EP0863898A1 - Antagonistes des recepteurs de l'endotheline - Google Patents

Antagonistes des recepteurs de l'endotheline

Info

Publication number
EP0863898A1
EP0863898A1 EP96939865A EP96939865A EP0863898A1 EP 0863898 A1 EP0863898 A1 EP 0863898A1 EP 96939865 A EP96939865 A EP 96939865A EP 96939865 A EP96939865 A EP 96939865A EP 0863898 A1 EP0863898 A1 EP 0863898A1
Authority
EP
European Patent Office
Prior art keywords
indole
benzothiadiazol
carboxylic acid
ylmethyl
ethyl ester
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP96939865A
Other languages
German (de)
English (en)
Inventor
Werner Mederski
Mathias Osswald
Dieter Dorsch
Claus Jochen Schmitges
Claudia Wilm
Maria Christadler
Soheila Anzali
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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 GmbH filed Critical Merck Patent GmbH
Publication of EP0863898A1 publication Critical patent/EP0863898A1/fr
Pending legal-status Critical Current

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.

Landscapes

  • 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>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> et n ont les significations données dans la revendication 1, ainsi que leurs sels, présentent des propriétés antagonistes des récepteurs de l'endothéline.
EP96939865A 1995-11-23 1996-11-20 Antagonistes des recepteurs de l'endotheline Pending EP0863898A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19543639 1995-11-23
DE19543639A DE19543639A1 (de) 1995-11-23 1995-11-23 Endothelin-Rezeptor-Antagonisten
PCT/EP1996/005120 WO1997019077A1 (fr) 1995-11-23 1996-11-20 Antagonistes des recepteurs de l'endotheline

Publications (1)

Publication Number Publication Date
EP0863898A1 true EP0863898A1 (fr) 1998-09-16

Family

ID=7778192

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96939865A Pending EP0863898A1 (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)

Families Citing this family (27)

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EP1341761A1 (fr) * 2000-10-10 2003-09-10 Smithkline Beecham Corporation Indoles substituees, compositions pharmaceutiques contenant ces indoles et leur utilisation comme agent de fixation de ppar-$g(g)
TWI224101B (en) 2001-06-20 2004-11-21 Wyeth Corp Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
DK1397130T3 (da) 2001-06-20 2007-11-12 Wyeth Corp Substituerede indolsyrederivater som inhibitorer af plasminogenaktivatorinhibitor-1 (PAI-1)
DE10155076A1 (de) * 2001-11-09 2003-05-22 Merck Patent Gmbh Verwendung von Endothelin-Rezeptor-Antagonisten zur Behandlung von Tumorerkrankungen
CA2509170A1 (fr) 2002-12-10 2004-06-24 Wyeth Derives substitues de l'acide acetique de 3-alkyle et 3-arylalkyle 1h-indol-1-yle en tant qu'inhibiteurs de l'inhibiteur des activateurs du plasminogene (pai-1)
JP2006510673A (ja) 2002-12-10 2006-03-30 ワイス プラスミノゲンアクティベータインヒビター１（ｐａｉ−１）のインヒビターとしての、アリール、アリールオキシ、および、アルキルオキシ置換１ｈ−インドール−３−イルグリオキシル酸誘導体
UA80453C2 (en) 2002-12-10 2007-09-25 Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1)
EP1569900B1 (fr) 2002-12-10 2006-06-28 Wyeth Derives substitues d'acides 3-carbonyl- indol-1-yl acetique comme inhibiteurs-1dd'activation plasminogenique
WO2004052856A1 (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)
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7442805B2 (en) * 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
RU2007106869A (ru) 2004-08-23 2008-09-27 Вайет (Us) Тиазол-нафтиловые кислоты как ингибиторы ингибитора активации плазминогена-1
JP2008510814A (ja) 2004-08-23 2008-04-10 ワイス Ｐａｉ−１阻害剤としてのピロロ−ナフチル酸
AU2005277138A1 (en) 2004-08-23 2006-03-02 Wyeth Holdings Corporation Oxazolo-naphthyl acids as plaminogen activator inhibtor type-1 (PAI-1) modulators useful in the treatment of thrombosis and cardiovascular diseases
CA2617372A1 (fr) 2005-08-17 2007-02-22 Wyeth Indoles substitues et procedes d'utilisation de ceux-ci
UA95788C2 (en) 2005-12-15 2011-09-12 Ф. Хоффманн-Ля Рош Аг Fused pyrrole derivatives

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AU669866B2 (en) * 1991-11-05 1996-06-27 Smithkline Beecham Corporation Endothelin receptor antagonists
ZA939516B (en) * 1992-12-22 1994-06-06 Smithkline Beecham Corp Endothelin receptor antagonists
DE19509950A1 (de) * 1995-03-18 1996-09-19 Merck Patent Gmbh Endothelin-Rezeptor-Antagonisten

Non-Patent Citations (1)

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Title
See references of WO9719077A1 *

Also Published As

Publication number Publication date
AU7694496A (en) 1997-06-11
ID16742A (id) 1997-11-06
WO1997019077A1 (fr) 1997-05-29
DE19543639A1 (de) 1997-05-28
ZA969775B (en) 1998-05-21

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