WO1996016963A1 - Sulfonamides et leur utilisation comme medicaments - Google Patents

Sulfonamides et leur utilisation comme medicaments Download PDF

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Publication number
WO1996016963A1
WO1996016963A1 PCT/CH1995/000131 CH9500131W WO9616963A1 WO 1996016963 A1 WO1996016963 A1 WO 1996016963A1 CH 9500131 W CH9500131 W CH 9500131W WO 9616963 A1 WO9616963 A1 WO 9616963A1
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WIPO (PCT)
Prior art keywords
methoxy
phenoxy
pyridin
pyrimidin
isopropyl
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PCT/CH1995/000131
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German (de)
English (en)
Inventor
Volker Breu
Kaspar Burri
Jean-Marie Cassal
Martine Clozel
Georg Hirth
Bernd-Michael Löffler
Marcel Müller
Werner Neidhart
Henri Ramuz
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F. Hoffmann-La Roche Ag
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Publication of WO1996016963A1 publication Critical patent/WO1996016963A1/fr
Priority to US08/730,422 priority Critical patent/US5837708A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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

Definitions

  • the present invention relates to new sulfonamides and their use as medicines.
  • the invention relates to new compounds of the formula
  • R 2 is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy lower alkyl, lower alkylsulfonyl lower alkoxy, phenyl, lower alkoxyphenyl, lower alkylenedioxyphenyl or heterocyclyl;
  • R 3 lower-alkyl, lower-alkoxy, formyl, halogen-lower-alkyl, hydroxy-lower-alkyl, amino-lower-alkyl or a radical -CH 2 ⁇ -A-lower-alkyl, - (CH 2 ) m - 0- (CRaRb) n OH, - (CH 2 ) m-0- (CRaRb) n NH 2 or - (CH 2 ) m -0- (CR a Rb) n - BR 9 ;
  • R 4 -R 8 are hydrogen, lower alkoxy or halogen
  • R 9 heterocyclyl; Phenyl or phenyl substituted by lower alkyl, lower alkoxy and / or halogen, or lower alkyl;
  • R a and Rb are hydrogen or lower alkyl;
  • A is a ketalized 1,2-dihydroxyethylene group;
  • lower used here denotes groups with 1-7 C atoms, preferably 1-4 C atoms.
  • Alkyl, alkoxy and alkylthio groups and alkyl groups as constituents of alkanoyl groups can be straight-chain or branched. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec. and tert-butyl.
  • Halogen denotes fluorine, chlorine, bromine and iodine, with chlorine being preferred.
  • a lower alkylenedioxyphenyl radical is, for example, an ethylenedioxyphenyl radical.
  • a ketalized 1,2-dihydroxyaethylene group is, for example, the 2,2-dimethyl-1,3-dioxolane-4,5-diyl group.
  • heterocyclyl radicals are in particular substituted, for example mono- or di-substituted or unsubstituted mono- or bicyclic 5- and 6-membered heterocyclic radicals with oxygen, substituted by lower alkyl, lower alkanoyl, halogen, or by a further heterocyclic radical, Nitrogen or sulfur as a heteroatom, such as 2- and 3-furyl, pyrimidinyl, 2-, 3- and 4-pyridyl, 1,2- and 1,4-diazinyl, morpholino, 2- and 3-thienyl, isoxazolyl, oxazolyl, Thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and
  • heterocyclyl radicals R 1 are in particular substituted and unsubstituted pyridyl, pyrimidinyl, thienyl and isoxazolyl.
  • heterocyclic radicals R 2 are in particular pyrimidinyl and morpholino.
  • heterocyclyl radicals R 9 are in particular pyridyl and furyl.
  • Preferred compounds of the formula I are those in which R 1 is a monocyclic S, N and or 0 heterocyclic radical, in particular unsubstituted or by lower alkyl, halogen, amino, mono- or di-lower alkylamino or lower alkanoyl substituted pyridyl, pyrimidinyl, isoxazolyl, furyl or thienyl.
  • R 2 is hydrogen, pyrimidinyl, pyridyl, morpholino, thiomorpholino, piperidino, pyrrolidino, benzodioxolyl, lower alkoxyphenyl or lower alkylthio and those R 3 is a radical -0- (CR a R b ) n OH, -O- (CR a R b ) n NH 2 or a radical -O (CH 2 ) 2 -BR 9 , and R 9 is a monocyclic N- and / or O-heterocyclic radical, in particular pyridyl, pyrazinyl or furyl.
  • R 1 is a pyridyl radical which is substituted by lower alkyl
  • R 2 is morpholino
  • R 3 is a radical -0 (CH 2 ) 2 ⁇ C (O) NHR 9
  • R 4 is lower alkoxy
  • R5- R8 are hydrogen.
  • Preferred R 9 radicals are heterocyclyl radicals, especially pyridyl radicals, such as 2-pyridyl.
  • the compounds of formula I above are inhibitors of endothelin receptors. They can therefore be used to treat diseases which are associated with endothelin activities, in particular circulatory diseases such as hypertension, ischemia, vasospasm and angina pectoris.
  • the compounds of formula I can be prepared by
  • R 1 , R 2 and R 4 - R 8 have the meaning given above and shark is halogen, with a compound of the formula HO (CR a R) n XH
  • n, R a , and R b have the meaning given above and X represents 0 or NH, or
  • R 1 has the meaning given above and where Y is halogen and Z is amino, or Y amino and Z is halogen, or
  • R ⁇ R 2 , R 4 - R 8 , R a , R b , X, m and n are the above
  • A represents a ketalized 1,2-dihydroxyethylene group
  • Alkali metal alcoholate used.
  • the alkali metal alcoholate is preferably sodium alcoholate.
  • the reaction is expediently carried out with heating, for example to 40-120 ° C.
  • the compound HO (CR a R b ) n XH is used as the monosodium salt of ethylene, propylene or butylene glycol or aminoethanol, propanol or butanol.
  • reaction of a compound of the formula III with a compound of the formula R 1 SÜ 2 Z can be carried out in a manner known per se for the production of sulfonamides, for example in an inert organic solvent, such as ethyl sulfoxide, expediently with heating and in one Protective gas atmosphere, e.g. under argon.
  • an inert organic solvent such as ethyl sulfoxide
  • the reaction according to process variant cl) can be carried out in a manner known per se for the production of carbamates and ureas from alcohols or amines.
  • a compound of formula IV with an isocyanate of formula R 9 NCO in a suitable anhydrous organic solvent, for example a hydrocarbon such as toluene, expediently with heating, to give a compound of formula I in which B is -OC (0) NH- are implemented.
  • the isocyanate can be generated in situ, for example from an azide of the formula R 9 CON3, by thermal decomposition.
  • a compound of the formula IV in which B is oxygen can be combined with phosgene and then with an alcohol of the formula R 9 OH to give a compound of the formula I in which A is a radical -OC (0) 0-, be implemented.
  • a phosgene salt such as diphosgene (CI-COOCCI 3 ) or triphosgene (CO (OCCl3) can be used.
  • the phosgene is there appropriately used as a solution in an inert anhydrous organic solvent, for example a hydrocarbon such as toluene.
  • the reaction with phosgene can be carried out at room temperature.
  • the acid chloride obtained as an intermediate is reacted directly with the alcohol R 9 OH, expediently with heating.
  • reaction according to process variant d) can be carried out under the reaction conditions described for process variant a) and gives compounds of the formula I in which R 3 is a radical -CH 2 O- A-lower alkyl.
  • substituents present therein can be modified.
  • a methyl group R 3 can be converted into a formyl group by oxidation.
  • the oxidation can be carried out in a manner known per se, for example using selenium dioxide.
  • the formyl group can be reduced to the hydroxymethyl group. This reduction can be accomplished in a manner known per se, for example using reducing agents such as NaBH 4 .
  • the hydroxymethyl group can be converted into a halogenomethyl group by reaction with a halogenating agent such as POCI 3 / PCI5.
  • N-heterocyclic radicals such as pyridyl, can be oxidized to N-oxides.
  • the compounds of the formula I can be converted into salts in a manner known per se, for example alkali metal salts such as Na and K salts or alkaline earth metal salts such as Ca or Mg salts.
  • a cDNA encoding human placenta ETA receptor was cloned (M. Adachi, Y.-Y. Yang, Y. Furuichi and C- Miyamoto, BBRC____, 1265-1272) and in Baculo virus insect cell system expressed.
  • Baculovirus-infected insect cells from a 23 1 fermenter are centrifuged off 60 hours after the infection (3,000 ⁇ g, 15 minutes, 4 ° C. ) , resuspended in Tris buffer (5 mM, pH 7.4, 1 mM MgC) and centrifuged again. After resuspension and centrifugation, the cells are suspended in 800 ml of the same buffer and frozen at -120 ° C.
  • the cells are broken open when the suspension is thawed in this hypotonic buffer mixture. After repeated freeze / thaw cycle, the suspension is homogenized and centrifuged (25,000 xg, 15 minutes, 4 ° C). After suspension in Tris buffer (75 mM, pH 7.4, 25 mM MgC, 250 mM sucrose), 1 ml aliquots (protein content approx. 3.5 mg ml) are stored at -85 ° C.
  • the frozen membrane preparations are thawed and after 10 minutes of centrifugation with 25000 g at 20 ° C. in assay buffer (50 mM Tris buffer pH 7.4, containing 25 mM MnCl 2. 1 mM EDTA and 0.5 % Bovine serum albumin) resuspended.
  • assay buffer 50 mM Tris buffer pH 7.4, containing 25 mM MnCl 2. 1 mM EDTA and 0.5 % Bovine serum albumin
  • 100 ⁇ l of this membrane suspension, containing 70 ⁇ g protein are mixed with 50 ⁇ l 125 I-endothelin (specific activity 2200 Ci / mmol) in assay buffer (25000 cpm, final concentration 20 pM) and 100 ⁇ l assay buffer, the varying concentrations of the test compound contains, incubated. Incubation is carried out at 20 ° C for 2 hours or at 4 ° C for 24 hours.
  • the free and membrane-bound radio ligands are separated by filtration
  • Table 1 shows the inhibitory activity of compounds of the formula I determined in this test arrangement as IC50, ie as the concentration [nM] which is required to inhibit 50% of the specific binding of 125 I-endothelin.
  • Rings of 5 mm in length were excised from the thoracic aorta of adult Wistar Kyoto rats. The endothelium was removed by lightly rubbing the inner surface. Each ring was immersed in an isolated bath at 37 ° C in 10 ml of Krebs-Henseleit solution with gassing with 95% O2 and 5% CO2. The isometric tension of the rings was measured. The rings were stretched to a preload of 3 g. After 10 minutes incubation with the test compound or vehicle, cumulative doses of endothelin-1 were added. The activity of the test compound was determined by the observed shift to the right of the dose-effect curve of endothelin-1 in the presence of various concentrations of antagonist.
  • This shift to the right corresponds to the quotient of the ECso values of endothelin-1 in the presence and in the absence of an antagonist, the ECso value denoting the endothelin concentration required for a half-maximum contraction.
  • the corresponding PA2 value was calculated for each individual dose-effect curve according to the equation below, which represents a measure of the activity of the test compound, using a computer program.
  • PA2 log (DR-1) -log (antagonist concentration)
  • Endothelin's EC50 in the absence of test compounds is 0.3 nM.
  • the values for pA2 thus obtained with compounds of the formula I are given in Table 2.
  • the compounds of formula I because of their ability to inhibit endothelin binding, can be used as agents for treating diseases associated with vasoconstriction-increasing processes.
  • diseases are high blood pressure, coronary diseases, heart failure, renal and myocardial ischemia, renal failure, dialysis, cerebral ischemia, cerebral infarction, migraines, subarachnoid hemorrhage, Raynaud's syndrome and pulmonary high pressure.
  • the compounds of formula I can be administered orally, rectally, parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecal or transdermally; or sublingually or as an ophthalmic preparation, or as an aerosol.
  • parenterally e.g. intravenously, intramuscularly, subcutaneously, intrathecal or transdermally; or sublingually or as an ophthalmic preparation, or as an aerosol.
  • application forms are capsules, tablets, orally administrable suspensions or solutions, suppositories, injection solutions, eye drops, ointments or spray solutions.
  • a preferred form of application is intravenous, intramuscular or oral application.
  • the dosage in which the compounds of formula I are administered in effective amounts depend on the type of specific active ingredient, the age and the needs of the patient and the mode of administration. Doses of about 0.1-100 mg / kg body weight per day are generally suitable.
  • the preparations containing the compounds of formula I can contain inert or pharmacodynamically active additives. Tablets or granules, for example, can contain a number of binders, fillers, carriers or diluents. Liquid preparations can, for example, be in the form of a sterile, water-miscible solution. In addition to the active ingredient, capsules can also contain a filler or thickener.
  • taste-improving additives as well as the substances usually used as preservatives, stabilizers, humectants and emulsifiers, as well as salts for changing the osmotic pressure, buffers and other additives can also be present.
  • the above-mentioned carrier substances and diluents can consist of organic or inorganic substances, for example water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. The prerequisite is that all auxiliary substances used in the manufacture of the preparations are non-toxic.
  • Section b) Analogously to Example 1, Section b) was obtained by reacting (5- n-pentylthiophene-2-sulfonamide) -K and 4,6-dichloro-5- (2-methoxyphenoxy) -2.2 '-bipvrimidine the 5-pentyl-thiophene-2-sulfonic acid 6-chloro-5- (2-methoxy-phenoxy) -2,2'-bipyrimidin-4-ylamide as a white solid. MS: 545 (M).
  • the crystals were suspended in dilute, aqueous hydrochloric acid (100 ml of water and 50 ml of HCl) and stirred for 5 minutes, suction filtered and washed again with water and dried in a high vacuum.
  • the 5-isopropyl-pyridine-2-sulfonic acid 6-chloro-5- (2-methoxy-phenoxy) -2 ) 2'-bipyrimidin-4-ylamide was thus obtained as a white, crystalline solid.
  • Example 11 2.0 g of 5-isopropyl-pyridine-2-sulfonic acid 6- (2-hydroxy-ethoxy) - were dissolved.
  • the brownish foam obtained (219 mg) was dissolved in 15 ml of acetonitrile, 1.5 ml of HF solution (40% strength) were added at room temperature and the mixture was stirred for 2 hours.
  • the reaction mixture was between ethyl acetate and semi-saturated NaCl solution vmd distributed the organic phase processed as usual.
  • the crude product was chromatographed on silica gel with methylene chloride / ethyl acetate (4/1) as the eluent and recrystallized from ether / hexane.
  • the above material (8.3 g) was dissolved in 300 ml of methylene chloride, mixed with 8.15 g of dimethylaminopyridine and finally at room temperature with 10.05 g of t-butyldimethylchlorosilane.
  • the reaction solution was stirred for 5 hours at room temperature.
  • the intestine was filtered, the solution was concentrated, the evaporation residue was distributed between semi-saturated NH-iCl solution and ethyl acetate and the organic phase was worked up.
  • Ethanol crystallized 175 mg of white crystals were obtained, which decompose at 180 ° C.
  • Example 39 0.130 g of the compound obtained in Example 39 was added to a sodium glycolate solution composed of 0.35 g of ethylene glycol and 0.021 g of sodium. The reaction mixture was stirred under argon at 80 ° C for 2 hours. The ethylene glycol was then distilled off and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue was recrystallized from ether-petroleum ether. 0.104 g of 5- (2-chloro-5-methoxy-phenoxy) -6- (2-hydroxy-ethoxymethyl) -2-morpholin-4-yl-pyrimidin-4-ylamide were obtained. Mp 166 ° C.
  • Example 45 345 mg sodium were at 80 ° C in 50 ml abs. Dissolved ethylene glycol.
  • Example 47 In analogy to Example 45, the reaction time was 3 hours
  • Example 43 In analogy to Example 45, the reaction time was 3.5 hours
  • Example 49 110 mg of sodium were dissolved in 2.5 ml of ethylene glycol at 50 ° C.
  • the Na salt was suspended in water and the suspension was acidified with acetic acid and extracted with ethyl acetate to which a little CH2Cl2 was added.
  • the organic phase was washed twice with saturated sodium chloride solution, dried with M S ⁇ and evaporated under reduced pressure. The residue was briefly washed with diethyl ether and hexane and then dried. 0.30 g (54%) was obtained as a beige powder with a melting point of 140 ° C. (dec.).
  • Example 51 Analogously to Example 51, the one prepared in Example 49 was used
  • Example 51 Analogously to Example 51, the compound prepared in Example 50 was pyridin-2-ylcarbamic acid 2- [5- (2-methoxyphenoxy) -6- (3,5-dimethyl-isoxazol-4-ylsu_fonylamino) in 68% yield in 68% yield ) -2,2'- bipyrimidin-4-yloxy] ethyl ester as light yellow crystals of mp. 217-218 ° C, MS: 635.3 (M + H) + , IR (KBr) 1736 cm- 1 (carbamate) .
  • Example 55 the pyridin-2-ylcarbamic acid pyridine-2-ylcarbamic acid prepared from the compound prepared in Example 46 was 2- [6- (5-tert-butylthiophen-2-ylsulfonylamino) -5- (2-methoxy-phenoxy ) -2-morpholin-4-yl-pyrimidin-4-yloxy] ethyl ester, as a white foam, MS: 683.5 (MH) - obtained.
  • Example 55 2- [6- (5-tert-butylthiophen-2-ylsulfonylamino) -5- (2-methoxy-phenoxy ) -2-morpholin-4-yl-pyrimidin-4-yloxy] ethyl ester
  • Example 47 Analogously to Example 51, the compound prepared in Example 47 was converted into 2- [6- (2,5-dichloro-thiophen-3-ylsulfonylamino) -5- (2-methoxy-phenoxy) in 55% yield of pyridin-2-ylcarbamic acid ) -2-morpholin-4-yl-pyrimidn-4-yloxy] ethyl ester, white crystals of mp. 194-196 ° C, MS:
  • Example 48 Analogously to Example 51, the compound prepared in Example 48 was pyridin-2-ylcarbamic acid 2- [6- (3,5-dimethyl-isoxazol-4-ylsulfonylamino) -5- (2-methoxy -phenoxy) -2-morpholin-4-yl-pyrimidin-4-yloxy] ethyl ester, white crystals of mp. 106-109 ° C, MS:
  • Tablets containing the following components can be produced in a conventional manner:
  • Capsules containing the following components can be produced in a conventional manner:
  • Injection solutions can have the following composition:

Abstract

Des composés ont la formule (I), dans laquelle R1 désigne hétérocyclyle; R2 désigne hydrogène, alkyle inférieur, alcoxy inférieur, alkylthio inférieur, alkyle-inférieur-alcoxy-inférieur, alcoxy-inférieur-alkylsulfonyle-inférieur, phényle, alcoxyphényle inférieur, dioxyphényle d'alcylène inférieur ou hétérocyclyle; R3 désigne alkyle inférieur, alcoxy inférieur, formyle, halogénure d'alkyle inférieur, hydroxyalkyle inférieur, aminoalkyle inférieur ou un résidu -CH¿2?O-A-alkyle inférieur, -(CH2)m-O-(CR?aRb)¿nOH, -(CH2)m-O-(CRaRb)nNH2 ou -(CH2)m-O-(CRaRb)n-B-R?9; R4 à R8¿ désignent hydrogène, alcoxy inférieur ou halogène; R9 désigne hétérocyclyle, phényle substitué ou non par alkyle inférieur, alcoxy inférieur et/ou halogène, ou alkyle inférieur; Ra et Rb désignent hydrogène ou alkyle inférieur; A désigne un groupe 1,2-dihydroxy-éthylène cétalisé; B désigne -OC(O)O-, -O(C(O)NH-, -NH(C(O)NH- ou -NHC(O)O-; n vaut 2, 3 ou 4; et m vaut 0 ou 1. Ces composés sont utiles pour traiter des maladies associées à l'activité de l'endothéline, notamment des maladies vasculaires telles que l'hypertonie, l'ischémie, les angiospasmes et l'angine de poitrine.
PCT/CH1995/000131 1994-11-25 1995-06-06 Sulfonamides et leur utilisation comme medicaments WO1996016963A1 (fr)

Priority Applications (1)

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US08/730,422 US5837708A (en) 1994-11-25 1996-10-15 Sulphonamides

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Application Number Priority Date Filing Date Title
CH355994 1994-11-25
CH3559/94-4 1994-11-25

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AR (2) AR002251A1 (fr)
BR (1) BR9505528A (fr)
CO (1) CO4650181A1 (fr)
PE (1) PE52496A1 (fr)
PL (1) PL185692B1 (fr)
TR (1) TR199501486A2 (fr)
UY (1) UY24100A1 (fr)
WO (1) WO1996016963A1 (fr)
ZA (1) ZA959808B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242601B1 (en) * 1999-01-18 2001-06-05 Hoffman-La Roche Inc. Heterocyclic sulfamides
WO2002053557A1 (fr) * 2000-12-18 2002-07-11 Actelion Pharmaceuticals Ltd Nouveaux sulfamides et leur utilisation comme antagonistes du recepteur de l'endotheline
US7858632B2 (en) 2004-03-05 2010-12-28 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US8268847B2 (en) 2006-08-29 2012-09-18 Actelion Pharmaceuticals, Ltd. Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526708A1 (fr) * 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, sa préparation et son usage comme médicament et intermédiaire

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526708A1 (fr) * 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, sa préparation et son usage comme médicament et intermédiaire

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242601B1 (en) * 1999-01-18 2001-06-05 Hoffman-La Roche Inc. Heterocyclic sulfamides
WO2002053557A1 (fr) * 2000-12-18 2002-07-11 Actelion Pharmaceuticals Ltd Nouveaux sulfamides et leur utilisation comme antagonistes du recepteur de l'endotheline
US7094781B2 (en) 2000-12-18 2006-08-22 Actelion Pharmaceuticals Ltd. Sulfamides and their use as endothelin receptor antagonists
EP1693372A1 (fr) * 2000-12-18 2006-08-23 Actelion Pharmaceuticals Ltd. Nouveaux sulfamides et leur utilisation comme antagoniste du récepteur d'endotheline
US7285549B2 (en) 2000-12-18 2007-10-23 Actelion Pharmaceuticals Ltd. Sulfamides and their use as endothelin receptor antagonists
KR100819668B1 (ko) * 2000-12-18 2008-04-04 액테리온 파마슈티칼 리미티드 신규한 피리미딘-설퍼아마이드
US7858632B2 (en) 2004-03-05 2010-12-28 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US8846705B2 (en) 2004-03-05 2014-09-30 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
US9556127B2 (en) 2004-03-05 2017-01-31 Roche Palo Alto Llc Diaminopyrimidines as P2X3 and P2X2/3 antagonists
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US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative

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PE52496A1 (es) 1996-12-12
UY24100A1 (es) 2000-12-29
ZA959808B (en) 1996-05-27
TR199501486A2 (tr) 1996-07-21
CO4650181A1 (es) 1998-09-03
AR010549A2 (es) 2000-06-28
PL185692B1 (pl) 2003-07-31
PL311487A1 (en) 1996-05-27
BR9505528A (pt) 1997-11-04
AR002251A1 (es) 1998-03-11

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