ZA200202897B - Enzyme inhibitors. - Google Patents

Enzyme inhibitors. Download PDF

Info

Publication number
ZA200202897B
ZA200202897B ZA200202897A ZA200202897A ZA200202897B ZA 200202897 B ZA200202897 B ZA 200202897B ZA 200202897 A ZA200202897 A ZA 200202897A ZA 200202897 A ZA200202897 A ZA 200202897A ZA 200202897 B ZA200202897 B ZA 200202897B
Authority
ZA
South Africa
Prior art keywords
alkyl
aryl
heteroaryl
hydrogen
different
Prior art date
Application number
ZA200202897A
Inventor
David Madge
Grant Wishart
Mark Dolman
Peter Maunder
Original Assignee
Arrow Therapeutics Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arrow Therapeutics Ltd filed Critical Arrow Therapeutics Ltd
Publication of ZA200202897B publication Critical patent/ZA200202897B/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Apparatus For Disinfection Or Sterilisation (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Description

; .
ENZYME INHIBITORS
The present invention relates to a series of bissulfonamide derivatives which act as inhibitors of dehydroquinate synthetase and type II dehydroquinase enzymes.
Dehydroquinate synthetase and dehydroquinase enzymes form an essential part of the shikimate pathway by which erythrose-4-phosphate is converted to aromatic amino acids such as tryptophan, tyrosine and phenylalanine. Two types of biosynthetic dehydroquinase have been characterised, a Type I, or AroD, variety and a Type II, or AroQ, variety (Garbe et al, Mol. Gen. Genet., 228, pgs 385-392 (1991), Hawkins et dl, ]. Gen. Microbiol. 139, pgs 2891-2899 (1993)).
The shikimate pathway is essential in bacteria, algae, fungi and higher plants. Further, recent work shows evidence for the presence of enzymes of the shikimate pathway in apicomplexan parasites (Roberts et al, Nature, 393, 1998, pgs 801-805). Compounds which can inhibit the biosynthesis of amino acids via the shikimate pathway therefore have a variety of commercial applications.
In addition to their biosynthetic function, type II dehydroquinase p enzymes form an important part of the catabolic pathway by which quinic acid catabolism is effected. This catabolic pathway is found in many fungi and bacteria. »
Inhibitors of type II dehydroquinase enzymes therefore have commercial applications as fungicides and antibiotics.
Numerous diaminobissulfonamides are known. For example J.
Chem. Soc., 1161 (1970) describes the synthesis of many of these compounds as intermediates to tetrahydrodibenzodiazocines, and J. Chem. Soc., 1170 (1962) describes electrophilic substitution reactions involving diaminobissulfonamides. No pharmaceutical utility is described in these publications, however. The synthesis and use of 1,2-bis(4-methylphenylsulfonylamino)-4,5-dibromobenzene as an intermediate to substituted phthalocyanines has been reported (Acta. Chemica. Scand., 658 (1995)). Some diaminobissulfonamides are of interest as candidates for non-linear optical studies (Acta. Cryst., 2395 (1995)).
. y
Oncolytic activity has previously been ascribed to some diaminobissulfonamides (J. Med. Chem., 599 (1963)). The oncolytic activity was found to operate via inhibition of the biosynthetic conversion of 1,2-dimethyl-4,5- diaminobenzene to vitamin B,, by certain types of tumour cells (Biochem.
Pharmacol., 1163 (1962)).
It has now surprisingly been found that particular bissulfonamide derivatives of the general formula (I) set out below act as inhibitors of dehydroquinate synthetase enzymes and as inhibitors of type II dehydroquinase enzymes. Accordingly, the present invention provides, in a first embodiment, the use of a bissulfonamide derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in inhibiting the biosynthesis of aromatic amino acids via the shikimate pathway, : R 0—S=0 te, nd - AN @ . NR; “. o= eo
L wherein: - Ar is an aryl or heteroaryl group; - R, and R, are the same or different and each represent hydrogen or alkyl or R, and R, together form a C,-C; alkylene group, -CO- or -CS-; and - R; and R, are the same or different and each represent -alkyl-aryl, -alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl, -alkynyl-heteroaryl, aryl or heteroaryl.
Typically, the medicament is for use in the inhibition of a dehydroquinate synthetase enzyme, in particular AroB, and/or a type II dehydroquinase enzyme, in particular AroQ.
As used herein, an alkyl group or moiety is typically a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms, such as a C,-C, alkyl group or moiety, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
An alkyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, cyano, nitro, amino, hydroxy, oxo and -CO,R, -SOR and -S(O),R wherein R is hydrogen or alkyl.
As used herein, an alkenyl group or moiety is typically a linear or branched alkenyl group or moiety containing from 2 to 6 carbon atoms, such as a C,-
C, alkenyl group or moiety, for example ethenyl, propenyl and butenyl. : An alkenyl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, amino and hydroxy. : .
As used herein, an alkynyl group or moiety is typically a linear or branched alkynyl group or moiety containing from 2 to 6 carbon atoms, such as a C,- \g
C, alkynyl group or moiety, for example ethynyl, propynyl and butynyl.
An alkynyl group or moiety may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries one or two substituents. Suitable substituents include halogen, amino and hydroxy.
A C,-C, alkylene group is a methylene, ethylene or propylene group.
It may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries one substituent. Suitable substituents include halogen, cyano, nitro, oxo and -CO,R, -SOR and -S(O),R wherein R is hydrogen or alkyl.
As used herein, an aryl group is typically a C,-C,, aryl group such as phenyl or naphthyl. Phenyl is preferred. An aryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2, 3 or 4 substituents. Suitable substituents include aryl, carbocyclyl, heteroaryl and heterocyclic groups, nitro,
! " cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO,R and -S(O),R wherein R is aryl, heteroaryl, hydrogen or alkyl, -CONR'R” wherein R’ and R” are the same or different and each represent aryl, heteroaryl, hydrogen or alkyl, -Z-NR” R” and -NR” R" wherein Z is alkyl or alkenyl and R”and R” are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, and -O-Z-R* wherein Z is as defined above and Ris aryl, heteroaryl or heterocyclyl.
Typically, R in the moiety -S(O),R is hydrogen or alkyl. Typically, R” and R* in the moieties -Z-NR”R” and -NR”R" are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably, at least one of R” and R” is hydrogen or alkyl. Typically, Z is alkyl, for example methyl. Typically, R*” in the moiety -O-Z-
R" is heteroaryl, for example thiazolyl. : A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocyclic substituents are 5- or 6- membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S. Examples include 5- or . 6- membered rings containing 1, 2 or 3 heteroatoms, for example pyridyl, isoxazolyl, isothiazolyl, pyrazolyl, thiadiazolyl and oxadiazolyl. Other preferred substituents . 4 include nitro, hydroxy, halogen, for example chlorine, bromine and fluorine, C,-C, haloalkyl such as -CF, and -CCl,, C,-C, alkyl, -CO,R wherein R is hydrogen or C,-C, alkyl, C,-C, alkoxy, C,-C, haloalkoxy, for example -OCCl, and -OCF;, -S(0),-C,-C, alkyl, -CONR'R” wherein R’ and R” are the same or different and are heteroaryl or, preferably, aryl, hydrogen or C,-C, alkyl, -NR”R” wherein R” and R" are the same or different and each represent hydrogen, alkyl or -CO-alkyl, and -O-alkyl-R*, wherein R” is heteroaryl, for example thiazolyl.
The above substituents are themselves preferably unsubstituted or substituted by one or more further substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkythio, alkoxy, for example haloalkoxy, and hydroxy.
Typically, these further substituents are themselves unsubstituted.
An aryl group may optionally be fused to a further said aryl group or to a carbocyclic, heterocyclic or heteroaryl group. For example, it may be fused to a
, ‘. pyridine ring to form a quinoline group, to a thiadiazole ring, for example a 1,2,5- thiadiazole ring to form an isobenzo([1,2,5]-thiadiazole group, or to a 1,4 dioxane or 1,3 dioxolane ring.
As used herein, a heteroaryl group is typically a 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, isoxazyl, thiadiazolyl, thiazolyl, imidazolyl and pyrazolyl groups. Thienyl groups are preferred. A heteroaryl group may be unsubstituted or substituted at any position. Typically, it carries 1, 2 or 3 substituents. Suitable substituents include aryl, for example phenyl, carbocyclyl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO,R and -S(O),R wherein R is aryl, heteroaryl, hydrogen or alkyl, -CONR'R” wherein R’ and R” are the same or different and each represent aryl, heteroaryl, hydrogen or alkyl, -Z-NR”R" and -NR"R" - wherein Z is alkyl or alkenyl and R” and R” are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, and -O-Z-R" wherein Z is as defined above and R is aryl, heteroaryl or ] heterocyclyl.
Typically, R in the moiety -S(O),R is hydrogen or alkyl. Typically, R” > and R” in the moieties -Z-NR”R" and -Z-NR”R" are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably at least one of R” and R” is hydrogen or alkyl. Typically, Z is alkyl, for example methyl. Typically, R”” in the moiety -O-Z-R™ is heteroaryl, for example thiazolyl.
A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocyclic substituents are 5- or 6- membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S. Examples include 5- or 6- membered rings containing 1, 2 or 3 heteroatoms, for example isoxazolyl, pyridyl imidazolyl, thiazolyl, isothiazolyl, pyrazolyl and thiadiazolyl. Other preferred substituents include nitro, halogen such as chlorine, bromine or fluorine, C,-C, haloalkyl such as -CF; and -CCl,;, C,-C, alkyl, -CO,R wherein R is hydrogen or C,-C, alkyl, C,-C, alkoxy, -S(0),-C,-C, alkyl and -(C,-C, alkyl) -NR”R" wherein R” and
= J
R™ are the same or different and each represent hydrogen, alkyl or -CO-aryl, for example -CO-phenyl.
The above substituents are themselves preferably unsubstitued or substituted by one or more further substituents selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, and hydroxy.
Typically, these further substituents are themselves unsubstituted.
A heteroaryl group may optionally be fused to a said aryl group, to a further heteroaryl group or to a heterocyclic or carbocyclic group. Examples of such fused heteroaryl groups include, for example, a thiophene ring fused to an imidazolyl group. - As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, fluorine or bromine. : As used herein, a said alkoxy group is typically a said alkyl group - attached to an oxygen atom. An alkylthio group is typically a said alkyl group attached to a thio group. A haloalkyl or haloalkoxy group is typically a said alkyl or alkoxy group substituted by one or more said halogen atoms. Typically, it is - substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl and halealkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX; and -OCX, - wherein X is a said halogen atom. Particularly preferred haloalkyl groups are CF, and
CCl,. Particularly preferred haloalkoxy groups are -OCF; and -OCCl,.
As used herein, a carbocyclic group is a non-aromatic saturated or unsaturated hydrocarbon ring, typically having from 3 to 6 carbon atoms. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl group) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Itis preferably cyclohexyl. A carbocyclic group may be unsubstituted or substituted at any position. Suitable substituents include nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO,R and -S(O),R wherein R is hydrogen or alkyl, cyano, and -NRR” and -CONR'R” wherein R’ and R” are the same or different and each represent hydrogen or alkyl. Preferred substituents are nitro, halogen such as chlorine, bromine or fluorine, C,-C, haloalkyl such as -CF, and -CCl;, C,-C, alkyl, -CO,R wherein R is hydrogen or C,-C, alkyl,
, -
C,-C, alkoxy, C,-C, haloalkoxy, for example -OCCl; and ~OCF;, and -S5(0),-C,-C, alkyl. The above substituents are typically themselves unsubstituted.
As used herein, a heterocyclic group is typically a non-aromatic, . saturated or unsaturated C;-C,, carbocyclic ring in which one or more, for example 1,
N 2 or 3, of the carbon atoms are replaced by a heteroatom selected from N, O and S.
Saturated heterocyclic groups are preferred. Examples of suitable heterocyclic groups include piperidine, morpholine, 1,4 dioxane and 1,3 dioxolane.
A heterocyclic group may be unsubstituted or substituted at any position. Suitable substituents include nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO,R and -S(O),R wherein R is hydrogen or alkyl, cyano, and -NRR” and -CONR'R” wherein R’ and R” are the same or different and each represent hydrogen or alkyl. Preferred substituents are nitro, halogen such as chlorine, bromine or fluorine, C,-C, haloalkyl such as -CF; and -CCl,, C,-C, alkyl, -CO,R wherein R is hydrogen or C,-C, alkyl, C,-C, alkoxy and -S(0),-C,-C, alkyl. The above substituents are typically themselves unsubstituted.
Typically, the groups -NR,S(O),R, and -NR,S(O),R, are attached to adjacent carbon atoms on the Ar moiety. When Ar is a heteroaryl group it is 3 typically a pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl group. Preferably, Ar is an aryl group, in particular a phenyl group or a naphthyl group. Typically, it is unsubstituted > or carries 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents. Preferred substituents include aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO,R wherein R is aryl, heteroaryl, or, preferably, hydrogen or alkyl, and -NR’ R” and -CONRR” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl. These substituents are preferably unsubstituted or substituted by one or more further substituent selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy and hydroxy. Typically, these further substituents are themselves unsubstituted.
Typically, at least one of R' and R” in the moieties -NR'R” and -CONRR” is hydrogen or alkyl. A preferred aryl substituent is phenyl. Preferred heteroaryl and heterocyclic substituents are 5- or 6- membered heteroaryl or heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S, for example oxadiazolyl groups. Further preferred substituents on the group Ar include hydroxyl nitro, cyano, halogen such as chlorine, fluorine and bromine, C,-C, : haloalkyl, C,-C, alkyl, -CO,R wherein R is hydrogen or C,-C, alkyl, C,-C, alkoxy and -CONRR’ wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or C,-C, alkyl.
When Ar is an aryl group fused to an aryl, cycloalkyl, heterocyclic or heteroaryl group, it is typically fused to a said heterocyclic group. Preferably, it is fused to a saturated heterocyclic group containing, as heteroatoms, 2 oxygen atoms, for example 1,4 dioxane or 1,3 dioxolane.
More preferably, Ar is a group of formula Ar
Rs pet .
Ry
Rg
CC o~ wherein R; to Ry are the same or different and represent aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NRR” or -CONR'R” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or Ry and R; or Rs and R; or R; and R; together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.
Typically, R, to Rg are the same or different and represent cyano, nitro, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, hydroxy, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R” or -CONRR” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R; and R; or R, and R, or R; and R, together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.
Typically, R in the moiety -CO,R is hydrogen or alkyl. Typically, R/ : and R” in the moiety -NR'R” are the same or different and are hydrogen or alkyl.
Typically, R and R” in the moiety -CONRR” are the same or different and are hydrogen, alkyl or aryl.
Typically, R; and R, are the same or different and represent hydrogen, halogen, for example bromine, alkyl, hydroxy, alkoxy or -NR'R” wherein R and R” are the same or different and are hydrogen or alkyl, and R, and R; are the same or different and represent hydrogen, halogen, for example, bromine, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, heterocyclyl, nitro, cyano, halogen, alkyl, for example haloalkyl, alkoxy, for example haloalkoxy, alkylthio, hydroxy, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR’R” or -CONR'R” wherein R/ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R; and
R; together form an alkylenedioxy group such as a methylenedioxy or ethylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety. -
Typically, R; and R; are the same or different and represent hydrogen, alkyl, hydroxy, alkoxy or -NR'R” wherein R’ and R” are the same or different and are v hydrogen or alkyl, and Rs and R, are the same or different and represent hydrogen, nitro, cyano, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R” or -CONR'R” wherein R/ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R; and R, together form an alkylenedioxy group such as a methylenedioxy or ethylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.
Typically, R’ and R” in the -NR'R” moiety are the same or different and are hydrogen or alkyl. Typically R’ and R” in the moiety -CONR'R” are the same or different and are hydrogen, alkyl or aryl.
Preferably, at least one of R; and Ry is hydrogen. More preferably,
one of R; and Ry is hydrogen and the other is halogen or, preferably, hydrogen or hydroxy. More preferably still, both R; and Rg are hydrogen.
Typically, R; to Rg are unsubstituted or substituted by one or more further substituent selected from nitro, cyano, halogen, alkyl, for example haloalkyl, alkylthio, alkoxy, for example haloalkoxy, and hydroxy. Typically, these further substituents are themselves unsubstituted.
Preferably, R; and R, represent hydrogen, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, nitro, cyano, alkyl, alkoxy, haloalkyl, halogen, -
CO,H, -CO,-alkyl or -CONR/R” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R; and R; together form a said alkylenedioxy group or a phenyl moiety. More preferably, R, and R, represent hydrogen, heteroaryl, for example oxadiazolyl, nitro, cyano, C,-C, alkyl such as methyl or ethyl, halogen such as chlorine, fluorine or bromine, -CO,-(C,-C, alkyl) such as -CO,-Et and -CO,- - Me, C,-C, alkoxy such as -OMe, or -CONR'R” wherein R’ and R” are the same or different and are heteroaryl, or, preferably, aryl, for example phenyl, hydrogen or C,-
C, alkyl, or R; and R;, together with the carbon atoms to which they are attached, . form a further phenyl moiety. More preferably still, Rsand R; are the same or different and are selected from hydrogen, oxadiazolyl, chlorine, fluorine, bromine, hs nitro, cyano, methyl, methoxy, -CO,H, -CO,Et, -CO,Me, -CONH,, -CONHMe and ~ -CONMe,, -CONH-phenyl, -CONH- (4-trifluoromethoxyphenyl) or -CONH-(3,5- dimethoxyphenyl), or R; and R;, together with the carbon atoms to which they are attached, form a further phenyl moiety.
When R, and/or R, is an alkyl group it is typically an unsubstituted alkyl group. Preferably, R; and R, are the same or different and are hydrogen or alkyl or R, and R, together from a C,-C, alkylene group. More preferably, R, and R; are both hydrogen.
Typically, R; and R, are not simultaneously -alkynyl-aryl or -alkynyl- heteroaryl groups. Preferred -alkyl-aryl and -alkyl-heteroaryl groups are -(C,-C,- alkyl)-aryl and -(C,-C, alkyl)-heteroaryl groups, for example -(C,-C, alkyl)-phenyl groups such as benzyl groups. Preferred -alkenyl-aryl and -alkenyl-heteroaryl groups are -(C,-C, alkenyl)-aryl and -(C,-C, alkenyl)-heteroaryl groups, for example
-ethenyl-aryl groups such as -ethenyl-phenyl groups.
Typically, R; and R, are the same or different and each represent an aryl or heteroaryl group. Preferred aryl and heteroaryl groups include phenyl, naphthyl, pyridyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, isoxazolyl and pyrrolyl groups. More preferred aryl and heteroaryl groups are phenyl, naphthyl, furanyl, thienyl and isoxazolyl groups.
When R; or R, contains an aryl or heteroaryl moiety which is fused to an aryl, cycloalkyl, heterocyclic or heteroaryl group, it is typically fused to a said heterocyclic group or to a said heteroaryl group. Examples of such fused groups include (1,2-cyclo(3-thioethyl)-imidazoyl, benzothienyl, indole and quinoline groups.
Quinoline groups are preferred.
Typically, R; and R, are unsubstituted or carry 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents. Preferred substituents include aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S(O),-alkyl, : haloalkoxy, cyano, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy, -CONR/R” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, -Z-NR”R” and -NR”R" wherein Z is alkyl or alkenyl . and R” and R" are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, and -O-Z-R* wherein Z . is as defined above and R" is aryl, heteroaryl or heterocyclyl.
Typically, Z is alkyl, for example methyl, in the above moieties.
Typically, R” and R” in the moieties -Z-NR”R" and -NR”R" are the same or different and are hydrogen, alkyl, -CO-alkyl or -CO-phenyl. Preferably, at least one of R” and R" is hydrogen or alkyl. Typically, R” in the moiety -O-Z-R" is heteroaryl, for example thiazolyl.
More typically, R, and R, are unsubstituted or carry 1, 2, 3 or 4 substituents, preferably 1 or 2 substituents selected from aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S(O),-alkyl, haloalkoxy, cyano, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy and -NR'R’/ and -CONR'R” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl. :
I

Claims (1)

1. Use of a bissulfonamide derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in inhibiting the biosynthesis of aromatic amino acids via the shikimate pathway, Fe o= 7 0 Pan Ar \ MD i O— To R4 wherein: - Ar is an aryl or heteroaryl group; “ - R, and R, are the same or different and each represent hydrogen or alkyl or R, and R, together form a C,-C; alkylene group, - : -CO- or -CS-; and - R; and R, are the same or different and each represent -alkyl-aryl, -alkyl-heteroaryl, -alkenyl-aryl, -alkenyl-heteroaryl, -alkynyl-aryl -alkynyl- heteroaryl, aryl or heteroaryl.
2. Use according to claim 1 wherein R, and R, are the same or different and each represent an aryl or heteroaryl group.
3. Use according to claim 1 wherein Ar is a group Ar/
; KE Rs Ry Rs wherein R; to Rg are the same or different and represent aryl, heteroaryl, heterocyclyl, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R” or -CONR'R” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or Rs; and R; or Rg; and R; or R; and R, together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.
4. Use according to claim 3, wherein R; and R; are the same or different and represent hydrogen, halogen, alkyl, hydroxy, alkoxy or -NR'R” wherein R’ and .. R” are the same or different and are hydrogen or alkyl and R, and R, are the same or different and represent hydrogen, aryl, heteroaryl, heterocyclyl, nitro, cyano, halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, or -NR'R” or -CONR'R’ wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R and R, together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a phenyl moiety.
5. Use according to claim 4 wherein one of Ry and Rg is hydrogen, and the other is hydrogen, halogen or hydroxy and R and R, represent hydrogen, aryl, heteroaryl, nitro, cyano, alkyl, alkoxy, haloalkyl, halogen, -CO,H, -CO,-alkyl or -CONR'R” wherein R’ and R” are the same or different and are aryl,
t heteroaryl, hydrogen or alkyl, or R¢ and R; together form an alkylenedioxy group or a phenyl moiety.
6. Use according to any one of the preceding claims wherein R, and R, are the same or different and represent hydrogen or alkyl or R, and R; together form a C,-C; alkylene group.
7. Use according to any one of the preceding claims wherein R, and/or R, is phenyl, naphthyl, pyridyl, furanyl, thienyl, imidazolyl, pyrazolidinyl, isoxazolyl, pyrrolyl, (1,2-cyclo(3-thioethyl)-imidazolyl, benzothienyl, indolyl or quinolinyl.
8. Use according to any one of the preceding claims, wherein R; and/or R, are unsubstituted or are substituted by one or two substituents selected from aryl, : heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -5(0),-alkyl, haloalkoxy, cyano, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, alkoxy, hydroxy, -CONRR” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, -Z-NR”R” and ’ NR/R™ wherein Z is alkyl or alkenyl and R” and R” are the same or B different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group, and -O-Z-R” wherein Z is as defined above and R” is aryl, heteroaryl or heterocyclyl. 9, Use according to claim 1, wherein the bissulfonamide derivative of formula (I) is a bissulfonamide derivative of formula (Ia)
(R3)n xX / 0=—=S=0 PO Ry NH Rg o= ] =0 Y N Rm wherein R; to Ry are as defined in claim 3, X and Y are the same or different and represent phenyl or thienyl, n represents an integer of from 0 to 4 when X dg is phenyl and an integer of from 0 to 3 when X is thienyl, m represents an integer of from 0 to 4 when Y is phenyl and an integer of from O to 3 when Y B is thienyl, and R;’ and R/ are the same or different and are selected from aryl, heteroaryl and heterocyclic groups, alkyl, haloalkyl, halogen, nitro, -S(O),- alkyl, alkoxy, haloalkoxy, cyano, -CO,R wherein R is aryl, heteroaryl, hydrogen or alkyl, hydroxy, -CONR'R” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, -Z-NR”R” and -NR*R" wherein Z is alkyl or alkenyl and R” and R are the same or different and each represent aryl, heteroaryl, hydrogen, alkyl or -CO-L wherein L is an alkyl or aryl group and -O-Z-R* wherein Z is as defined above and R” is aryl, heteroaryl or heterocyclyl.
10. Use according to claim 9, wherein, in the formula (Ia), R; and R, are hydrogen, R and R, are the same or different and are selected from aryl,
heteroaryl, nitro, cyano, alkyl, haloalkyl, halogen, hydrogen, -CO,H, -CO,- alkyl, alkoxy and -CONR'R” wherein R’ and R” are the same or different and are aryl, heteroaryl, hydrogen or alkyl, or R; and R, together form an alkylenedioxy group or, together with the carbon atoms to which they are attached, form a further phenyl moiety, X and Y are the same or different and are phenyl or thienyl, n and m are the same or different and are 0, 1 or 2 and R; and R/ are the same or different and are selected from: (a) when attached to a phenyl moiety, aryl, C,-C, alkyl, C,-C, haloalkyl, halogen, nitro, cyano, C,-C, alkoxy, -CO,R wherein R is hydrogen or C,-C, alkyl, -NR'R” wherein R’ and R” are the same or different and are hydrogen, C,-C, alkyl or -CO-(C,-C, alkyl), -O-(C,-C, alkyl)-R” wherein R” is heteroaryl or heterocyclyl, and -5(O),-C,-C, alkyl; and (b) when attached to a thienyl moiety, pyridyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, nitro, halogen, C,-C, haloalkyl, C,-C, alkyl, -CO,R wherein R is hydrogen or C,-C, alkyl, C,-C, alkoxy, -(C,-C, alkyl)-NH-aryl and -S(0),-C,-C, alkyl.
11. Use according to any one of the preceding claims, wherein the medicament is ) for use in the inhibition of a dehydroquinate synthetase enzyme. .
12. Use according to claim 11, wherein the dehydroquinate synthetase enzyme is AroB.
13. Use according to any one of the preceding claims, wherein the medicament is for use in the inhibition of a type II dehydroquinase enzyme.
14. Use according to claim 13, wherein the type II dehydroquinase enzyme is AroQ).
15. Use accordingly to any one of the preceding claims, wherein the medicament is for use in treating or preventing a bacterial or fungal infection.
Seg
16. Use according to claim 15 wherein the medicament is for use in the treatment or prevention of a Methicillin Resistant Staphylococcus Aureus infection.
17. Use accordingly to any one of claims 1 to 12, wherein the medicament is for use in the treatment or prevention of an infection by a parasite in which the biosynthesis of aromatic amino acids is effected via the shikimate pathway.
18. Use according to claim 17 wherein the medicament is for use in the treatment or prevention of malaria.
19. A herbicidal or fungicidal composition, comprising: - a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or an agriculturally acceptable salt thereof; - at least one surfactant; and - an agriculturally acceptable carrier or diluent; .
20. Use of a bissulfonamide derivative of formula (I), as defined in any one of . claims 1 to 10, or an agriculturally acceptable salt thereof, as a herbicide or a fungicide.
21. A method of controlling weeds or fungi at a locus, which method comprises administering thereto a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or an agriculturally acceptable salt thereof, or a composition according to claim 19 or 32.
22. A method according to claim 21, wherein the locus comprises agricultural or horticultural plants or a medium in which such plants grow.
23. Use of a bissulfonamide derivative of formula (I) as defined in any one of claims 1 to 10, or a salt thereof, in controlling algae.
WL.
24. A method of treating algae in a fish tank or pond, which method comprises applying to the fish tank or pond a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or a salt thereof.
25. Non-therapeutic use of a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or a salt thereof, in inhibiting bacterial growth.
26. A surgical instrument having thereon an antibiotic coating comprising a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
217. A bissulfonamide derivative of formula (I), or a pharmaceutically acceptable salt thereof, i 0—S=—0 . Pan
Ar . 0 ® o—= 7 0 Ry wherein: - Ar is an aryl or heteroaryl group; - R, and R, are the same or different and each represent hydrogen or alkyl or R, and R, together form a C,-C, alkylene group, -CO- or -CS-; and - R, and R, are the same or different and each represent an aryl or heteroaryl group,
Yr 8 for use in a method of treating the human or animal body, provided that, when R, and R; are hydrogen and R; and R, are phenyl, 4-methylphenyl, or 4- aminophenyl Ar is not R Rr wherein R’ and R” are methyl or chlorine.
28. A pharmaceutical composition comprising a bissulfonamide derivative according to claim 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. ] 29. A bissulfonamide derivative of formula (Id), or a salt thereof, Bs AR Ar Id) iil o= TT (0) : Ry wherein: - R, and R, are as defined in any one of claims 1 and 6; - R; and R, are as defined in any one of claims 1, 7 and 8, and
. Ar is as defined in any one of claims 3 to 5 ce et provided that when R, and R, are both hydrogen and Ar is an unsubstituted napthyl group, a phenanthracene group or a phenyl group optionally substituted by 1 or 2 dimethylmethylenedioxy, hydroxy, methoxy, ethoxy, methyl, chlorine, bromine, fluorine, nitro, CF; or amino groups, R, . and R, are not (a) unsubstituted quinoline groups, (b) unsubstituted phenyl groups, (c) phenyl groups monosubstituted by a methyl, methoxy, -CO,H, chlorine, cyano, nitro or amino group, or by a group -O-CO-N(CH,)- or (d) phenyl groups disubstituted by a nitro group and a methyl group.
30. A compound according to claim 29, wherein the bissulfonamide derivative of formula (1d) is a bissulfonamide derviate of formula (1a), as defined in claim 9 or 10.
31. A compound according to claim 30 wherein Ar represents a group Rg ) » R7 Rg -* wherein R, to Rg are as defined in any one of claims 3 to 5, provided that neither Rs and Rg nor R, and R, together form a phenyl moiety.
32. A compound according to claim 29, which is 1,2-Bis(4-trifluoromethyoxyphenylsulfonylamino)-4-chlorobenzene, 1,2-Bis(3-trifluoromethylphenylsulfonylamino)-4-chlorobenzene, 1,2-Bis(2,5-dichloro-3-thienylsulfonylamino) -4-chlorobenzene; 1,2-Bis(2-chloro-5-thienylsulfonylamino)-4-chlorobenzene; 1,2-Bis(2-methyl-3-chlorophenylsulfonylamino)-4-fluorobenzene; 1,2-Bis(2-chloro-5-thienylsulfonylamino)-4-flucrobenzene;
A » * or a salt thereof.
33. A herbicidal or fungicidal composition comprising a bissulfonamide derivative of the formula (I), as defined in any one of claims 29 to 32, or an agriculturally acceptable salt thereof, and an agriculturally acceptable carrier or diluent.
34. Use of a bissulfonamide derivative of formula (I), as defined in any one of claims 1 to 10, or a salt thereof, in the inhibition of quinic acid catabolism.
35. Use according to claim 34, wherein the bissulfonamide or salt thereof is used to inhibit the catabolism of quinic acid by a fungus or a bacterium. i"
ZA200202897A 1999-10-15 2002-04-12 Enzyme inhibitors. ZA200202897B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GBGB9924522.7A GB9924522D0 (en) 1999-10-15 1999-10-15 Enzyme inhibitors

Publications (1)

Publication Number Publication Date
ZA200202897B true ZA200202897B (en) 2003-04-14

Family

ID=10862854

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA200202897A ZA200202897B (en) 1999-10-15 2002-04-12 Enzyme inhibitors.

Country Status (8)

Country Link
EP (1) EP1239852A2 (en)
JP (1) JP2003512319A (en)
KR (1) KR20020057973A (en)
AU (1) AU7805400A (en)
CA (1) CA2387593A1 (en)
GB (1) GB9924522D0 (en)
WO (1) WO2001028537A2 (en)
ZA (1) ZA200202897B (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPR738301A0 (en) * 2001-08-30 2001-09-20 Starpharma Limited Chemotherapeutic agents
AU2003213661A1 (en) * 2002-02-28 2003-09-09 Onconova Therapeutics, Inc. Amino-substituted sulfonanilides and derivatives thereof for treating proliferative disorders
US20040204493A1 (en) * 2003-04-11 2004-10-14 Scott David R. Carbonic anhydrase inhibitors as drugs to eradicate Helicobacter pylori in the mammalian, including human, stomach
EP1809619A1 (en) 2004-10-21 2007-07-25 Transtech Pharma, Inc. Bissulfonamide compounds as agonists of galr1, compositions, and methods of use
GB0526255D0 (en) 2005-12-22 2006-02-01 Novartis Ag Organic compounds
CA2640304A1 (en) * 2006-02-13 2007-08-23 Laboratoires Serono S.A. Sulfonamide derivatives for the treatment of bacterial infections
WO2008114831A1 (en) * 2007-03-20 2008-09-25 National University Corporation Okayama University Antibacterial agent having sulfonamide group
EP2955173B1 (en) 2010-12-16 2017-10-04 Allergan, Inc. 1,2-bis-sulfonamide derivatives as chemokine receptor modulators
GB201223308D0 (en) * 2012-12-21 2013-02-06 Univ Sunderland Enzyme inhibitors
CN109042741A (en) * 2018-06-28 2018-12-21 贵州省松桃武陵源苗王茶业有限公司 A kind of microbial pesticide of the tealeaves prevention and control of plant diseases, pest control and its application
CN116283677B (en) * 2023-02-24 2024-05-17 中国科学院广州生物医药与健康研究院 Small molecular chemical cross-linking agent and preparation method and application thereof

Also Published As

Publication number Publication date
GB9924522D0 (en) 1999-12-15
EP1239852A2 (en) 2002-09-18
WO2001028537A3 (en) 2001-06-14
JP2003512319A (en) 2003-04-02
WO2001028537A2 (en) 2001-04-26
KR20020057973A (en) 2002-07-12
CA2387593A1 (en) 2001-04-26
AU7805400A (en) 2001-04-30

Similar Documents

Publication Publication Date Title
ZA200202897B (en) Enzyme inhibitors.
DE69221290D1 (en) AROMATIC SULPHONAMID-BASED HYDROXAMIC ACID DERIVATIVES
CA2344290A1 (en) Quinazoline derivatives
DK1104760T3 (en) Sulfamoyl heteroarylpyrazole compounds as anti-inflammatory / analgesic agents
AU4313797A (en) Qinoline derivatives inhibiting the effect of growth factors such as vegf
CA2132199A1 (en) Depsipeptide derivative, production thereof and use thereof
AU692090B2 (en) Novel 4,6-diarylpyrimidine derivatives and salts thereof
GB1265165A (en)
FI942499A (en) Indole derivatives, a process for preparing the same and its medical use
ES2074544T3 (en) NAFTILOXAZOLIDONE DERIVATIVES.
FR2801587B1 (en) NOVEL BENZOTHIADIAZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
CN113754595A (en) Preparation method and application of 6-fluoroquinazoline derivatives containing disulfide structures
CA1218071A (en) Thiazolidinone compounds and processes for treating plants
ATE200622T1 (en) USE OF HYDANTOIN DERIVATIVES FOR THE PRODUCTION OF A MEDICATION FOR THE TREATMENT OF DISEASES RELATED TO ACTIVE OXYGEN AND FREE RADICALS
FI971584A (en) Preventive and curative agents for type I allergic diseases
JP2003512464A (en) New indole compounds
SU965338A3 (en) Herbicidal composition
SU1410860A3 (en) Method of controlling fungi
IL133653A0 (en) Angiogenesis inhibiting 5-substituted - 1, 2, 4 - thiadiazolyl derivatives
CN113880777A (en) Preparation method and application of quinazolinone derivatives containing disulfide structures
FR2764290A1 (en) HYDRAZIDE DERIVATIVES OF ISONICOTINIC ACID
JPS61227573A (en) Pyrimidine derivative, production thereof and fungicide for agricultural use
CS252814B2 (en) Insecticide and acaricide and method of its efficient componenent production
DE3277811D1 (en) Quinolin-3-yloxy(amino)phenoxyalkane carboxylic acid derivatives, process for their synthesis, herbicidal compositions containing them, and their use as herbicides
JPH02115161A (en) 4-trifluoromethyl-2-pyrrolidinone derivative, production thereof and herbicide containing the same as active ingredient