WO1999028316A1 - Composes thiophene-sulfamides - Google Patents

Composes thiophene-sulfamides Download PDF

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Publication number
WO1999028316A1
WO1999028316A1 PCT/EP1998/006993 EP9806993W WO9928316A1 WO 1999028316 A1 WO1999028316 A1 WO 1999028316A1 EP 9806993 W EP9806993 W EP 9806993W WO 9928316 A1 WO9928316 A1 WO 9928316A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
alkoxy
thiophene
amide
sulfonic acid
Prior art date
Application number
PCT/EP1998/006993
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English (en)
Inventor
Paolo Pevarello
Mario Varasi
Franco Heidempergher
Salvatore Toma
Carmela Speciale
Original Assignee
Pharmacia & Upjohn S.P.A.
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Publication date
Application filed by Pharmacia & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to AU16661/99A priority Critical patent/AU1666199A/en
Priority to CA002310054A priority patent/CA2310054A1/fr
Priority to JP2000523208A priority patent/JP2001524551A/ja
Priority to EP98961128A priority patent/EP1034176A1/fr
Publication of WO1999028316A1 publication Critical patent/WO1999028316A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel thiophene-sulfonamides, to a process for their preparation, to pharmaceutical compositions containing them and their use in therapy.
  • the compounds of the invention act as inhibitors of kynurenine-3-hydroxylase (KYN-OH), an enzyme which forms part of the metabolic pathway of kynurenine. It is well known that through the kynurenine pathway, tryptophan metabolism gives rise to the formation of 3-hydroxy-kynurenine (3-OH-KYN) and quinolinic acid (QUIN), on the one side, and kynurenic acid (KYNA), on the other side, as shown in Figure 1. (The legend to Figure 1 is to be found on the last page of the experimental part of the specification). KYNA is endowed with neuroprotective properties (J. Neurosci.
  • QUIN is a relatively potent neurotoxin which has been implicated in the pathogenesis of a variety of neurological disorders including Huntington's disease and epilepsy (Life Sci. 1984, 35, 19-32; Nature, 1986, 321. 168-171 ; Science, 1983, 219, 316- 318).
  • each of R, R b and R 2 which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino ⁇ !
  • R 3 is hydrogen, C,-C 6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, Cp alkoxy, nitro, amino, hydroxy, formyla
  • each of R, R and R 2 which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino,C ⁇ -C 6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy.
  • the present invention also provides a method of treating a mammal, including humans, in need of a kynurenine-3-hydroxylase enzyme inhibitor, such method comprising administering thereto a therapeutically effective .amount of a thiophene- sulfon-amide compound of formula (I)
  • each of R, R b and R 2 which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino,C
  • each of R, R,, and R 2 which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino, ⁇ -C 6 alkoxy-carbonyl, or an unsaturated pentatomic heteromonocyclic ring containing one to three heteroatoms chosen independently from oxygen, sulphur and nitrogen, wherein the heteromonocyclic ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C,-C 6 alkyl, C r C 6 alkoxy, C 2 -C 6 alkanoylamino, formylamino and C,-C 6 alkoxy-carbon
  • R 3 is hydrogen, C r C 6 alkyl or a phenyl or benzyl group, in which the phenyl ring or phenyl moiety is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 6 alkyl, C,-C 6 alkoxy, nitro, amino, hydroxy, formylamino.
  • each of R and R 5 which are the same or different, is independently hydrogen or a phenyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 6 alkyl, C,-C 6 alkoxy.
  • the present invention includes within its scope all the possible isomers, stereoisomers. optical isomers and their mixtures and the metabolites and the metabolic precursors (or bioprecursors) of the compounds of formula (I).
  • Examples of pharmaceutically acceptable salts of the compounds of the invention are either those with inorganic bases, such as sodium, potassium hydroxydes as well as the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfonic acids.
  • inorganic bases such as sodium, potassium hydroxydes
  • organic acids e.g. citric, tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfonic acids.
  • the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I). i.e. compounds which have a different to formula (I) but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
  • pharmaceutically acceptable bioprecursors otherwise known as pro-drugs
  • the alkyl, alkoxy, alkanoylamino and alkoxy-carbonyl groups may be branched or straight chain groups.
  • a C r C 6 alkyl group is preferably a C,-C 4 alkyl group.
  • Representative examples of C,-C 4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec-, and tert-butyl.
  • a C C 6 alkoxy group is preferably a C r C 4 alkoxy group.
  • Representative examples of C,-C 4 alkoxy groups include methoxy, and ethoxy.
  • a C 2 -C 6 alkanoylamino group is preferably an acetylamino or propionylamino group.
  • a C,-C 6 alkoxy-carbonyl group is preferably a C r C 4 alkoxy-carbonyl group typically a C,-C 2 one.
  • a halogen is fluorine, bromine, chlorine or iodine, in particular chlorine, bromine or fluorine.
  • Preferred examplex of R, R ⁇ and R 2 as unsaturated pentatomic heteromonocyclic rings include pyrrole, furane, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1 ,2,4-oxadiazole and 1 ,3,4-thiadiazole ring.
  • R 4 and R 5 taken together form a C 6 -C 1 aromatic ring system, it is preferably a phenyl or napththalene ring system, which is thus condensed with the oxazole or thiazole moietv.
  • Preferred compounds of formula (I) are those wherein;
  • X is O or S; each of R, R and R 2 , which are the same or different, is independently hydrogen, halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 4 alkyl, C r C alkoxy, C 2 -C 4 alkanoylamino, formylamino, ⁇ -C 4 alkoxy-carbonyl, or a pyrrole, furan, oxazole, isoxazole, thiazole, pyrazole, imidazole, 1 ,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole and
  • R 3 is hydrogen, C r C 4 alkyl, or a benzyl or phenyl group in which the phenyl moiety or the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C r C 4 alkyl, C r C 4 alkoxy, nitro, amino, hydroxy, formylamino, C 2 -C 4 alkanoylamino and C C 4 alkoxy-carbonyl; each of R 4 and R 5 , which are the same or different, is independently hydrogen or phenyl wherein the phenyl ring is unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro, amino, phenyl, benzyl, C r C 4 alkyl, C,-C 4 alkoxy, C 2 -C 4 alkanoylamino, formylamino and C r C
  • R 5 taken together form a phenyl or napththyl ring unsubstituted or substituted by one or two substituents chosen independently from halogen, hydroxy, trifluoromethyl, nitro. amino, phenyl, benzyl, C r C 4 alkyl, C r C 4 alkoxy, C 2 -C 4 alkanoylamino, formylamino and
  • 5-Thiazol-2-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide.
  • 5-Isoxazol-3-yl-thiophene-2-sulfonic acid (benzoxazol-2-yl)-amide;
  • a compound of formula (I) may be converted into another compound of formula(I) by known methods.
  • a nitro group may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid using, an organic cosolvent such as dioxane, tetrahydro furan at a temperature varying between room temperature and about 100 °C.
  • an organic cosolvent such as dioxane, tetrahydro furan at a temperature varying between room temperature and about 100 °C.
  • an amino group may be converted into a formylamino or a C 2 - C 4 alkanoylamino group, for example by reacting with formic acid or with a suitable C 2 -C 4 alkanoyl -anhydride without any solvent or in a organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as triethylamine, at a temperature varying between 0 °C and about 100 °C.
  • Y as leaving group is a good leaving group, for example a halogen atom, typically chlorine, iodine, or bromine, in particular chlorine.
  • the reaction between a compound of formula (II) and a compound of formula (III) can be carried out, for example, in the presence of a base such as triethylamine or pyridine, in a inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide. dichloromethane at a temperature varying between 0 °C and about 100 °C.
  • a base such as triethylamine or pyridine
  • a inert solvent such as toluene, dioxane, tetrahydrofuran, dimethylformamide.
  • dichloromethane at a temperature varying between 0 °C and about 100 °C.
  • the reaction can be also carried out without base and solvent at a temperature varying between 100 °C and about 200 °C.
  • the conversion of a compound of formula (I) wherein R 3 is hydrogen in another compound of formula (I) wherein R 3 is as defined above except hydrogen can be carried out, for example, in the presence of a base such as sodium hydride, potassium t-butoxide. potassium carbonate in a solvent such as 1 ,2-dimethoxyethane, dioxane. dimethylformamide, acetone and in the presence of a phase-transfer catalyst such as tetra- n-butylammonium iodide at a temperature ranging from about 0 °C to 100 °C, or in the presence of copper bronze and a base such as potassium carbonate at a temperature varying between 100 °C and about 200 °C.
  • the intermediate compounds (II) and (III) are either commercially available or or can be obtained by known methods.
  • the compounds of the invention are active as kynurenine-3-hydroxylase enzyme inhibitors and therefore are useful in the prevention and/or treatment of neuropathological processes, related to a deranged production of quinolinic acid and/or 3 -hydroxy kynurenine due to excessive activation of neuro transmission mediated by excitatory amino acid receptors and or oxidative stress.
  • neuropathological processes are neurodegenerative pathologies including, e.g. Huntington's chorea, Alzheimer's disease.
  • a human or animal in need of a kynurenine-3-hydroxylase enzyme inhibitor can thus be treated by a method which comprises the administration thereto of a therapeutically effective amount of a compound of the invention or a salt thereof. The condition of the human or animal can thereby be improved.
  • the efficacy of the compounds of the invention in the inhibition of the enzyme kynurenine - 3-hydroxylase was evaluated e.g., in rat liver mitochondrial extract following the method reported below, according to the procedure described in "Analytical Biochem. (1992), 205, 257-262", with minor modifications.
  • the assay for kynurenine 3-hydroxylase is based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. Rat liver mitochondrial extract was used as enzymatic preparation for this assay.
  • the assay for kynurenine 3-hydroxylase activity was carried out at 37°C for a time of 30 min.
  • the reaction mixture of a total volume of 30 ⁇ l was constituted of 44 ⁇ g of suspended extract, 100 mM Tris ICY buffer pH 8.1, 10 mM EDTA, 100 mM KC1, 0.8 mM NADPH, 0.025 mM- L-Kynurenine, 0.3 ⁇ Ci L-(3,5 - H)Kynurenine (10 Ci/mmol) and 3 ⁇ l of different concentration of inhibitor solutions.
  • the reaction was terminated by the addition of 300 ⁇ l of 7.5 (W/v) activated charcoal, and centrifuged for 7 min..
  • the dosage level suitable for administration to a mammal, e.g.: to humans, depends on the age, weight, conditions of the patient and on the administration route; for example, the dosage adopted for oral administration e.g. for one representative compound of the invention PNU 191386 may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily.
  • the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
  • the invention includes also pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient (which can be a carrier or a diluent).
  • compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; desegregating agents, e.g.
  • a starch alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscolar injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine hydrochloride.
  • the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, acqueous. isotonic saline solutions or they may contain as a carrier propylene glycol.
  • the suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • Thiophene-2-sulfonic acid (thiazol-2-yl)-amide; Thiophene-2-sulfonic acid (4-phenyl-oxazol-2-yl)-amide;
  • the mixture was stirred under nitrogen at 25°C for 24 h.
  • Capsule each weighing 0.23 g and containing 50 mg of the active substance can be prepared as follow: Composition for 500 capsules:
  • This formulation can be encapsulated in two hard gelatin capsules of two pieces, each with each capsule weighing 0.23 g.
  • a pharmaceutical injectable composition can be manufactured dissolving 50 g of 5- Isoxazol-3-yl-thiophene-2-sulfonic acid (5-chloro-benzoxazol-2-yl)-amide in sterile propylenglycol (1000 mL) and sealed in 1-5 ampoules.
  • IDO Indolamineoxigenase
  • KYN-OH Kynurenine-3 -hydroxy lase
  • KYNA Kynurenic acid
  • 3-OHAA 3 -Hydroxy anthranilic acid
  • KYNase Kynureninase
  • KAT Kynurenine amino transferase
  • 3-OH-KYN 3-Hydroxy-kynurenine.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à des composés représentés par la formule (I) dans laquelle X est O ou S; l'un au moins des groupes que sont R, R1 et R2, qui sont identiques ou différents, est indépendamment hydrogène, halogène, hydroxy, trifluorométhyle, nitro, amino, phényle, benzyle, alkyle C1-C6, alcoxy C1-C6, alcanoylamino C2-C6, formylamino et alcoxy C1-C6-carbonyle ou un noyau hétéromonocyclique pentatomique non saturé comportant un à trois hétéroatomes sélectionnés indépendamment parmi l'oxygène, le soufre et l'azote, ledit noyau hétéromonocyclique étant non substitué ou substitué par un ou deux substituants sélectionnés indépendamment parmi halogène, hydroxy, trifluorométhyle, nitro, amino, phényle, benzyle, alkyle C1-C6, alcoxy C1-C6, alcanoylamino C2-C6, formylamino et alcoxy C1-C6-carbonyle; R3 est hydrogène, alkyle C1-C6, un groupe benzyle ou phényle dans lequel la fraction phényle ou le cycle phényle est non substitué ou substitué par un ou deux substituants sélectionnés indépendamment parmi halogène, trifluorométhyle, alkyle C1-C6, alcoxy C1-C6, nitro, amino, hydroxy, formylamino, alcanoylamino C2-C6 et alcoxy C1-C6-carbonyle; R4 et R5, qui sont identiques ou différents, sont chacun indépendamment hydrogène ou un noyau phényle non substitué ou substitué par un ou deux substituants sélectionnés indépendamment parmi halogène, hydroxy, trifluorométhyle, nitro, amino, phényle, benzyle, alkyle C1-C6, alcoxy C1-C6, alcanoylamino C2-C6, formylamino et alcoxy C1-C6-carbonyle; ou bien R4 et R5 forment conjointement un système cyclique aromatique C6-C14 non substitué ou substitué par un ou deux substituants sélectionnés indépendamment parmi halogène, hydroxy, trifluorométhyle, nitro, amino, phényle, benzyle, alkyle C1-C6, alcoxy C1-C6, alcanoylamino C2-C6, formylamino et alcoxy C1-C6-carbonyle. L'invention se rapporte également à des sels pharmaceutiquement acceptables de ces composés qui présentent une activité inhibitrice dirigée contre l'enzyme kynurénine-3-hydroxylase.
PCT/EP1998/006993 1997-11-27 1998-10-27 Composes thiophene-sulfamides WO1999028316A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU16661/99A AU1666199A (en) 1997-11-27 1998-10-27 Thiophene-sulfonamide compounds
CA002310054A CA2310054A1 (fr) 1997-11-27 1998-10-27 Composes thiophene-sulfamides
JP2000523208A JP2001524551A (ja) 1997-11-27 1998-10-27 チオフェン−スルホンアミド組成物
EP98961128A EP1034176A1 (fr) 1997-11-27 1998-10-27 Composes thiophene-sulfamides

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GB9725138.3 1997-11-27
GBGB9725138.3A GB9725138D0 (en) 1997-11-27 1997-11-27 Thiophenesulfonamide compounds

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WO (1) WO1999028316A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004517892A (ja) * 2000-12-13 2004-06-17 ワイス β−アミロイド産生の複素環スルホンアミド阻害剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027979A1 (fr) * 1993-05-20 1994-12-08 Immunopharmaceutics, Inc. Sulfonamides et leurs derives modulant l'activite de l'endotheline
EP0819681A2 (fr) * 1996-07-19 1998-01-21 F. Hoffmann-La Roche Ag N-(4-Aryl-thiazole-2-yl)-sulfonamides et leur utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994027979A1 (fr) * 1993-05-20 1994-12-08 Immunopharmaceutics, Inc. Sulfonamides et leurs derives modulant l'activite de l'endotheline
EP0819681A2 (fr) * 1996-07-19 1998-01-21 F. Hoffmann-La Roche Ag N-(4-Aryl-thiazole-2-yl)-sulfonamides et leur utilisation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004517892A (ja) * 2000-12-13 2004-06-17 ワイス β−アミロイド産生の複素環スルホンアミド阻害剤
US7691884B2 (en) 2000-12-13 2010-04-06 Wyeth Heterocyclic sulfonamide inhibitors of β amyloid production
US7842718B2 (en) 2000-12-13 2010-11-30 Wyeth Llc Heterocyclic sulfonamide inhibitors of beta amyloid production

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EP1034176A1 (fr) 2000-09-13
GB9725138D0 (en) 1998-01-28
CA2310054A1 (fr) 1999-06-10
AU1666199A (en) 1999-06-16
JP2001524551A (ja) 2001-12-04

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