or prevention of an attack by one of the organisms, or the patient is typically vulnerable to an attack by one of the organisms. Have or are susceptible to infection.

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

The shikimate pathway is also involved in parasite metabolism. For example, it is involved in the treatment of Apicomplexan parasites. Therefore, the compounds of the present invention are effective in treating or preventing infections by parasites in which aromatic amino acid biosynthesis occurs via the shikimate pathway. Such parasites may, for example, (a) determine whether growth in vitro is inhibited by a well-characterized inhibitor of the shikimate pathway, such as glyphosphate, and (b ) Can be identified by determining whether such inhibition is abolished by the addition of p-aminobenzoate. Growth in vitro is inhibited by glyphosphate and such inhibition
Parasites that are disabled by the addition of p-aminobenzoate use the shikimate pathway in the metabolic process. Therefore, the compounds of the invention will be active against such parasites.

In particular, the compounds of the present invention are suitable for the apicomplexan parasite
, For example, Toxoplasma gondii, Cryptosporidium parvum (Cryptosporidi
um parvum) and temperate falciparum malaria. Plasmodium falciparum is known to cause malaria. Thus, the patient is typically susceptible to or susceptible to infection by the Apicomplexa parasite, and the agent is typically for use in treating or preventing infection by the Apicomplexa parasite. In particular, said patient typically suffers from malaria,
Or susceptible to infection, the drug is typically for the treatment or prevention of malaria.

When used to treat the above 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 may also be administered parenterally (either subcutaneously, intravenously, intramuscularly, intrasternally, transdermally, or by infusion techniques).

Certain compounds of formula (I) have not previously been disclosed in a therapeutic setting.
Accordingly, the invention also relates to formula (I) as defined above, wherein Ar, R ₁ , R ₂ , R ₃ and R ₄ are for use in a method of treating the human or animal body.
As defined above, provided that R ₁ and R ₂ are hydrogen and R ₃ and R ₄ are phenyl, 4-methylphenyl or 4-aminophenyl, Ar is:

[0114]

[Chemical 19] (Wherein R ′ and R ″ are not methyl or chlorine)), and bissulfonamide derivatives thereof, and pharmaceutically acceptable salts thereof.

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

The compounds of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, a solid oral form may consist of a diluent (with the active compound
For example, lactose, dextrose, saccharose, cellulose, corn starch or potato starch), lubricants (eg silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol), binders (eg starch, acacia) , Gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone), separating agents (eg starch, alginic acid, alginate or sodium starch glycolate), effervescent mixtures, dyes, sweeteners, wetting agents (eg lecithin, polysorbates, laurylsulfates). , And generally may contain non-toxic, pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in a known manner, for example using mixing, granulating, tabletting, sugar coating or film coating processes.

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

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Intramuscular injection suspensions or solutions, together with the active compound, in a pharmaceutically acceptable carrier, such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, an appropriate amount of hydrochloric acid. It may contain lidocaine.

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

A therapeutically effective amount of a compound of the invention is administered to the patient. A typical dose will be from about 0.001 to 5 per kg body weight, depending on the activity of the particular compound, age, weight and condition of the subject being treated, type and severity of the illness, and frequency and route of administration.
It is 0 mg. Preferably, the daily dose level is about 5 mg to 2 g.

The shikimate pathway is also essential in advanced plants, algae and fungi. Furthermore, a pathway for quinic acid catabolism is also found in fungi. Therefore,
The compounds of the present invention are effective in controlling advanced plants, algae and fungi.
They can be used, for example, as selective herbicides and fungicides. Accordingly, the present invention 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 controlling weeds or fungi in a locus, which method comprises treating the locus with a compound of formula (I) or an agriculturally acceptable salt thereof.

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

A preferred method for controlling fungi is to treat the plant with respect to fungal attack or to protect the plant against fungal attack, which method comprises:
A.) Or an agriculturally acceptable salt thereof, to a plant. Plant smuts and rusts can be treated, for example, by this method.

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

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

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

The herbicidal or fungicide composition is prepared by mixing a compound of formula (I), or an agriculturally acceptable salt thereof, with an agriculturally acceptable carrier or diluent. Good. Suitable such compositions include wettable powders, granules, water dispersible granules, emulsion concentrates, suspension concentrates, and powders suitable for application to plants. The fungicide or herbicide composition is a further agrochemical, such as a further fungicide and herbicide, or an insecticide, acaricide, plant growth regulator,
Fertilizers and soil conditioners may be included.

The herbicide or fungicide composition preferably comprises an additional fungicide or herbicide. This leads to a broadening of the herbicide or fungicide spectrum as well as a reduction in dose and manpower. This spread is due to cooperative activity.

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

Examples of solid carriers or diluents include kaolinite, montmorillonite, illite and polygloskite, and more particularly pyrophyllite, attapulgite, sepiolite, kaolinite, bentonite, vermiculite, mica and Examples include clay such as talc. Other inorganic materials such as gypsum, calcium carbonate, dolomite, diatomaceous earth, magnesium lime, phosphorous lime, zeolites, anhydrous silicic acid and synthetic calcium silicates may also be used. Suitable organic carriers and diluents include soy flour, tobacco flour, walnut flour, wheat flour, wood flour, starch and crystalline cellulose. Coumarone resin, petroleum resin,
Further synthetic or natural polymers such as alkyd resins, polyvinyl chloride, polyalkylene glycols, ketone resins, ester gums, copal gums and dammal gums are suitable, as are waxes such as carnauba wax and beeswax.

Examples of suitable liquid carriers and diluents are kerosene, paraffinic or naphthenic hydrocarbons such as mineral oil, spindle oil and white oil, aromatic hydrocarbons such as xylene, ethylbenzene, cumene and methylnaphthalene, Chlorinated hydrocarbons such as trichloroethylene, monochlorobenzene and o-chlorotoluene, ethers such as dioxane and tetrahydrofuran, acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, ketones such as acetophenone and isophorone, ethyl acetate, amyl acetate, ethylene glycol. Acetates, esters such as diethylene glycol acetate, dibutyl maleate and diethyl succinate, methanol, n-hexanol, ethylene glycol, diester Mention may be made of alcohols such as ethylene glycol, cyclohexanol and benzyl alcohol, ether alcohols such as ethylene glycol ethyl ether and diethylene glycol butyl ether, and polar solvents such as dimethylformamide, dimethylsulfoxide and water.

Typically herbicidal and fungicide compositions comprise a surfactant and / or an emulsifying agent,
Dispersion, humidification, spreading, dilution, combined use destruction control, stabilization of active ingredient, improvement of fluidity,
It contains other auxiliaries which are suitable for various purposes such as corrosion protection and freeze protection. Preferably, the herbicidal and fungicidal composition of the present invention comprises at least one surfactant. The present invention also provides a herbicide or a killing agent comprising: a bissulfonamide of formula (I) or an agriculturally acceptable salt thereof, at least one surfactant, and an agriculturally acceptable carrier or diluent. A fungal composition is provided.

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

Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic surface-active compounds.

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

However, more often so-called synthetic surfactants are used, especially aliphatic sulfonates, aliphatic sulphates, sulphonated benzimidazole derivatives or alkylaryl sulphonates.

[0137] Aliphatic sulfonates or sulfates are usually in the form of alkali metal salts, in the form of alkaline earth metal salts or unsubstituted or substituted ammonium salts,, C ₈ -C _{2 2} alkyl group (which also includes the alkyl alkyl group Or a portion thereof) and is, for example, the sodium or potassium salt of a mixture of lignosulfonic acid, dodecyl sulfate or a fatty alcohol sulfate obtained from natural fatty acids. These compounds also include sulfates of fatty alcohol / ethylene oxide adducts and salts of sulfonic acids. The sulfonated benzimidazole derivative is
It preferably contains two sulfonic acid groups and one fatty acid group containing 8 to 22 carbon atoms. Examples of alkylaryl sulphonates are the sodium, calcium or triethanolamine salts of dodecylbenzene sulphonic acid, dibutylnaphthalene sulphonic acid or of naphthalene sulphonic acid / formamide condensates. Also suitable are the corresponding phosphates (eg salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4 to 14 mol of ethylene oxide).

The nonionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, or saturated or unsaturated fatty acids and alkylphenols, said derivatives having 3 to 30 glycol ether groups. and(
The (aliphatic) hydrocarbon portion contains 8 to 20 carbon atoms and the alkyl portion of the alkylphenol contains 6 to 18 carbon atoms.

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

[0140]   The cationic surfactant is preferably at least one C as N substituent. ₈ ~ C_{twenty two}An alkyl group of, and as a further substituent, a lower unsubstituted or halo
Quaternary ammonium having a benzylated alkyl, benzyl or lower hydroxyalkyl group
It is a nickel salt. The salt is preferably halide, methylsulfate or
In the form of ethylsulfate, for example stearyltrimethylammonium
Chloride or benzyldi (2-chloroethyl) ethylammonium bromide
Is.

Surfactants include, for example, McCuycheon's Detergents and Emulsifiers Annual,
MC Publishing Corp. Ringwood, New Jersey, 1979 and Sisely and Wood, Enc
yclopaedia of Surface Active Agents, Chemical Publishing Co., Inc. New Y
Conventionally used in the prior art in formulations such as those described in ork, 1980.

Examples of the above-mentioned auxiliary agents include casein, gelatin, albumin, glue, sodium alginate, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol.

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

The active compound content of the herbicidal and fungicidal compositions according to the invention can be varied within wide limits depending on the form of formulation. Typically, the amount of active compound will be from 0.1 to 99% by weight of the composition, preferably from 1 to 80%.

More specifically, wettable powders typically contain 25-90% by weight of active compound. Granules typically contain 1 to 35% by weight of active compound, which is intimately mixed with the solid carrier or diluent or on the surface of the solid carrier or diluent, Alternatively, it may be absorbed. The diameter of the granules is 0.
It is preferably 2 to 1.5 mm. Emulsion concentrates typically contain 5-30% by weight of active compound, and additionally 5-20% by weight of emulsifier. Suspension concentrates typically contain 5-50% by weight of active compound, and additionally 3-10% by weight.
Of the dispersion wetting agent.

The compounds of the invention may be applied in effective amounts to various locations to be protected, for example agricultural lands such as paddy fields and uplands, or non-agricultural lands. When used as herbicides, they may be applied pre-emergence of weeds or to weeds at various stages of post-emergence to growth. When using the compounds according to the invention as herbicides, the dosage is generally 0.1 to 10,000 g / ha, preferably 1 to 5, as the amount of active ingredient.
000 g / ha, more preferably about 50 to 3,000 g / ha. The dose may vary depending on the type of weeds of interest, their stage of development, location of application and weather. If a compound of the invention is used as a fungicide, the dose will typically be 50 g to 5 kg per hectare, preferably 100 per hectare.
g to 2 kg, more preferably 200 g to 500 g of active ingredient per hectare.

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

As mentioned above, the type II dehydrokinase enzyme forms an important part of the catabolic pathway in which quinic acid catabolism takes place. Accordingly, the invention also provides the use of a bissulfonamide derivative of formula (I) as defined above, or a salt thereof, in the inhibition of quinic acid catabolism. Suitable salts include those mentioned above as examples of pharmaceutically acceptable salts.

The catabolic pathway is found in many fungi and bacteria. Therefore, the compounds of the invention are typically used to inhibit the catabolic effects of quinic acid by fungi or bacteria. They may be formulated for use as a herbicide or fungicide composition, as defined above, and may be used in the dosage ranges mentioned above.

[0150]   The following example illustrates the invention.

Example 1 1,2-Bis (3-nitrophenylsulfonylamino) -benzene A solution of 1,2-phenylenediamine (10 mM) in dry pyridine (50 ml) was stirred at room temperature under nitrogen to give 3- Nitrobenzenesulfonyl chloride (20 mM
) Was added little by little over a few minutes. The resulting solution was heated at reflux for 5 hours, then cooled and poured onto cold 1N hydrochloric acid (500 ml). The product was extracted into ethyl acetate (3 × 200 ml), the organic extracts were combined, washed with water, 1N sodium hydroxide, then again with water, then dried over anhydrous sodium sulfate,
Evaporated under reduced pressure. Column chromatography on silica gave the desired product (3.1 g, 65%).

Examples 2-8 The compounds set out below were prepared in the same manner as Example 1 using the appropriate starting materials.

[0153]

[Table 1]

Example 9 1,2-Bis (4-toluenesulfonylamino) -benzene 1,2-Phenylenediamine (10 mM) in dry acetonitrile (50 ml).
, 1.08 g) was stirred at room temperature under nitrogen. After adding diisopropylethylamine (5 ml), benzenesulfonyl chloride (4.19 g, 22 mM)
) Was added. The resulting solution was heated at reflux for 10 hours, then cooled and evaporated under reduced pressure. The resulting solid was partitioned between water and chloroform, the organic layer was separated, washed with 1N sodium hydroxide solution, then water, finally dried over anhydrous sodium sulfate and evaporated under reduced pressure. It was The crude product was purified by column chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane. The product was isolated as a white powder (1.8 g, 4
3%). Melting point 203-205 [deg.] C.

Examples 10-21 The compounds shown below were prepared in the same manner as Example 9 using the appropriate starting materials.

[0156]

[Table 2]

Example 22 3- (3-Trifluoromethylphenylsulfonylamino) -4- (4-methylphenylsulfonylamino) toluene A solution of 3,4-diaminotoluene (10 mM) in dry pyridine (50 ml) is brought to room temperature. And stirred under nitrogen and 3- (3-trifluoromethylphenyl) sulfonyl chloride (10 mM) was added portionwise over a few minutes. The resulting solution for 5 hours,
Heat at reflux, then cool and pour onto cold water. The product was converted into ethyl acetate (
3 × 200 ml), the combined organic extracts were washed with water, 1N sodium hydroxide, then again with water, then dried over anhydrous sodium sulfate and evaporated under reduced pressure. Obtained 4- (4-methylphenylsulfonylamino)-
3-Aminotriene was exposed to the same reaction conditions with 3- (trifluoromethylphenyl) sulfonyl chloride (10 mM). Column chromatography on silica gave the desired product.

Examples 23 and 24 The compounds set out below were prepared in the same manner as Example 22 using the appropriate starting materials.

[0159]

[Table 3]

Example 25 1,2-Bis (4-toluenesulfonylamino) -4,5-dibromobenzene 1,2-Bis (4-toluenesulfonylamino) -benzene (500 mg, 1 0.2 mM) solution was stirred and sodium acetate (200 mg
) Was added. Bromine (385 mg, 0.13 ml, 2.4 mM) was added dropwise and the resulting dark solution was heated at 80 ° C. for 3 hours. Water (50 ml) was added and the resulting precipitate was isolated by filtration and purified by recrystallisation from acetic acid to give the desired product as white needles. Melting point 213 to 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 × 10 4) ^-4 mol) and dibromoethane (57 mg, 3x
10 ⁻⁴ mol) in potassium carbonate (1.0 ml) in dry acetonitrile (250 ml).
g, 7.25 × 10 ⁻⁴ mol) under nitrogen for 4 hours and then stirred overnight at room temperature. The solution was filtered, drained and removed to dryness to give the product as a light 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
) Was dissolved in dry pyridine (100 ml) and stirred under nitrogen at room temperature. To this solution was added a solution of 5-chloro-2-thienylsulfonyl chloride (21 mM, 4.55 g) in pyridine (15 ml) and the resulting solution was heated to 85 ° C. under nitrogen.
It was stirred for 18 hours. The solution was then poured into cold 0.5M dilute hydrochloric acid (125ml) and the product extracted into chloroform. The solution was then dried over anhydrous sodium hydrogen carbonate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica eluting with a mixture of chloroform and methanol. The product was further purified by recrystallisation from ethanol / water and dried under vacuum overnight. The product was obtained as an off-white crystalline solid (2
． 18 g, 42%).

Examples 28-58 The compounds set out below were prepared in the same manner as Example 27 using the appropriate starting materials.

[0164]

[Table 4]

Example 59 1,2-Bis (4-trifluoromethoxyphenylsulfonylamino) -benzene 1,2-Phenylenediamine (24 mg, 0.
22 mmol) solution, pyridine (0.05 ml, 0.66 mmol, 3 eq)
Was added. To this solution was added a solution of (4-trifluoromethoxy) phenylsulfonyl chloride (84 mg, 0.44 mmol) in acetonitrile (2 ml). The reaction mixture was allowed to stand at ambient temperature for 24 hours. Upon completion, the reaction mixture was concentrated in vacuo to give a thick syrup. Syrup in dichloromethane (1m
1) and water (1 ml). The phases are separated and the organic phase is water (1 ml).
Washed with citric acid (10%, 1 ml) and brine (1 ml). The organic solution was dried in vacuo to give the final product, which was analyzed by liquid chromatography coupled with mass spectrometry.

Examples 60-64 The compounds set out below were prepared in the same manner as Example 59 using the appropriate starting materials.

[0167]

[Table 5]

The above compound was analyzed by liquid chromatography coupled to a mass spectrometer as a detector. The instrument used was a Waters 27 equipped with a Water 2690 Combined Solvent Delivery System and a Water 966 Photodiode Array Detector.
00 sample manager. The mass spectrometer used was a Micromass M
Microm running assLynx software v3.2 build004
It was an ass Platform LCZ mass spectrometer. Chromatography was performed at a flow rate of 0.5 ml / min for 3 minutes from 10 mM formic acid in 5% acetonitrile and 10 mM formic acid in 95% water to 10 mM in 95% acetonitrile.
Waters with gradient elution to 10 mM formic acid in formic acid and 5% water.
Symmetry 3.5 μm C18 50 × 2.0 mm (WAT20065
0) run by column. UV detection was 200-300 nm and mass spectra were collected by positive and negative electrospray. All reaction products showed the desired compound with satisfactory purity.

Example 65 1,2-Bis (3-trifluoromethylphenylsulfonylamino) -4,5
-Dimethylbenzene To a solution of 4,5-dimethyl-1,2-phenylenediamine (30 mg, 0.22 mmol) in acetonitrile (2 ml), pyridine (0.05 ml, 0.66).
mmol, 3 eq) was added. Dimethylformamide (2 ml) was added to this solution.
3-trifluoromethylphenylsulfonyl chloride in (108 mg, 0.4
4 mmol) solution was added. The reaction mixture was allowed to stand at ambient temperature for 24 hours. Upon completion, the reaction mixture was concentrated in vacuo to give a thick syrup. The syrup was dissolved in dichloromethane (1 ml) and water (1 ml). Separate the phases,
The organic phase is water (1 ml), citric acid (10%, 1 ml) and saturated saline (1 ml).
) Was washed with. The organic solution was dried in vacuo to give the final product, which was analyzed by liquid chromatography coupled with mass spectrometry.

Examples 66-256 The compounds shown below were prepared in the same manner as Example 65 using the appropriate starting materials.

[0171]

[Table 6]

The above compound was analyzed by liquid chromatography coupled to a mass spectrometer as a detector. The equipment used was a Waters 2690 Union Solvent Delivery System and a Waters 966 Photodiode Array Detector equipped Water detector.
It was a 2700 sample manager. The mass spectrometer used was a Micromass
Micr running MassLynx software v3.2 build004
It was an omas Platform LCZ mass spectrometer. Chromatography was performed at a flow rate of 0.5 ml / min for 3 minutes at 10 mM in 5% acetonitrile.
From 10 mM formic acid in formic acid and 95% water to 10% in 95% acetonitrile.
Waste elution with gradient elution to 10 mM formic acid in mM formic acid and 5% water.
rs Symmetry 3.5 μm C18 50 × 2.0 mm (WAT20
0650) column. UV detection was 200-300 nm and mass spectra were collected by positive and negative electrospray. All reaction products showed the desired compound with satisfactory purity.

Example 257 3,4-bis (4-methylphenylsulfonylamino) -benzoic acid 3,4-bis (4-methylphenylsulfonylamino) -benzoic acid methyl ester (Example 8, 3.5 g, 7 (.38 × 10 ⁻⁴ mol) was stirred in 1N sodium hydroxide solution (250 mL) at 60 ° C. for 5 hours. After this time, the solution was cooled, the precipitate was filtered, washed with water, recrystallized from acetic acid and water,
Obtained 2.0 g, 59% of the title compound.

Example 258 1,2-bis (3-trifluoromethylphenylsulfonylamino) -4- (
3-Methyloxadiazol-5-yl) benzene N-hydroxy-acetamidine (0.028) in THF (dry, 15 ml).
g, 0.39 mmol) with sodium hydride (0.015 g, 0.39 mmo)
l) was added to a stirred solution of dry THF (5 ml). The mixture was heated to 60 ° C under nitrogen. 3,4-Bis (3-trifluoromethylphenylsulfonylamino) -benzoic acid methyl ester (Example 207) in dry THF (5 ml).
, 76 mg, 0.13 mM) solution was added dropwise over 15 minutes. The reaction was refluxed overnight. Methanol (5 ml) and then water (5 ml) were added sequentially and the mixture was concentrated to dryness. The crude product was column chromatographed on silica with methanol / dichloromethane to give the product (21 mg, 27%).

Example 259 3,4-bis (4-methylphenylsulfonylamino) -N-phenyl-benzamide 3,4-bis (4-methylphenylsulfonylamino) -benzoic acid (Example 2
57, 0.092 g, 0.2 mmol), aniline (0.0186 g, 0.2 m)
mol), N, N- (diisopropyl) amino-methyl polystyrene resin (PS
-DIEA) (0.172 g, 0.6 mmol, loading 3.5 mmol / g) and O- (7-azabenzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate ( HATU) (0.076 g, 0.
2 mmol) in anhydrous acetonitrile (8 mL) under nitrogen and stirred at 50 ° C.
It was heated for 40 hours. After this time had passed, the reaction mixture was cooled to room temperature.
Next, sequestration-enabling reagent-tetrafluorophthalic anhydride (0.132 g, 0.6
mmol) and the reaction mixture was stirred under nitrogen for 18 hours. Macroporous triethylammonium methylpolystyrene carbonate resin (MP-carbonate, 0.630 g, 2.0 mM, loading 3.18 mM / g) was then added and the reaction mixture was stirred under nitrogen for a further 48 hours. The reaction mixture was then filtered through a filter syringe into a vial and the precipitate washed with methanol. The combined solvent was removed on a vacuum concentrator to give 0.051 g, 48%. This product is LC-M
It was analyzed by S and had a purity of 85.0%.

Examples 260 and 261 The compounds set out below were prepared in the same manner as Example 259, using the appropriate starting materials.

[0177]

[Table 7]

Example 262 3- (2-phenyl-ethenesulfonylamino) -4- (3-trifluoromethylbenzenesulfonylamino) -benzoic acid ethyl ester 4- (3-trifluoromethylsulfonylamino) -3-nitro Benzoic acid ethyl ester (prepared according to Example 22 using appropriate starting materials, 1.00 g,
2.66 mmol) was dissolved in ethanol (50 ml). The solution was stirred and palladium on carbon (5%) was added slowly, then ethanol was added to wash the sides of the vessel, then excess hydrazine hydrate (2 ml) was added. The solution was refluxed for 18 hours, filtered and evaporated to dryness. The product was then purified on silica using methanol / chloroform as eluent to give 3-amino-4- (3-trifluoromethylbenzenesulfonylamino).
-Benzoic acid ethyl ester was obtained as a dry white solid (0.81 g, 89%).
This material was then reacted with 2-phenylethenesulfonyl chloride according to Example 22 to give the title product.

Examples 263-271 The following compounds were prepared in the same manner as Example 262, using the appropriate starting materials.

[0180]

[Table 8]

Example 272 1- (4-methylphenylsulfonylamino) -2- (3-trifluoromethylphenylsulfonylamino) -4-fluorobenzene 1-nitro-2- (3-trifluoromethylphenylsulfonylamino) -4
-Fluorobenzene (prepared according to Example 22 using appropriate starting materials, 0.1
3 g, 0.32 mmol) with tin (II) chloride (0.28 g, 1.25 mmo)
It was stirred in dimethylformamide (1 ml) containing 1). The reaction was allowed to stir under nitrogen at room temperature overnight. The mixture was diluted with water (15 ml) and the pH was adjusted to 7 with 1M sodium hydroxide solution. The aqueous solution was extracted with chloroform and the chloroform was removed under vacuum to give an orange oil. It was purified by flash chromatography on silica with methanol / chloroform to give 1
-Amino-2- (3-trifluoromethylphenylsulfonylamino) -4-fluorobenzene was obtained (0.07 g, 58%). This material was then reacted with 4-methylphenylsulfonyl chloride in the same manner as in Example 22 to obtain the title compound.

Examples 273-285 The following compounds were prepared in the same manner as Example 272, using the appropriate starting materials.

[0183]

[Table 9]

[0184]   Example 286   Analytical data for representative compounds of Examples 1-285

[0185]

[Table 10]

Example 287 Inhibition of purified dehydroquinate synthetase (AroB) was tested at a single concentration (50 μM).
) In a 96-well plate. Briefly, a three-enzyme linkage assay was constructed using dehydroquinate synthase (AroB), dehydrokinase (type I) and dehydroshikimate dehydrase (DHSD). In the presence of this enzyme mixture, the substrate 3-deoxy-D-arabinohepturonic acid-7-phosphate (D
AHP) is converted to protocatechuic acid, which can be quantified using a spectrophotometric plate reader set at 290 nm. After the addition of 0.1% ferric chloride, the subsequent incubation resulted in protocatechuic acid-at 570 nm.
Measurement of iron complex is possible. DAH in the assay in the absence of inhibitor
Adjust the P concentration to obtain an absorbance of 1 unit at 290 nm after the initial steps of the assay. Compounds were tested at 290 nm and 570 at each step of the assay.
The ability to reduce absorbance at nm is tested at 50 μm to determine the reduction of DAHP conversion to protocatechuic acid by the enzyme mixture. The assay medium also contained buffer (morpholinopropanesulfonic acid at pH 7.0), cobalt chloride (final concentration 40 μM), zinc sulfate (40 μM) and magnesium sulfate (2.5 mM). NAD was added as a cofactor at 20 μM.

A follow-up dehydrokinase assay was used to confirm that active compounds were inhibiting dehydroquinate synthase. The assay was similar to that described above, but with dehydroquinate as the substrate and dehydroquinate synthase removed from the assay medium. None of the test compounds showed any activity in the modified assay, therefore all actives were found to inhibit only dehydroquinate synthase.

[0188]

[Table 11]

Example 288 Inhibition of purified dehydroquinate synthetase (AroB) was measured in 96-well plates using the method described in Example 287. The experiment was repeated at various concentrations so that IC ₅₀ values could be calculated. IC ₅₀ values were calculated at 290 nm.

[0190]

[Table 12]

Example 289 Purified M. Inhibition of tuberculosis type II dehydrokinase (AroQ) was measured in 96-well plates at a single concentration (50 μM). Briefly, a two enzyme chain assay was constructed using AroQ and dehydroshikimate dehydrase (DHSD). In the presence of this enzyme mixture, the substrate, quinate, was converted to protocatechuic acid, which after 2 minutes incubation with 0.1% ferric chloride (using a spectrophotometric plate reader set at 570 nm). It can be quantified. Compounds were 50μ for their ability to reduce absorbance at 570nm.
m and tested for the reduction of conversion of quinate to protocatechuic acid by the enzyme mixture. The assay medium also contained buffer (morpholinopropanesulfonic acid at pH 7.0), cobalt chloride (final concentration 40 μM), zinc sulfate (40 μM) and magnesium sulfate (2.5 mM).

A follow-up assay was used to confirm that the active compound was inhibiting dehydrokinase. Briefly, compounds were incubated in the presence of AroQ in a conventional buffer mixture and their ability to reduce the conversion of quinate to dehydroshikimic acid was measured spectrophotometrically at 240 nm. All test compounds show activity in the modified assay and are therefore found to be inhibitors of dehydrokinase.

[0193]

[Table 13]

Example 290 Purified Mycobacterium tuberculosis type II dehydrokinase (AroQ
) Inhibition was measured in 96-well plates using the method described in Example 289. The experiment was repeated at various concentrations so that IC ₅₀ values could be calculated. IC ₅₀ values were calculated using the results at 570 nm.

[0195]

[Table 14]

Example 291 Antibacterial Activity of Compounds Against Staphylococcus aureus The minimum inhibitory concentration (MIC) of compounds against methicillin sensitive and resistant strains of S. aureus was determined using the method described below. Measuring antimicrobial susceptibility is a modification of the method used for clinical testing (NCCLS M7-A4.
Diluted antimicrobial susceptibility testing method for aerobic, growing bacteria, 4th edition).

The broth medium used for the assay was 90% of M9 Minimal Salts and 10% of Luria (Lennox Media) (9: 1 M9: L).
B).

[0198]

[Table 15]

For the agar plates, the medium was solidified by adding 1.5% (w / v) Noble Agar.

3 ml of 9: 1 M9: LB broth was inoculated with a single colony from a fresh culture of a methicillin-sensitive and methicillin-resistant strain of S. aureus grown on 9: 1 M9: LB agar. . Shake this (~ 250 rpm) at 37 ° C for 4
Incubated for ~ 5 hours. The optical density of broth was measured at 600 nm, and the culture solution was diluted with sterile 0.85% saline to obtain an A ₆₀₀ of 0.1 or less. For the diluted inoculum, use the Miles and Misla method as follows:
ra's) was performed: a) 90 μl of sterile 0.85% saline was added to the remaining wells (rows B to H) of the microtiter plate. b) 10 μl of culture was removed from row A to row B and mixed well. Serial dilutions continued down the plate, changing tips after each transfer. c) Triplicate 5 μl volumes of each dilution were transferred to the surface of dry agar plates. The plate was left for about 1 hour to dry the droplets into agar. And d) Incubating the plate at 37 ° C. overnight, 10-5 per spot.
Colonies were counted in the dilution where there were 0 distinct colonies. Then the appropriate calculations (see below) were made.

200 μl of 9: 1 M9: LB broth was added to the top row of wells in sterile microtiter plates to which 10 μl of the compound of Example 25 in dimethylsulfoxide (DMSO) was duplicated. Added to wells. 10 in 1 of 2 sets
mg / ml phenylalanine 2 μl, 10 mg / ml tryptophan 2 μl, 0
． 40 μl of 5 mg / ml tyrosine and 2 μl of 5 μg / ml p-aminobenzoic acid
Was added. The wells were then inoculated with 5 μl of diluted bacterial culture (see above). 16-20 at 37 ° C with shaking (~ 150 rpm) on microtiter plate
Incubated for hours, recorded A ₆₀₀ , then performed Miles and Mithra method on the culture (see above).

The criterion used to establish> MIC = (bactericidal concentration) is the concentration at which the sub-cultured broth from the drug treated batch does not show growth on media containing no antimicrobial agent. It was Bactericidal concentrations were calculated by testing compounds in a narrow range of molar concentrations just above the MIC. A curve of the total number of bacteria in the wells of the microplate was then plotted as a percentage of the number of bacteria inoculated into the well.

The calculations used on the results were c. f. u. / Ml = (number of colonies x dilution factor)
It was × 200. The bacterial count in the inoculum is c. f. u. / Ml / 200. The total number of bacteria in the well is c. f. u. / Ml / 5.

[0204]

[Table 16]

[0205]

[Table 17]

Example 292 Toxicity to VERO Cell Line Dulbecco's Modified Eagle Medium containing 10% fetal bovine serum (FBS) (Gibco 16000-044) with L-alanyl-L-glutamine (Gibco 21855-025) (
Cells are routinely cultured in DMEM). The process that follows is as follows: On day 1.1, 100 μl of cells in a 96-well plate are 5 × 10 ⁴ cells / m 2.
Inoculate with l. 2.2. On day 2, after attaching cells, dilute compounds in growth medium (DMEM) from a 20 mM stock made in DMSO to twice the final required concentration, 100 μl per well. Added. 0.5% DMSO made in growth medium
Is added to control wells. 3. Cells are incubated for 72-96 hours at 37 ° C., 5% CO ₂ . 4. Remove the medium by aspiration and use 1 methylene blue (50% E per well).
100 μl of 0.5% in tOH) are added to stain the cells and incubated for 1 hour at room temperature. The dye is then washed off with running water and air dried. 5. Cells may be examined for signs of morphological changes. 6. Solubilization solution (1% N-lauryl sarcosine, Sigma L-5125,
The dye is released from the cells by adding 100 μl of distilled water) and shaken gently for 1 hour. The plate is then read and the OD at 620 nm is measured. Percentage inhibition of cell growth was calculated for untreated control wells.

[0207]

[Table 18]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/426 A61K 31/426 4H011 31/4436 31/4436 31/517 31/517 A61L 2/18 A61L 2 / 18 A61P 31/04 A61P 31/04 31/10 31/10 33/06 33/06 43/00 111 43/00 111 C07C 311/21 C07C 311/21 311/29 311/29 C07D 239/74 C07D 239 / 74 333/34 333/34 409/04 409/04 413/04 413/04 417/04 417/04 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR , GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD) , TG), AP (GH, GM, K E, LS, M W, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM , HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN , YU, ZA, ZW (72) Inventor Wishart, Grant London Dubley, England C1E6A You Gower Street Cruciform Building The Wolfson Institute For Biomedical Research (72) Inventor Dolman, Mark United Kingdom London W1C6E6A You Gower Street Cruciform Building The Wolfson Institute Four Biomedical Research (72) Inventor Mounder, Peter UK Cornwall IX 23 8 Elwy Bud Budo-Stratton Business Park Trypos Receptor Research Limited F-term (reference) 4C058 AA09 AA14 BB07 CC01 CC02 JJ08 JJ21 4C063 AA01 BB02 CC92 DD12 DD58 DD61 DD62 EE01 4C086 AA01 AA02 AA03 BB02 BC17 BC69 BC78 BC79 GA04 GA08 GA09 GA10 MA01 MA04 MA05 MA17 MA23 MA35 MA37 MA52 MA55 MA63 MA66 NA14 ZB32 ZB35 ZB38 ZC20 4C206 AA01 AA02 AA03 JA13 MA01 MA04 MA05 MA37 MA43 MA52 MA55 MA57 MA83 MA86 ZB32 ZB35 ZB38 ZC20 4H006 AA01 AA03 AB03 AB04 AB28 4H011 AA01 AA02 AA03 AB01 AB02 AD01 BA01 BB07 DA02 DA15 DA16 DD01 DD03

Claims (35)

[Claims] 1. The following formula (I) in the manufacture of a medicament for use in inhibiting the biosynthesis of aromatic amino acids via the shikimate pathway: Wherein Ar is an aryl or heteroaryl group, R ₁ and R ₂ are the same or different and each represents hydrogen or alkyl, or R ₁ and R ₂ together are C _1- C ₃ alkylene group, -CO- or -
Forming 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) bissulfonamide derivative or a pharmaceutically acceptable salt thereof. use. 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. 3. Ar is the following Ar ′ group: (Wherein 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 ( 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 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 a phenyl moiety). 4. 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, differently, is 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 (where, R represents aryl, heteroaryl, hydrogen or alkyl), or -N
R'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 The use according to claim 3, wherein together form an alkylenedioxy group, or they together form a phenyl moiety with the carbon atom to which they are attached. 5. One of R ₅ and R ₈ is hydrogen and the other is hydrogen, halogen or hydroxy, and R ₆ and R ₇ are hydrogen, aryl, heteroaryl,
Nitro, cyano, alkyl, alkoxy, haloalkyl, halogen, -CO ₂ H
, —CO ₂ -alkyl 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 forms a alkylenedioxy group or phenyl moiety together, use of claim 4. 6. 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. Use according to any one of 5 to 5. 7. R ₃ and / or R ₄ is phenyl, naphthyl, pyridyl,
Furanyl, thienyl, imidazolyl, pyrazolidinyl, isoxazolyl, pyrrolyl, (1,2-cyclo (3-thioethyl) -imidazolyl, benzothienyl,
Use according to any one of claims 1 to 6, which is indolyl or quinolinyl. 8. R ₃ and / or R ₄ are unsubstituted or are aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, —S (O) ₂ -alkyl, haloalkoxy, cyano, -CO ₂ R (where, R represents aryl, heteroaryl, hydrogen or alkyl) or, alkoxy, hydroxy, -CONR'R "(where, R 'and R" are the same, Or, differently, is aryl, heteroaryl, hydrogen or alkyl), -Z-NR
'"R""and-NR'" R "" (where Z is alkyl or alkenyl and R '"and R""are the same or different and are each aryl,
Heteroaryl, hydrogen, alkyl or -CO-L (wherein L is an alkyl or aryl group), as well as -O-Z-R '"", where Z is defined above. And R ′ ″ ″ is substituted with one or two substituents selected from aryl, heteroaryl or heterocyclyl). 9. The bissulfonamide derivative of formula (I) has the formula (Ia)
): [Chemical 3] Where R _{5 to} R ₈ are as defined in claim 3, X and Y are the same or different and represent phenyl or thienyl, and n is when X is phenyl. , 0 to 4, an integer of 0 to 3 when X is thienyl, m is an integer of 0 to 4 when Y is phenyl, and 0 when Y is thienyl. Represents an integer of ₃ and R ₃ 'and R ₄ ' are the same or different,
Aryl, heteroaryl and heterocyclic group, alkyl, haloalkyl, halogen, nitro, -S- (O) ₂ -, alkyl, alkoxy, haloalkoxy, cyano, -CO ₂ R (where, R represents aryl, heteroaryl , Hydrogen or alkyl), hydroxy, —CONR′R ″ (where R ′ and R ″ are the same or different and are aryl, heteroaryl, hydrogen or alkyl), —Z—NR '"R""and-NR'" R "" (where Z is alkyl or alkenyl and R '"and R""are the same or different;
Each is aryl, heteroaryl, hydrogen, alkyl or -CO-L (wherein L
Represents an alkyl or aryl group), and —O—Z—R ′ ″ ″
(Z is as defined above, R ′ ″ ″ is selected from aryl, heteroaryl or heterocyclyl)) and the bissulfonamide derivative thereof is used. 10. In the formula (Ia), R_FiveAnd R₈Is hydrogen and R ₆ And R₇Are the same or different and are aryl, heteroaryl, nit
B, cyano, alkyl, haloalkyl, halogen, hydrogen, -CO₂H, -CO₂−
Alkyl, alkoxy and -CONR'R "(wherein R'and R" are the same as
Same or different, aryl, heteroaryl, hydrogen or alkyl)
Selected from R₆And R₇Together form an alkylenedioxy group
Or form an additional phenyl moiety with the carbon atom to which they are attached
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, R₃
'And R_Four'Is the same or different and is as follows:   (A) aryl, C when attached to the phenyl moiety₁~ C_FourAlkyl, C₁
~ C_FourHaloalkyl, halogen, nitro, cyano, C₁~ C_FourAlkoxy, -CO₂ R (where R is hydrogen or C₁~ C_FourAlkyl), -NR'R "(here
And R'and R "are the same or different and are hydrogen, C₁~ C_FourAlkyl
Or -CO- (C₁~ C_FourAlkyl), -O- (C₁~ C_FourAlkyl) -R "(here
And R ″ is heteroaryl or heterocyclyl), and —S (O) ₂ -C₁~ C_FourAlkyl   (B) when attached to a thienyl moiety, pyridyl, thiazolyl, isoxa
Zolyl, isothiazolyl, pyrazolyl, nitro, halogen, C₁~ C_FourHalo Archi
Le, C₁~ C_FourAlkyl, -CO₂R (where R is hydrogen or C₁~ C_FourArchi
C)₁~ C_FourAlkoxy,-(C₁~ C_FourAlkyl) -NH-aryl
And -S (O)₂-C₁~ C_FourAlkyl Use according to claim 9, selected from 11. The use according to any one of claims 1-10, wherein the agent is for use in inhibiting the dehydroquinate synthetase enzyme. 12. The use according to claim 11, wherein the dehydroquinate synthetase enzyme is AroB. 13. The use according to any one of claims 1 to 12, wherein the agent is for use in inhibiting type II dehydrokinase enzyme. 14. The use according to claim 13, wherein the type II dehydrokinase enzyme is AroQ. 15. Use according to any one of claims 1-14, wherein the medicament is for use in the treatment or prevention of bacterial or fungal infections. 16. The use according to claim 15, wherein the agent is for use in the treatment or prevention of methicillin-resistant Staphylococcus aureus infection. 17. The drug is for the treatment or prevention of infection by a parasite in which aromatic amino acid biosynthesis is carried out via the shikimate pathway.
The use according to any one of 1. 18. The use according to claim 17, wherein the drug is for the treatment or prevention of malaria. 19. The following: a bissulfonamide derivative of formula (I) as defined in any one of claims 1 to 10, or an agriculturally acceptable salt thereof, at least one surfactant, And a herbicidal or fungicidal composition comprising an agriculturally acceptable carrier or diluent. 20. A bissulfonamide derivative of formula (I) as defined in any one of claims 1 to 10, or agronomically acceptable salt thereof, as a herbicide or fungicide. use. 21. A method for controlling weeds or fungi in a location, comprising a bissulfonamide derivative of formula (I) as defined in any one of claims 1 to 10, or an agricultural method thereof. 33. An acceptable salt, or a method comprising administering to it a composition according to any one of claims 19 or 32. 22. The method of claim 21, wherein the location comprises an agricultural or horticultural plant, or a medium in which such plant grows. 23. Use of a bissulfonamide derivative of formula (I) as defined in any one of claims 1 to 10 or a salt thereof in controlling algae. 24. A method for treating algae in an aquarium or pond, comprising:
10. A method comprising applying a bissulfonamide derivative of formula (I), or a salt thereof, as defined in any one of 10 to 10 to an aquarium or pond. 25. A non-therapeutic use of a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or a salt thereof, in inhibiting bacterial growth. 26. A formula (I) as defined in any one of claims 1-10.
) A surgical instrument having an antibiotic coating containing the bissulfonamide derivative of), or a pharmaceutically acceptable salt thereof. 27. A compound of formula (I): for use in a method of treating the human or animal body. 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 are C _1- C ₃ alkylene group, -CO- or -
Forming 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, R ₃ and R ₄ are , Phenyl, 4-methylphenyl, or 4-aminophenyl, and Ar is as follows: (Wherein R ′ and R ″ are not methyl or chlorine)), or a pharmaceutically acceptable salt thereof. 28. A pharmaceutical composition comprising the bissulfonamide derivative according to claim 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 29. The following formula (Id): (In the formulae, R ₁ and R ₂ are as defined in any one of claims 1 and 6, and R ₃ and R ₄ are defined in any one of claims 1, 7 and 8. As defined, Ar is as defined in any one of claims 3 to 5, provided that R ₁ and R ₂ are both hydrogen, Ar is an unsubstituted naphthyl group, 1 One or two dimethylmethylenedioxy, hydroxy, methoxy, ethoxy, methyl, chlorine, bromine, fluorine, nitro, CF ₃ or a phenanthracene group optionally substituted with an amino group or a phenyl group, R ₃ and R ₄ is (a) an unsubstituted quinoline group, (b) an unsubstituted phenyl group, (c) methyl, methoxy, —CO ₂
By H, chlorine, cyano, nitro or amino groups, or -O-CO-N (
CH ₃₎ bis sulfonamide derivatives of mono-substituted phenyl group by group or, (d) is not a disubstituted phenyl group by a nitro group and a methyl group) or a salt thereof. 30. The compound of claim 29, wherein the bissulfonamide derivative of formula (Id) is a bissulfonamide derivative of formula (Ia) as defined in claim 9 or 10. 31. Ar is as follows: (In the formula, R _{5 to} R ₈ are as defined in any one of claims 3 to 5,
However, neither R ₅ nor R ₆ nor R ₇ and R ₈ together form a phenyl moiety). 32. 1,2-Bis (4-trifluoromethoxyphenylsulfonylamino) -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) The compound according to claim 29, which is -chlorophenylsulfonylamino) -4-fluorobenzene, 1,2-bis (2-chloro-5-thienylsulfonylamino) -4-fluorobenzene, or a salt thereof. 33. A bissulfonamide derivative of formula (I) as defined in any one of claims 29 to 32, or an agriculturally acceptable salt thereof, and an agriculturally acceptable carrier or diluent. A herbicide or fungicide composition comprising: 34. Use of a bissulfonamide derivative of formula (I) as defined in any one of claims 1 to 10 or a salt thereof in inhibiting quinic acid catabolism. 35. The use according to claim 34, wherein the bissulfonamide or salt thereof is used to inhibit the catabolism of quinic acid by fungi or bacteria.