WO1991014690A1 - Unsaturated n-benzoxodiazopyranyl lactams, their production and use - Google Patents

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

Unsaturated N-benzoxadiazolopyranyllactams, their preparation and

use

description

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.

It has now been found that unsaturated N-benzoxadiazolopyranyllactams of the formula I

I,

wherein

R ¹ and R ^{2 are the} same or different and C ₁ -C ₄ alkyl or

together represent C ₂ -C ₆ alkylene,

R ^{3 is} hydroxy, acyloxy or -O-NO ₂ ,

R ^{4 is} hydrogen or C ₁ -C ₄ alkyl,

R ^{5 is} hydrogen or

R ³ and R ⁵ together form a bond,

X oxygen or sulfur l,

Y the group

(mit R⁶, R⁷, R⁸, R⁹ und R^10, die gleich oder verschieden sind, in der Bedeutung von Wasserstoff, C₁-C₄-Alkyl, Z the group

(with R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ^10, which are the same or different, in the meaning of hydrogen, C ₁ -C ₄ alkyl,

Trifluoromethyl, hydroxy, acyloxy, C ₁ -C ₄ alkoxy, halogen, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, nitro, cyano, acyl, C ₂ -C ₃ alkylcarbonyl, which in the Alkyl radical optionally substituted by hydroxy or C ₁ -C ₄ alkoxy, or arylcarbonyl, which in the aryl radical optionally by one or more halogen atoms, trifluoromethyl radicals, acyloxy,

C ₁ -C ₄ alkyl or C ₁ -C ₄ alkylenedioxy groups), and their salts with physiologically compatible acids 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

Generate carbon atom, then 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.

Compounds of the formula I are particularly preferred in which 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. Also particularly preferred are 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.

Also particularly preferred are compounds of formula I in which R ¹ and R ^{2 are} methyl, R ⁴ and R ^{5 are} hydrogen, R ^{3 is} hydroxy, X is oxygen, Y is Group -CR ⁶ = CR ⁷ - and Z is the grouping -CR ⁸ = CR ⁹ -, where 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 rest are hydrogen. Compounds of the formula I are very particularly preferred in which R ¹ and R ^{2 are} methyl, R ^{4 is} hydrogen, R ³ and R ^{5 are} together a bond, X is oxygen, Y is the group -CR ⁶ = CR ⁷ - or -NR ⁹ -CO - and Z the group -CR ⁸ = CR ⁹ -,

-N = CR ⁷ -or -NR ¹⁰ -CO-, where 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 are particularly worth mentioning as individual connections:

6,6-Dimethyl-8- (1,2-dihydro-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo

2, 1, 3-oxadi azole,

6,6-diethyl-8- (1,2-di hydro-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-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-pyrano [2,3-f] benzo-2,1,3- oxadiazole,

 6,6-dimethyl-8- (1,2-dihydro-2-oxopyrazin-1-yl) -6H-pyrano [2,3-f] - benzo-2,1,3-oxadiazole,

 6,6-dimethyl-8- (1,2,5,6-tetrahydro-2,5-dioxo-6-methyl-pyridazin-1-yl) -

6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and

7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2,5,6-tetrahydro-2,5-dioxo-6-methyl-pyridazin-1-yl) -6H-pyrano [ 2,3-f] benzo-2,1,3-oxadiazole.

If the compounds form salts, 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

in which R ¹ , R ² and R ^{4 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 the formula V

in which all of the 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 are as defined above - compounds of Formula I, in which X is oxygen, is reacted with Lawesson reagent, and optionally converting the compounds thus obtained into their salts with physiologically acceptable acids.

When carrying out process a), 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. 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.

Compounds of the formula I in which R ³ and R ^{5 represent} a bond can best be prepared from the corresponding hydroxy compounds (R ³ = OH, R ⁵ = H) by elimination of water. Compounds of the formula II or VI are known from EP 327 127, silyl compounds of the formula III and IV can easily be prepared from the corresponding lactams by methods known from the literature, for example by heating with hexamethyldisilazane or in situ, for example with

Lithium bis-trimethylsilyl amide.

When carrying out process b), the compounds of

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. When carrying out process c), a lactam of the formula I (X = O) with Lawesson's reagent (2,4-bis- (4-methoxyphenyl) -2,4-dithioxo-1,3,2,4-dithiophosphetane) is in a non-polar solvent, preferably toluene, preferably heated to the reflux temperature of the solvent used. Enantiomerically pure end products of the formula I (for R ³ = hydroxy) can be obtained from the racemates by customary cleavage methods such as, for example, chromatographic separation using chiral phases or by esterification of the 7-hydroxy groups of oxadiazolochromane with optically active acid derivatives or by carbamate formation with optically active isocyanates become. 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

3-menthoxyacetates. Surprisingly, the introduction of unsaturated cyclic amides in the 8-position of the 6H-pyrano [2,3-f] -benzo-2,1,3-oxadiazole system leads to new active compounds with better tolerability. They lower blood pressure and / or have a relaxing effect on organs such as the bladder, bile, uterus, trachea and ureter. The pharmacological test for activation of K ⁺ channels was carried out with the aid of the following test methods: a) in vitro: The aortic strips of the rat were examined by a fine

graded K ⁺ dose-response curve (DWK) induced contraction measured. After incubation with the test substance in test concentration, it was examined whether the right shift of the lower area of the K ⁺ -DWK, which is characteristic of K ⁺ channel activators (eg Cromakalim), occurred. The percentage difference in the contractile effect of 22 mmol / l K ⁺ before and 35 min after substance administration was evaluated:

b) in vivo: On normotonic, anesthetized rats after intravenous and on awake, spontaneously hypertensive rats (SHR) after oral administration, the test was carried out for influencing blood pressure (PB) and heart rate (HR):

Cromakalim ist (±)-trans-3,4-Dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1- pyrrolidinyl)-2H-1-benzopyran-6-carbonitril, vgl. Drugs of the Future 11, 175 (1986). Die erfindungsgemäßen Verbindungen der Formel I eignen sich somit als Antihypertensi va, als Coronartherapeutika, als Mittel zur Behandlung der Herzinsuffizienz oder auch als Gehirnprotektiva. Sie können als Antiasthmatika oder als Mittel gegen Glaukom 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.

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. As a rule, 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. The mixture was then extracted several times with methylene chloride, the combined extracts were washed twice with water, dried over anhydrous sodium sulfate and the solvent was stripped off. The residue was chromatographed on silica gel with ethyl acetate as the eluent. An oil was obtained which crystallized completely. After recrystallization from isopropanol, 6,6-dimethyl-8- (1,2-dihydro-2-oxopyrid-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole was obtained, Mp 196.2 to 197.4 ° C.

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 , Mp 101-103 ° C;

 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-pyrano- [2,3-f] benzo-2,3,1-oxadi azole;

 6,6-dimethyl-8- (1,2-dihydro-5-trifluoromethyl-2-oxopyrid-1-yl) -6H-pyrano-

[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 ;

6,6-dimethyl-8- (1,2-dihydro-2-oxopyridazin-1-yl) -6H-pyrano [2,3-f] benzo

2,1,3-oxadiazole, mp 131-132 ° C, 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,

Mp 218-220 ° C;

 6,6-dimethyl-8- (1,2-dihydro-2-oxo-5-methoxy-pyridazin-1-yl) -6H-pyrano- [2,3-f] benzo-2,1,3-oxadiazole , Mp 192-194 ° C, and 7,8-dihydro-6,6-dimethyl-

7-hydroxy-8- (1,2-dihydro-2-oxo-5-methoxypyridazin-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, mp 135-137 ° C, and 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-oxadiazole, mp 173-175 ° C;

 6,6-dimethyl-8- (1,2-dihydro-2-oxo-5-hydroxy-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-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 , Mp 143-145 ° C 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-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-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-pyrano- [22,3-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-pyranot2,3-f] benzo-2,1,3-oxadiazole;

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. It was poured onto ice water, extracted several times with methylene chloride, the combined extracts were washed twice with water, dried over anhydrous sodium sulfate and the solvent was stripped off. The residue was chromatographed on silica gel with a mixture of toluene and ethyl acetate (1: 1) as the eluent. There was obtained 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, mp 196-199 ° C. Analogously you get:

7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2-dihydro-4-methoxy-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-ethoxy-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-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-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-3-methoxy-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-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-oxadi azole;

 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-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-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.

Example 3

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 (10 mmol) of a 1-molar solution of lithium-bis-trimethylsilylamide were added under dried nitrogen while stirring and cooling with ice. The mixture was stirred until the epoxide was no longer detectable by thin layer chromatography and poured onto ice. It was extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to a few ml. The residue was chromatographed on silica gel with ethyl acetate as the eluent. This gave a) 6,6-dimethyl-8- (1,2-dihydro-2-oxopyrazin-1-yl) -6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, Mp 230-232 ° C, and b) 7,8-dihydro-6,6-dimethy1-7-hydroxy-8- (1,2-dihydro-2-oxopyrazin-1-yl) -6H-pyrano [2,3-f] - benzo-2,1,3-oxadiazole. Example 4

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 added in 50 ml of anhydrous THF dissolved, 5.95 g (30 mmol) of 5,6-dihydro-6-methyl-5-oxo-2-trimethylsilyloxypyridazine added under dried nitrogen at room temperature and 12.2 ml of a 1 molar solution of tetrabutylammonium fluoride in THF (corresponding

3.2 g = 10 mmol) was added dropwise. The mixture was then heated under reflux for 20 h, then a further 6.1 ml (5 mmol) of tetrabutylammonium fluoride (1 molar solution in THF) were added and the mixture was heated under reflux for a further 8 h until all the epoxide had reacted. The solvent was removed on a rotary evaporator, the residue was mixed with methylene chloride and ice water and the organic phase was washed three times with water. After drying over anhydrous sodium sulfate, the solvent was drawn off, the solid

Residue taken up in a little ethyl acetate and in the same

Chromatograph solvent as eluent on silica gel. In addition to a little [6,6-dimethyl-8- (1,2,5,6-tetrahydro-2,5-dioxo-6-methyl-pyri dazi ny l) -6H-pyrano [2, 3-f] benzo-2, 1, 3-oxadi azole], mp. 173-175 ° C

(Compound a) was obtained as the main product [7,8-dihydro-6,6-dimethyl-7-hydroxy-8- (1,2,5,6-tetrahydro-2,5-dioxo-6-methyl-pyridazin-1 -yl) - 6H-pyrano- [2,3-f] benzo-2,1,3-oxadiazole], mp. 215-218 ° C (compound b).

Example 5

295 mg (1 mmol) 6,6-dimethyl-8- (1,2-dihydro-2-oxopyrid-l-yl) -6H-pyrano- [2,3-f] benzo-2,1,3 -oxadiazole, 808 mg (2 mmol) Lawesson's reagent and 50 ml toluene were boiled under reflux until the starting compound had disappeared (TLC control) 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 was obtained.

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. The mixture was stirred until the epoxide was no longer detectable by thin layer chromatography, poured onto ice water, extracted several times with ethyl acetate, the combined extracts were washed with saturated NaCl solution, dried over NaSO ₄ and concentrated 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, mp. 133, 8-135, 8 ° C.

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. 53.8-55, 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-oxadiazole-3-oxide by reduction with triethyl phosphite, mp. 62-63 ° C.

 6,6-Dϊethyl-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazol-3-oxide was obtained from 2,2-diethyl-6-amino-7-nitro-chroman by treatment with Sodium hypochlorite solution as a yellow oil.

Claims

Claims 1. Unsaturated N-benzoxadiazolopyranyl lactams of the formula I I,

 wherein R ¹ and R ^{2 are the} same or different and C ₁ -C ₄ alkyl or together represent C ₂ -C ₆ alkylene, R ^{3 is} hydroxy, acyloxy or -O-NO ₂ , R ^{4 is} hydrogen or C ₁ -C ₄ alkyl, R ^{5 is} hydrogen or R ³ and R ⁵ together form a bond,  X oxygen or sulfur,  Y the group -

(with R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , the same as or are different in the meaning of hydrogen, C ₁ -C ₄ alkyl, trifluoromethyl, hydroxy, acyloxy, C ₁ -C ₄ alkoxy, halogen, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, nitro, cyano, acyl, C ₂ -C ₃ alkylcarbonyl, which is optionally substituted in the alkyl radical by hydroxy or C ₁ -C ₄ alkoxy, or arylcarbonyl, which is optionally substituted in the aryl radical or more halogen atoms, Trifluormethylreste, acyloxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ - alkylenedioxy groups), and optionally their salts with physiological  compatible acids. 2. Compound I according to claim 1, characterized in that R ¹ and R ^{2 are} methyl or ethyl, R ^{4 is} hydrogen, R ³ and R ^{5 are} a common bond and X is oxygen. 3. Compound I according to claim 1, characterized in that Y is the group and Z is the group or Y is the group

 or and Z the group

 or Y the group and Z the group

 mean. 4. A process for the preparation of unsaturated N-benzoxadiazolopyranyl lactams of the formula I according to claim 1, characterized in that a) compounds of the formula II (11),

in which R ¹ , R ² and R ^{4 have} the meaning given above, either with N-silyl lactams of the formula III (III),

in which X is oxygen and Y and Z are defined as 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 the formula V

 in which all of the 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 are as defined above - compounds of Formula I, in which X is oxygen, is reacted with Lawessen's reagent, and the compounds thus obtained are optionally converted into their salts with physiologically acceptable acids. 5. Compounds of formula I according to claim 1 for use in combating diseases.