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WO1997019077A1 - Antagonistes des recepteurs de l'endotheline - Google Patents

Antagonistes des recepteurs de l'endotheline Download PDF

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Publication number
WO1997019077A1
WO1997019077A1 PCT/EP1996/005120 EP9605120W WO9719077A1 WO 1997019077 A1 WO1997019077 A1 WO 1997019077A1 EP 9605120 W EP9605120 W EP 9605120W WO 9719077 A1 WO9719077 A1 WO 9719077A1
Authority
WO
WIPO (PCT)
Prior art keywords
indole
benzothiadiazol
carboxylic acid
ylmethyl
ethyl ester
Prior art date
Application number
PCT/EP1996/005120
Other languages
German (de)
English (en)
Inventor
Werner Mederski
Mathias Osswald
Dieter Dorsch
Claus Jochen Schmitges
Claudia Wilm
Maria Christadler
Soheila Anzali
Original Assignee
MERCK Patent Gesellschaft mit beschränkter Haftung
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 MERCK Patent Gesellschaft mit beschränkter Haftung filed Critical MERCK Patent Gesellschaft mit beschränkter Haftung
Priority to AU76944/96A priority Critical patent/AU7694496A/en
Priority to EP96939865A priority patent/EP0863898A1/fr
Publication of WO1997019077A1 publication Critical patent/WO1997019077A1/fr

Links

Classifications

    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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 invention relates to compounds of the formula
  • R 1 H shark, OH, OA, A, alkylene-OA, NO 2l NH 2 , NH-acyl, SO 2 NH2, SO3-A, SO 2 NH-A, CN or formyl,
  • R 3 , R 5 each independently of one another H, Hai, OH, OA, O-Alk- R 6 , R 7 , R 8 ylen-R 4 , A, SA, NO 2 , NH 2 , NHA, NA2, NH- Acyl, NHSOA NHSO 2 R 4 , NASO2A, NASO 2 -R 4 , NH (CO) NH 2 , NH (CO) NHA, Formyl, NH (CO) NHPhenyl, NHCOOA, NAAcyl, NHR 4 , NHCOOR 4 , NHCOOBenzyl, NHSO 2 benzyl, NHCOO-alkylene-OA, NH (CO) NA 2 , N-piperidinyl-CONH, N-pyrrolidinyl-CONH, O (CH 2 ) n COOR 2 , O (CH 2 ) n OR 2 , CH 2 OH or CH 2 OA,
  • R 3 and R 6 together also -O-CH 2 -O-, -O-CH 2 -CH 2 -O-, -O-CH2-CH2-, -O-CF2-O- or -O-CF2-CF2 -O-, R 4 is unsubstituted or one or more times by R 3 and / or
  • R 6 substituted phenyl
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability.
  • they show endothelin receptor antagonistic properties and can therefore be used for the treatment of diseases such as hypertension, heart failure, coronary heart disease, renal, cerebral and myocardial ischemia, renal failure, cerebral infarction, subarachnoid hemorrhage, arteriosclerosis, pulmonary high pressure, inflammation, pro-inflammatory disorders, asthma Shock and complications after the administration of substances such as Cyclosporin, as well as other diseases associated with endothelin activities.
  • connections show i.a. a high affinity for the endothelin
  • Subreceptors ET A and ET B are effects that can, according to usual in vitro or in vivo methods can be determined, as described, for example, by PD Stein et al., J. Med. Chem. 37, 1994, 329-331 and E. Ohistein et al., Proc. Natl. Acad. Be. USA 91, 1994, 8052-8056.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of cardiac, circulatory and vascular diseases, especially hypertension and heart failure.
  • the invention relates to the compounds of formula I and their
  • Salts and a process for the preparation of these compounds and their salts, characterized in that for the preparation of compounds of the formula I according to Claim 1 and their salts,
  • R 1 , R 2 , R 3 , R 8 and X have the meaning given in claim 1,
  • L means Cl, Br, I or a free or reactively functionally modified OH group
  • R means
  • R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are those specified in claim 1
  • R 1 and n have the meaning given in claim 1,
  • A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4, carbon atoms.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, moreover also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-,
  • Alkylene preferably means methylene, ethylene, propylene, butylene, furthermore pentylene or hexylene.
  • Acyl preferably means formyl, acetyl, propionyl, but also butyryl, pentanoyl or hexanoyl.
  • n is preferably 1, further preferably 2.
  • R 3 , R 5 , R 6 , R 7 and R 8 each independently of one another are preferably H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, Propoxy, butoxy, pentyloxy, hexyloxy, cyclopentyloxy, cyclohexyloxy, benzyloxy, phenethyloxy, methylthio, ethylthio, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, N-methylacetamido, N-ethylacylacetamido, N-ethylacetamido Butylacetamido, propionylamino, butyrylamino, methylsulfonamido,
  • R 4 is unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p -Aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p
  • the compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.
  • Formula I encompasses all of these forms.
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following partial formulas Ia to Ik, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • R 1 represents H
  • XS and R 1 is H
  • XS, R 1 H, R 3 , R 6 and R 7 each independently of one another are H, OA, formyl,
  • R 3 and R 6 together also -O-CH 2 -O-, -O-CH 2 -CH 2 -O-,
  • R 5 and R 8 each independently of one another H, OA, O-benzyl,
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • R is preferably obtained by reacting compounds of the formula II with compounds of the formula III.
  • L preferably denotes Cl, Br, I or a reactively modified OH group such as alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl or p -Tolylsulfonyloxy).
  • the reaction is usually carried out in an inert solvent, preferably in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal of potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the indole component of the formula II or of the alkylation derivative of the formula III can also be favorable.
  • the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or
  • Dichloromethane Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert. Butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures
  • L preferably denotes Cl, Br, I or a reactively modified OH group such as alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl or p- Tolylsulfonyloxy).
  • the reaction is generally carried out in an inert solvent, in the presence of an acid-binding agent and at temperatures as indicated above.
  • the starting compounds of the formula IV and V are generally new, but can be prepared by methods known per se
  • a compound of the formula I into another compound of the formula I by one or more radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and / or R ⁇ into one or more radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and / or R ⁇ , for example by converting nitro groups (for example by hydrogenation on Raney nickel or Pd- Coal in an inert solvent such as methanol or ethanol) reduced to amino groups and / or an ester group hydrolyzed to a carboxy group and / or bromine substituents converted into cyano groups by reaction with, for example, copper-1-cyanide.
  • nitro groups for example by hydrogenation on Raney nickel or Pd- Coal in an inert solvent such as methanol or ethanol
  • free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between 60 and + 30 °.
  • a functionally modified amino and / or hydroxyl group in a compound of the formula I can be liberated by solvolysis or hydrogenolysis by customary methods.
  • a compound of formula I which is an NH-acyl or
  • COOA groups are converted into the corresponding compound of formula I, which instead contains an NH 2 - or a HOOC group.
  • COOA groups can be saponified, for example, with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids are particularly suitable, the physiologically harmless ones Deliver salts.
  • inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon atoms.
  • Sulfonic or sulfuric acids for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid or nicotinic acid, isonic acid, methonic acid Ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disutonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.
  • compounds of formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular in a non-chemical way. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), Parenteral or topical application are suitable and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets,
  • the new compounds can also be lyophilized and the ones obtained
  • Lyophilisates e.g. be used for the production of injection preparations.
  • the specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances included, e.g. one or more vitamins.
  • the compounds of formula I and their physiologically acceptable salts can be used in combating diseases, in particular hypertension and heart failure.
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the special compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion ,
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product to a pH between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, the organic phase dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1.
  • Ethyl bromo-5-propoxy-indole-2-carboxylate mp 145-147 °, with 3,4-methylenedioxyphenylboronic acid
  • Ethyl 3-bromo-5-propoxy-indole-2-carboxylate can be obtained by reacting ethyl 2-propoxy-1H-indole-2-carboxylate [preparation described by Profft et al. in J. Prakt. Chem. 1954/1955, 110 and 123] with N-bromosuccinimide) and 1.0 g
  • the individual components are obtained from the carboxylic acid mixtures by chromatography in the customary manner.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile . Each injection glass contains 5 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient .
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, under sterile conditions. lyophilized and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

De nouveaux composés de formule (I), dans laquelle R est (a) ou (b), X désigne un O ou un S, et R?1, R2, R3, R4, R5, R6, R7, R8¿ et n ont les significations données dans la revendication 1, ainsi que leurs sels, présentent des propriétés antagonistes des récepteurs de l'endothéline.
PCT/EP1996/005120 1995-11-23 1996-11-20 Antagonistes des recepteurs de l'endotheline WO1997019077A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU76944/96A AU7694496A (en) 1995-11-23 1996-11-20 Endothelin receptor antagonists
EP96939865A EP0863898A1 (fr) 1995-11-23 1996-11-20 Antagonistes des recepteurs de l'endotheline

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19543639A DE19543639A1 (de) 1995-11-23 1995-11-23 Endothelin-Rezeptor-Antagonisten
DE19543639.3 1995-11-23

Publications (1)

Publication Number Publication Date
WO1997019077A1 true WO1997019077A1 (fr) 1997-05-29

Family

ID=7778192

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/005120 WO1997019077A1 (fr) 1995-11-23 1996-11-20 Antagonistes des recepteurs de l'endotheline

Country Status (6)

Country Link
EP (1) EP0863898A1 (fr)
AU (1) AU7694496A (fr)
DE (1) DE19543639A1 (fr)
ID (1) ID16742A (fr)
WO (1) WO1997019077A1 (fr)
ZA (1) ZA969775B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030895A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham Corporation Indoles substituees, compositions pharmaceutiques contenant ces indoles et leur utilisation comme agent de fixation de ppar-$g(g)
WO2003039539A2 (fr) * 2001-11-09 2003-05-15 Merck Patent Gmbh Utilisation d'antagonistes du recepteur de l'endotheline dans le traitement de maladies tumorales
JP2007506769A (ja) * 2003-09-25 2007-03-22 ワイス Ｐａｉ−１阻害剤としての置換スルホンアミド−インドール−２−カルボン酸誘導体
WO2007068621A1 (fr) 2005-12-15 2007-06-21 F. Hoffmann-La Roche Ag Nouveaux dérivés de pyrrole à cycles fusionnés

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI224101B (en) 2001-06-20 2004-11-21 Wyeth Corp Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
ES2290318T3 (es) 2001-06-20 2008-02-16 Wyeth Derivados sustituidos de acido indolico como inhibidores del inhibidor del activador del plasminogeno-1 (pai-1).
CA2509222A1 (fr) 2002-12-10 2004-06-24 Wyeth Derives d'acide indole oxo-acetyl amino acetique substitue comme inhibiteurs d'inhibiteur-1 de l'activateur du plasminogene (pai-1)
CN1723197A (zh) 2002-12-10 2006-01-18 惠氏公司 作为纤溶酶原激活物抑制剂－1(pai－1)的抑制剂的取代3－烷基和3－芳基烷基1h－吲哚－1－基乙酸衍生物
UA80453C2 (en) 2002-12-10 2007-09-25 Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1)
ATE411288T1 (de) 2002-12-10 2008-10-15 Wyeth Corp Aryl-, aryloxy- und alkyloxysubstituierte 1h- indol-3-yl-glyoxylsäurederivateals inhibitoren des plasminogenaktivatorinhibitors-1 (pai-1)
BR0316574A (pt) 2002-12-10 2005-10-04 Wyeth Corp Derivados de ácido acético 3-carbonil-1h-indol-1-il substituìdo como inibidores do inibidor-1 do ativador do plasminogênio (pai-1)
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
CN101044127A (zh) 2004-08-23 2007-09-26 惠氏公司 用作纤溶酶原激活剂抑制剂－1的噻唑基－萘基酸
EP1781641A1 (fr) 2004-08-23 2007-05-09 Wyeth Acides pyrrolo-naphtyliques en tant qu"inhibiteurs du pai-1
JP2008510815A (ja) 2004-08-23 2008-04-10 ワイス 血栓症および心臓血管疾患の治療にて有用な調節剤であるプラスミノゲン活性化因子阻害剤１型（ｐａｉ−１）としてのオキサゾロ−ナフチル酸
CN101263115A (zh) 2005-08-17 2008-09-10 惠氏公司 经取代吲哚和其用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008799A1 (fr) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Antagonistes recepteurs de l'endotheline
WO1994014434A1 (fr) * 1992-12-22 1994-07-07 Smithkline Beecham Corporation Antagonistes des recepteurs de l'endotheline
EP0733626A1 (fr) * 1995-03-18 1996-09-25 MERCK PATENT GmbH N-(Benzofurazanyl)-arylsulfonamides et leurs analogues utiles comme antagonistes du récepteur d'endothéline

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008799A1 (fr) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Antagonistes recepteurs de l'endotheline
WO1994014434A1 (fr) * 1992-12-22 1994-07-07 Smithkline Beecham Corporation Antagonistes des recepteurs de l'endotheline
EP0733626A1 (fr) * 1995-03-18 1996-09-25 MERCK PATENT GmbH N-(Benzofurazanyl)-arylsulfonamides et leurs analogues utiles comme antagonistes du récepteur d'endothéline

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030895A1 (fr) * 2000-10-10 2002-04-18 Smithkline Beecham Corporation Indoles substituees, compositions pharmaceutiques contenant ces indoles et leur utilisation comme agent de fixation de ppar-$g(g)
US6787651B2 (en) 2000-10-10 2004-09-07 Smithkline Beecham Corporation Substituted indoles, pharmaceutical compounds containing such indoles and their use as PPAR-γ binding agents
WO2003039539A2 (fr) * 2001-11-09 2003-05-15 Merck Patent Gmbh Utilisation d'antagonistes du recepteur de l'endotheline dans le traitement de maladies tumorales
WO2003039539A3 (fr) * 2001-11-09 2003-11-06 Merck Patent Gmbh Utilisation d'antagonistes du recepteur de l'endotheline dans le traitement de maladies tumorales
JP2007506769A (ja) * 2003-09-25 2007-03-22 ワイス Ｐａｉ−１阻害剤としての置換スルホンアミド−インドール−２−カルボン酸誘導体
WO2007068621A1 (fr) 2005-12-15 2007-06-21 F. Hoffmann-La Roche Ag Nouveaux dérivés de pyrrole à cycles fusionnés
US7696240B2 (en) 2005-12-15 2010-04-13 Hoffmann-La Roche Inc. Fused pyrrole derivatives

Also Published As

Publication number Publication date
DE19543639A1 (de) 1997-05-28
ZA969775B (en) 1998-05-21
ID16742A (id) 1997-11-06
EP0863898A1 (fr) 1998-09-16
AU7694496A (en) 1997-06-11

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