WO1991014690A1 - Lactames de n-benzoxodiazolopyranyl insatures, leur fabrication et utilisation - Google Patents

Lactames de n-benzoxodiazolopyranyl insatures, leur fabrication et utilisation Download PDF

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Publication number
WO1991014690A1
WO1991014690A1 PCT/EP1991/000537 EP9100537W WO9114690A1 WO 1991014690 A1 WO1991014690 A1 WO 1991014690A1 EP 9100537 W EP9100537 W EP 9100537W WO 9114690 A1 WO9114690 A1 WO 9114690A1
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WO
WIPO (PCT)
Prior art keywords
formula
dihydro
compounds
benzo
pyrano
Prior art date
Application number
PCT/EP1991/000537
Other languages
German (de)
English (en)
Inventor
Hans-Joachim May
Manfred Raschack
Sabine Schult
Original Assignee
Basf Aktiengesellschaft
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 Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to JP91506303A priority Critical patent/JPH05505801A/ja
Publication of WO1991014690A1 publication Critical patent/WO1991014690A1/fr

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Classifications

    • 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

Definitions

  • the present invention relates to new unsaturated N-benzoxadiazolylpyranyllactams, their preparation and their use for combating diseases.
  • Unsaturated lactams are already known, cf. EP 273 262, EP 340 718, EP 308 792 and J. Med. Chem., 33, 492 (1990). The production of such lactams is also described in EP 337 179.
  • R 1 and R 2 are the same or different and C 1 -C 4 alkyl or
  • R 3 is hydroxy, acyloxy or -O-NO 2 ,
  • R 4 is hydrogen or C 1 -C 4 alkyl
  • R 5 is hydrogen or
  • C 1 -C 4 alkyl or C 1 -C 4 alkylenedioxy groups have valuable pharmacological properties. If the C atoms 7 and 8 of the 6H-pyrano [2,3-f] -benzo-2,1,3-oxadiazole system are asymmetrically substituted, preference is given to those compounds which have opposite configurations at these centers, that is to say a "trans orientation" of the substituents on these carbon atoms. If the substituents R 1 and R 2 are not the same and are therefore asymmetrical
  • the invention includes both compounds with S and R configuration.
  • the compounds can exist as diastereomers, as racemates or as mixtures thereof.
  • the optically active enantiomers can be prepared from a diastereomer or racemate by conventional methods of racemate resolution.
  • Preferred compounds of the formula I are those in which R 1 and R 2 are methyl or ethyl and R 4 is hydrogen and R 3 , R 5 , X, Y and Z are as defined above. Also preferred are compounds in which R 1 and R 2 are methyl or ethyl, R 4 is hydrogen and R 3 and R 5 together are a bond and X, Y and Z are as defined above.
  • R 1 and R 2 are methyl
  • R 4 is hydrogen and X is oxygen and R 3 , R 5 , Y and Z are as defined above.
  • compounds of formula I in which R 1 and R 2 are methyl, R 4 is hydrogen, R 3 and R 5 are together a bond and X is oxygen and Y and Z are as defined above.
  • R 6 to R 9 are hydrogen or one of the radicals R 6 to R 9 is C 1 -C 4 alkoxy and the remaining hydrogen.
  • the following may be considered as physiologically acceptable acids: 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.
  • the compounds of formula I can be prepared by a) Compounds of formula II
  • the compounds of the formula II and the compounds of the formula III or IV are dissolved in a dipolar, aprotic solvent, preferably THF, in the presence of a desilylating agent.
  • a dipolar, aprotic solvent preferably THF
  • the reaction can also be carried out in an excess of the usually liquid silyl compounds without a solvent.
  • the reaction temperature can vary between room temperature and approx. 120 ° C.
  • Lithium bis-trimethylsilyl amide Lithium bis-trimethylsilyl amide.
  • Formula I obtained by reducing the N-oxide of the compounds of the formula V by dissolving them in a polar solvent of, for example, ethanol or ethylene glycol and in the presence of an alkali metal azide, preferably sodium azide, or a phosphoric acid ester, preferably triethyl phosphite or hydroxylamine in the presence of an alkali metal hydroxide, such as NaOH, preferably heated to the reflux temperature of the solvent used.
  • a polar solvent of, for example, ethanol or ethylene glycol and in the presence of an alkali metal azide, preferably sodium azide, or a phosphoric acid ester, preferably triethyl phosphite or hydroxylamine
  • an alkali metal hydroxide such as NaOH
  • the diastereomeric esters or carbamates obtained in this way can be separated by conventional methods of crystallization or chromatography and converted into the optically uniform end compounds by splitting off the optically active auxiliary groups on the 7-hydroxy group. The separation of the diastereoisomers is particularly advantageous here
  • Cromakalim is ( ⁇ ) -trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4- (2-oxo-1-pyrrolidinyl) -2H-1-benzopyran-6-carbonitrile, cf. Drugs of the Future 11, 175 (1986).
  • the compounds of the formula I according to the invention are therefore suitable as antihypertensives, in particular as coronary therapeutics, as agents for the treatment of heart failure or as brain protective agents. They can be used as anti-asthmatics or as agents against glaucoma, but also as spasmolytics for the above-mentioned organs. They can be used in both human and veterinary medicine.
  • the compounds according to the invention can be administered in the usual way orally or parenterally (percutaneously, intravenously, intramuscularly, intraperitoneally, buccally). It can also be applied with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active ingredient is between approximately 0.005 and 1 mg / kg body weight when administered orally and between approximately 0.0005 and 0.1 mg / kg body weight when administered parenterally.
  • the new compounds can be used in the customary pharmaceutical application forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, plasters, ointments, creams or sprays. These are manufactured in the usual way.
  • the active ingredients can be processed with the usual galenic auxiliary agents such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et al: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978).
  • Example 1 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 dissolved in 10 ml of anhydrous THF, and 5.02 g (30 mmol) of 2-trimethylsilyloxypyridine were added dropwise under dried nitrogen and at room temperature. After adding 3.2 g (10 mmol) of tetrabutylammonium fluoride trihydrate, self-heating to approx. 35 ° C. took place. The mixture was then heated to 60 ° C. in a water bath for 10 h, cooled and poured onto ice water.
  • Example 2 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 dissolved in 30 ml of anhydrous THF, and 5.97 g (30 mmol) of 2-trimethylsilyloxy-5-methoxy-pyridazine were added dropwise under dried nitrogen at 0 ° C. Then 3.2 g (10 mmol) of tetrabutylammonium fluoride trihydrate were added in portions. The mixture was allowed to come to room temperature and stirred until the epoxide could no longer be detected by thin layer chromatography.
  • Example 6 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 obtained in 10 ml of anhydrous THF was dissolved and 3.35 g (20 mmol) of 2-trimethylsilyloxypyridine were added dropwise with stirring and under dried nitrogen at room temperature, and 3.2 g (10 mmol) of tetrabutylammonium umfluoride tri hydrate were then added in portions.
  • 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-3-oxide by reduction with triethyl phosphite, mp. 62-63 ° C.

Landscapes

  • Health & Medical Sciences (AREA)
  • 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)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

On décrit des composés de formule (I), où R1 à R5, X, Y et Z possèdent la signification indiquée, ainsi que leur fabrication. Ces composés conviennent au traitement de maladies.
PCT/EP1991/000537 1990-03-29 1991-03-20 Lactames de n-benzoxodiazolopyranyl insatures, leur fabrication et utilisation WO1991014690A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP91506303A JPH05505801A (ja) 1990-03-29 1991-03-20 不飽和ｎ―ベンズオキサジアゾロピラニルラクタム、その製造及び使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4010097.9 1990-03-29
DE4010097A DE4010097A1 (de) 1990-03-29 1990-03-29 Ungesaettigte n-benzoxodiazolopyranyllactame, ihre herstellung und verwendung

Publications (1)

Publication Number Publication Date
WO1991014690A1 true WO1991014690A1 (fr) 1991-10-03

Family

ID=6403333

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/000537 WO1991014690A1 (fr) 1990-03-29 1991-03-20 Lactames de n-benzoxodiazolopyranyl insatures, leur fabrication et utilisation

Country Status (6)

Country Link
EP (1) EP0521936A1 (fr)
JP (1) JPH05505801A (fr)
CA (1) CA2078139A1 (fr)
DE (1) DE4010097A1 (fr)
HU (1) HU9203092D0 (fr)
WO (1) WO1991014690A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0488107A2 (fr) * 1990-11-26 1992-06-03 E.R. SQUIBB & SONS, INC. Analogues tricycliques de benzodiazole et leur utilisation dans le traitement des troubles cardiovasculaires
WO1996034871A1 (fr) * 1995-05-01 1996-11-07 Nissan Chemical Industries, Ltd. Derives de benzopyrane

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU677643B2 (en) * 1993-04-02 1997-05-01 Nissan Chemical Industries Ltd. Heart failure remedy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0033612A1 (fr) * 1980-02-02 1981-08-12 Beecham Group Plc Dérivés pyraniques, procédé pour leur préparation et compositions antihypertensives les contenant
EP0273262A2 (fr) * 1986-12-23 1988-07-06 MERCK PATENT GmbH Dérivés de chromane
EP0327127A1 (fr) * 1988-02-03 1989-08-09 Nissan Chemical Industries Ltd. Dérivés de pyranobenzoxadiazole, préparation, application et compositions les contenant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0033612A1 (fr) * 1980-02-02 1981-08-12 Beecham Group Plc Dérivés pyraniques, procédé pour leur préparation et compositions antihypertensives les contenant
EP0273262A2 (fr) * 1986-12-23 1988-07-06 MERCK PATENT GmbH Dérivés de chromane
EP0327127A1 (fr) * 1988-02-03 1989-08-09 Nissan Chemical Industries Ltd. Dérivés de pyranobenzoxadiazole, préparation, application et compositions les contenant

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0488107A2 (fr) * 1990-11-26 1992-06-03 E.R. SQUIBB & SONS, INC. Analogues tricycliques de benzodiazole et leur utilisation dans le traitement des troubles cardiovasculaires
EP0488107A3 (en) * 1990-11-26 1992-07-01 E.R. Squibb & Sons, Inc. Tricyclic benzodiazole analogs and their use in the treatment of cardiovascular disorders
US5164509A (en) * 1990-11-26 1992-11-17 E. R. Squibb & Sons, Inc. Benzodiazolo analogs
WO1996034871A1 (fr) * 1995-05-01 1996-11-07 Nissan Chemical Industries, Ltd. Derives de benzopyrane

Also Published As

Publication number Publication date
CA2078139A1 (fr) 1991-09-30
EP0521936A1 (fr) 1993-01-13
DE4010097A1 (de) 1991-10-02
JPH05505801A (ja) 1993-08-26
HU9203092D0 (en) 1992-12-28

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