EP1274691A1 - 2-guanidino-4-arylquinazolines utilisees comme inhibiteurs de nhe-3 - Google Patents

2-guanidino-4-arylquinazolines utilisees comme inhibiteurs de nhe-3

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Publication number
EP1274691A1
EP1274691A1 EP01969043A EP01969043A EP1274691A1 EP 1274691 A1 EP1274691 A1 EP 1274691A1 EP 01969043 A EP01969043 A EP 01969043A EP 01969043 A EP01969043 A EP 01969043A EP 1274691 A1 EP1274691 A1 EP 1274691A1
Authority
EP
European Patent Office
Prior art keywords
guanidine
quinazolinyl
chloro
phenyl
formula
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.)
Withdrawn
Application number
EP01969043A
Other languages
German (de)
English (en)
Inventor
Rolf Gericke
Norbert Beier
Claudia Wilm
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 EP1274691A1 publication Critical patent/EP1274691A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to compounds of the formula I.
  • Ar is unsubstituted or simply substituted by R 3 phenyl or naphthyl, R 1 , R 2 each independently of one another H, A, OA, Hai or CF 3 , R 3 A, OA, Hai or CF 3 ,
  • a alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms having 1, 2, 3, 4, 5 or 6 carbon atoms
  • Formula I also includes the tautomeric compounds of formula I '
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine.
  • the Na + / H + exchanger is a family with at least 6 different isoforms (NHE-1 to NHE-6), all of which are now cloned. While the NHE-1 subtype is ubiquitously distributed throughout the body in all tissues, the other NHE subtypes are selectively expressed in specific organs such as the kidney or in the lumen wall and contraluminal wall of the small intestine. This distribution reflects the specific functions that the different isoforms serve, namely on the one hand the regulation of the intracellular pH and cell volume by the subtype NHE-1 and on the other hand the Na + uptake and reuptake in the intestine and kidney by the isoforms
  • NHE-2 or NHE-3 The isoform NHE-4 was mainly found in the stomach.
  • the expression of NHE-5 is limited to brain and neuronal tissue.
  • NHE-6 represents the isoform that forms the sodium proton exchanger in the mitochondria.
  • the NHE-3 isoform is expressed in particular in the apical membrane of the proximal kidney tubules; an NHE-3 inhibitor therefore exercises a kidney protection effect.
  • NHE-3 inhibitors inhibit or reduce weave damage and cell necrosis following pathophysiological hypoxic and ischemic events that lead to activation of NHE activity, as is the case during renal ischemia or during removal, transport and reperfusion of a kidney during kidney transplantation.
  • the compounds of the formula I have a cytoprotective effect by preventing the excessive absorption of sodium and water in the cells of organs which are under-supplied with oxygen.
  • the compounds of formula I lower blood pressure and are suitable as active pharmaceutical ingredients for the treatment of hypertension. They are also suitable as diuretics.
  • the compounds of formula I alone or in combination with NHE inhibitors of other subtype specificity, have anti-ischemic effects and can be used in thromboses, atherosclerosis, vascular spasms, for protecting organs, e.g. Kidney and liver, before and during operations, as well as with chronic or acute kidney failure.
  • the compounds of the formula I have an inhibitory effect on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of smooth vascular muscle cells and can therefore be used for the treatment of diseases in which cell proliferation is a primary or secondary cause.
  • the compounds of formula I can be used against late diabetic complications, cancer, fibrotic diseases, endothelial dysfunction, organ hypertrophies and organ hyperplasias, in particular in prostate hyperplasia or prostate hypertrophy. They are also suitable as diagnostics for the determination and differentiation of certain forms of hypertension, atherosclerosis, diabetes and proliferative diseases.
  • the compounds of the formula I also have an advantageous effect on the level of the serum lipoproteins, they can be used to treat an elevated level
  • Blood lipid levels can be used alone or in combination with other medicines.
  • the invention relates to the use of compounds of the formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of thromboses, ischemic conditions of the heart, peripheral and central nervous system and stroke, ischemic conditions of peripheral organs and limbs and for the treatment of shock conditions.
  • the invention further relates to the use of compounds of the formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the production of a medicament for use in surgical operations and organ transplants and for the preservation and storage of transplants for surgical measures.
  • the invention also relates to the use of compounds of the formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause, for the treatment or prophylaxis of disorders of fat metabolism or disturbed respiratory drive.
  • the invention further relates to the use of compounds of the formula I according to claim 1 and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of ischemic kidney, ischemic bowel disease or for the prophylaxis of acute or chronic kidney disease.
  • Methods for identifying substances which inhibit the sodium / proton exchanger subtype 3 are described, for example, in US Pat. No. 5,871,919.
  • Hydrates and solvates are e.g. the hemi, mono- or dihydrates, among solvates e.g. Alcohol addition compounds such as with methanol or ethanol.
  • A means alkyl, is linear or branched, and has 1, 2, 3, 4, 5 or 6 carbon atoms.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further 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-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3 , 3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl.
  • OA preferably means methoxy, ethoxy, propoxy, isopropoxy or butoxy.
  • Shark preferably means F, CI or Br, but also I.
  • Ar preferably denotes unsubstituted phenyl or naphthyl, further preferably, for example, A, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, butoxy or CF 3 monosubstituted phenyl or naphthyl.
  • the invention relates in particular to the use of 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 sub-formulas Ia to II, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but reside
  • R 2 is H; in Ic R 1 H or shark,
  • Ar is phenyl
  • R 3 is A, OA or shark; in le Ar means phenyl; in lf Ar phenyl,
  • R 1 , R 2 each independently of one another H, A, OA, Hai or
  • R 1 is H or shark, R 2 HR 3 A, OA or shark;
  • R 3 represents shark
  • R 3 represents shark
  • R 3 represents shark
  • A is alkyl with 1, 2, 3 or 4 carbon atoms or CF 3 .
  • the invention also relates to the new compounds selected from the group
  • the 2-guanidino-4-aryl-quinazolines of the formula I are preferably prepared by o-aminophenyl ketones of the formula II
  • R 1 , R 2 and Ar have the meanings given in claim 1, reacted with 1-cyanguanidine.
  • the reaction takes place in an inert solvent.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as thchlorethylene, 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 glycoidimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidon
  • DMF water or an alcohol
  • the reaction is very particularly preferably carried out without a solvent, ie in the melt, at temperatures between 100 and 200.degree.
  • an acidic catalyst such as AICI 3 , TiCI, p-toluenesulfonic acid, BF 3 , acetic acid, sulfuric acid, oxalic acid, POCI 3 or phosphorus pentoxide is advantageous.
  • a preferred variant is that one of the reactants is already in the form of a salt, e.g. is used as the hydrochloride.
  • X -SA, -SAr, OA or OAr and Ar and A have, for example, the meanings given in Claim 1,
  • 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.
  • an acid for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • So 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, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polycarbonate, sulfonic or Sulfuric acids, e.g.
  • the invention furthermore relates to the use of the compounds of the formula I as NHE-3 inhibitors and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. 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 NHE-3 inhibitor of the formula I and / or one of its physiologically acceptable salts and solvates.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application 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, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powders, or transdermally in patches.
  • the new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables.
  • the specified preparations can be sterilized and / or contain 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, eg one or more vitamins.
  • Suitable pharmaceutical preparations for administration in the form of aerosols or sprays are e.g. Solutions, suspensions or emulsions of the active ingredient of formula I in a pharmaceutically acceptable solvent.
  • the compounds of the formula I and their physiologically acceptable salts and solvates can be used for the treatment and / or prophylaxis of the diseases or disease states described above.
  • the substances according to the invention are generally preferably administered in doses between about 0.1 and 100 mg, in particular between 1 and 10 mg, per dosage unit.
  • the daily dosage is preferably between about 0.001 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 particular 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 and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred. Examples
  • the compounds selected from the group are preferred as NHE-3 inhibitors
  • the compounds of the formula I were characterized with regard to their selectivity towards the isoforms NHE-1 to NHE-3.
  • the three isoforms were stably expressed in mouse fibroblast cell lines.
  • the inhibitory activity of the compounds was assessed by determining the ElPA-sensitive 22 Na + uptake into the cells after intracellular acidosis.
  • the LAP1 cell lines that express the NHE-1, -2 and -3 isoforms (a)
  • mice fibroblast cell lines expressing the isoforms NHE-1, NHE-2 and NHE-3 compounds according to the method described by Counillon et al. (1993) and Scholz et al. (1995) tested the procedure for selectivity compared to the isoforms.
  • the cells were acidified intracellularly using the NH 4 CI prepulse method and then by incubation in a bicarbonate-free 22 Na + -containing buffer. Due to the intracellular acidification, NHE was activated and sodium was absorbed into the cells. The effect of the test compound was expressed as an inhibition of EIPA (ethyl isopropylamiloride) sensitive 22 Na + uptake.
  • EIPA ethyl isopropylamiloride
  • the cells expressing NHE-1, NHE-2 and NHE-3 were seeded at a density of 5-7.5 x 10 4 cells / well in 24-well microtiter plates and grown to confluence for 24 to 48 hours. The medium was aspirated and the cells were incubated for 60 minutes at 37 ° C. in the NH 4 CI buffer (50 mM NH 4 CI, 70 mM choline chloride, 15 mM MOPS, pH 7.0).
  • the buffer was then removed and the cells were rapidly overlaid twice with the choline chloride wash buffer (120 mM choline chloride, 15 mM PIPES / Ths, 0.1 mM ouabain, 1 mM MgCl 2 , 2 mM CaCl 2 , pH 7.4) ; the cells were incubated in this buffer for 6 minutes.
  • the choline chloride wash buffer 120 mM choline chloride, 15 mM PIPES / Ths, 0.1 mM ouabain, 1 mM MgCl 2 , 2 mM CaCl 2 , pH 7.4
  • the incubation buffer was aspirated. To remove extracellular radioactivity, the cells were quickly washed four times with ice-cold phosphate-buffered saline (PBS). The cells were then solubilized by adding 0.3 ml of 0.1 N NaOH per well. The cell fragment-containing solutions were transferred to scintillation tubes. Each well was washed twice with 0.3 ml Washed 0.1 N NaOH and the washes were also added to the appropriate scintillation vials. Scintillation cocktail was added to the tubes containing the cell lysate and the radioactivity absorbed into the cells was determined by determining the ⁇ radiation.
  • PBS ice-cold phosphate-buffered saline
  • Example A Injection glasses
  • a solution of 100 g of an NHE-3 inhibitor 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 sterile closed. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an NHE-3 inhibitor of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of an NHE-3 inhibitor 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 benzalko - nium 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
  • 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.
  • a solution of 1 kg of NHE-3 inhibitor of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Neurology (AREA)
  • Vascular Medicine (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) dans laquelle Ar représente phényle ou naphtyle non substitué ou substitué une fois par R<3 >; R<1> et R<2> représentent indépendamment l'un de l'autre H, A, OA, Hal ou CF3 ; R<3> représente A, OA, Hal ou CF3 ; A représente alkyle comportant 1, 2, 3, 4, 5 ou 6 atomes de C ; Hal représente F, Cl, Br ou I. L'invention concerne également les sels et solvates de ces composés, ainsi que leur utilisation comme inhibiteurs de NHE-3.
EP01969043A 2000-04-18 2001-03-22 2-guanidino-4-arylquinazolines utilisees comme inhibiteurs de nhe-3 Withdrawn EP1274691A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10019062A DE10019062A1 (de) 2000-04-18 2000-04-18 2-Guanidino-4-aryl-chinazoline als NHE-3 Inhibitoren
DE10019062 2000-04-18
PCT/EP2001/003281 WO2001079186A1 (fr) 2000-04-18 2001-03-22 2-guanidino-4-arylquinazolines utilisees comme inhibiteurs de nhe-3

Publications (1)

Publication Number Publication Date
EP1274691A1 true EP1274691A1 (fr) 2003-01-15

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EP01969043A Withdrawn EP1274691A1 (fr) 2000-04-18 2001-03-22 2-guanidino-4-arylquinazolines utilisees comme inhibiteurs de nhe-3

Country Status (18)

Country Link
US (1) US20040224965A1 (fr)
EP (1) EP1274691A1 (fr)
JP (1) JP2004501082A (fr)
KR (1) KR20030011789A (fr)
CN (1) CN1422260A (fr)
AR (1) AR028914A1 (fr)
AU (1) AU2001293373A1 (fr)
BR (1) BR0109867A (fr)
CA (1) CA2406161A1 (fr)
DE (1) DE10019062A1 (fr)
HU (1) HUP0300909A3 (fr)
MX (1) MXPA02010264A (fr)
NO (1) NO20024997L (fr)
PL (1) PL356559A1 (fr)
RU (1) RU2002130246A (fr)
SK (1) SK13472002A3 (fr)
WO (1) WO2001079186A1 (fr)
ZA (1) ZA200209274B (fr)

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DE10161767A1 (de) * 2001-12-15 2003-06-26 Merck Patent Gmbh 2-Guanidino-4-heterocyclyl-chinazoline
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DE10163992A1 (de) * 2001-12-24 2003-07-03 Merck Patent Gmbh 4-Aryl-chinazoline
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CN1422260A (zh) 2003-06-04
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BR0109867A (pt) 2003-06-03
NO20024997D0 (no) 2002-10-17
HUP0300909A2 (hu) 2003-10-28
ZA200209274B (en) 2004-02-16
RU2002130246A (ru) 2004-03-27
US20040224965A1 (en) 2004-11-11
PL356559A1 (en) 2004-06-28
NO20024997L (no) 2002-10-17
DE10019062A1 (de) 2001-10-25
AU2001293373A1 (en) 2001-10-30
KR20030011789A (ko) 2003-02-11
SK13472002A3 (sk) 2003-02-04
WO2001079186A1 (fr) 2001-10-25
AR028914A1 (es) 2003-05-28
HUP0300909A3 (en) 2004-01-28

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