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DE4010097A1 - UNSATURATED N-BENZOXODIAZOLOPYRANYLLACTAME, THEIR PRODUCTION AND USE - Google Patents

UNSATURATED N-BENZOXODIAZOLOPYRANYLLACTAME, THEIR PRODUCTION AND USE

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Publication number
DE4010097A1
DE4010097A1 DE4010097A DE4010097A DE4010097A1 DE 4010097 A1 DE4010097 A1 DE 4010097A1 DE 4010097 A DE4010097 A DE 4010097A DE 4010097 A DE4010097 A DE 4010097A DE 4010097 A1 DE4010097 A1 DE 4010097A1
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Prior art keywords
dihydro
oxadiazole
pyrano
benzo
dimethyl
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DE4010097A
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German (de)
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Hans-Joachim Dr May
Manfred Dr Raschack
Sabine Dr Schult
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BASF SE
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BASF SE
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Priority to DE4010097A priority Critical patent/DE4010097A1/en
Priority to PCT/EP1991/000537 priority patent/WO1991014690A1/en
Priority to HU9230V priority patent/HU9203092D0/en
Priority to CA002078139A priority patent/CA2078139A1/en
Priority to JP91506303A priority patent/JPH05505801A/en
Priority to EP91906395A priority patent/EP0521936A1/en
Publication of DE4010097A1 publication Critical patent/DE4010097A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • A61P9/12—Antihypertensives

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Compounds of formula (I), where R<1> to R<5>, X, Y and Z have the indicated meaning, and their production are described. The compounds are useful therapeutic agents.

Description

Die vorliegende Erfindung betrifft neue ungesättigte N-Benzoxadiazolylpyranyllactame, deren Herstellung sowie deren Verwendung zur Bekämpfung von Krankheiten.The present invention relates to new unsaturated N-benzoxadiazolylpyranyllactams, their manufacture and their use in combating of diseases.

Ungesättigte Lactame sind bereits bekannt, vgl. EP 2 73 262, EP 3 40 718, EP 3 08 792 und J. Med. Chem., 33, 492 (1990). Die Herstellung derartiger Lactame ist auch in der EP 3 37 179 beschrieben.Unsaturated lactams are already known, cf. EP 2 73 262, EP 3 40 718, EP 3 08 792 and J. Med. Chem., 33, 492 (1990). The manufacture of such Lactame is also described in EP 3 37 179.

Es wurde nun gefunden, daß ungesättigte N-Benzoxadiazolopyranyllactame der Formel IIt has now been found that unsaturated N-benzoxadiazolopyranyllactams of Formula I.

worin
R¹ und R² gleich oder verschieden sind und C₁-C₄-Alkyl oder zusammen C₂-C₆-Alkylen bedeuten,
R³ Hydroxy, Acyloxy oder -O-NO₂,
R⁴ Wasserstoff oder C₁-C₄-Alkyl,
R⁵ Wasserstoff oder
R³ und R⁵ zusammen eine Bindung,
X Sauerstoff oder Schwefel,
Y die Gruppewherein
R¹ and R² are the same or different and are C₁-C₄-alkyl or together are C₂-C₆-alkylene,
R³ is hydroxy, acyloxy or -O-NO₂,
R⁴ is hydrogen or C₁-C₄ alkyl,
R⁵ is hydrogen or
R³ and R⁵ together form a bond,
X oxygen or sulfur,
Y the group

Z die GruppeZ the group

(mit R⁶, R⁷, R⁸ und R⁹, die gleich oder verschieden sind, in der Bedeutung von Wasserstoff, C₁-C₄-Alkyl, Trifluormethyl, Hydroxy, Acyloxy, C₁-C₄-Alkoxy, Halogen, Amino, C₁-C₄-Alkylamino, C₁-C₄-Dialkylamino, Nitro, Cyano, Acyl, C₂-C₃-Alkylcarbonyl, das im Alkylrest gegebenenfalls durch Hydroxy oder C₁-C₄-Alkoxy substituiert ist, oder Arylcarbonyl, das im Arylrest gegebenenfalls durch ein oder mehrere Halogenatome, Trifluormethylreste, Acyloxy-, C₁-C₄-Alkyl oder C₁-C₄- Alkylendioxygruppen substituiert ist),
bedeuten, sowie deren Salze mit physiologisch verträglichen Säuren, wertvolle pharmakologische Eigenschaften besitzen.(with R⁶, R⁷, R⁸ and R⁹, which are the same or different, in the meaning of hydrogen, C₁-C₄-alkyl, trifluoromethyl, hydroxy, acyloxy, C₁-C₄-alkoxy, halogen, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, nitro, cyano, acyl, C₂-C₃-alkylcarbonyl, which is optionally substituted in the alkyl radical by hydroxy or C₁-C₄-alkoxy, or arylcarbonyl, which is optionally in the aryl radical by one or more halogen atoms, trifluoromethyl radicals, acyloxy- , C₁-C₄-alkyl or C₁-C₄-alkylenedioxy groups is substituted),
mean, and their salts with physiologically acceptable acids, have valuable pharmacological properties.

Wenn die C-Atome 7 und 8 des 6H-Pyrano[2,3-f]-benzo-2,1,3-oxadiazolsystems asymmetrisch substituiert sind, umfaßt die Erfindung nur solche Verbindungen, die an diesen Zentren entgegengesetzte Konfigurationen, also eine "trans-Orientierung" der Substituenten an diesen C-Atomen aufweisen. Falls die Substituenten R¹ und R² ungleich sind und somit ein asymmetrisches Kohlenstoffatom erzeugen, dann umfaßt die Erfindung sowohl Verbindungen mit S- als auch R-Konfiguration.If the C atoms 7 and 8 of the 6H-pyrano [2,3-f] -benzo-2,1,3-oxadiazole system are asymmetrically substituted, the invention includes only those compounds the opposite configurations at these centers, i.e. one Have "trans-orientation" of the substituents on these carbon atoms. If the substituents R¹ and R² are not the same and are therefore asymmetrical Generate carbon atom, then the invention includes both compounds with S and R configuration.

Die Verbindungen können als Diastereomere, als Racemate oder als Gemische derselben vorliegen. Aus einem Diastereomeren oder Racemat lassen sich nach herkömmlichen Methoden der Racematspaltung die optisch aktiven Enantiomeren herstellen.The compounds can be used as diastereomers, as racemates or as mixtures the same are present. A diastereomer or racemate can be used using conventional methods of resolving racemates, the optically active ones Prepare enantiomers.

Bevorzugt sind Verbindungen der Formel I, in dem R¹ und R² Methyl oder Ethyl und R⁴ Wasserstoff bedeuten und R³, R⁵, X, Y und Z wie oben definiert sind. Ebenfalls bevorzugt sind Verbindungen, in denen R¹ und R² Methyl oder Ethyl, R⁴ Wasserstoff und R³ und R⁵ zusammen eine Bindung bedeuten und X, Y und Z wie oben definiert sind.Preferred compounds of the formula I are those in which R 1 and R 2 are methyl or Ethyl and R⁴ are hydrogen and R³, R⁵, X, Y and Z as defined above are. Also preferred are compounds in which R¹ and R² Methyl or ethyl, R⁴ hydrogen and R³ and R⁵ together form a bond mean and X, Y and Z are as defined above.

Besonders bevorzugt sind Verbindungen der Formel I, in denen R¹ und R² Methyl, R⁴ Wasserstoff und X Sauerstoff bedeuten und R³, R⁵, Y und Z wie oben definiert sind. Ebenfalls besonders bevorzugt sind Verbindungen der Formel I, in denen R¹ und R² Methyl, R⁴ Wasserstoff, R³ und R⁵ zusammen eine Bindung und X Sauerstoff bedeuten und Y und Z wie oben definiert sind.Compounds of the formula I in which R 1 and R 2 are particularly preferred Methyl, R⁴ is hydrogen and X is oxygen and R³, R⁵, Y and Z are like are defined above. Compounds of Formula I in which R¹ and R² are methyl, R⁴ is hydrogen, R³ and R⁵ together a bond and X are oxygen and Y and Z are as defined above are.

Ganz besonders bevorzugt sind Verbindungen der Formel I, in denen R¹ und R² Methyl, R⁴ und R⁵ Wasserstoff, R³ Hydroxy, X Sauerstoff, Y die GruppeCompounds of the formula I in which R 1 and R² methyl, R⁴ and R⁵ hydrogen, R³ hydroxy, X oxygen, Y the group

bedeuten, wobei R⁶ bis R⁹ Wasserstoff oder einer der Reste R⁶ bis R⁹ C₁-C₄-Alkoxy und die restlichen Wasserstoff bedeuten. Ebenfalls besonders bevorzugt sind Verbindungen der Formel I, in denen R¹ und R² Methyl, R⁴ Wasserstoff, R³ und R⁵ zusammen eine Bindung, X Sauerstoff, Y die Gruppemean, where R⁶ to R⁹ is hydrogen or one of the radicals R⁶ to R⁹ C₁-C₄ alkoxy and the remaining hydrogen. Also special preferred compounds of formula I are those in which R¹ and R² are methyl, R⁴ Hydrogen, R³ and R⁵ together form a bond, X oxygen, Y the group

bedeuten, wobei R⁶ bis R⁹ Wasserstoff oder einer der Reste R⁶ bis R⁹ C₁-C₄-Alkoxy und die restlichen Wasserstoff bedeuten.mean, where R⁶ to R⁹ is hydrogen or one of the radicals R⁶ to R⁹ C₁-C₄ alkoxy and the remaining hydrogen.

Als physiologisch verträgliche Säuren kommen in Betracht: Salzsäure, Zitronensäure, Weinsäure, Milchsäure, Phosphorsäure, Methansulfonsäure, Essigsäure, Ameisensäure, Maleinsäure, Fumarsäure, Äpfelsäure, Bernsteinsäure, Maleinsäure, Schwefelsäure, L-Glutaminsäure, L-Asparaginsäure, Brenztraubensäure, Schleimsäure, Benzoesäure, Glucuronsäure, Oxalsäure, Ascorbinsäure und Acetylglycin.Possible physiologically acceptable acids are: hydrochloric acid, Citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, Acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, Maleic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, Pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, Ascorbic acid and acetylglycine.

Die Verbndungen der Formel I lassen sich herstellen, indem manThe compounds of formula I can be produced by

  • a) Verbindungen der Formel II in den R¹, R² und R⁴ die oben angegebene Bedeutung haben, entweder mit N-Silyllactamen der Formel III in denen X Sauerstoff bedeutet und Y und Z wie oben definiert sind, oder mit O-Silyllactamen der Formel IV in denen X Sauerstoff bedeutet und Y und Z wie oben definiert sind, umsetzt, odera) Compounds of formula II in the R¹, R² and R⁴ have the meaning given above, either with N-silyl lactams of the formula III in which X is oxygen and Y and Z are as defined above, or with O-silyl lactams of the formula IV in which X is oxygen and Y and Z are as defined above, or
  • b) Verbindungen der Formel V in denen alle Reste wie in Formel I definiert sind, mit einem Phosphorigsäuretriester, einem Alkalimetallazid oder Hydroxylamin umsetzt oderb) compounds of formula V in which all radicals are as defined in formula I, reacted with a phosphorous triester, an alkali metal azide or hydroxylamine or
  • c) - falls Verbindungen der Formel I, in denen X Schwefel bedeutet und die übrigen Reste die oben angegebene Bedeutung haben, hergestellt werden - Verbindungen der Formel I, in denen X Sauerstoff bedeutet, mit Lawesson Reagenz umsetzt,c) - if compounds of the formula I in which X is sulfur and the remaining radicals have the meaning given above - compounds of the formula I in which X is oxygen, with Lawesson reagent,

und die so erhaltenen Verbindungen gegebenenfalls in ihre Salze mit physiologisch verträglichen Säuren überführt.and optionally the compounds thus obtained in their salts transferred physiologically acceptable acids.

Bei der Durchführung der Verfahren a) rührt man die Verbindungen der Formel II und die Verbindungen der Formel III oder IV gelöst in einem dipolaren, aprotischen Lösungsmittel, vorzugsweise THF, in Gegenwart eines Desilylierungsmittels. Die Reaktion läßt sich auch in einem Überschuß der gewöhnlich flüssigen Silylverbindungen ohne Lösungsmittel durchführen. Die Reaktionstemperatur kann zwischen Raumtemperatur und ca. 120°C variieren.When carrying out the process a), the compounds of Formula II and the compounds of formula III or IV dissolved in one dipolar, aprotic solvent, preferably THF, in the presence of a Desilylating agent. The reaction can also be in an excess of usually perform liquid silyl compounds without solvents. The The reaction temperature can vary between room temperature and approx. 120 ° C.

Verbindungen der Formel I, in denen R³ und R⁵ eine Bindung darstellen, lassen sich am besten aus den entsprechenden Hydroxyverbindungen (R³=OH, R⁵=H) durch Wasserabspaltung herstellen.Compounds of the formula I in which R³ and R⁵ represent a bond, can best be derived from the corresponding hydroxy compounds (R³ = OH, R⁵ = H) by elimination of water.

Verbindungen der Formel II bzw. VI sind aus der EP 3 27 127 bekannt, Silylverbindungen der Formel III und IV können leicht nach literaturbekannten Methoden aus den entsprechenden Lactamen hergestellt werden, beispielsweise durch Erhitzen mit Hexamethyldisilazan oder in situ z. B. mit Lithium-bis-trimethylsilyl-amid.Compounds of formula II and VI are known from EP 3 27 127, silyl compounds of the formula III and IV can easily according to literature Methods can be prepared from the corresponding lactams, for example by heating with hexamethyldisilazane or in situ e.g. B. with Lithium bis-trimethylsilyl amide.

Bei der Durchführung des Verfahrens b) werden die Verbindungen der Formel I durch Reduktion des N-Oxids der Verbindungen der Formel V erhalten, indem man diese in einem polaren Lösungsmittel von z. B. Ethanol oder Ethylenglykol löst und in Gegenwart eines Alkalimetallazids, bevorzugt Natriumazid, oder einem Phosphorigsäureester, bevorzugt Triethylphosphit oder Hydroxylamin in Gegenwart eines Alkalihydroxids, wie z. B. NaOH, bevorzugt auf die Rückflußtemperatur des verwendeten Lösungsmittels erhitzt.When carrying out process b), the compounds of Formula I obtained by reducing the N-oxide of the compounds of the formula V, by placing them in a polar solvent of e.g. B. ethanol  or ethylene glycol dissolves and is preferred in the presence of an alkali metal azide Sodium azide, or a phosphorous acid ester, preferably triethyl phosphite or hydroxylamine in the presence of an alkali hydroxide, such as. B. NaOH, preferably to the reflux temperature of the solvent used heated.

Bei der Durchführung des Verfahrens c) wird ein Lactam der Formel I (X=O) mit Lawesson Reagenz (2,4-Bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiophosphetan) in einem unpolaren Lösungsmittel, bevorzugt Toluol, vorzugsweise auf Rückflußtemperatur des verwendeten Lösungsmittels erhitzt.When carrying out process c), a lactam of the formula I (X = O) with Lawesson reagent (2,4-bis- (4-methoxyphenyl) -2,4-dithioxo-1,3,2,4-dithiophosphetane) in a non-polar solvent, preferably toluene, preferably heated to the reflux temperature of the solvent used.

Entantiomerenreine Endprodukte der Formel I (für R³=Hydroxy) können aus den Racematen durch gängige Spaltungsmethoden wie z. B. chromatographische Trennung unter Verwendung von chiralen Phasen oder durch Veresterung der 7-Hydroxygruppen des Oxadiazolochromans mit optisch aktiven Säurederivaten bzw. durch Carbamatbildung mit optisch aktiven Isocyanaten erhalten werden. Die dabei erhaltenen diastereomeren Ester oder Carbamate lassen sich durch gängige Methoden der Kristallisation oder Chromatographie trennen und unter Abspaltung der optisch aktiven Hilfsgruppen an der 7-Hydroxygruppe in die optisch einheitlichen Endverbindungen umwandeln.Entantiomerically pure end products of the formula I (for R³ = hydroxy) can be obtained from the racemates by common cleavage methods such. B. chromatographic Separation using chiral phases or by esterification of the 7-hydroxy groups of oxadiazolochromans with optically active acid derivatives or obtained by carbamate formation with optically active isocyanates will. The resulting diastereomeric esters or carbamates are left through common methods of crystallization or chromatography separate and split off the optically active auxiliary groups on the Convert 7-hydroxy group into the optically uniform end compounds.

Besonders vorteilhaft ist hierbei die Trennung der diastereomeren 3-Menthoxyacetate.The separation of the diastereoisomers is particularly advantageous here 3-menthoxyacetates.

Überraschenderweise führt die Einführung von ungesättigten cyclischen Amiden in die 8-Position des 6H-Pyrano[2,3-f]-benzo-2,1,3-oxadiazolsystems zu neuen wirksamen Verbindungen bei besserer Verträglichkeit. Sie wirken blutdrucksenkend und/oder haben eine relaxierende Wirkung an Organen wie Blase, Galle, Uterus, Trachea und Ureter. Die erfindungsgemäßen Verbindungen der Formel I eignen sich somit als Antihypertensiva, als Coronartherapeutika, als Mittel zur Behandlung der Herzinsuffizienz oder auch als Gehirnprotektiva. Sie können aber auch als Spasmolytika für die obengenannten Organe Verwendung finden. Sie können dabei sowohl in der Human- als auch in der Veterinärmedizin zur Anwendung kommen.Surprisingly, the introduction of unsaturated cyclic leads Amides in the 8-position of the 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole system to new effective compounds with better tolerance. they seem lowers blood pressure and / or has a relaxing effect on organs such as Bladder, bile, uterus, trachea and ureter. The compounds of the invention of the formula I are therefore suitable as antihypertensives, as coronary therapeutic agents, as a means of treating heart failure or as Brain protective agents. But they can also be used as antispasmodics for the above Organs are used. You can do both in human as well as in veterinary medicine.

Die erfindungsgemäßen Verbindungen können in üblicher Weise oral oder parenteral (perkutan, intravenös, intramuskulär, intraperitoneal, bukkal) verabfolgt werden. Die Applikation kann auch mit Dämpfen oder Sprays durch den Nasen-Rachenraum erfolgen.The compounds according to the invention can be administered orally or in the usual way parenteral (percutaneous, intravenous, intramuscular, intraperitoneal, buccal) be administered. The application can also be carried out with vapors or sprays the nasopharynx.

Die Dosierung hängt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsart ab. In der Regel beträgt die tägliche Wirkstoffdosis zwischen etwa 0,005 und 1 mg/kg Körpergewicht bei oraler Gabe und zwischen etwa 0,0005 und 0,1 mg/kg Körpergewicht bei parenteraler Gabe. The dosage depends on the age, condition and weight of the patient as well as the type of application. As a rule, the daily dose of active ingredient is between about 0.005 and 1 mg / kg body weight with oral administration and between approximately 0.0005 and 0.1 mg / kg body weight when administered parenterally.  

Die neuen Verbindungen können in den gebräuchlichen galenischen Applikationsformen fest oder flüssig angewendet werden, z. B. als Tabletten, Filmtabletten, Kapseln, Pulver, Granulate, Dragees, Suppositorien, Lösungen, Pflaster, Salben, Cremes oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füllstoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließreguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln, Antioxidantien und/oder Treibgasen verarbeitet werden (vgl. H. Sucker et al: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978).The new compounds can be used in the usual pharmaceutical form solid or liquid applied, e.g. B. as tablets, film-coated tablets, Capsules, powders, granules, dragees, suppositories, solutions, Plasters, ointments, creams or sprays. These are done in the usual way produced. The active ingredients can use the usual galenic Auxiliaries such as tablet binders, fillers, preservatives, Tablet disintegrants, flow regulators, plasticizers, wetting agents, Dispersants, emulsifiers, solvents, retardants, Antioxidants and / or propellants are processed (see H. Sucker et al: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978).

Beispiel 1Example 1

2,18 g (10 mmol) 7,8-Dihydro-7,8-epoxy-6,6-dimethyl-6H-pyrano-[2,3-f]­ benzo-2,1,3-oxadiazol wurden in 10 ml wasserfreiem THF gelöst, und unter getrocknetem Stickstoff und bei Raumtemperatur 5,02 g (30 mmol) 2-Trimethylsilyloxypyridin zugetropft. Nach Zugabe von 3,2 g (10 mmol) Tetrabutylammoniumfluorid- Trihydrat fand Selbsterwärmung auf ca. 35°C statt. Anschließend wurde im Wasser 10 h auf 60°C erwärmt, abgekühlt und auf Eiswasser gegossen. Dann wurde mehrfach mit Methylenchlorid extrahiert, die vereinigten Extrakte zweimal mit Wasser gewaschen, über wasserfreiem Natriumsulfat getrocknet und das Lösungsmittel abgezogen. Der Rückstand wurde an Kieselgel mit Essigsäureethylester als Elutionsmittel chromatographiert. Man erhielt ein Öl, das durchkristallisierte. Nach Umkristallisation aus Isopropanol erhielt man 6,6-Dimethyl-8-(1,2-dihydro-2-oxopyrid- 1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol, Fp. 196,2 bis 197,4°C.2.18 g (10 mmol) of 7,8-dihydro-7,8-epoxy-6,6-dimethyl-6H-pyrano- [2,3-f] benzo-2,1,3-oxadiazole were dissolved in 10 ml of anhydrous THF, and under dried nitrogen and 5.02 g (30 mmol) of 2-trimethylsilyloxypyridine at room temperature dripped. After adding 3.2 g (10 mmol) of tetrabutylammonium fluoride Trihydrate self-heating took place at approx. 35 ° C. The mixture was then heated to 60 ° C. in the water for 10 h, cooled and heated up Poured ice water. Then was extracted several times with methylene chloride, the combined extracts washed twice with water, over anhydrous Dried sodium sulfate and the solvent removed. The residue was chromatographed on silica gel with ethyl acetate as the eluent. An oil was obtained which crystallized completely. After recrystallization 6,6-dimethyl-8- (1,2-dihydro-2-oxopyrid- 1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, mp 196.2 to 197.4 ° C.

Analog erhält man:
6,6-Dimethyl-8-(1,2-dihydro-4-methoxy-2-oxo-pyrid-1-yl)-6H-pyrano[2,-3-f]­ benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-4-ethoxy-2-oxo-pyrid-1-yl)-6H-pyrano[2,3--f]­ benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-4-hydroxy-2-oxo-pyrid-1-yl)-6H-pyrano[2,-3-f]­ benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-4-acetoxy-2-oxo-pyrid-1-yl)-6H-pyrano[2,-3-f]­ benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-3-methoxy-2-oxo-pyrid-1-yl)-6H-pyrano[2,-3-f]­ benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-5-chlor-2-oxo-pyrid-1-yl)-6H-pyrano[2,3--f]­ benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-5-nitro-2-oxo-pyrid-1-yl)-6H-pyrano[2,3--f]­ benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-5-amino-2-oxo-pyrid-1-yl)-6H-pyrano[2,3--f]­ benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-5-acetylamino-2-oxo-pyrid-1-yl)-6H-pyran-o[2,3-f]- benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-5-trifluormethyl-2-oxo-pyrid-1-yl)-6H-py-rano[2,3-f]- benzo-2,1,3-oxadiazol
6,6-Dimethyl-8-(1,2-dihydro-5-methyl-2-oxo-pyrid-1-yl)-6H-pyrano[2,3--f]­ benzo-2,1,3-oxadiazol.Analogously you get:
6,6-dimethyl-8- (1,2-dihydro-4-methoxy-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole
6,6-dimethyl-8- (1,2-dihydro-4-ethoxy-2-oxopyrid-1-yl) -6H-pyrano [2,3 - f] benzo-2,1,3-oxadiazole
6,6-Dimethyl-8- (1,2-dihydro-4-hydroxy-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole
6,6-dimethyl-8- (1,2-dihydro-4-acetoxy-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole
6,6-dimethyl-8- (1,2-dihydro-3-methoxy-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole
6,6-Dimethyl-8- (1,2-dihydro-5-chloro-2-oxopyrid-1-yl) -6H-pyrano [2,3 - f] benzo-2,1,3-oxadiazole
6,6-dimethyl-8- (1,2-dihydro-5-nitro-2-oxopyrid-1-yl) -6H-pyrano [2,3 - f] benzo-2,1,3-oxadiazole
6,6-Dimethyl-8- (1,2-dihydro-5-amino-2-oxopyrid-1-yl) -6H-pyrano [2,3 - f] benzo-2,1,3-oxadiazole
6,6-dimethyl-8- (1,2-dihydro-5-acetylamino-2-oxopyrid-1-yl) -6H-pyran-o [2,3-f] - benzo-2,1,3 -oxadiazole
6,6-Dimethyl-8- (1,2-dihydro-5-trifluoromethyl-2-oxopyrid-1-yl) -6H-pyroano [2,3-f] - benzo-2,1,3 -oxadiazole
6,6-dimethyl-8- (1,2-dihydro-5-methyl-2-oxopyrid-1-yl) -6H-pyrano [2,3 - f] benzo-2,1,3-oxadiazole .

Beispiel 2Example 2

2,18 g (10 mmol) 7,8-Dihydro-7,8-epoxy-6,6-dimethyl-6H-pyrano-[2,3-f]­ benzo-2,1,3-oxadiazol wurden in 10 ml wasserfreiem THF gelöst, und unter getrocknetem Stickstoff bei 0°C 3,35 g (20 mmol) 2-Trimethylsilyloxypyridin zugetropft und dann portionsweise 3,2 g (10 mmol) Tetrabutylammoniumfluorid- Trihydrat zugegeben. Man ließ auf Zimmertemperatur kommen und rührte, bis das Epoxid dünnschichtchromatographisch nicht mehr nachweisbar war. Man goß auf Eiswasser, extrahierte mehrmals mit Methylenchlorid, wusch die vereinigten Extrakte zweimal mit Wasser, trocknete über wasserfreiem Natriumsulfat und zog das Lösungsmittel ab. Der Rückstand wurde an Kieselgel mit Essigsäureethylester als Elutionsmittel chromatographiert. Man erhielt 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro- 2-oxopyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol.2.18 g (10 mmol) of 7,8-dihydro-7,8-epoxy-6,6-dimethyl-6H-pyrano- [2,3-f] benzo-2,1,3-oxadiazole were dissolved in 10 ml of anhydrous THF, and under dried nitrogen at 0 ° C 3.35 g (20 mmol) 2-trimethylsilyloxypyridine added dropwise and then in portions 3.2 g (10 mmol) of tetrabutylammonium fluoride Trihydrate added. They were allowed to come to room temperature and stirred until the epoxy was no longer detectable by thin layer chromatography was. It was poured onto ice water, extracted several times with methylene chloride, washed the combined extracts twice with water, dried over anhydrous sodium sulfate and stripped the solvent. The residue was chromatographed on silica gel with ethyl acetate as the eluent. 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro- 2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole.

Analog erhält man:
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-4-methoxy-2-oxo-py-rid-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-4-ethoxy-2-oxo-pyr-id-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-4-hydroxy-2-oxo-py-rid-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-4-acetoxy-2-oxo-py-rid-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-3-methoxy-2-oxo-py-rid-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-5-chlor-2-oxo-pyri-d-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-5-nitro-2-oxo-pyri-d-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-5-amino-2-oxo-pyri-d-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-5-acetylamino-2-ox-o- pyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-5-trifluormethyl-2--oxo- pyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-5-methyl-2-oxo- pyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol.Analogously you get:
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-4-methoxy-2-oxo-py-rid-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-4-ethoxy-2-oxo-pyr-id-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-4-hydroxy-2-oxopyrid-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-4-acetoxy-2-oxo-py-rid-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-3-methoxy-2-oxo-py-rid-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-5-chloro-2-oxopyrid-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-5-nitro-2-oxopyrid-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-5-amino-2-oxopyrid-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-5-acetylamino-2-ox-o-pyrid-1-yl) -6H-pyrano [2,3- f] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-5-trifluoromethyl-2-oxopyrid-1-yl) -6H-pyrano [2,3-f ] benzo-2,1,3-oxadiazole
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-5-methyl-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole.

Beispiel 3Example 3

2,18 g (10 mmol) 7,8-Dihydro-7,8-epoxy-6,6-dimethyl-6H-pyrano-[2,3-f]­ benzo-2,1,3-oxadiazol und 0,96 g (10 mmol) 1H-Pyrazin-2-on wurden mit 10 ml absolutem THF versetzt und unter getrocknetem Stickstoff 13,25 ml (10 mmol) mit einer 1molaren Lösung von Lithium-bis-trimethylsilylamid unter Rühren und Eiskühlung versetzt. Man rührte bis das Epoxid dünnschichtchromatographisch nicht mehr nachweisbar war und goß auf Eis. Man extrahierte mehrmals mit Essigester, wusch mit gesättigter Kochsalzlösung, trocknete über Natriumsulfat und engte bis auf einige ml ein. Der Rückstand wurde an Kieselgel mit Essigester als Elutionsmittel chromatographiert. Man erhielt 6,6-Dimethyl-8-(1,2-dihydro-2-oxopyrazin-1-yl)-6H- pyrano[2,3-f]benzo-2,1,3-oxadiazol und 7,8-Dihydro-6,6-dimethyl-7-hydroxy- 8-(1,2-dihydro-2-oxopyrazin-1-yl)-6H-pyrano[2,3-f]-benzo-2,1,3-oxadi-azol.2.18 g (10 mmol) of 7,8-dihydro-7,8-epoxy-6,6-dimethyl-6H-pyrano- [2,3-f] benzo-2,1,3-oxadiazole and 0.96 g (10 mmol) of 1H-pyrazin-2-one were mixed with 10 ml of absolute THF and 13.25 ml under dried nitrogen (10 mmol) with a 1 molar solution of lithium bis-trimethylsilylamide added with stirring and ice cooling. The mixture was stirred by thin layer chromatography was no longer detectable and poured on ice. Man extracted several times with ethyl acetate, washed with saturated saline, dried over sodium sulfate and concentrated to a few ml. The residue was chromatographed on silica gel with ethyl acetate as the eluent. 6,6-Dimethyl-8- (1,2-dihydro-2-oxopyrazin-1-yl) -6H- was obtained. pyrano [2,3-f] benzo-2,1,3-oxadiazole and 7,8-dihydro-6,6-dimethyl-7-hydroxy- 8- (1,2-dihydro-2-oxopyrazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole.

Analog erhält man:
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-pyridazin-1-yl)-6H-pyrano[2,3-f]be-nzo- 2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxopyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-5-methoxy-pyridazin-1-yl)-6H-pyran-o- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-5-methoxy-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;-
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-5-ethoxy-pyridazin-1-yl)-6H-pyrano-- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-5-ethoxy-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-5-hydroxy-pyridazin-1-yl)-6H-pyran-o- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-5-hydroxy-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;-
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-5-methyl-pyridazin-1-yl)-6H-pyrano-- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-5-methyl-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-4-methoxy-pyridazin-1-yl)-6H-pyran-o- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-4-methoxy-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;-
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-4-ethoxy-pyridazin-1-yl)-6H-pyrano-- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-4-ethoxy-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-4-hydroxy-pyridazin-1-yl)-6H-pyran-o- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-4-hydroxy-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;-
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-4-amino-pyridazin-1-yl)-6H-pyrano-- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-4-amino-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol;
6,6-Dimethyl-8-(1,2-dihydro-2-oxo-4-dimethylamino-pyridazin-1-yl)-6H--pyrano- [2,3-f]benzo-2,1,3-oxadiazol und
7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2- oxo-4-dimethylamino-pyridazin-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxad-iazol.Analogously you get:
6,6-dimethyl-8- (1,2-dihydro-2-oxopyridazin-1-yl) -6H-pyrano [2,3-f] be-nzo-2,1,3-oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxopyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1, 3-oxadiazole;
6,6-Dimethyl-8- (1,2-dihydro-2-oxo-5-methoxy-pyridazin-1-yl) -6H-pyran-o- [2,3-f] benzo-2,1,3 -oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-5-methoxy-pyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole; -
6,6-Dimethyl-8- (1,2-dihydro-2-oxo-5-ethoxypyridazin-1-yl) -6H-pyrano-- [2,3-f] benzo-2,1,3- oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-5-ethoxypyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole;
6,6-Dimethyl-8- (1,2-dihydro-2-oxo-5-hydroxy-pyridazin-1-yl) -6H-pyran-o- [2,3-f] benzo-2,1,3 -oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-5-hydroxy-pyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole; -
6,6-dimethyl-8- (1,2-dihydro-2-oxo-5-methyl-pyridazin-1-yl) -6H-pyrano-- [2,3-f] benzo-2,1,3- oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-5-methyl-pyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole;
6,6-Dimethyl-8- (1,2-dihydro-2-oxo-4-methoxy-pyridazin-1-yl) -6H-pyran-o- [2,3-f] benzo-2,1,3 -oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-4-methoxy-pyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole; -
6,6-Dimethyl-8- (1,2-dihydro-2-oxo-4-ethoxypyridazin-1-yl) -6H-pyrano-- [2,3-f] benzo-2,1,3- oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-4-ethoxypyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole;
6,6-Dimethyl-8- (1,2-dihydro-2-oxo-4-hydroxy-pyridazin-1-yl) -6H-pyran-o- [2,3-f] benzo-2,1,3 -oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-4-hydroxy-pyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole; -
6,6-Dimethyl-8- (1,2-dihydro-2-oxo-4-aminopyridazin-1-yl) -6H-pyrano-- [2,3-f] benzo-2,1,3- oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-4-aminopyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole;
6,6-dimethyl-8- (1,2-dihydro-2-oxo-4-dimethylamino-pyridazin-1-yl) -6H - pyrano- [2,3-f] benzo-2,1,3- oxadiazole and
7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-4-dimethylamino-pyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxad-iazole.

Beispiel 4Example 4

2,19 g (7 mmol) 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2-oxo- pyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol, 11,7 ml Ameisensäure und 3,3 ml Acetanhydrid ließ man 16 h bei Raumtemperatur stehen und erwärmte anschließend 2 h auf 40°C. Nach dem Einengen nahm man mit Eiswasser auf, extrahierte mit Essigester, wusch mit Kochsalzlösung, trocknete über Natriumsulfat und zog das Lösungmittel ab. Man chromatographierte den Rückstand an Kieselgel mit Essigester als Elutionsmittel. Man erhielt 7,8-Dihydro-6,6-dimethyl-7-formyloxy-8-(1,2-dihydro-2-oxo-pyrid-1-yl-)-6H- pyrano[2,3-f]benzo-2,1,3-oxadiazol.2.19 g (7 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo pyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 11.7 ml formic acid and 3.3 ml of acetic anhydride were allowed to stand at room temperature for 16 hours and heated then 2 hours at 40 ° C. After the concentration was taken with ice water on, extracted with ethyl acetate, washed with saline, dried over Sodium sulfate and stripped the solvent. The was chromatographed Residue on silica gel with ethyl acetate as the eluent. You got 7,8-dihydro-6,6-dimethyl-7-formyloxy-8- (1,2-dihydro-2-oxopyrid-1-yl -) - 6H- pyrano [2,3-f] benzo-2,1,3-oxadiazole.

Beispiel 5Example 5

295 mg (1 mmol) 6,6-Dimethyl-8-(1,2-dihydro-2-oxo-pyrid-1-yl)-6H-pyrano- [2,3-f]benzo-2,1,3-oxadiazol, 808 mg (2 mmol) Lawesson-Reagenz und 50 ml Toluol wurden bis zum Verschwinden der Ausgangsverbindung (DC-Kontrolle) unter Rückfluß gekocht und wie üblich aufgearbeitet. Man erhielt 6,6-Dimethyl- 8-(1,2-dihydro-2-thio-pyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3- oxadiazol. 295 mg (1 mmol) 6,6-dimethyl-8- (1,2-dihydro-2-oxopyrid-1-yl) -6H-pyrano- [2,3-f] benzo-2,1,3-oxadiazole, 808 mg (2 mmol) Lawesson's reagent and 50 ml Toluene were removed until the starting compound disappeared (TLC control) boiled under reflux and worked up as usual. 6,6-dimethyl 8- (1,2-dihydro-2-thio-pyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3- oxadiazole.  

Beispiel 6Example 6

2,32 g (10 mmol) 7,8-Dihydro-7,8-epoxy-6,6-diethyl-6H-pyrano[2,3-f]benzo- 2,1,3-oxadiazol wurden in 10 ml wasserfreiem THF gelöst und unter Rühren und unter getrocknetem Stickstoff bei Raumtemperatur 3,35 g (20 mmol) 2-Trimethylsilyloxypyridin zugetropft und anschließend portionsweise 3,2 g (10 mmol) Tetrabutylammoniumfluorid-trihydrat zugegeben. Man rührte bis das Epoxid dünnschichtchromatographisch nicht mehr nachweisbar war, goß auf Eiswasser, extrahierte mehrmals mit Essigester, wusch die vereinigten Extrakte mit gesättigter NaCl-Lösung, trocknete über NaSO₄ und engte bis auf wenige ml ein. Der Rückstand wurde an Kieselgel mit Essigester chromatographiert. Man erhielt 6,6-Diethyl-8-(1,2-dihydro-2-oxo-pyrid-1- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol und 7,8-Dihydro-6,6-diethyl-7- hydroxy-8-(1,2-dihydro-2-oxo-pyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-- oxadiazol.2.32 g (10 mmol) of 7,8-dihydro-7,8-epoxy-6,6-diethyl-6H-pyrano [2,3-f] benzo 2,1,3-oxadiazole were dissolved in 10 ml of anhydrous THF and with stirring and under dried nitrogen at room temperature 3.35 g (20 mmol) 2-Trimethylsilyloxypyridin added dropwise and then in portions 3.2 g (10 mmol) tetrabutylammonium fluoride trihydrate added. One stirred up the epoxy was no longer detectable by thin layer chromatography, poured on ice water, extracted several times with ethyl acetate, washed the combined Extracts with saturated NaCl solution, dried over NaSO₄ and constricted to to a few ml. The residue was on silica gel with ethyl acetate chromatographed. 6,6-Diethyl-8- (1,2-dihydro-2-oxopyrid-1- yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 7,8-dihydro-6,6-diethyl-7- hydroxy-8- (1,2-dihydro-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-- oxadiazole.

Herstellung des Ausgangsmaterials:
7,8-Dihydro-7,8-epoxy-6,6-diethyl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadi-azol erhielt man aus 6,6-Diethyl-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol mit m-Chlorperbenzoesäure in Methylenchlorid als gelbes Öl, das kristallisierte, Fp. 53,8 bis 55,1°C.
6,6-Diethyl-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol erhielt man aus 6,6-Diethyl- 6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol-3-oxid durch Reduktion mit Triethylphosphit, Fp. 62 bis 63°C.
6,6-Diethyl-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol-3-oxid erhielt man aus 2,2-Diethyl-6-amino-7-nitro-chroman durch Behandeln mit Natriumhypochloritlösung als gelbes Öl.Production of the starting material:
7,8-dihydro-7,8-epoxy-6,6-diethyl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole was obtained from 6,6-diethyl-6H -pyrano [2,3-f] benzo-2,1,3-oxadiazole with m-chloroperbenzoic acid in methylene chloride as a yellow oil, which crystallized, mp. 53.8 to 55.1 ° C.
6,6-Diethyl-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole was obtained from 6,6-diethyl-6H-pyrano [2,3-f] benzo-2,1, 3-oxadiazol-3-oxide by reduction with triethyl phosphite, mp. 62 to 63 ° C.
6,6-Diethyl-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole-3-oxide was obtained from 2,2-diethyl-6-amino-7-nitro-chroman by treatment with Sodium hypochlorite solution as a yellow oil.

Claims (24)

1. Ungesättigte N-Benzoxadiazolopyranyllactame der Formel I worin
R¹ und R² gleich oder verschieden sind und C₁-C₄-Alkyl oder zusammen C₂-C₆-Alkylen bedeuten,
R³ Hydroxy, Acyloxy oder -O-NO₂,
R⁴ Wasserstoff oder C₁-C₄-Alkyl,
R⁵ Wasserstoff oder
R³ und R⁵ zusammen eine Bindung,
X Sauerstoff oder Schwefel,
Y die Gruppe Z die Gruppe (mit R⁶, R⁷, R⁸ und R⁹, die gleich oder verschieden sind, in der Bedeutung von Wasserstoff, C₁-C₄-Alkyl, Trifluormethyl, Hydroxy, Acyloxy, C₁-C₄-Alkoxy, Halogen, Amino, C₁-C₄-Alkylamino, C₁-C₄-Dialkylamino, Nitro, Cyano, Acyl, C₂-C₃-Alkoxycarbonyl, das im Alkylrest gegebenenfalls durch Hydroxy oder C₁-C₄-Alkoxy substituiert ist, oder Arylcarbonyl, das im Arylrest gegebenenfalls durch ein oder mehrere Halogenatome, Trifluormethylreste, Acyloxy-, C₁-C₄-Alkyl oder C₁-C₄- Alkylendioxygruppen substituiert ist),
bedeuten, sowie deren Salze mit physiologisch verträglichen Säuren.1. Unsaturated N-benzoxadiazolopyranyl lactams of the formula I wherein
R¹ and R² are the same or different and are C₁-C₄-alkyl or together are C₂-C₆-alkylene,
R³ is hydroxy, acyloxy or -O-NO₂,
R⁴ is hydrogen or C₁-C₄ alkyl,
R⁵ is hydrogen or
R³ and R⁵ together form a bond,
X oxygen or sulfur,
Y the group Z the group (with R⁶, R⁷, R⁸ and R⁹, which are the same or different, in the meaning of hydrogen, C₁-C₄-alkyl, trifluoromethyl, hydroxy, acyloxy, C₁-C₄-alkoxy, halogen, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, nitro, cyano, acyl, C₂-C₃-alkoxycarbonyl, which is optionally substituted in the alkyl radical by hydroxy or C₁-C₄-alkoxy, or arylcarbonyl, which in the aryl radical is optionally substituted by one or more halogen atoms, trifluoromethyl radicals, acyloxy- , C₁-C₄-alkyl or C₁-C₄-alkylenedioxy groups is substituted),
mean, and their salts with physiologically acceptable acids. 2. Verbindung I nach Anspruch 1, dadurch gekennzeichnet, daß R¹ und R² Methyl oder Ethyl bedeuten.2. Compound I according to claim 1, characterized in that R¹ and R² Mean methyl or ethyl. 3. Verbindung I nach Anspruch 1, dadurch gekennzeichnet, daß R⁴ und R⁵ Wasserstoff und R³ Hydroxy bedeuten.3. Compound I according to claim 1, characterized in that R⁴ and R⁵ Hydrogen and R³ are hydroxy. 4. Verbindung I nach Anspruch 1, dadurch gekennzeichnet, daß R⁴ Wasserstoff bedeutet und R³ und R⁵ eine gemeinsame Bindung bilden.4. Compound I according to claim 1, characterized in that R⁴ is hydrogen means and R³ and R⁵ form a common bond. 5. Verbindung I nach Anspruch 1, dadurch gekennzeichnet, daß X Sauerstoff bedeutet.5. Compound I according to claim 1, characterized in that X is oxygen means. 6. Verbindung I nach Anspruch 1, dadurch gekennzeichnet, daß Y die Gruppe bedeuten.6. Compound I according to claim 1, characterized in that Y is the group mean. 7. Verbindung I nach Anspruch 1, dadurch gekennzeichnet, daß Y die Gruppe bedeuten.7. Compound I according to claim 1, characterized in that Y is the group mean. 8. Verbindung I nach Anspruch 1, dadurch gekennzeichnet, daß Y die Gruppe bedeuten.8. Compound I according to claim 1, characterized in that Y is the group mean. 9. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2-oxo-pyrid-1-yl)-- 6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol.9. 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxopyrid-1-yl) - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 10. 7,8-Dihydro-6,6-dimethyl-7-formyloxy-8-(1,2-dihydro-2-oxo-pyrid-1-yl-)- 6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol. 10. 7,8-dihydro-6,6-dimethyl-7-formyloxy-8- (1,2-dihydro-2-oxopyrid-1-yl -) - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole.   11. 6,6-Dimethyl-8-(1,2-dihydro-2-oxo-pyrid-1-yl)-6H-pyrano[2,3-f]benzo-- 2,1,3-oxadiazol.11. 6,6-dimethyl-8- (1,2-dihydro-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-- 2,1,3-oxadiazole. 12. 7,8-Dihydro-6,6-diethyl-7-hydroxy-8-(1,2-dihydro-2-oxo-pyrid-1-yl)- 6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol.12. 7,8-dihydro-6,6-diethyl-7-hydroxy-8- (1,2-dihydro-2-oxopyrid-1-yl) - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 13. 6,6-Diethyl-8-(1,2-dihydro-2-oxo-pyrid-1-yl)-6H-pyrano[2,3-f]benzo- 2,1,3-oxadiazol.13. 6,6-diethyl-8- (1,2-dihydro-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo 2,1,3-oxadiazole. 14. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-4-methoxy-2-oxo- pyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol.14. 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-4-methoxy-2-oxo pyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 15. 6,6-Dimethyl-8-(1,2-dihydro-4-methoxy-2-oxo-pyrid-1-yl)-6H-pyrano [2,3-f]benzo-2,1,3-oxadiazol.15. 6,6-Dimethyl-8- (1,2-dihydro-4-methoxy-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 16. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-4-ethoxy-2-oxo- pyrid-1-yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol.16. 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-4-ethoxy-2-oxo pyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 17. 6,6-Dimethyl-8-(1,2-dihydro-4-ethoxy-2-oxo-pyrid-1-yl)-6H-pyrano [2,3-f]benzo-2,1,3-oxadiazol.17. 6,6-Dimethyl-8- (1,2-dihydro-4-ethoxy-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 18. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2-oxo-pyridazin-1-- yl)-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol.18. 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxopyridazin-1-- yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 19. 6,6-Dimethyl-8-(1,2-dihydro-2-oxo-pyridazin-1-yl)-6H-pyrano[2,3-f] benzo-2,1,3-oxadiazol.19. 6,6-dimethyl-8- (1,2-dihydro-2-oxopyridazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 20. 7,8-Dihydro-6,6-dimethyl-7-hydroxy-8-(1,2-dihydro-2-oxo-pyrazin-1-yl-)- 6H-pyrano[2,3-f]benzo-2,1,3-oxadiazol.20. 7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-2-oxo-pyrazin-1-yl -) - 6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole. 21. 6,6-Dimethyl-8-(1,2-dihydro-2-oxo-pyrazin-1-yl)-6H-pyrano[2,3-f]benz-o- 2,1,3-oxadiazol.21. 6,6-Dimethyl-8- (1,2-dihydro-2-oxopyrazin-1-yl) -6H-pyrano [2,3-f] benz-o- 2,1,3-oxadiazole. 22. Verfahren zur Herstellung von ungesättigten N-Benzoxadiazolopyranyllactamen der Formel I gemäß Anspruch 1, dadurch gekennzeichnet, daß man
  • a) Verbindungen der Formel II in den R¹, R² und R⁴ die oben angegebene Bedeutung haben, entweder mit N-Silyllactamen der Formel III in denen X Sauerstoff bedeutet und Y und Z wie oben definiert sind, oder mit O-Silyllactamen der Formel IV in denen X Sauerstoff bedeutet und Y und Z wie oben definiert sind umsetzt, oder
  • b) Verbindungen der Formel V in denen alle Reste wie in Formel I definiert sind, mit einem Phosphorigsäuretriester, einem Alkalimetallazid oder Hydroxylamin umsetzt oder
  • c) - falls Verbindungen der Formel I, in denen X Schwefel bedeutet und die übrigen Reste die oben angegebene Bedeutung haben, hergestellt werden - Verbindungen der Formel I, in denen X Sauerstoff bedeutet, mit Lawessen Reagenz umsetzt,
22. A process for the preparation of unsaturated N-benzoxadiazolopyranyllactams of the formula I according to claim 1, characterized in that
  • a) Compounds of formula II in the R¹, R² and R⁴ have the meaning given above, either with N-silyl lactams of the formula III in which X is oxygen and Y and Z are as defined above, or with O-silyl lactams of the formula IV in which X is oxygen and Y and Z are as defined above, or
  • b) compounds of formula V in which all radicals are as defined in formula I, reacted with a phosphorous triester, an alkali metal azide or hydroxylamine or
  • c) if compounds of the formula I in which X is sulfur and the other radicals have the meaning given above are prepared, compounds of the formula I in which X is oxygen are reacted with Lawessen's reagent,
und die so erhaltenen Verbindungen gegebenenfalls in ihre Salze mit physiologisch verträglichen Säuren überführt.and optionally the compounds thus obtained in their salts transferred physiologically acceptable acids. 23. Arzneimittel, enthaltend eine Verbindung gemäß Anspruch 1.23. Medicament containing a compound according to claim 1.
DE4010097A 1990-03-29 1990-03-29 UNSATURATED N-BENZOXODIAZOLOPYRANYLLACTAME, THEIR PRODUCTION AND USE Withdrawn DE4010097A1 (en)

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PCT/EP1991/000537 WO1991014690A1 (en) 1990-03-29 1991-03-20 Unsaturated n-benzoxodiazopyranyl lactams, their production and use
HU9230V HU9203092D0 (en) 1990-03-29 1991-03-20 Method for producing n-benzoxa-diazolo-pyranyl-lactames and pharmaceutical preparatives containing them
CA002078139A CA2078139A1 (en) 1990-03-29 1991-03-20 Unsaturated n-benzoxadiazolopyranyllactams, the preparation and use thereof
JP91506303A JPH05505801A (en) 1990-03-29 1991-03-20 Unsaturated N-benzoxadiazolopyranyl lactam, its production and use
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EP0693283A4 (en) * 1993-04-02 1997-07-23 Nissan Chemical Ind Ltd Heart failure remedy

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US5164509A (en) * 1990-11-26 1992-11-17 E. R. Squibb & Sons, Inc. Benzodiazolo analogs
IL118090A0 (en) * 1995-05-01 1996-08-04 Nissan Chemical Ind Ltd Benzopyran derivatives

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EP0033612B1 (en) * 1980-02-02 1984-04-11 Beecham Group Plc Pyrano derivatives, a process for their preparation and antihypertensive compositions containing them
DE3726261A1 (en) * 1986-12-23 1988-07-07 Merck Patent Gmbh CHROME DERIVATIVES
JPH0699439B2 (en) * 1988-02-03 1994-12-07 日産化学工業株式会社 Pyranobenzoxadiazole derivative

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EP0693283A4 (en) * 1993-04-02 1997-07-23 Nissan Chemical Ind Ltd Heart failure remedy
US5919806A (en) * 1993-04-02 1999-07-06 Nissan Chemical Industries, Ltd. Medicines for cardiac insufficiency

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