DE3528601A1 - Hydropyrans, process for preparation and use thereof - Google Patents

Abstract

The invention relates to novel hydropyrans of the general formula (I) <IMAGE> having the substituent definitions characterized in more detail in the description, a process for their preparation and their use in medicaments, and also as intermediates for the preparation of pharmaceutical active compounds.

Description

The invention affects new hydropyrans, processes too their manufacture and their use in pharmaceuticals, as well as intermediates for the production of pharmaceutical Active ingredients.

The new substances are characterized by the general formula (I) in which
R ¹ - for aryl (C ₆ -C ₁₂ ) or for a heterocycle from the series thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzoxidazolyl , Benzothiazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, thionaphthenyl, chromenyl, thiochromenyl, benzoxadiazolyl, benzothiadiazolyl, where the aryl radical and the heterocycles optionally 1 to 3 identical or different substituents from the group C ₁ -C ₈ alkyl, C _{1 8} alkoxy, C ₁ -C ₈ alkylthio, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₈ monofluoroalkoxy, C ₁ -C ₈ polyfluoroalkoxy, hydroxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ -dialkylamino, carboxy, C ₁ -C ₆ -alkoxycarbonyl, phenyl, benzyl, benzyloxy or benzylthio, or
represents straight-chain, branched or cyclic C ₁ -C ₈ -alkyl which is optionally substituted by thienyl, furyl, pyridyl or pyrimidyl,
R ² - for hydrogen, nitro, cyano, C ₁ -C ₈ alkylsulfonyl or for the group stands
in which
R ⁶ - represents straight-chain, branched or cyclic C ₁ -C ₈ alkyl, or
- represents a group of formula -OR ⁷ , wherein
R ^{7 represents} straight-chain, branched or cyclic C ₁ -C ₁₀ alkyl, which may be replaced by one or
two oxygen and / or sulfur atoms in the chain is interrupted, and which is optionally substituted by one or more halogen, hydroxy, cyano, nitro, phenyl, pyridyl, or by an amino group, this amino group being one or two, identical or different can be substituted by C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl or C ₇ -C ₁₄ aralkyl
R ³ - for C ₆ -C ₁₂ aryl or
- stands for straight-chain or branched C ₁ -C ₈ alkyl which is optionally substituted by hydroxy, halogen or C ₂ -C ₇ acyloxy
R ⁴ , R ⁵ - are the same or different and
- stand for straight-chain or branched C ₁ -C ₈ alkyl
or
R ⁴ , R ⁵ - together represent a methylene chain with up to 20 carbon atoms,
X - for the group C = O or
- stands for a direct bond,
and
Y - for a direct bond,
- for oxygen, sulfur, NH, N-alkyl (C ₁ -C ₆ ),
or
represents a methylene chain with up to 4 carbon atoms,
in the form of their isomers, isomer mixtures, racemates, optical antipodes and their physiologically acceptable salts.

Of particular interest are compounds of the general formula (I) in which
R ^{1 represents} phenyl or thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, thiochromenyl, benzoxadiazolyl, phenyl and the heterocycles optionally having 1 to 2 of the same or different substituents C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, fluorine chlorine, bromine, nitro, cyano, trifluoromethyl, C ₁ -C ₄ monofluoroalkoxy, C ₁ -C ₄ polyfluoroalkoxy , Hydroxy, amino, C ₁ -C ₃ alkylamino, C ₁ -C ₃ dialkylamino, carboxy, C ₁ -C ₄ alkoxycarbonyl, phenyl, benzyl, benzyloxy or benzylthio, or
represents straight-chain, branched or cyclic C ₁ -C ₆ -alkyl optionally substituted by pyridyl or pyrimidyl,
R ² - for hydrogen, nitro or cyano - for C ₁ -C ₆ alkylsulfonyl or - for the group stands,
in which
R ⁶ - represents straight-chain, branched or cyclic C ₁ -C ₆ -alkyl, or - represents a group of the formula -OR ⁷ ,
in which
R ⁷ - straight-chain, branched or cyclic C ₁ -C ₈ alkyl, which is optionally interrupted by one or two oxygen atoms in the chain and which is optionally substituted by one or more fluorine, chlorine, bromine, hydroxy, cyano, nitro, phenyl , Pyridiyl or by an amino group, this amino group optionally being mono- or disubstituted identically or differently by C ₁ -C ₄ alkyl, phenyl or benzyl.
R ³ - for phenyl or
stands for straight-chain or branched C ₁ -C ₆ -alkyl which is optionally substituted by hydroxy, one or more fluorine, chlorine, bromine or C ₂ -C ₅ -acyloxy,
R ⁴ , R ⁵ - are the same or different and stand for straight-chain or branched C ₁ -C ₆ alkyl,
or
R ⁴ and R ⁵ together represent a methylene chain with up to 16 carbon atoms,
X - for the group ⁻C = O or
- stands for a direct bond,
and
Y - for a direct bond,
represents oxygen, sulfur, NH, N-alkyl, (C ₁ -C ₄ ),
or
- stands for a methylene chain with up to 2 carbon atoms in the form of its isomers, isomer mixtures, racemates, optical antipodes and their physiologically acceptable salts.

Compounds of the general formula (I) in which
R ¹ - represents phenyl, thienyl, furyl, pyridyl, pyrimidyl, benzoxadiazolyl or thiochromenyl, the radicals mentioned optionally having 1 to 2 identical or different substituents from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio, fluorine, chlorine, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, phenyl, benzyl, benzyloxy or benzylthio,
R ² - for hydrogen, nitro or cyano, - for C ₁ -C ₄ alkylsulfonyl or - for the group stands,
in which
R ⁶ - represents straight-chain or branched C ₁ -C ₄ alkyl, or
- represents a group of the formula -OR ⁷ ,
in which
R ^{7 represents} straight-chain, branched or cyclic C ₁ -C ₆ alkyl which is optionally interrupted by an oxygen atom in the chain and which is optionally substituted by one or more fluorine, hydroxyl, cyano, phenyl or benzylmethylamino,
R ³ - for phenyl or
represents straight-chain or branched C ₁ -C ₄ -alkyl which is optionally substituted by hydroxy, chlorine, bromine or acetyloxy,
R ⁴ , R ⁵ - are the same or different and
stand for straight-chain or branched C ₁ -C ₄ -alkyl,
or
R ⁴ and R ⁵ together represent a methylene chain with up to 12 carbon atoms
X - for the group ⁻C = O or
- stands for a bond,
and
Y - stands for a direct bond,
- for oxygen, sulfur, NH, N-methyl or
stands for a methylene chain with up to 2 carbon atoms, in the form of its isomers, isomer mixtures, racemates, optical antipodes and their physiologically acceptable salts.

Physiologically acceptable salts of the inventive Substances can be salts with inorganic or organic Be acids. Examples include: halides such as Bromides, chlorides, hydrogen sulfates, sulfates, hydrogen phosphates, Acetates, maleates, fumarates, citrates, tartrates, Lactates or benzoates.

The compounds according to the invention exist in stereoisomers Shapes that are either like images and mirror images (Enantiomers) or which are not like picture and Mirror image (diastereomers) behave. The invention affects both the antipodes and the racemic forms as well as mixtures of diastereomers. The racemic forms can be as well as the diastereomers in a known manner in the separate stereoisomerically uniform constituents (see E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

Furthermore, it was found that the substances according to the invention can be obtained if benzylidene compounds of the general formula II in which
R ¹ -R ^{3 have} the meaning given, and enamines of the general formula (III), in which
R ⁴ , R ⁵ , X and Y have the meaning given, if appropriate in the presence of water and / or inert organic solvents.

If methyl benzylideneacetoacetate and morpholinocyclohexene are used as starting materials, the course of the reaction can be illustrated by the following scheme: The benzylidene compounds of the general formula (II) used as starting materials are known or can be prepared by methods known from the literature [cf. G. Jones "The Knoevenagel Condensation" in Organic Reactions XV, 204 (1967), A. Dornow, W. Sassenberg, Liebigs Ann. Chem. 602, 14 (1957)].

The enamines of the general used as starting materials Formula (III) are known or can according to literature Methods are produced [cf. J. Szmuszkovicz "Enamines", Adv. Org. Chem. 4, 1 (1963); A.G. Cook "Enamines-Synthesis, Structure and Reactions", M. Dekker, New York 1969, H. O. House "Modern Synthetic Reactions ", 2nd ed., P. 570, W.A. Benjamin Inc. Menlo Park, 1972].

Water or all inert organic solvents are used as solvents Solvent in question. These preferably include Alcohols such as methanol, ethanol, propanol or isopropanol, Ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol mono- or dimethyl ether, dimethylformamide, dimethyl sulfoxide, Acetonitrile, ethyl acetate, hexamethylphosphoric triamide, Pyridine, halogenated hydrocarbons such as di-, Tri-, carbon tetrachloride, dichloroethane or trichlorethylene, or aromatic hydrocarbons such as benzene, Toluene or xylene. However, it is also possible to use mixtures to use the solvents mentioned.

The reaction temperatures can be in a wide range can be varied. Generally you work in one Temperature range from 0 ° C to 200 ° C, preferably from 10 ° C up to 150 ° C.

The process according to the invention is generally described in Normal pressure. But it is also possible to use the procedure to be carried out under vacuum or overpressure.

In general, ma uses 0.5 to 4 mol of enamine, preferably 1 to 2 mol of enamine, based on 1 mol of benzylidene compound a.  

The new connections have a broad and versatile pharmacological spectrum of activity. In detail, Animal experiment demonstrated the following main effects will.

1. The compounds cause parenteral, oral or perlingual addition an expansion of the coronary vessels. This effect on the coronary vessels is due to a simultaneous nitrite-like heart strain Effect intensified. Influence or change the heart metabolism in the sense of energy saving.

2. The excitability of the stimulation and excitation system within the heart is degraded, so that a detectable in therapeutic doses Anti-flicker effect results.

3. The tone of the smooth muscles of the vessels becomes diminished under the action of the compounds. These Vascular spasmolytic effects can affect the entire vascular system take place, or more or less isolated in circumscribed vascular areas (such as the Manifest central nervous system.

4. The compounds lower the blood pressure of normotonic and hypertensive animals and can therefore be considered antihypertensive Funds are used.  

5. The compounds have muscular spasmolytic effects, on the smooth muscles of the stomach, Intestinal tract, urogenital tract and respiratory system become clear.

The cardiac and vascular effects were found on isolated perfused hearts of the guinea pig. The hearts of 250 to 350 g albino guinea pigs are used for this. The animals are killed with one blow to the head, the thorax is opened, a metal cannula is inserted into the free aorta and the left atrium is opened. The heart is separated from the chest with the lungs and connected to the perfusion apparatus via the aortic cannula while the perfusion is ongoing. The lungs are separated at the roots of the lungs. Krebs-Henseleit solution ( 1 ) (118.5 mmol / l NaCl, 4.75 mmol / 1KCl, 1.19 mmol / 1 KH ₂ PO ₄ , 119 mol / 1 MgSO ₄ , 25 mmol / 1 NaHCO) serves as the perfusion medium ₃ , 0.013 mmol / 1 NaEDTA), the CaCl _{2 of which is} varied as required, but is usually 1.2 mmol / 1. 10 mmol / 1 glucose are added as the energy-supplying substrate. The solution is filtered particle-free before perfusion. The solution is gassed with carbogen (95% O ₂ , 5% CO ₂ to maintain the pH of 7.4). The hearts are perfused with constant flow (10 ml / min) at 32 ° C using a roller squeeze pump.

A liquid-filled device is used to measure the heart function Latex balloon over a liquid column with a Pressure transducer is connected through the left atrium inserted the left ventricle and the isovolumetric  Contractions registered on a high-speed recorder (Opie, L., J. Physiol. 180 (1965) 529-541). The perfusion pressure is by means of a pressure sensor, which before Heart connected to the perfusion system, registered. Under these conditions, a decrease in Perfusion pressure a coronary dilation, an increase the left ventricular pressure amplitude a decrease of the Heart contractility. The compounds of the invention are in appropriate dilutions in the perfusion system infused just before the isolated heart.

The following table shows effects on contractility and coronary resistance of some examples on the isolated perfused guinea pig heart.

Because of their circulatory effects the active compounds according to the invention as antihypertensive agents as vasodilators, as cerebral therapeutics and as Coronary drugs are used.  

The new active ingredients can in a known manner conventional formulations, such as tablets, Capsules, coated tablets, pills, granules, aerosols, syrups, Emulsions, suspensions and solutions using inert, non-toxic, pharmaceutically suitable carriers or solvent. Here, the therapeutic effective connection in a concentration from about 0.5 to 90% by weight of the total mixture is present be d. H. in amounts sufficient to meet the specified Achieve dosage range.

The formulations are prepared, for example, by Stretching the active ingredients with solvents and / or Carriers, optionally using emulsifiers and / or dispersants, z. B. in the case the use of water as a diluent if necessary organic solvents used as auxiliary solvents can be.

Examples of auxiliary substances are:

Water, non-toxic organic solvents, such as Paraffins (e.g. petroleum fractions), vegetable oils (e.g. Peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerin), Glycols (e.g. propylene glycol, polyethylene glycol), solid Carriers such as B. natural stone powder (e.g. Kaolins, clays, talc, chalk), synthetic stone powder (e.g. finely divided silica, silicates), sugar (such as cane, milk and dextrose), emulsifiers (e.g. polyoxyethylene fatty acid esters), polyoxyethylene  Fatty alcohol ethers (e.g. lignin, sulfite liquor, methyl cellulose, Starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium sulfate).

It is preferably applied in the usual way orally or parenterally, especially perlingually or intravenously. In the case of oral use, tablets can be used of course, in addition to the carriers mentioned Additives such as sodium citrate, calcium carbonate and dicalcium phosphate along with various additives, such as Starch, preferably potato starch, gelatin and the like contain. Lubricants such as Magnesium stearate, sodium lauryl sulfate and talc Tableting can also be used. In the case of an aqueous suspension and / or elixirs intended for oral use are the active ingredients other than the above Excipients with various flavor enhancers or Dyes are added.

In the case of parenteral applications, solutions can be found of the active ingredients using suitable liquid Carrier materials are used.

In general, it has been found to be beneficial in intravenous administration amounts from about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to deliver effective results, and in the case of oral administration, the dosage is approximately 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg, body weight.  

Nevertheless, it may be necessary from the deviate quantities mentioned, depending on Body weight of the test animal or the type of application, but also due to the animal species and their individual Behavior towards the drug or its type of its formulation and the time or interval which is administered. So it may be in some Cases should be sufficient with less than the above Minimum amount to get by, while in other cases the mentioned upper limit must be exceeded. In the event of it is recommended to apply larger quantities be divided into several individual doses throughout the day. For application in human medicine, the same dosage range provided. Apply accordingly here also the above statements.

In addition, the hydropyrans according to the invention valuable intermediates for the manufacture of pharmaceutical Active ingredients.

The compounds of the formula I can be converted into partially known dihydropyridines of the formula IV by a simple process in which
R ¹ - for aryl (C ₆ -C ₁₂ ) or
- for a heterocycle from the series thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridil, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothylazolyl, benzothiazolylol, benzothiazolyl, benzothiazolyl, , Chromenyl, thiochromenyl, benzoxadiazolyl, benzothiadiazolyl, the aryl radical and the heterocycles optionally 1 to 3 identical or different substituents from the group C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkylthio, Halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₈ monofluoroalkoxy, C ₁ -C ₈ polyfluoroalkoxy, hydroxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, carboxy, C ₁ -C ₆ -Alkoxycarbonyl, phenyl, benzyl, benzyloxy or benzylthio contain or
represents straight-chain, branched or cyclic C ₁ -C ₈ -alkyl which is optionally substituted by thienyl, furyl, pyridyl or pyrimidyl,
R ² - for hydrogen, nitro or cyano,
- for C ₁ -C ₈ -alkylsulfonyl or
- for the group stands,
in which
R ⁶ - represents straight-chain, branched or cyclic C ₁ -C ₈ alkyl, or
- represents a group of formula -OR ⁷ , wherein
R ^{7 represents} straight-chain, branched or cyclic C ₁ -C ₁₀ alkyl, which is optionally interrupted by one or two oxygen and / or sulfur atoms in the chain, and which is optionally substituted by one or more halogen, hydroxy, cyano, nitro , Phenyl, pyridyl or by an amino group, this amino group optionally being mono- or disubstituted identically or differently by C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl or C ₇ -C ₁₄ aralkyl.
R ³ - for C ₆ -C ₁₂ aryl or
represents straight-chain or branched C ₁ -C ₈ -alkyl which is optionally substituted by hydroxy, halogen or C ₂ -C ₇ -acyloxy,
R ⁴ , R ⁵ - are the same or different and
- stand for straight-chain or branched C ₁ -C ₈ alkyl
or
R ⁴ and R ⁵ together represent a methylene chain with up to 20 carbon atoms
R ⁸ - for hydrogen or
represents a straight-chain, branched or cyclic C ₁ -C ₈ -alkyl,
X - for the group ⁻C = O or
- stands for a direct bond,
convict.

This method is characterized in that the Hydropyridines according to the invention with acids such as, for example Hydrochloric acid, sulfuric acid, acetic acid or sulfonic acids and amines of the general formula V

in which
R ^{8 has} the meaning given
or with their addition products in water or inert organic solvents such as alcohols, e.g. B. methanol, ethanol, propanol or isopropanol, or ethers, such as diethyl ether, dioxane, tetrahydrofuran, or in dimethylformamide, dimethyl sulfoxide, acetonitrile or ethyl acetate in a temperature range from 0 ° C to 200 ° C.

In the implementation of the hydropyrans according to the invention to dihydropyridines different process variants are possible. In variant A, acid becomes the intermediate then amine, with variant B only amine then acid and Variant C amine and acid in the form of the addition product the acid added to the amine.  

The dihydropyridines represent valuable pharmacological Active substances that are used to treat circulatory diseases, coronary artery disease, heart failure as well Metabolic diseases can be used.  

Manufacturing examples example 1

8a-Morpholino-4- (3-nitrophenyl) -2-phenyl-4a, 5,6,7,8,8a- hexahydro-4H-chromen-3-carboxylic acid ethyl ester A solution of 10.9 g (0.033 mol) of 3-nitrobenzylidenbenzoylacetic acid and 5.6 g / 0.033 mol) of morpholinocyclohexene in 80 ml of ethanol is boiled under reflux for 4 hours. The mixture is concentrated, rubbed with ether, suction filtered and recrystallized from ethanol.
Yield: 7.3 g (44.5% of theory)
Melting point: 134-136 ° C.

The following were prepared as in Example 1:

Example 2

2-Methyl-8a-morpholino-4- (3-nitrophenyl) -4a, 5,6,7,8,8a- hexahdro-4H-chromen-3-carboxylic acid ethyl ester Melting point: 133 ° C

Example 3

3-Acetyl-2-methyl-8a-morpholino-4- (3-nitrophenyl) -4a, 5,6, 7,8,8a-hexahydro-4H-chromene Melting point: 166 ° C

Example 4

2-Methyl-8a-morpholino-3-nitro-4- (2-trifluoromethylphenyl) -4a, 5,6,7,8,8a-hexahydro-4H-chromene 10.4 g (40 mmol) of 2-nitro-1- (2-trifluoromethylphenyl) -butene-1-one-3 and 6.7 g (40 mmol) of 1-morpholinocyclohexene are combined in 20 ml of ethanol at room temperature. An exothermic reaction takes place, after a short time the product crystallizes in pale yellow crystals as a mixture of isomers.
Yield: 13.4 g (77% of theory)
Melting point: 133 ° C.

Examples of use Process variant A Example I

2-Phenyl-4- (3-nitrophenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester 25 g (0.05 mol) are mixed with about 100 ml of ethanol in an Erlenmeyer flask (magnetic stirrer). Then you give 200 ml of a mixture of 50% ethanol / 50% conc. HCI and wait for the complete solution (if necessary, filter off insoluble material).

With conc. Ammonia is then made alkaline, allowed to cool to room temperature (possibly adding some water), the precipitate is filtered off and recrystallized from ethanol.
Yield: 15 g (74% of theory)
Melting point: 155 ° C.

The following are obtained analogously:

Example II: from 2)

2-Methyl-4- (3-nitrophenyl) -1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester Melting point: 131 ° C.

Example III: from 3)

3-acetyl-2-methyl-4- (3-nitrophenyl) -1,4,5,6,7,8-hexahydroquinoline Melting point: 161 ° C.

Process variant B: Example IV:

2-methyl-3-nitro-4- (2-trifluoromethylphenyl) -1,4,5,6,7,8-hexahydroquinoline.

2 g (4.7 mmol) 4) are suspended in 15 ml of ethanol and brought into solution with approx. 3 ml of concentrated aqueous ammonia solution at 30 to 45 ° C. The pH is then adjusted to 3 with concentrated hydrochloric acid, the solution is diluted with 5 ml of water and extracted 2 × with 10 ml of chloroform. After the chloroform has been evaporated off, the residue crystallizes from a little ethanol in yellow crystals. Yield: 580 mg (36% of theory)
Melting point: 222 ° C (dec.)

Process variant C Example V

1,2-dimethyl-3-nitro-4- (2-trifluoromethylphenyl) -1,4,5,6,7,8-hexahydroquinoline 2 g (4.7 mmol) 4) are refluxed in 15 ml of ethanol with 2 g of methylammonium chloride for 6 hours. After cooling, the salts are suctioned off, the solution is evaporated, the residue is taken up in chloroform and washed with water. The organic phase is dried and concentrated, the residue is chromatographed on silica gel with chloroform plus 1% methanol. Intensely yellow crystals are obtained from ethanol.
Yield: 880 mg (52% of theory)
Melting point: 149 ° C.

The hydropyrans listed in Table 1 were prepared according to the following general working procedure:
0.1 mol of benzylidene compound is stirred in 50 ml of alcohol with 0.1 mol of enamine at room temperature. The starting materials go into solution after a short time with an exothermic reaction. After a further 12 hours at room temperature, the product crystallizes out, optionally with the addition of seed crystals. It is suctioned off, washed with a little alcohol and dried in vacuo.

Table 1

Claims (8)

1. Hydropyran of the general formula I in which
R ¹ - for aryl (C ₆ -C ₁₂ ) or for a heterocycle from the series thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzoxidazolyl , Benzothiazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, thionaphthenyl, chromenyl, thiochromenyl, benzoxadiazolyl, benzothiadiazolyl, the aryl radical and the heterocycles optionally having 1 to 3 identical or different substituents from the group C ₁ -C ₈ alkyl, C ₁ C ₈ alkoxy, C ₁ -C ₈ alkylthio, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₈ monofluoroalkoxy, C ₁ -C ₈ polyfluoroalkoxy, hydroxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, carboxy, C ₁ -C ₆ alkoxycarbonyl, phenyl, benzyl, benzyloxy or benzylthio, or
represents straight-chain, branched or cyclic C ₁ -C ₈ -alkyl which is optionally substituted by thienyl, furyl, pyridyl or pyrimidyl,
R ² - for hydrogen, nitro, cyano, C ₁ -C ₈ alkylsulfonyl or for the group stands
in which
R ⁶ - stands for straight-chain, branched or cyclic C ₁ -C ₈ alkyl, or - stands for a group of the formula -OR ⁷ , where
R ^{7 represents} straight-chain, branched or cyclic C ₁ -C ₁₀ alkyl which is optionally interrupted by one or two oxygen and / or sulfur atoms in the chain and which is optionally substituted by one or more halogen, hydroxy, cyano, Nitro, phenyl, pyridyl, or by an amino group, where this amino group can be substituted once or twice, identically or differently, by C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl or C ₇ -C ₁₄ aralkyl,
R ³ - for C ₆ -C ₁₂ aryl or
represents straight-chain or branched C ₁ -C ₈ -alkyl which is optionally substituted by hydroxy, halogen or C ₂ -C ₇ -acyloxy,
R ⁴ , R ⁵ - are the same or different and
- stand for straight-chain or branched C ₁ -C ₈ alkyl
or
R ⁴ , R ⁵ - together represent a methylene chain with up to 20 carbon atoms,
X - for the group C = O or
- stands for a direct bond,
and
Y - for a direct bond,
- for oxygen, sulfur, NH, N-alkyl (C ₁ -C ₆ ), or
represents a methylene chain with up to 4 carbon atoms,
in the form of their isomers, isomer mixtures, racemates, optical antipodes and their physiologically acceptable salts. 2. hydropyran of the general formula I in claim 1, in which
R ¹ - for phenyl or thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, quinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, thiochromenyl, benzoxadiazolyl
is phenyl and the heterocycles optionally 1 to 2 identical or different substituents from the group C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, fluorine, chlorine, bromine, nitro, Cyano, trifluoromethyl, C ₁ -C ₄ monofluoroalkoxy, C ₁ -C ₄ polyfluoroalkoxy, hydroxy, amino, C ₁ -C ₃ alkylamino, C ₁ -C ₃ dialkylamino, carboxy, C ₁ -C ₄ alkoxycarbonyl, Contain phenyl, benzyl, benzyloxy or benzylthio, or
represents straight-chain, branched or cyclic C ₁ -C ₆ -alkyl optionally substituted by pyridyl or pyrimidyl,
R ² - for hydrogen, nitro or cyano
- for C ₁ -C ₆ alkylsulfonyl or
- for the group stands,
in which
R ⁶ - represents straight-chain, branched or cyclic C ₁ -C ₆ alkyl, or
- represents a group of the formula -OR ⁷ , where R ^{7 represents} straight-chain, branched or cyclic C ₁ -C ₈ alkyl, which is optionally interrupted by one or two oxygen atoms in the chain and which is optionally substituted by one or more Fluorine, chlorine, bromine, hydroxy, cyano. Nitro, phenyl, pyridyl or by an amino group, this amino group optionally being substituted one or two times in the same or different way by C ₁ -C ₄ alkyl, phenyl or benzyl.
R ₃ - for phenyl or
stands for straight-chain or branched C ₁ -C ₆ -alkyl which is optionally substituted by hydroxy, one or more fluorine, chlorine, bromine or C ₂ -C ₅ -acyloxy,
R ⁴ , R ⁵ - are the same or different and stand for straight-chain or branched C ₁ -C ₆ alkyl, or
R ⁴ and R ⁵ together represent a methylene chain with up to 16 carbon atoms,
X - for the group ⁻C = O
- stands for a direct bond,
and
Y - for a direct bond,
- represents oxygen, sulfur, NH, N-alkyl (C ₁ -C ₄ ), or
- stands for a methylene chain with up to 2 carbon atoms in the form of its isomers, isomer mixtures, racemates, optical antipodes and their physiologically acceptable salts. 3. hydropyrans of the general formula I in claim 1, in which
R ^{1 represents} phenyl, thienyl, furyl, pridyl, pyrimidyl, benzoxadiazolyl or thiochromenyl, the said radicals optionally 1 or 2 identical or different substituents from the group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C Contain ₁ -C ₄ alkylthio, fluorine, chlorine, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, phenyl, benzyl, benzyloxy or benzylthio,
R ² - for hydrogen, nitro or cyano,
- for C ₁ -C ₄ alkylsulfonyl or
- for the group stands
in which
R ⁶ - represents straight-chain or branched C ₁ -C ₄ alkyl, or
- represents a group of formula -OR ⁷ , wherein
R ^{7 represents} straight-chain, branched or cyclic C ₁ -C ₆ -alkyl which is optionally interrupted by an oxygen atom in the chain and which is optionally substituted by one or more fluorine, hydroxyl, cyano, phenyl or benzylmethylamino,
R ³ - represents phenyl or straight-chain or branched C ₁ -C ₄ alkyl, which is optionally substituted by hydroxy, chlorine, bromine or acetyloxy,
R ⁴ , R ⁵ - are the same or different and
- Stand for straight-chain or branched C ₁ -C ₄ alkyl
or
R ⁴ and R ⁵ together represent a methylene chain with up to 12 carbon atoms
X - for a group ⁻C = O or
- stands for a bond,
and
Y - stands for a direct bond,
- for oxygen, sulfur, NH, N-methyl, or
- stands for a methylene chain with up to 2 carbon atoms. 4. Process for the preparation of hydropyrans of the general formula 1
in which R ¹ - for aryl (C ₆ -C ₁₂ ) or for a heterocycle from the series thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzoxidazolyl , Benzothiazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, thionaphthenyl, chromenyl, thiochromenyl, benzoxadiazolyl, benzothiadiazolyl, the aryl radical and the heterocycles optionally having 1 to 3 identical or different substituents from the group C ₁ -C ₈ alkyl, C ₁ C ₈ alkoxy, C ₁ -C ₈ alkylthio, halogen, nitro, cyano, trifluoromethyl, C ₁ -C ₈ monofluoroalkoxy, C ₁ -C ₈ polyfluoroalkoxy, hydroxy, amino, C ₁ -C ₆ alkylamino, C Contain ₁ -C ₆ -dialkylamino, carboxy, C ₁ -C ₆ -alkoxycarbonyl, phenyl, benzyl, benzyloxy or benzylthio, or
represents straight-chain, branched or cyclic C ₁ -C ₈ -alkyl which is optionally substituted by thienyl, furyl, pyridyl or pyrimidyl,
R ² - for hydrogen, nitro, cyano, C ₁ -C ₈ alkylsulfonyl or for the group stands
in which
R ⁶ - represents straight-chain, branched or cyclic C ₁ -C ₈ alkyl, or
- represents a group of formula -OR ⁷ , wherein
R ⁷ - represents straight-chain, branched or cyclic C ₁ -C ₁₀ alkyl which is optionally interrupted by one or two oxygen and / or sulfur atoms in the chain and which is optionally substituted by one or more halogen, hydroxy, cyano, Nitro, phenyl, pyridyl, or by an amino group, where this amino group can be substituted once or twice, identically or differently, by C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl or C ₇ -C ₁₄ aralkyl,
R ³ - for C ₆ -C ₁₂ aryl or
represents straight-chain or branched C ₁ -C ₈ -alkyl which is optionally substituted by hydroxy, halogen or C ₂ -C ₇ -acyloxy,
R ⁴ , R ⁵ - are the same or different and
- for straight-chain or branched
C ₁ -C ₈ alkyl
or
R ⁴ , R ⁵ - together represent a methylene chain with up to 20 carbon atoms,
X - for a group C = O or
stands for a direct bond,
and
Y - for a direct bond,
- for oxygen, sulfur, NH, N-alkyl (C ₁ -C ₆ ), or
- stands for a methylene chain with up to 4 carbon atoms
in the form of their isomers, isomer mixtures, racemates, optical antipodes and their physiologically acceptable salts,
characterized in that benzylidene compounds of the general formula (II), in which
R ¹ -R ^{3 have} the meaning given above, and enamines of the general formula (III), in which
R ⁴ , R ⁵ , X and Y have the meaning given above,
if appropriate in the presence of water and / or inert organic solvents. 5. Medicament containing hydropyrans of claims 1-3. 6. Use of the hydropyrans according to claims 1-3 in Medicines. 7. Use of the hydropyrans according to claims 1-3 the manufacture of pharmaceuticals. 8. Use of the hydropyrans according to claims 1-3 for the preparation of dihydropyridines of the general formula IV in which R ¹ -R ⁵ and X correspond to the identical substituents of the hydropyrans and R ^{8 is} hydrogen or a C ₁ -C ₈ alkyl.