DE1518005C3 - 2-Alkoxy-flavans and processes for their production and medicaments containing them - Google Patents

Description

in which R ^{1 is} a methyl or ethyl group, R ^{2 is} a methoxy or ethoxy group and R ^{3 is} a hydrogen atom or an acetyl group.

2. 2,4'-dimethoxy-3-ethoxy-6-acetoxyflavan.

3. A process for the preparation of 2-alkoxyflavans of the general given in claim 1 Formula I, characterized in that there is a substituted 3-Flaven of the general Formula II

OR ¹

R ³ O

OCH ₃ (II)

in which the radicals R ¹ , R ² and R ^{3 have} the meaning given in claim 1, catalytically hydrogenated in a manner known per se and that, if appropriate, a compound of the formula I in which R ^{3 represents} a hydrogen atom is converted in the customary manner introducing the acetyl radical or, if appropriate, saponifying a compound of the formula I obtained in which R ^{3 represents} an acetyl group.

4. Medicament containing a compound of the general formula I given in claim 1 in addition to the usual inert carriers and additives.

The invention relates to 2-alkoxy-flavans of the general formula I.

OR ¹

R ³ O

OCH ₁

(I)

in which R ¹ denotes a methyl or ethyl group, R ² denotes a methoxy or ethoxy group and R ³ denotes a hydrogen atom or an acetyl group, and a process for their preparation and medicaments containing them.

It has been found that these 2-alkoxy-flavans have valuable pharmacological properties. Above all, they show an excellent cholesterol-lowering effectiveness, which in comparative tests has been checked.

Oral administration of 25 mg / kg each of the compounds tested below gave the following values for the lowering of the cholesterol level in the serum of rats according to that of C ο u η s e 11 and co-workers in J. med. pharm. Chem., Vol. 5, p. 720, 1224 (1962), described method:

2,4'-dimethoxy-3-ethoxy-6-acetoxy-

flavan (Example 2) 94%. .

2-Ethoxy-3,4'-dimethoxy-6-hydroxyflavan (Example 1) 31%

In contrast, the compound known from British patent 860 303 showed ethyl 2-p-chlorophenoxy-2-methylpropionate in the higher doses of 50 (or 100) mg / kg under otherwise identical conditions only lowering of the cholesterol level of 8 (or 12)%.

Compared to known cholesterol level lowerers such as 20.25-diaza-cholesterol, 22.25-diaza-cholesterol, 25-aza-cholesterol, S ^ -diethylaminoethoxy-S-androsten-17-one, trans-1,4-bis (2-chlorobenzylaminomethyl) cyclohexane and 1- [p- (2-diethylaminoethoxy) phenyl] -1- (p-tolyl) -2- (p-chlorophenyl) ethanol the compounds obtainable according to the invention are distinguished by the fact that after their administration no unphysiological Enrichment of desmosterin or 7-dehydro-cholesterol in the sterols of the serum occurs and thus the total level of sterols in the serum decreases.

Furthermore, the compounds according to the invention differ from the last-mentioned known compounds by their low toxicity. For example, while the DL ₅₀ values (determined orally on rats) of 22.25-diaza-cholesterol dihydrochloride and 25-aza-cholesterol hydrochloride were 1.63 and 1.1.4 g / kg, 4'-Dimethoxy-3-ethoxy-6-acetoxy-flavan up to 6.4 g / kg no DL ₅₀ value can be determined.

The 2-alkoxy-flavans of the general formula I given above are prepared by a substituted 3-flame of the general formula II

OR ¹ / . .

R ³ O

OCH ₃

(Π)

in which the radicals R ¹ , R ² and R ^{3 have} the meaning given above, catalytically hydrogenated in a manner known per se, and ^{the acetyl radical is optionally converted into a compound of the formula I in which R 3 represents} a hydrogen atom in the customary manner or that optionally a compound of the formula I obtained in which R ^{3 represents} an acetyl group is saponified. ~

The 3-flavens of the general formula II to be used as starting materials are obtained by adding corresponding alcohols of the general formula R ¹ OH, where R ^{1 has} the above meaning, to the corresponding flavylium salts of the general formula III

R ³ O

OCH,

(III)

in which X ^{e is} an anion of a strong acid and R ² and R ³

1 Ü1O UUO

have the above meanings, accessible in a manner known per se. ■

Suitable catalysts for the hydrogenation of the 2-alkoxy-3-flavenes of the general formula II are, for example, noble metal, nickel and cobalt-oxide catalysts, as well as copper-chromium oxide. The noble metal catalysts can be present as supported catalysts (e.g. palladium on carbon, calcium carbonate or strontium carbonate), as oxide catalysts (e.g. platinum oxide) or as finely divided metal catalysts 10 '. Nickel and cobalt catalysts are expediently used as Raney metals, nickel also on kieselguhr or pumice stone as supports. The hydrogenation can be carried out at room temperature and normal pressure or else at elevated temperature and / or elevated pressure. It is preferred to work at pressures between 1 and 100 at and at temperatures between -80 and + 150 ^° C., primarily between room temperature and 100 ^° C. The hydrogenation is expediently carried out in the presence of a solvent. As solvents are mainly methanol, ethanol, isopropanol, tert. Butanol, ethyl acetate, acetic acid, tetrahydrofuran, dioxane or water and mixtures of these solvents with one another are suitable.

During the hydrogenation, care must be taken that the aromatic rings are not also attacked will. In the case of a number of the catalysts used, this risk is only slight. If a more active hydrogenation catalyst, for example platinum oxide, is used, the procedure is preferred at normal pressure in such a way that the hydrogenation can be carried out after the calculated amount has been taken up Hydrogen breaks off.

The saponification, if necessary, of 6-acetoxy-flavans formed to give the corresponding ones 6-Hydroxy-flavans are preferably carried out by treatment with a strong base. Are suitable before especially sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate and potassium carbonate. You usually work in alcoholic (methanolic or ethanolic) or in aqueous-alcoholic (aqueous-methanolic or aqueous-ethanolic) Solution. Although the saponification occurs gradually at room temperature, it is expedient, if appropriate, to heat the mixture to the boiling point of the solvent used. Depending on the temperature used, the saponification is complete after 0.2 to 24 hours.

The acetylation of the 6-hydroxy group, which may have to be carried out, can be carried out by heating with acetic anhydride or a halide of acetic acid. It is advantageous to esterify in the presence a base or an alkali salt of acetic acid, such as sodium acetate, or a small amount of mineral acid. The esterification can be carried out at room temperature or, if appropriate, at the boiling point of the used Solvent or solvent mixture take place. It is usually over after 1 to 48 hours.

The new compounds can be mixed with conventional drug carriers in the human or Veterinary medicine can be used. The carrier substances used are organic or inorganic Substances in question that are suitable for parenteral, enteral or topical application and that contain the new compounds do not react, such as water, vegetable oils, polyethylene glycols, Gelatin, milk sugar, starch, magnesium stearate, talc, petroleum jelly, cholesterol. For parenteral Application are especially solutions, preferably oily or aqueous solutions and suspensions, Emulsions or implants. For enteral application, tablets or dragees, for topical application ointments or creams, optionally sterilized or with auxiliary substances, such as Preservatives, stabilizers or wetting agents or salts for influencing the osmotic pressure or mixed with buffer substances. "

The inventively substituted flavan derivatives "are preferably used in a dosage of 1 to 500 mg applied per dosage unit.

: For example

5.1 g of 2-ethoxy-3,4'-dimethoxy-6-hydroxy-3-fiaven are hydrogenated in 300 ml of methanol with addition of 15 g methanol moist Raney-nickel at 8O ⁰ C and 100 atm to a standstill. The catalyst is filtered off, the methanol is distilled off under reduced pressure and the residue is chromatographed on 70 g of silica gel using benzene. The 2-ethoxy-3,4'-dimethoxy-6-hydroxyflavan eluted with benzene / chloroform 3: 2 is recrystallized from ether / pentane (1: 5). M.p. 132 to 134 ° C; Yield 13%.

B e i s ρ i-e 12

a) 1 g of 2,4'-dimethoxy-3-ethoxy-6-hydroxy-3-flaven is prereduced in 160 ml of methanol with 150 mg Catalytically hydrogenated platinum dioxide. After 72 hours the calculated amount of water is substance added. The catalyst is filtered off, the filtrate is mixed with 3 drops of pyridine " and distilled to dryness. Crude 2,4'-dimethoxy-3-ethoxy-6-hydroxy-flavan and

b) the crude product obtained from a) is then poured into 5 ml of pyridine and 5 ml of acetic anhydride Left for the night. One works up with chloroform and water, the chromatographed Crude product on 10 mg of silica gel and the 2,4'-dimethoxy-3-ethoxy-6-acetoxy-fiavan eluted with Benzene / chloroform 1: 1. The product obtained crystallizes on trituration with methanol. The 2,4 '- dimethoxy - 3 - ethoxy - 6 - acetoxy - flavan melts at 91 to 92 ° C; Yield 10%.

Claims (1)

1 KJ \ J \ J \ J Patent claims: 1. 2-alkoxy-flavans of the general formula I OR ¹ R ³ O OCH, (I)