4h-1-benzopyran-4-one derivatives, process for their preparation and their use as medicaments

0001The present invention relates to new 4H-1-benzopyran-4-one derivatives, processes for their preparation and their use as anti-inflammatory drugs, analgesics, immunosuppressants and antiallergics. In particular, the present invention relates to new ones

0002Compounds of formula I in cis form<chemistry id="chem0001" num="0001"><img file="EP0241003B1_D0001.tif" /></chemistry>and their pharmacologically acceptable acid addition salts and optical isomers, in which:<ul id="ul0001" list-style="none"><li>R₁ unsubstituted or substituted with halogen, hydroxyl or carboxy groups₁-C₆Alkyl or pyridyl or phenyl, optionally mono- or polysubstituted with halogen, C1-C4-alkoxy, nitro, hydroxy, carbonyl, amino, pyridyl or trifluoromethyl,</li><li>R₃ Hydroxy or C₁-C₄-Alkoxy,</li><li>R₅ Hydrogen, C₁-C₆-Alkyl or C3-C6-cycloalkyl-C1-C4-alkyl,</li><li>m is an integer between 0 and 3,</li></ul>with the exception of all forms of the compound -cis-5,7-di-hydroxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4- on.

0003The compounds according to the invention have two asymmetric centers, one at the point of attachment of the nitrogen heterocycle to the benzopyr portion (C-4 ') and the other at R₄ substituted carbon atom (C-3 '), so that two optical isomer pairs are possible. It goes without saying that all possible stereoisomers and their mixtures are included in the definition of the compounds according to the invention . In particular, both the racemic forms and the isolated optical isomers possessing the stated activity are included. The two racemates can be separated using physical methods such as fractional crystallization. The individual optical isomers can be obtained from the racemates by standard methods such as salt formation with an optically active acid and subsequent crystallization.

0004EP-A2-0 137 193 already contains the compound (+) - cis-5,7-dihydroxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H -1-benzopyrano-4-one, their isolation from the plant Dysoxylum binectariferum and their use as agents for immunomodulation are described. This connection is therefore excluded from the present invention.

0005As alkyl groups for R₁ and R₅ For example, straight-chain or branched radicals having up to 6 and preferably up to 5 carbon atoms are suitable, for example methyl, ethyl, propyl, isopropyl, t-butyl, pentyl or isopentyl groups.

0006As substituted alkyl groups for R₁ are, for example, haloalkyl such as trifluoromethyl, hydroxyalkyl such as hydroxyethyl or carboxyalkyl such as carboxyethyl.

0007The cycloalkylalkyl group R₅ is, for example, cyclopropylmethyl.

0008Suitable examples of salts of the compounds according to the invention with inorganic or organic acids are the hydrochloride, hydrobromide, sulfate, phosphate, acetate, oxalate, tartrate, citrate, maleinate or fumarate.

0009Preferred compounds correspond to the formella,<chemistry id="chem0002" num="0002"><img file="EP0241003B1_D0002.tif" /></chemistry>where Ri, R₂ and R₅ have the same meanings as described above and in particular mean:<ul id="ul0002" list-style="none"><li>R₁ Hydrogen or C₁-C₃-Alkyl</li><li>R₅ C.₁-C₃-Alkyl or C₃-C₅-Cycloalkyl-C₁ -C₃-alkyl.</li></ul>

0010Particularly preferred compounds according to the invention are:<ul id="ul0003" list-style="none"><li>cis - (-) - 5,7-dihydroxy-2-methyl-8- [4 '- (1'-cyclopropylmethyl-3'-hydroxy) piperidinyl] -4H-1-benzopyran-4-one,</li><li>cis- (±) -5,7-dihydroxy-2-ethyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one and</li><li>cis- (±) -5,7-dihydroxy-2-n-propyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (+) -5,7-dihydroxy-2-n-propyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidingl-4H-1-benzopyran-4-one.</li><li>cis - (-) - 5,7-Dihydroxy-2-n-propyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl -] - 4H-1-benzopyran-4-one.</li><li>cis- (±) -2-n-butyl-5,7-dihydroxy-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (±) -5,7-dihydroxy-2-phenyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis - (-) - 5,7-Dihydroxy-2-phenyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinylj-4H-1-benzopyran-4-one.</li><li>cis- (±) -2- (2-chlorophenyl) -5,7-dihydroxy-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-benzopyran-4-one.</li><li>cis - (-) - 2- (2-chlorophenyl) -5,7-dihydroxy-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (±) -2- (4-aminophenyl) -5,7-dihydroxy-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (±) -2- (4-bromophenyl) -5,7-dihydroxy-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (±) -2- (4-chlorophenyl) -5,7-dihydroxy-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (±) -2- (2,4-dichlorophenyl) -5,7-dihydroxy-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4- on.</li><li>cis- (±) -5,7-dihydroxy-2- (4-fluorophenyi) -8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (±) -5,7-dihydroxy-2- (2-fluorophenyl) -8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (±) -5,7-dihydroxy-2- (2-pyridyl) -8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li><li>cis- (±) -5,7-dihydroxy-2- (4-pyridyl) -8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one.</li></ul>

0011New 4H-1 benzopyran-4-one derivatives according to the invention are listed in Tables 1 to 5 below, reference being made to the following formulas:<chemistry id="chem0003" num="0003"><img file="EP0241003B1_D0003.tif" /></chemistry><chemistry id="chem0004" num="0004"><img file="EP0241003B1_D0004.tif" /></chemistry><chemistry id="chem0005" num="0005"><img file="EP0241003B1_D0005.tif" /></chemistry><chemistry id="chem0006" num="0006"><img file="EP0241003B1_D0006.tif" /></chemistry><chemistry id="chem0007" num="0007"><img file="EP0241003B1_D0007.tif" /></chemistry><tables id="tabl0001" num="0001"><img file="EP0241003B1_D0008.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0241003B1_D0009.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0241003B1_D0010.tif" /></tables><tables id="tabl0004" num="0004"><img file="EP0241003B1_D0011.tif" /></tables><tables id="tabl0005" num="0005"><img file="EP0241003B1_D0012.tif" /></tables><tables id="tabl0006" num="0006"><img file="EP0241003B1_D0013.tif" /></tables><tables id="tabl0007" num="0007"><img file="EP0241003B1_D0014.tif" /></tables>

0012The present invention also relates to a process for the preparation of compounds of the general formula I, which comprises the stages outlined in the diagram in the attached FIG. 1. If desired, further chromone derivatives according to the invention can be obtained by treating compounds of the formula I 'in FIG. 1 by known methods. The general scheme depicted in FIG. 1 is explained and described in more detail by the reaction sequence depicted in FIG. 2, which relates to the preparation of one of the preferred compounds according to the invention; it goes without saying that the scope of the invention is not restricted thereby.

0013The preparation of the compound of formula VIII with n = 1 is known to the person skilled in the art [SM McClavain and RS Berger, J. Am. Chem. Soc., 77, 2848 (1955); A. Ziering, L. Berger, SD Heineman and J. Lec., J. Org. Chem., 12, 894 (1947)]. Two methods are described there. In the first, 1,3,5, -trimethoxybenzene is stirred with n-butyllithium at low temperatures, preferably between -60 and -90_°C, in inert solvents such as hydrocarbons, for example pentane or hexane, or ether solvents, for example diethyl ether or tetrahydrofuran, to produce the lithio salt which, when stirred with 1-methyl-4-piperidone and subsequent acidification, gives the tetrahydropyridine derivative. In the second and particularly preferred method, 1,3,5-trimethoxybenzene is stirred under acidic conditions with 1-methyl-4-piperidone in solvents such as water, acetic acid, alcoholic solvents or a suitable mixture thereof, glacial acetic acid being particularly preferred.

0014With reference to the scheme in Figure 2, the tetrahydropyridine derivative of the depicted formula VIIIA (ie formula VIII with n = 1) is used by itself by adding BF₃Etherate to a slurry of sodium borohydride in diethylene glycol dimethyl ether under anhydrous conditions and in a diborane directly forming in an inert atmosphere maintained by continuous passage of nitrogen or argon. The reaction temperature is kept between 20 and 90_°C, but a temperature range of 50-60 ° C is preferred. The resulting organoborane complex is first treated with hydrochloric acid and then oxidized by adding alkali and hydrogen peroxide. The compound thus obtained is a trans alcohol of the formula IXA and is converted into the cis alcohol of the formula XIA by oxidation and subsequent reduction. The trans alcohol of the formula IXA is oxidized by means of a reagent combination, namely acid chlorides, with oxalkyl chloride being preferred, dimethyl sulfoxide and triethylamine and is known to the person skilled in the art as oxidation according to Swern. The ketone of the formula XA formed by oxidation of the compound of the formula IXA is reduced by means of hydride reagents, preferably diborane, lithium borohydride or sodium borohydride. A wide range of solvents are compatible with sodium borohydride, but proton-containing solvents such as methanol, ethanol and isopropanol are preferred. By maintaining a higher reaction temperature, the cis isomer can be obtained stereoselectively.

0015The cis isomer can also be obtained by fractional crystallization of its acid addition salts, which are formed with optically active acids such as. B. (-) - and / or (+) - dibenzoyl tartaric acid. The cis isomer can optionally also be esterified with an optically active acid such as (-) - menthyloxyacetic acid and the resulting diastereomeric esters can then be separated by conventional methods such as fractional crystallization or chromatography.

0016The cis-hydroxy compound of formula XIA is acetylated with acetic anhydride and acidic catalysts such as aluminum chloride, boron trifluoride etherate and tin (IV) chloride, boron trifluoride etherate being particularly preferred as the reagent. If a large excess of boron trifluoride etherate is used, demethylation also takes place at the same time, and only the desired methoxyl group is demethylated in a region-specific manner, a compound of the formula XIIA being obtained in which R is the radical -COCH₃ represents. The hydrolysis of this compound with an alkali metal hydroxide leads to compounds of the formula XIIA with R = H. The compound of the formula XIIA is then converted into the chromone by methods known per se, two of which are described here. In the first method, the compound of formula XIIA with R = H is stirred at room temperature and in inert solvents such as ether, tetrahydrofuran, dioxane or hydrocarbon solvents such as hexane with ethyl acetate and alkali metal or NaH, preferably sodium metal; if the ester is a low-boiling liquid as in the present example, it can also be used as a solvent. The reaction is usually complete after one to ten hours and gives the diketone of the formula XIIIA with R = H, which is cycled to give the chromone of the formula IA when stirred with mineral acids such as hydrochloric acid or sulfuric acid. In the second method, a compound of formula XII A with R = Ac is esterified with a suitable acid, e.g. B. benzoic acid, and the ester obtained with a base such as. B. alkali hydroxide, in an inert solvent such as. B. THF, dioxane or pyridine stirred, the chromone of the formula XIII A with R = Ac and R₁ = Phenyl is formed. Compounds of formula la with R = H and R₁ = CH₃ are demethoxylated with pyridine hydrochloride to obtain the hydroxy compound of the formula IB shown. Different 2-substituted chromones can be produced using the corresponding esters instead of ethyl acetate.

0017The dimethoxychromone of formula IA can in addition to AICb, BBr₃ or HBr / acetic acid can also be demethoxylated using other acidic reagents. Demethoxylation is carried out by heating the dimethoxychromone derivatives with pyridine hydrochloride for a period of 2 to 10 hours to 180_°C. In some cases, the addition of high boiling amines to the pyridine hydrochloride can be beneficial.

0018The synthesis scheme of Figure 2 can be used to prepare compounds of formula I with R₅ = H, alkyl (other than methyl), cycloalkyl, aralkyl and aryl. Compounds of formula I, wherein R₅ has the same meaning as above, can also be derived from the corresponding N-methyl compounds, ie R₅ = CH₃ (Compounds of formula IB) by one of the known methods. A typical procedure can be seen from the diagram in FIG. 3, where a compound of the formula IB with R₅ = CH₃ treated with cyanogen bromide after protection of the hydroxyl groups and then acidic or alkaline to give compounds with R₅ = H (compound of formula XIV) is hydrolyzed. When treated with suitable electrophilic reagents such as halides, acid chlorides, tosylates or enones, this compound gives compounds with R.₅ = Alkyl, cycloalkyl, aralkyl or aryl, the compound of the formula XVII shown being a specific example. According to FIG. 3, 5,7-dihydroxy-2-methyl-8- [4 '- (1'-cyclopropylmethyl-3'-hydroxy) -piperidinyl] -4H-1-benzopyran-4-one of the depicted formula XVII is obtained by peracetylation of 5,7-dihydroxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one of formula IB with acetic anhydride and sodium acetate at 80 -90_°C. The peracetylated product of formula XIV is stirred with cyanogen bromide in chloroform and gives 5,7-diacetyl-2-methyl-8- [4 '- (3'-acetoxy-1'-cyan) -piperidinyl] -4H in the presence of potassium carbonate -1-benzopyran-4-one of the formula XV which, when heated for 5 hours with 2N hydrochloric acid at 110 ° C., gives the hydrolyzed and N-demethylated product 5,7-dihydroxy-2-methyl-8- [4 '- ( 3'-hydroxy) -piperidinyl] -4H-1-benzopyran-4-one of the formula XVI provides. When heated with cyclopropylmethyl chloride in isobutyl alcohol, the N-cyclopropylmethyl derivative of the formula XVII shown is obtained.

0019Compounds of formula I, wherein R₂ Dialkylaminomethyl means are prepared by the corresponding chromon with R₂ = H heated to reflux with a secondary amine hydrochloride and paraformaldehyde in dioxane or alcoholic solvents. Compounds of formula I with R₂ = N0₂ are expedient by stirring the corresponding chromon with R₂ = H made with acetic acid and concentrated nitric acid. Compounds of formula I with R₂ = NH₂ is obtained from the corresponding nitroderivatives by hydrogenation over 10% Pd / C.

0020Compounds of formula I, wherein one of the R₃-Groups for bromine is established by stirring the corresponding chromones with R.₃ = H with N-bromosuccinimide in dimethylformamide.

0021Another feature of the invention is that the compounds according to the invention represented by the formula I have pharmacological properties. In particular, they show an anti-inflammatory and immunomodulating effect on laboratory animals. These properties are confirmed by the results of the subsequent pharmacological tests which were carried out to assess the compounds according to the invention and their salts.

Systemic anti-inflammatory effects on carrageenin-induced paw edema in the rat

0022Male Charles Foster rats (120-150 g) were fasted with water ad libitum for 18 hours. The test compound dissolved in distilled water was administered orally. The control group received distilled water. 0.05 ml of 0.5% carrageenin suspension was injected subcutaneously into the sole area of ​​the left hind paw. The paw volume was determined using a Maclab differential volume meter from the carrageenan injection and 3 and 6 hours thereafter. The percent paw volume decrease was calculated using the following equation:<tables id="tabl0008" num="0008"><img file="EP0241003B1_D0015.tif" /></tables>The ED 50 value was calculated from the dose / effect curve. Six animals were used per group.

0023The results with representative compounds according to the invention and their salts are shown in Table 4, the substituents relating to the following formula Ia:<tables id="tabl0009" num="0009"><img file="EP0241003B1_D0016.tif" /></tables><tables id="tabl0010" num="0010"><img file="EP0241003B1_D0017.tif" /></tables>

Reverse passive arthus response (RPA) in the rat

0024Charles Foster rats of both sexes, weighing 150-180 g, were sorted into groups of six animals each. 24 hours before the RPA was triggered, the rats were sheared from the mid-back region and fasted overnight. The test compounds were administered orally one hour before induction of the Arthus response. The RPA response was induced by intradermal injection of 0.1 ml of appropriately diluted rabbit anti-BSA serum. Immediately after the intradermal injections, the rats received 0.5 ml of 0.4% bovine serum albumin intravenously. Four hours after the intradermal exposure, the animal groups were each killed by a broken neck. The entire thickness of the skin was removed from the back of each animal and a 12 mm diameter disc was punched out with a metal punch at the site of the antiserum injection. The wet weight of the skin area was determined as soon as possible. The edema caused by the RPA was measured as the difference (expressed in mg) between the wet weight of the antibody injected site and the normal rabbit serum injected site.

0025The results are expressed as a percentage inhibition or potentiation of the edema by the compound compared to the edema induced in the untreated control animals.

0026The results with representative compounds according to the invention and their salts are shown in Table 7.<tables id="tabl0011" num="0011"><img file="EP0241003B1_D0018.tif" /></tables><tables id="tabl0012" num="0012"><img file="EP0241003B1_D0019.tif" /></tables><tables id="tabl0013" num="0013"><img file="EP0241003B1_D0020.tif" /></tables>

0027The invention is illustrated by the following examples, but is not restricted.

example 1

1-methyl-4- (2,4,6-trimethoxyphenyl) -1,2,3,6-tetrahydropyridine

0028N-Methylpiperidone (2.8 mol) is added with stirring to a solution of trimethoxybenzene (2.38 mol) in glacial acetic acid (750 ml), the temperature of the reaction mixture being kept below 25 ° C. When the addition is complete, hydrogen chloride is bubbled through the reaction mixture, heated to 95-100 ° C. for 3 hours, then concentrated and the residue is diluted with water. The aqueous solution is extracted with ether, the ether is separated off and the aqueous layer is made alkaline with concentrated sodium hydroxide solution. The precipitate thus obtained is filtered off, washed with water and dried. Recrystallization from petroleum ether (60 ° -80 ° C) gives 550 g of 1-methyl-3- (2,4,6-trimethoxyphenyl) -1,2,3,6-tetrahydropyridine with a melting point of 118-122 ° C.<tables id="tabl0014" num="0014"><img file="EP0241003B1_D0021.tif" /></tables>

Example 2

(±) trans-3-hydroxy-4- (2,4,6-trimethoxyphenyl) -1-methylpiperidine

0029A solution of BF is dropped₃Etherate (42 ml) in diethylene glycol dimethyl ether (42 ml) to a cooled mixture of 1-methyl-4- (2,4,6-trimethoxyphenyl) -1,2,3,6-tetrahydropyridine (20 g) and sodium borohydride (12 g) in diethylene glycol dimethyl ether (140 ml). The mixture is heated at 50 ° C. for one hour and the cooled reaction mixture is then treated with water (20 ml) and then with concentrated HCl (116 ml). The mixture is stirred at 50-60 ° C for two hours, cooled and made alkaline with sodium hydroxide solution. Hydrogen peroxide solution (30%, 20 ml) is then added and the mixture is heated to 50-60 ° C. for two hours with stirring. The solution is cooled and extracted with ethyl acetate. The ethyl acetate extract is concentrated in vacuo. The residue is acidified with 2N HCl, extracted with ethyl acetate and the organic layer is separated off. The aqueous layer is then made alkaline with sodium hydroxide solution and extracted with ether. The ether extract is washed with brine, dried over sodium sulfate and concentrated to give a solid residue which is recrystallized from hot water to give trans-3-hydroxy-4- (2,4,6-trimethoxyphenyl) -1-methylpiperidine ( 12 g) results. Yield: 12g; Melting point 88 ° -89 ° C.<tables id="tabl0015" num="0015"><img file="EP0241003B1_D0022.tif" /></tables>

Example 3

(±) 1-Methyl-4- (2,4,6-trimethoxyphenyl) piperidin-3-one

0030Dimethyl sulfoxide (35 ml) is added dropwise to a solution of oxyalkyl chloride (20 ml) in dry methylene chloride (500 ml), cooled to -60 ° C., and the mixture is stirred for 5-10 minutes. A solution of (±) -trans-3-hydroxy-4- (2,4,6-trimethoxyphenyl) -1-methylpiperidine (62 g) in methylene chloride (300 ml) is then added while the temperature of the reaction mixture is at -60_°C holds. After the addition, stir for 15 minutes and add triethylamine (155 ml). Then the reaction mixture is allowed to warm to a temperature of -30 ° C., diluted with water and made alkaline with sodium carbonate.

0031The organic layer is separated and the aqueous layer extracted with ethyl acetate. The organic layers are combined, washed with brine, over anhydrous Na₂S0₄ dried and concentrated to a solid residue, which gives the desired product (47 g) of melting point 110-112 ° C when crystallized from isopropanol.<tables id="tabl0016" num="0016"><img file="EP0241003B1_D0023.tif" /></tables>

Example 4

(±) cis-3-Hydroxy-4- (2,4,6-trimethoxyphenyl) -1-methylpiperidine

0032Sodium borohydride (10 g) is added with stirring to a refluxing solution of 1-methyl-4- (2,4,6-trimethoxyphenyl) piperidin-3-one in absolute ethanol. Then the mixture is stirred for a further hour and heated to reflux. When cooling, the reaction mixture is diluted with water, then concentrated to remove the ethanol and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and concentrated to a solid residue which, when crystallized from acetone, gives the desired product (29.2 g), melting point 124-125 ° C.<tables id="tabl0017" num="0017"><img file="EP0241003B1_D0024.tif" /></tables>

Example 5

(±) cis-3-Hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) phenyl-1-methylpiperidine

0033You drop BF₃Etherate (107.6 ml) to a solution of cis-3-hydroxy-4- (2,4,6-trimethoxyphenyl) -1-methylpiperidine (35 g) in methylene chloride (500 ml) with cooling in an ice bath. Then 76.2 ml of acetic anhydride are added dropwise. Then the reaction mixture is stirred for 24 hours at room temperature, diluted with water, made alkaline with sodium carbonate and extracted with methylene chloride. The extract is concentrated and the residue (37 g) is dissolved in methanol (200 ml) and stirred for 2 hours with 5% aqueous potassium hydroxide solution (500 ml). Then the mixture is concentrated in vacuo and the residue is extracted with chloroform. The residue obtained after concentrating the chloroform extract is then purified by chromatography on silica gel, giving cis-3-hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) -phenyl-1-methylpiperidine (28 g) melting point 215-218_°C (as HCl salt).<tables id="tabl0018" num="0018"><img file="EP0241003B1_D0025.tif" /></tables>

Example 6:

0034General procedure for the preparation of cis / trans5,7-dimethoxy-2- (R₁) -8- [4 '- (3'-hydroxy-1-methyl) piperidinyl] -4H-1-benzopyran-4-one

0035The solution of cis / trans-3-hydroxy-4- (3'-acetyl-4,6-dimethoxy-2'-hydroxy) phenyl-1-methylpiperidine (1 equivalent) is mixed with a suitable ester (3 equivalents). and Na metal (-10 equivalents) or Na hydride (-5 equivalents) in dry dioxane or dimethylformamide at room temperature or at 70-80 ° C. (see Table 8). Then water is carefully added and extracted with chloroform. The organic phase is separated off, somewhat concentrated, saturated with HCl gas and then stirred for one hour. The solution is then by adding Na₂C0₃ made basic and extracted with chloroform. The chloroform extract is over anhydrous Na₂S0₄ dried, concentrated in vacuo and purified with the aid of column chromatography (over silica gel). Thin layer chromatography (5% methanol in CHCI₃ + 1 vol% NH₄0H: Rf value 0.5 - 0.7).

0036The compounds listed in Table 8 below and in Example 6a were prepared using the general procedure given:<tables id="tabl0019" num="0019"><img file="EP0241003B1_D0026.tif" /></tables>

Example 6a

cis-5,7-dimethoxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one

0037A solution of cis-3-hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) -phenyl-1-methylpiperidine (10 g) in ethyl acetate (500 ml) is heated to reflux and add sodium (7 g) in small portions. Stir and reflux for 2 to 3 hours. After cooling, the mixture is diluted with water and the organic layer is separated. This is then concentrated to half the volume, treated with concentrated HCl (10 ml) and stirred for about an hour. Then diluted with water, the aqueous layer is made with Na₂C0₃ alkaline and extracted with chloroform. The chloroform extract is over anhydrous Na₂S0₄ dried, concentrated in vacuo and purified by column chromatography over silica gel to give the desired product (8 g). Recrystallized from chloroform / petroleum ether, melting point 236-238 ° C (HCl salt).<tables id="tabl0020" num="0020"><img file="EP0241003B1_D0027.tif" /></tables>

Example 7:

0038General demethylation process for the preparation of cis / trans-5,7-dihydroxy-2- (R₁) -8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one hydrochloride:

0039Dimethoxychromone (1.0 g), pyridine hydrochloride (5-10 g) and quinoline (0.5 ml) are mixed and heated to 180-190 ° C for 2-3 hours. The reaction mixture is then allowed to cool, water (1 ml) is added and the mixture is made basic by adding solid sodium bicarbonate. The semi-solid product is extracted thoroughly with 20% methanol in chloroform, the organic phase is concentrated and with the aid of column chromatography (silica gel; 15% by volume methanol in chloroform with the addition of 1% by volume NH)₄0H as an element; Rf: 0.4 - 0.7) cleaned. The hydrochloride salt is obtained by treatment with ethereal HCl.

0040The compounds listed in Table 9 below are prepared using the general procedure given:<tables id="tabl0021" num="0021"><img file="EP0241003B1_D0028.tif" /></tables><tables id="tabl0022" num="0022"><img file="EP0241003B1_D0029.tif" /></tables>

Example 8

Cleavage of (±) -cis-3-hydroxy-1-methyl-4- (2,4,6-trimethoxyphenyl) piperidine

0041The racemic cis-3-hydroxy compound (90 g) is dissolved in methanol (300 ml), mixed with (-) - dibenzoyl tartaric acid (126.4 g) in methanol (200 ml) and heated to boiling. Then diisopropyl ether (approx. 500 ml) is slowly added and the clear solution is allowed to cool. The tartrate salt slowly crystallizes out. This is filtered off and recrystallized five times from methanol / diisopropyl ether, [α]<maths id="math0001"><img file="EP0241003B1_D0030.tif" /></maths> = + 48.3 (MeOH). The tartrate salt (43 g) is suspended in water (200 ml), hydrochloric acid (2N, 100 ml) is added and the mixture is stirred. The reaction mixture is extracted with ethyl acetate (5 times 100 ml each). The tartaric acid is recovered from the ethyl acetate extract. The aqueous layer is made alkaline with sodium carbonate and extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate and concentrated, giving the (+) - 3-hydroxy compound, 17.7 g, melting point 109-111 ° C., [α] -<maths id="math0002"><img file="EP0241003B1_D0031.tif" /></maths> = + ₅₃,8₁ ° (methanol).

0042The filtrates from the tartrate crystallizations are combined and the free base is recovered as described above. The free base (20 g) is dissolved in methanol (110 ml), (+) - dibenzoyl tartaric acid (29 g) is added and the solution is heated to boiling. Then slowly add diisopropyl ether (110 ml). When standing at room temperature, the tartrate crystallizes out. It is filtered off and recrystallized three times from methanol / diisopropyl ether mixture. Yield: 20.2 g, [α]<maths id="math0003"><img file="EP0241003B1_D0032.tif" /></maths> = -49 ° (MeOH). The free base is isolated as described above, yield: 8.2 g melting point 109-111_°C, [α]<maths id="math0004"><img file="EP0241003B1_D0033.tif" /></maths> = -54.13 ° (methanol).

0043Optically pure isomers were obtained from optically pure (±) - or (-) - cis-3-hydroxy-4- (3-acetyl-4,6-dimethoxy-2-hydroxy) -phenyl-1-methyl-piperidine as in the following examples 9 and 10:

Example 9

(-) - cis-3-Hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) phenyl-1-methylpiperidine

0044Treat (-) - cis-3-hydroxy-4- (2 ', 4', 6'-trimethoxyphenyl) -1-methylpiperidine in the same manner as in Example 5, which is (-) - cis-3-hydroxy- 4 (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) -phenyl-1-methylpiperidine, melting point 184-86 ° C, [α]<maths id="math0005"><img file="EP0241003B1_D0034.tif" /></maths> = -32.63 ° (MeOH, c = 0.614).

Example 10

(+) - cis-3-Hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) phenyl-1-methylpiperidine

0045Treat (+) - cis-3-hydroxy-4- (2 ', 4', 6'-trimethoxyphenyl) -1-methylpiperidine in the same manner as in Example 5, which is (+) - cis-3-hydroxy- 4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) -phenyl-1-methylpiperidine, melting point 184-85 ° C, [α]<maths id="math0006"><img file="EP0241003B1_D0035.tif" /></maths> = + 34.47 ° (MeOH, c = 0.586).

Example 11

(-) - cis-5,7-Dimethoxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one

0046Treat (-) - cis-3-hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) phenyl-1-methylpiperidine in the same manner as in Example 6, which ( -) - cis-5,7-dimethoxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) -piperidinyl] -4H-1-benzopyran-4-one, melting point 228 -30 ° C, [α]<maths id="math0007"><img file="EP0241003B1_D0036.tif" /></maths> = -80.59 ° (MeOH, c = 0.59).

Example 12

(+) - cis-5,7-Dimethoxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one

0047Treat (+) - cis-3-hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) -phenyl-1-methylpiperidine in the same manner as in Example 6, which ( +) - cis-5,6-dimethoxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one, melting point 228-29 ° C, [α]<maths id="math0008"><img file="EP0241003B1_D0037.tif" /></maths> = + 84.1 ° (MeOH, c = 0.618).

Example 13

(-) - cis-5,7-Dihydroxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one hydrochloride

0048Treated (-) - cis-5,7-dimethoxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) -piperidinyl] -4H-1-benzopyran-4-one on the same manner as in Example 7, which was (-) - cis-5,7-dihydroxy-2-methyl-8- [4 '- (3'-hydroxy-I'-methyl) piperidinyl] -4H-I-benzopyran -4-on hydrochloride with a melting point of 242-45 ° C, [α]<maths id="math0009"><img file="EP0241003B1_D0038.tif" /></maths> = -27.5 ° (MeOH, c = 0.653).

Example 14

(+) - cis-5,7-Dihydroxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one hydrochloride

0049Treated (+) - cis-5,7-dimethoxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) -piperidinyl] -4H-1-benzopyran-4-one on the same manner as in Example 7, which is (+) - cis-5,7-dihydroxy-2-methyl-8 - ['- (3'-hydroxy-I'-methyl) -piperidinyl] -4H-I-benzopyran 4-on hydrochloride with a melting point of 242-44 ° C, [α]<maths id="math0010"><img file="EP0241003B1_D0039.tif" /></maths> = + 29.57 ° (MeOH, c = 0.58).

Example 15

cis-5,7-dihydroxy-2-ethyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one hydrochloride

0050Cis-3-hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) -phenyl-1-methylpiperidine is treated as in Example 6 with ethyl propionate instead of ethyl acetate and the product is demethoxylated as in Example 7 described what cis-5,7-dihydroxy-2-ethyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one hydrochloride dated Delivers melting point 230-33 °.<tables id="tabl0023" num="0023"><img file="EP0241003B1_D0040.tif" /></tables>

Example 16

cis-5,7-dihydroxy-2-n-propyl-8- [4 '- (3'-hydroxy-1'-methyl) piperidinyl] -4H-1-benzopyran-4-one hydrochloride

0051Cis-3-hydroxy-4- (3'-acetyl-4 ', 6'-dimethoxy-2'-hydroxy) -phenyl-1-methylpiperidine is treated as in Example 6 with ethyl butyrate instead of ethyl acetate and the product is demethoxylated as in Example 7 described what cis-5,7-dihydroxy-2-n-propyl-8- [4 '- (3'-hydroxy-1'-methyl) -piperidinyl] -4H-1-benzopyran-4- one- supplies hydrochloride with a melting point of 190-92 ° C.<tables id="tabl0024" num="0024"><img file="EP0241003B1_D0041.tif" /></tables>

Example 17

cis - (-) - 5,7-Dihydroxy-2-methyl-8- [4 '- (3'-hydroxy) piperidinyl] -4H-1-benzopyran-4-one

0052The mixture is heated to cis - (-) - 5,7-dihydroxy-2-methyl-8- [4 '- (3'-hydroxy-1'-methyl) -piperidinyl] -4H-1-benzopyran-4-one (5 g) with acetic anhydride (25 ml) and sodium acetate (4.5 g) at 90 ° C for 12 hours. The acetic anhydride is distilled off in a high vacuum and the residue is mixed with ethyl acetate. The portion soluble in ethyl acetate is evaporated to dryness. The residue is dissolved in dry chloroform (27 ml), anhydrous potassium carbonate (5 g) is added and the mixture is cooled to 0.degree. Cyanogen bromide (6 g) in dry chloroform (25 ml) is added dropwise. After the addition, the reaction mixture is stirred for 4-5 hours at 40-50 ° C, filtered and the filtrate is washed with a small amount of brine, dried over anhydrous sodium sulfate and concentrated. The residue is heated on the steam bath with 1N hydrochloric acid (30 ml) for 7-8 hours. The reaction mixture is made alkaline by adding solid sodium carbonate and concentrated. The residue is passed through an HP-20 column and the product is eluted with 20% MeOH in H₂0. The product is crystallized from MeOH / diisopropyl ether, melting point 300 ° C., [α]<maths id="math0011"><img file="EP0241003B1_D0042.tif" /></maths> = -11.38 (MeOH, c = 0.9).<tables id="tabl0025" num="0025"><img file="EP0241003B1_D0043.tif" /></tables><tables id="tabl0026" num="0026"><img file="EP0241003B1_D0044.tif" /></tables>

Example 18

cis - (-) - 5,7-Dihydroxy-2-methyl-8- [4 '- (I'-cyclopropylmethyl 3'-hydroxy) piperidinyl] -4H-1-benzopyran-4-one hydrochloride

0053Mixing cis - (-) - 5,7-dihydroxy-2-methyl-8- [4 '- (3'-hydroxy) piperidinyl] -4H-1-benzopyran-4-one (1.0 g), Cyclopropyl methyl ketone (1.5 ml), isobutanol (15 ml) and potassium carbonate (3 g) and heated at 90 ° C for 15 hours. The reaction mixture is filtered and the residue is washed with chloroform. The filtrate is concentrated and column chromatographed on silica gel. The compound is eluted with 6% MeOH in chloroform. The hydrochloride is prepared by adding ethereal HCl, yield 0.7 g, melting point 249-51 ° C., [α]<maths id="math0012"><img file="EP0241003B1_D0045.tif" /></maths> = -35.4 ° (MeOH, c = 0.571<tables id="tabl0027" num="0027"><img file="EP0241003B1_D0046.tif" /></tables>