EP0550697A1 - Funktionalisierte vinylazole enthaltende pharmazeutische präparate, verwendung dieser vinylazole zur herstellung von arzneimitteln, vinylazole selbst sowie verfahren zu deren herstellung - Google Patents

Funktionalisierte vinylazole enthaltende pharmazeutische präparate, verwendung dieser vinylazole zur herstellung von arzneimitteln, vinylazole selbst sowie verfahren zu deren herstellung

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Publication number
EP0550697A1
EP0550697A1 EP19920900266 EP92900266A EP0550697A1 EP 0550697 A1 EP0550697 A1 EP 0550697A1 EP 19920900266 EP19920900266 EP 19920900266 EP 92900266 A EP92900266 A EP 92900266A EP 0550697 A1 EP0550697 A1 EP 0550697A1
Authority
EP
European Patent Office
Prior art keywords
group
atom
general formula
optionally substituted
imidazolyl
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Withdrawn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
EP19920900266
Other languages
German (de)
English (en)
French (fr)
Inventor
Peter Strehlke
Rolf Bohlmann
Martin Schneider
Yukishige Nishino
Hans-Peter Muhn-Seipoldy
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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 Schering AG filed Critical Schering AG
Publication of EP0550697A1 publication Critical patent/EP0550697A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to functionalized vinyl azoles of the general formula I
  • X is an N atom or a CH group
  • Z is a cyano group, a fluorine, chlorine or bromine atom and
  • R 1 or R 2 is an optionally esterified carboxyl group, an optionally substituted carboxamide group, an aldehyde group, an alkyl or aryl ketone group, an optionally substituted sulfonamide group or a nitrile group
  • R or R is a hydrogen atom, a lower alkyl group or cycloalkyl group, an optionally substituted aryl group, an aralkyl group, an optionally esterified carboxyl group, an optionally substituted carboxamide group, an aldehyde group, an alkyl or aryl ketone group and a nitrile group or 1 2 R and R together with the carbon atom to which they are attached, a 5-, 6- or 7-membered ring which contains a ketone, ester, lactone, lactam or imide grouping such that at least one
  • Carbonyl group is in conjugation with the vinyl double bond
  • the substituent Z preferably represents a fluorine atom or a cyano group.
  • R and / or R stands for an esterified carboxyl group, this is primarily with a straight-chain or branched-chain or cyclic 0-A1-alkyl radical with up to 10 carbon atoms, with an O-aryl radical, where aryl is optionally one to three Lower alkyl groups .1- '. Carbon atoms) or halogen atoms (F, Cl, Br, I) substituted phenyl or naphthyl radical or an O-aralkyl radical, in which the aryl and the alkyl fragment have the meaning given above, esterified.
  • methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, cyclohexyloxy, cyclopentyloxy, phenyloxy or 2,6-dichlorophenoxy radical are particularly preferred here.
  • R and / or R is a substituted carboxamide group, this is primarily substituted with one or two, in the latter case identical or different, radicals.
  • These radicals can be straight-chain or branched-chain alkyl radicals having 1 to 10 carbon atoms, or optionally aryl radicals having 6 to 10 carbon atoms substituted by one to three alkyl groups or halogen atoms.
  • the amidic nitrogen atom can also be part of a 5- to ⁇ -membered ring which also has the grouping ⁇ NR with R meaning a hydrogen atom or a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, an oxygen or sulfur atom can contain as a ring link.
  • the carboxamide group with a methyl, ethyl, propyl, phenyl, benzyl radical, two methyl, ethyl, propyl radicals, one phenyl and one methyl, one phenyl and one ethyl and one benzyl and one methyl radical or one together pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine or thio orpholine ring formed with the amidic nitrogen atom.
  • R and R each represent an alkyl substituent with 1 to 10 carbon atoms.
  • the radical is -CO-R, where R is a straight or branched chain alkyl radical having 1 to 10 or a cycloalkyl radical having 3 to 12 carbon atoms and the aryl ketone group is the
  • Radical -CO-R where R is optionally one or more alkyl
  • Heteroaryl radical such as e.g. is a thiophene, furan, pyridine, thiazole, oxazole or diazine ring, preferred.
  • R is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, cyclopentyl or cyclohexyl radical and R is a phenyl, hydroxyphenyl, methoxyphenyl or Chlorophenyl radical.
  • W is a hydrogen atom or an alkyl group with 1-10 C atoms.
  • the isomers are separated using common methods such as crystallization or chromatography.
  • the following connections are preferred:
  • estrogens are therefore suitable for the treatment of diseases which are caused by estrogens or are dependent on estrogens. They are suitable for the treatment of estrogen-induced or -stimulated tumors, such as, for example, breast cancer, endometrial cancer, melano or prostatic hyperplasia (The Lancet, 1984. 1237-1239).
  • the compounds mentioned are also valuable for influencing fertility. Male infertility resulting from increased levels of estrogen can be remedied with the new active ingredients.
  • the compounds can also be used in women of reproductive age as anti-fertility agents to inhibit ovulation by estrogen deprivation.
  • Aromatase inhibitors are probably also suitable for treating the impending heart attack, since increased estrogen levels in men can precede a heart attack (US Pat. No. 4,289,762).
  • the present invention therefore also relates to the use of the compounds of the general formula I for the production of medicaments for the treatment of estrogen-induced and estrogen-dependent diseases.
  • Phenylalkenones of the general formula RC (0) CH CR R, where R is an optionally substituted alkyl or cycloalkyl radical, R is a 1,2,4-triazolyl or 1-imidazolyl radical and R is a phenyl or naphthyl ring which optionally, among others, can be substituted with a fluorine, chlorine or bromine atom or a cyano group, are already apparent from EP-A-0 003 884. These phenylalkenones are described as compounds with herbicidal activity.
  • DE-A 28 26 760 relates to 3- (4-chlorophenyl) -3- (1,2,4-triazolyD-acrylic acid alkyl esters for use as fungicides and plant growth regulators.
  • X is an N atom or a CH group
  • Z is a cyano group or a fluorine or bromine atom
  • R 1a or R 2a is an optionally esterified carboxyl group, an optionally substituted carboxamide group, an aldehyde group, an aryl ketone group, an optionally substituted sulfonamide group or a nitrile group and the other group R 1a or R2a is a hydrogen atom, a lower alkyl group or cycloalkyl group, an optionally substituted one Aryl group, an aralkyl group, an optionally esterified carboxyl group, an optionally substituted carboxamide group, an aldehyde group, an aryl ketone group and a nitrile group or 1a 2a R and R together with the carbon atom to which they are attached form a 5-, 6- or 7-membered ring which contains a ketone, ester, lactone,
  • Lacta or imide grouping so arranged that at least one
  • Carbonyl group is in conjugation with the vinyl double bond
  • Known substances which have an aromatase-inhibiting effect are not only steroids but also non-steroidal substances, for example the various nitrogen heterocycles described in European patent applications EP-A 0165777 to 0165784, which are described in 3. Med. Chem. 1986, 2 £, pages 1362-1369 described substituted glutarimides, the substituted imidazobenzenes described in European patent application EP 0165904, the substituted heterocyclically substituted toluene nitriles described in European patent application EP-A 0236940 and those from US Pat.
  • Patent US-A-4, 728,465 resulting imidazo and 5,6,7, 8-tetrahydroimidazo [1, 5a] pyridines bearing an optionally substituted phenyl ring, from which in particular the 5- (p-cyanophenyl) 5, 6th , 7, 8tetrahydroimidazo [1, 5a] pyridine, hydrochloride stands out as a potent aromatase inhibitor (Cancer Res. 48, pp. 834-838. 1988).
  • the compounds of the general formula I are distinguished from the compounds known hitherto in that they inhibit the enzyme system of the aroatase more strongly and at the same time more selectively. The selective effect is evident from the fact that other enzyme systems are impaired to a lesser extent.
  • concentrations at which the aromatase activity is inhibited in vitro by the compounds of the general formula I are in the range from 10 ⁇ 7 to 10 -10 mol / 1.
  • the compounds of the general formula I on the carbon atom, on which both the cyanoaryl and the N-heteroaryl radical are located have no chirality center due to the introduction of the double bond more on. By eliminating the chirality center, an enantioselective synthesis or the costly separation of enantiomers is avoided.
  • the amount of the compounds to be administered fluctuates within a wide range and can cover any effective amount. Depending on the condition to be treated and the mode of administration, the amount of the compounds administered can be 0.0001-10 mg / kg body weight, preferably 0.001-1 mg / kg body weight, per day.
  • Capsules, pills, tablets, coated tablets, etc. can be used for oral administration.
  • the dosage units can contain a pharmaceutically acceptable carrier, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silica, talc, etc.
  • the individual dosage units for oral administration can contain, for example, 0.05-50 mg of the active ingredient (aromatase inhibitor).
  • the active ingredients can be dissolved or suspended in a physiologically acceptable diluent.
  • Oils with or without the addition of a solubilizer, a surface-active agent, a suspending or emulsifying mixture are very often used as diluents. Examples of oils used are; Olive oil, peanut oil, cotton oil, soybean oil, castor oil and sesa oil.
  • the compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated in such a way that delayed release of the active substance is made possible.
  • implants can contain, for example, biodegradable polymers or synthetic silicones, such as silicone rubber.
  • the active ingredients can also be incorporated into plasters for percutaneous application.
  • the tumor inhibitory effect of imidazole derivatives is based on an inhibition of P-450-dependent enzyme systems (cf. e.g. J.P. Van Wanne and P.A.J. Janssen; J. Med. Chem. 1 (1989) 2231).
  • the effect of antifungal therapeutic agents from the series of idazole and triazole derivatives is based on a blockade of P-450-dependent biochemical reactions (loc. Cit.). It is also known from the patent literature that azole derivatives have both antifungal and antitumor effects at the same time (cf. EPA 0165777, Eli Lilly).
  • the compounds according to the invention should therefore also have an antifungal activity against germs which are pathogenic to humans, animals and plants.
  • the invention also relates to a process for the preparation of the compounds of the general formula Ia and a process for the preparation of certain compounds of the general formula I, hereinafter referred to as compounds of the general formula I * .
  • R 1a, R2a, Y and Za have the meaning given in formula Ia and R * .
  • ' represents a hydrogen atom or R 3' together with R2a forms a ring of the partial structures listed above, with a compound of the general formula VII
  • X is an N atom or a CH group
  • A is a hydrogen atom, an alkali metal or a trialkylsilyl radical with the same or different straight-chain or branched C -C ß -alkyl groups, in an inert solvent at a temperature between room temperature and the boiling point of the solvent or without solvent, optionally with the addition of a catalyst first to a compound of the general formula Ili wherein R a , R a , R, X, Y and Z a have the meaning already given in formula II or VII, and these are eliminated by elimination of water above 60 ° C., if appropriate in a solvent and if appropriate using a catalyst allowed to react further a compound of general formula Ia or
  • R 1, R2 and Y have the meaning given in formula I, R3 'forms a hydrogen atom or, together with R 2, forms a ring of the partial structures listed above, and shark halogen atoms, in particular each a bromine atom, mean with a compound of the general formula VII converted by conventional methods with or without the addition of a foreign base to a compound of the general formula I or
  • Y and Z have the meaning given in formula I, and R Ia an esterified carboxyl group, an optionally substituted carboxamide group, an aldehyde group, an aryl ketone group, an optionally substituted sulfonamide group or a nitrile group, the optionally possible substituents and the alkoxy radicals of the esterified carboxyl group den correspond to the definitions already given, a compound of the general formula VII in a solvent between room temperature and the boiling point of this solvent to form a compound of the general formula IIIi
  • the compounds of general formula I according to variant i) according to the invention are prepared from an epoxide of general formula II and an azole of formula VII in a manner known per se.
  • the addition of the azole is carried out in an inert solvent such as, for example, benzene, toluene, xylene, tetrahydrofuran, dioxane, acetonitrile or dimethylformamide, preferably at a temperature between 60 ° C. and boiling point of the solvent or preferably without solvent between 60 ° C and 150 ° C performed.
  • a catalyst e.g. a metal salt such as lithium, magnesium, sodium perchlorate, zinc or calcium chloride can be added (Tetrahedron Letters 3 ⁇ . (1990) 4661).
  • the elimination of water takes place thermally, preferably at temperatures between 100 ° C and 200 ° C or the boiling point of an optionally used solvent such as e.g. Toluene, chlorobenzene or xylene.
  • an optionally used solvent such as e.g. Toluene, chlorobenzene or xylene.
  • Inorganic or organic acids such as, for example, sulfuric acid or p-toluenesulfonic acid are suitable as catalysts.
  • the elimination of water can also be carried out by using water-releasing agents such as thionyl chloride or phosphorus oxychloride with or without a solvent (for example dichloromethane, acetonitrile, tetrahydrofuran) at room temperature to the boiling point of the solvent, preferably between 20 ° C. and 50 ° C.
  • a solvent for example dichloromethane, acetonitrile, tetrahydrofuran
  • the reaction of the dihalide of the general formula III with an azole of the general formula VII according to ii) is likewise a method familiar to the person skilled in the art.
  • the additional use of a foreign base (Heterocycles ____ ⁇ __ ⁇ __ (1981), 961) may be useful to facilitate the reaction.
  • the halogen atom on the benzylic carbon atom is first exchanged and then hydrogen halide is eliminated.
  • the intermediate monohalogen compound is not isolated.
  • the required starting compounds of the general formula II or formula III can be obtained in a manner known per se by epoxidation or halogenation, preferably bromination, of the corresponding olefins; these in turn can be produced, for example, by a Wittig or Knoevenagel reaction of the corresponding starting materials.
  • reaction of compounds of the formula V with the optionally substituted azoles VII takes place preferably in solvents such as hydrocarbons (benzene, toluene), ethers (ethyl ether, dioxane, tetrahydrofuran), alcohols (tert-butanol) or halogenated hydrocarbons (dichloromethane, chloroform, 1, 2-dichloroethane) between room temperature and boiling temperature of the solvent.
  • solvents such as hydrocarbons (benzene, toluene), ethers (ethyl ether, dioxane, tetrahydrofuran), alcohols (tert-butanol) or halogenated hydrocarbons (dichloromethane, chloroform, 1, 2-dichloroethane) between room temperature and boiling temperature of the solvent.
  • L is an optionally substituted phenyl radical [with lower alkylK 1-6C),
  • acylazoles react with a phosphorane in the sense of a Wittig reaction. Rather, it is known that acylimidazole (generally also acylazoles) are good acylating agents (Comprehensive Heterocyclic Chemistry (Eds. A.R. Katritzky, K.T. Potts) Pergam ⁇ n Press 1984. Volume 4A, page 451 ff). Accordingly, it would have been expected that a Wittig reagent (phosphorane) would be acylated on the carbanion, e.g. the following is observed in the reaction with acid chlorides:
  • the ethyl acetate phase is then extracted three times with 2 M hydrochloric acid.
  • the hydrochloric acid phase is alkalized with potassium carbonate and extracted with ethyl acetate. After drying the ethyl acetate phase with sodium sulfate and evaporation, an oil remains which crystallizes through. After the crystals have been filtered off with ether, 3.5 g (81!) Of a Z / E mixture of the title compound are obtained.
  • the E compound is obtained in pure form by recrystallization from ethanol. Mp .: 144-147 ° C
  • Example 2 Analogously to Example 1, the title compound is obtained using cyanomethylene triphenyl phosphorane.
  • the E isomer is obtained pure from ethanol; Mp: 188-193 ° C.
  • the acid chloride is prepared from 2 g of 5-cyanothiophene-2-carboxylic acid by boiling with thionyl chloride and distilling off excess thionyl chloride. This is dissolved in 10 ml of ether and 1.9 ml of N-trimethylsilylimidazole are added. It is evaporated in vacuo, dissolved in a mixture of 150 ml of tetrahydrofuran and 50 ml of acetonitrile, and 4.9 g of tert-butoxycarbonylmethylene triphenylphosphorane are added. The mixture is refluxed for 20 hours and worked up as in Example 1.
  • the dibromo compound is refluxed with 372 mg imidazole and 2.52 ml triethylamine in 20 ml toluene for 7 hours.
  • the solution is partitioned between 1 M hydrochloric acid and ether, the acidic water phase is separated off and alkalized with potassium carbonate. After extraction with ethyl acetate and evaporation of the solvent, the crystals which remain are filtered off with ether, dried at 50 ° C. under reduced pressure and 140 mg of the title compound of mp: 260-268 ° C. are thus obtained.
  • Example 9 Analogously to Example 9 using 4-fluorobenzoic acid, a Z / E mixture of the title compound is obtained. After chromatography and recrystallization, the E isomer is pure, m.p .: 90-93 ° C.
  • Example 9 Analogously to Example 9 using 4-chlorobenzoic acid.
  • the E isomer melts at 114-121 ° C (from cyclohexane).
  • Example 9 Analogously to Example 9 using 4-bromobenzoic acid.
  • the E isomer melts at 131 -132 ° C (from isopropanol).
  • Example 9 Analogously to Example 9 using 4-fluorobenzoic acid and 1-trimethylsilyl-1, 2,4-triazole.
  • the E isomer melts at 72-74 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
EP19920900266 1990-12-07 1991-12-09 Funktionalisierte vinylazole enthaltende pharmazeutische präparate, verwendung dieser vinylazole zur herstellung von arzneimitteln, vinylazole selbst sowie verfahren zu deren herstellung Withdrawn EP0550697A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4039559A DE4039559A1 (de) 1990-12-07 1990-12-07 Funktionalisierte vinylazole, verfahren zu deren herstellung, pharmazeutische praeparate die diese vinylazole enthalten sowie deren verwendung zur herstellung von arzneimitteln
DE4039559 1990-12-07

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EP0550697A1 true EP0550697A1 (de) 1993-07-14

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US (1) US5344834A (no)
EP (1) EP0550697A1 (no)
JP (1) JPH06503818A (no)
KR (1) KR930703263A (no)
CN (1) CN1064863A (no)
AU (1) AU660296B2 (no)
CA (1) CA2097824C (no)
CS (1) CS369691A3 (no)
DE (1) DE4039559A1 (no)
FI (1) FI932572A0 (no)
HU (1) HUT64036A (no)
IE (1) IE914259A1 (no)
IL (1) IL100274A (no)
NO (1) NO304428B1 (no)
PT (1) PT99714B (no)
WO (1) WO1992010482A1 (no)
ZA (1) ZA919662B (no)

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GB2273704B (en) * 1992-12-16 1997-01-22 Orion Yhtymae Oy Triazolyl diaryl selective aromatase inhibiting compounds
US5395847A (en) * 1993-12-02 1995-03-07 Smithkline Beecham Corporation Imidazolyl-alkenoic acids
EP0943333A1 (de) * 1998-03-18 1999-09-22 S.W. Patentverwertungs GmbH Medikament zur Prophylaxe und/oder Behandlung des Mammakarzinoms enthaltend einen Hemmer der Bildung von Oestrogenen
US20020086856A1 (en) 1998-03-18 2002-07-04 Alfred Schmidt Medicament for preventing and/or treating a mammary carcinoma, containing a steroidal aromatase inhibitor
CN100358866C (zh) * 2004-04-08 2008-01-02 上海交通大学 含对强碱不稳定取代基的n-乙烯基取代吡咯的制备方法
JP6470984B2 (ja) * 2015-01-27 2019-02-13 学校法人東日本学園 アロマターゼ阻害剤及びこれを含む医薬
CN105732977B (zh) * 2016-01-30 2018-03-02 宝鸡文理学院 一种可溶性聚苯并二噻唑‑酰胺荧光聚合物及其制备方法和应用

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IL100274A0 (en) 1992-09-06
AU660296B2 (en) 1995-06-22
HUT64036A (en) 1993-11-29
ZA919662B (en) 1992-09-30
AU9045491A (en) 1992-07-08
HU9301657D0 (en) 1993-09-28
JPH06503818A (ja) 1994-04-28
NO304428B1 (no) 1998-12-14
NO932044L (no) 1993-06-04
PT99714B (pt) 1999-05-31
NO932044D0 (no) 1993-06-04
FI932572A (fi) 1993-06-04
IL100274A (en) 1996-08-04
CN1064863A (zh) 1992-09-30
DE4039559A1 (de) 1992-06-11
CS369691A3 (en) 1992-06-17
FI932572A0 (fi) 1993-06-04
US5344834A (en) 1994-09-06
WO1992010482A1 (de) 1992-06-25
KR930703263A (ko) 1993-11-29
PT99714A (pt) 1992-10-30
CA2097824A1 (en) 1992-06-08
IE914259A1 (en) 1992-06-17
CA2097824C (en) 2003-04-08

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