WO2001019369A1 - Utilisation de thiénopyrimidines - Google Patents

Utilisation de thiénopyrimidines Download PDF

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Publication number
WO2001019369A1
WO2001019369A1 PCT/EP2000/008258 EP0008258W WO0119369A1 WO 2001019369 A1 WO2001019369 A1 WO 2001019369A1 EP 0008258 W EP0008258 W EP 0008258W WO 0119369 A1 WO0119369 A1 WO 0119369A1
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WO
WIPO (PCT)
Prior art keywords
acid
chloro
benzothieno
benzo
pyrimidin
Prior art date
Application number
PCT/EP2000/008258
Other languages
German (de)
English (en)
Inventor
Rochus Jonas
Volker Eiermann
Sabine Bernotat-Danielowski
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
Priority to KR1020027003303A priority Critical patent/KR20020026011A/ko
Priority to HU0202614A priority patent/HUP0202614A3/hu
Priority to PL00353343A priority patent/PL353343A1/xx
Priority to BR0013957-2A priority patent/BR0013957A/pt
Priority to JP2001523002A priority patent/JP2003509370A/ja
Priority to CA002387123A priority patent/CA2387123A1/fr
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to SK332-2002A priority patent/SK3322002A3/sk
Priority to AU67032/00A priority patent/AU6703200A/en
Priority to EP00954650A priority patent/EP1212062A1/fr
Priority to MXPA02002746A priority patent/MXPA02002746A/es
Publication of WO2001019369A1 publication Critical patent/WO2001019369A1/fr
Priority to NO20021234A priority patent/NO20021234D0/no

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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 the use of compounds of the formula
  • R »1, r R-.2 each independently of one another H, A, OA, OH or Hai,
  • R 1 and R 2 together also alkylene with 3-5 C atoms, -0-CH 2 -CH 2 -, -CH 2 -0-CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -O-,
  • X is simply substituted by R 7, R 4 , R 5 or R 6 ,
  • R b cycloalkyl or cycloalkylalkylene with 5-12 C atoms
  • R 7 COOH, COOA, CONH 2 , CONHA, CON (A) 2 or CN,
  • a medicament for the treatment of angina high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female impotence.
  • Pyrimidine derivatives are known for example from DE 19819023, EP 201 188 or WO 93/06104.
  • 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 biological activity of the compounds of the formula I can be determined by methods as described, for example, in WO 93/06104 or in WO
  • the affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by determining their IC 50 values (concentration of the inhibitor which is required in order to achieve a 50% inhibition of the enzyme activity). Enzymes isolated according to known methods can be used to carry out the determinations (for example WJ Thompson et al., Biochem. 1971, 10, 311). A modified "batch" method by WJ Thompson and MM Appleman (Biochem. 1979, 18, 5228) can be used to carry out the experiments.
  • substituted pyrazolopyrimidinones for the treatment of female impotence is e.g. described in WO 94/28902.
  • the compounds are effective as inhibitors of phenyiephrine-induced contractions in corpus cavemosum preparations from rabbits. This biological effect can e.g. can be detected by the method described by F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993).
  • the inhibition of the contraction shows the effectiveness of the compounds according to the invention for the therapy and / or treatment of erectile dysfunction.
  • the invention relates to the use of the compounds of the formula I and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary high pressure, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases , Stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female impotence.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine. They can also be used as
  • radicals R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and L have the meanings given in the formulas I, II and III, unless expressly stated otherwise ,
  • A means alkyl with 1-6 C atoms.
  • alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl, more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl , but also n-pentyl, neopentyl, isopentyl or hexyl.
  • X denotes an R 4 , R 5 or R 6 radical which is simply substituted by R 7 .
  • R 4 represents a linear or branched alkylene radical having 1-10 C atoms, the alkylene radical preferably being, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3- Methylbutylene, 1, 1-, 1, 2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1 -, 2-, 3- or 4-methylpentylene, 1, 1 -, 1, 2-, 1, 3 -, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1, 1, 2- or 1, 2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene.
  • R 5 also means, for example, but-2-en-ylene or
  • R 5 denotes cycloalkylalkylene with 5-12 C atoms, preferably for example
  • R 5 also means cycloalkyl, preferably having 5-7 carbon atoms.
  • Cycloalkyl means, for example, cyclopentyl, cyclohexyl or cycloheptyl.
  • the radicals R 1 and R 2 can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They each mean, for example, independently of one another H, alkyl, F, Cl, Br or I or together alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They also preferably each represent alkoxy, such as methoxy, ethoxy or propoxy, furthermore hydroxy.
  • the radical R 7 is preferably, for example, COOH, COOCH 3 , COOC 2 H 5 , CONH 2 , CON (CH 3 ) 2 , CONHCH3 or CN.
  • the invention relates in particular to the use of those compounds of the formula I in which at least one of the radicals mentioned is one of the preferred ones indicated above
  • C denotes CNSsubstituted R 4 , phenyl or phenylmethyl
  • CN is substituted R 4 , phenyl or phenylmethyl
  • R 1 , R 2 each independently of one another H, A, OA or shark,
  • R 1 and R 2 together alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -,
  • CN is substituted R 4 , phenyl or phenylmethyl
  • R 1 , R 2 each independently of one another H, A, OA or shark,
  • R 1 and R 2 together also alkylene with 3-5 C atoms, -O-CH 2 -CH 2 -, -O-CH 2 -O- or
  • R 1 , R 2 , R 3 , R 4 , X and n have the meanings indicated, in particular the preferred meanings indicated.
  • L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, further also 2- naphthalenesulfonyloxy).
  • the compounds of formula I can preferably be obtained by using compounds of formula II
  • X has the meaning given, and L denotes Cl, Br, OH, SCH 3 or a reactive esterified OH group,
  • R 1 and R 2 have the meanings given
  • 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. On the other hand, it is possible to carry out the reaction in stages.
  • the starting compounds of the formula II and III are generally known.
  • hydroxypyrimidines are prepared either by dehydration of corresponding tetrahydrobenzthienopyrimidine compounds or by the cyclization of 2-aminobenzthiophene-3-carboxylic acid derivatives customary for the preparation of pyrimidine derivatives or with aldehydes or
  • Nitriles e.g. Houben Weyl E9b / 2.
  • the compounds of the formula II are reacted with the compounds of the formula III in the presence or absence of a inert solvent at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.
  • an acid-binding agent for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of an organic base such as triethylamine, Dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.
  • an acid-binding agent for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium
  • an organic base such as triethylamine, Dimethylamine, pyridine or quinoline or an excess of the amine component
  • 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, N-methylpyrrolidone
  • Ester groups can e.g. can be saponified with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • Carboxylic acids can e.g. with thionyl chloride in the corresponding carboxylic acid chlorides and these are converted into carboxamides. By splitting off water in a known manner, carbonitriles are obtained from these.
  • An acid of the formula I can be converted into the associated acid addition salt using a base, for example by reaction valent amounts of the acid and the base in an inert solvent such as ethanol and subsequent evaporation.
  • Bases that provide physiologically acceptable salts are particularly suitable for this implementation.
  • the acid of formula I can be converted with a base (for example sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salt.
  • Organic bases which provide physiologically acceptable salts, such as ethanolamine, are particularly suitable for this reaction.
  • 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 that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as
  • 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, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane acid or ethanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts and / or solvates for treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced patency of the heart vessels, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, liver cirrhosis, liver cirrhosis for the treatment of female impotence.
  • 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, coated tablets,
  • the new compounds can also be lyophilized and the resulting lyophilisates 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, e.g. one or more vitamins.
  • 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, e.g. one or more vitamins.
  • the compounds of the formula I and their physiologically acceptable salts can be used in combating diseases in which an increase in the cGMP (cyclo-guanosine monophosphate) level leads to inhibition or prevention of inflammation and muscle relaxation.
  • the compounds according to the invention can be used particularly in the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chro- African asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal failure, cirrhosis of the liver and for the treatment of female impotence.
  • the substances 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 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.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
  • Mass spectrometry (MS): El (electron impact ionization) M + FAB (Fast Atom Bombardment) (M + H) +
  • the invention relates in particular to the use of the compounds of the formula I listed in the examples below and their physiologically acceptable salts and / or solvates for the manufacture of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced patency of the cardiovascular system, peripheral vascular diseases, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumors, renal insufficiency, liver cirrhosis and for the treatment of female impotence.
  • example 1
  • Methyl 3- (4-chloro-benzothieno- [2,3-d] -pyamin-2-yl) -propionate [obtainable by cyclization of methyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylic acid with 3-cyanopropionic acid methyl ester, dehydrogenation with sulfur and subsequent chlorination with phosphorus oxichlo d / dimethylamine] and 3-chloro-4-methoxybenzylamine ("A") in N-methylpyrrolidone are stirred at 110 ° for 5 hours. The solvent is removed and worked up as usual. 3- [4- (3-Chloro-4-methoxy-benzylamino) benzothieno [2,3-d] pyrimidin-2-yl] propionic acid methyl ester is obtained as a colorless oil.
  • Example 6 Analogously to Examples 1, 2 and 3, the following carboxylic acids are obtained by reacting the corresponding chloropyrimidine derivatives with 3,4-ethylenedioxybenzylamine
  • 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 mixture of 20 g of an active ingredient 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 active ingredient of the formula I, 9.38 g
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Toxicology (AREA)
  • Hospice & Palliative Care (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Vascular Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Thiénopyrimidines de formule (I), ainsi que des sels et/ou solvates acceptables sur le plan physiologique desdites substances. Dans la formule (I), R1, R2 et X possèdent la signification figurant dans la revendication 1. Lesdites substances sont utilisées pour préparer un médicament destiné à traiter l'angine de poitrine, l'hypertension artérielle, l'hypertension pulmonaire, l'insuffisance cardiaque congestive, l'athérosclérose, la réduction du passage dans les vaisseaux cardiaques, les maladies vasculaires périphériques, l'accident vasculaire cérébral, la bronchite, l'asthme allergique, l'asthme chronique, la rhinite allergique, le glaucome, le syndrome du colon irritable, les tumeurs, l'insuffisance rénale, la cirrhose du foie et l'impuissance féminine.
PCT/EP2000/008258 1999-09-14 2000-08-24 Utilisation de thiénopyrimidines WO2001019369A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
HU0202614A HUP0202614A3 (en) 1999-09-14 2000-08-24 Use of thienopyrimidines
PL00353343A PL353343A1 (en) 1999-09-14 2000-08-24 Use of thienopyrimidines
BR0013957-2A BR0013957A (pt) 1999-09-14 2000-08-24 Uso de tienopirimidinas
JP2001523002A JP2003509370A (ja) 1999-09-14 2000-08-24 チエノピリミジン類の使用
CA002387123A CA2387123A1 (fr) 1999-09-14 2000-08-24 Utilisation de thienopyrimidines
KR1020027003303A KR20020026011A (ko) 1999-09-14 2000-08-24 티에노피리미딘의 용도
SK332-2002A SK3322002A3 (en) 1999-09-14 2000-08-24 Use of thienopyrimidines
AU67032/00A AU6703200A (en) 1999-09-14 2000-08-24 Use of thienopyrimidines
EP00954650A EP1212062A1 (fr) 1999-09-14 2000-08-24 Utilisation de thi nopyrimidines
MXPA02002746A MXPA02002746A (es) 1999-09-14 2000-08-24 Uso de tienopirimidas.
NO20021234A NO20021234D0 (no) 1999-09-14 2002-03-13 Anvendelse av tienopyrimidiner

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19943815.3 1999-09-14
DE19943815A DE19943815A1 (de) 1999-09-14 1999-09-14 Verwendung von Thienopyrimidinen

Publications (1)

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WO2001019369A1 true WO2001019369A1 (fr) 2001-03-22

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EP (1) EP1212062A1 (fr)
JP (1) JP2003509370A (fr)
KR (1) KR20020026011A (fr)
CN (1) CN1377271A (fr)
AR (1) AR025645A1 (fr)
AU (1) AU6703200A (fr)
BR (1) BR0013957A (fr)
CA (1) CA2387123A1 (fr)
CZ (1) CZ2002818A3 (fr)
DE (1) DE19943815A1 (fr)
HU (1) HUP0202614A3 (fr)
MX (1) MXPA02002746A (fr)
NO (1) NO20021234D0 (fr)
PL (1) PL353343A1 (fr)
RU (1) RU2002107441A (fr)
SK (1) SK3322002A3 (fr)
WO (1) WO2001019369A1 (fr)
ZA (1) ZA200202868B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002049649A2 (fr) * 2000-12-19 2002-06-27 Merck Patent Gmbh Formulation pharmaceutique contenant des thienopyrimidines et des antithrombotiques, des inhibiteurs calciques, des prostaglandines ou des derives de prostaglandine (2)
EP1733728A2 (fr) * 2001-07-23 2006-12-20 Bayer HealthCare AG Utilisation d'imidazotriazinones 2-alcoxyphenyl substituées en tant qu'inhibiteurs de la phosphodiestérase

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0728759A1 (fr) * 1995-02-24 1996-08-28 Ono Pharmaceutical Co., Ltd. Composés hétérocycliques
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WO1997038983A1 (fr) * 1996-04-12 1997-10-23 Warner-Lambert Company Inhibiteurs irreversibles de tyrosine kinases
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WO2000059912A1 (fr) * 1999-03-30 2000-10-12 Nippon Soda Co., Ltd. Composes de thienopyrimidine et leurs sels, et procede de preparation desdits composes et sels

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EP1733728A2 (fr) * 2001-07-23 2006-12-20 Bayer HealthCare AG Utilisation d'imidazotriazinones 2-alcoxyphenyl substituées en tant qu'inhibiteurs de la phosphodiestérase
EP1733728A3 (fr) * 2001-07-23 2007-03-21 Bayer HealthCare AG Utilisation d'imidazotriazinones 2-alcoxyphenyl substituées en tant qu'inhibiteurs de la phosphodiestérase

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HUP0202614A2 (hu) 2002-12-28
EP1212062A1 (fr) 2002-06-12
ZA200202868B (en) 2003-11-26
CN1377271A (zh) 2002-10-30
SK3322002A3 (en) 2002-07-02
CZ2002818A3 (cs) 2002-06-12
RU2002107441A (ru) 2003-11-20
MXPA02002746A (es) 2002-10-23
AU6703200A (en) 2001-04-17
AR025645A1 (es) 2002-12-04
KR20020026011A (ko) 2002-04-04
BR0013957A (pt) 2002-05-21
HUP0202614A3 (en) 2004-11-29
PL353343A1 (en) 2003-11-17
DE19943815A1 (de) 2001-03-15
NO20021234D0 (no) 2002-03-13
CA2387123A1 (fr) 2001-03-22

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