DE1543744C3 - 3-Alkylflavanones and processes for their preparation and pharmaceuticals containing them - Google Patents

Description

^ 3-methyl-6-hydroxyflavanone

pi 6-sulfuric acid ester-sodium-

O ^salt ( ^Beis P ^{iel l b} ) ⁸⁶ ' ^0% ( ²⁵ )

³⁰ S-methyl-o-hydroxyflavanone

•. "I - λ 1, 1 ·, u · c" ui rr (example la) 42.0% (30)

m of R ^{1 is} an alkyl group with 1 to 6 carbon- Sn-Propyl-o-nicotinoyloxy-

atoms means and, if applicable, of their _flavai f _{on (ßei Je} , _{2) G} ^ _mjsch

Sulfuric acid, nicotinic acid or acetic acid _cis . _trans . _{Isomers) 36j0} o _{/ o (30)}

esters and physiologically compatible ester salts 35 S-n-propyl-o-nicotinoyloxy-

characterized in that. one in per se flavanone hydrochloride

in a known manner, if necessary in situ (Example 2) ■ 25 0 ° / (25)

produced ketone of the general formula II 3-n-propyl-6-hydroxyflävänon '

. γ. . ₀ (example la) 14.7% (25)

/ \ ^ /. ⁴ ° 3-ethyl-6-hydroxyflavanone

Γ ■ Y ■ (example la) 15.0% (25)

I Il (II) \ ν ι. \)

/ \ / \ In contrast, the compound 2-p-chlorophenium known from the British patent HO CO-X — C ₆ H _{5 script 860 303}

45 ethyl oxy-2-methylpropionate in the higher

in the X the group —CR ¹ = CH— or doses of 50 (or 100) mg / kg below otherwise

- CHR ¹ - CHY- * and Y a chlorine, bromine- same conditions only lower cholesterol levels-

or iodine atom or the hydroxyl group means gene of 8 (or 12)%.

and R ^{1 has} the meaning given above Compared to other known cholesterol level

and where phenolic hydroxyl groups also lower in 50, such as 22,25-diaza-cholesterol, 25-aza-choleste-

protected form, with a rin, 3 /) '- diethylaminoethoxy-5-androsten-17-one, trans-

cyclizing agent treated, and if the er l, 4-bis (2-chlorobenzylaminomethyl) -cyclohexane and

holding product a protected hydroxy group 1 - [p- (2- diethylaminoethoxy) - phenyl] -1 - (p-tolyl) -

contains, one this in the usual way by loading. 2- (p-chlorophenyl) -ethanol are characterized by the

treatment with hydrolyzing or hydrogenolysis compounds according to the invention in that after

liberating agents and that their administration cannot be enriched in an unphysiological manner.

optionally the compound obtained in the tion of desmosterin or 7-dehydrocholesterol in

6-sulfuric acid ester or 6-nicotinic acid ester or the sterols of the serum or the liver occurs and

6-acetic acid ester transferred and this given - thus the total content of sterols in the serum decreases,

if in their physiologically compatible ester salt 60 in the Belgian patent 652 404

convicted. - without precise information on effects - among other things

6. Medicaments containing a compound of the substances mentioned, which are also Flavaim in claim 1 given general formula I none. However, those compounds could not satisfy the and / or their sulfuric acid, nicotinic acid or existing need for effective cholesterol / acetic acid esters or physiologically compatible level-lowering substances.
Ester salts in addition to customary inert carriers and the 3-alkylflavanones of the general additives indicated above. mean 'Formula I and its sulfuric acid, nicotine

acid or acetic acid esters and physiologically

Compatible ester salts are prepared by optionally adding, in a manner known per se in situ generated ketone of the general formula II

(Π)

optionally to be accelerated up to the boiling point of the solvent used. The response time takes a few minutes to a few days.

It is not necessary to use the ketones to be used as starting products as such, but you can also do this in situ by reacting a ketone, e.g. B. the general formula III

HO

CO-XC ₆ H ₅

in the X the group

- CHR ¹ -CHY- ' ⁵

and Y denotes a chlorine, bromine or iodine atom or the hydroxyl group and R ^{1 has} the meaning given above and where phenolic hydroxyl groups can also be present in protected form, treated with a cyclizing agent, and if the product obtained contains a protected hydroxyl group, one these are set free in the usual way by treatment with hydrolyzing or hydrogenolyzing agents and that the compound obtained is optionally converted into the 6-sulfuric acid ester or 6-nicotinic acid ester or 6-acetic acid ester and this is optionally converted into its physiologically acceptable ester salt.

Particularly suitable esters of the compounds of the general formula I are the acetates, also the nicotinates and their acid addition salts, especially their hydrochlorides. Particularly important are the sulfuric acid esters and their physiologically acceptable ester salts, e.g. B. corresponding metal, especially alkali metal (e.g. sodium) and ammonium salts, as these are water-soluble and therefore therapeutic Derivatives of the compounds of the general formula I which can be applied particularly well are represented.

^{The chalcones (X = —CR 1} —CH—) are particularly suitable as compounds of the general formula II.

The cyclization of the ketone of the general formula II can mainly be effected by the action of basic or acidic catalysts. Alkalis are preferably used as catalysts such as sodium or potassium hydroxide, sodium amide, sodium hydride, basic salts such as Sodium or potassium acetate, sodium or potassium carbonate, buffer solutions: for example, those from Citric acid and disodium phosphate or from sodium or potassium dihydrogen phosphate and borax or from boric acid, sodium hydroxide and potassium chloride, organic bases such as piperidine, pyridine, Tetramethylguanidine, benzyltrimethylammonium hydroxide, mineral acids such as hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, polyphosphoric acid; organic sulfonic acids such as toluenesulfonic acid or camphorsulfonic acid.

The cyclization can be carried out in the presence of an additive inert solvents such as methanol, ethanol, dioxane, tetrahydrofuran, ethyl acetate, acetic acid, tetralin, Benzene, toluene, are carried out, optionally also in mixtures of these solvents with one another or with water. It is also possible to use an excess of the cyclizing agent as a solvent to use. The cyclization takes place at room temperature and can be achieved by heating,

HO

OH

CO-CH ₇ R ¹

(III)

in which R ^{1 has} the meaning given above and hydroxyl groups can also be present in protected form, with benzaldehyde or by reacting a corresponding p-substituted phenol with a corresponding cinnamic acid derivative in the presence of aluminum chloride and treating the mixture directly with the cyclizing agent.

A particularly preferred embodiment consists in that a mixture of the ketone of the general Formula III and benzaldehyde treated with bases such as sodium hydroxide, potassium hydroxide or piperidine. The base serves both as a condensation agent in the formation of the chalcone and as a cyclizing agent. The reaction can be carried out with or without the presence of an additional inert solvent take place. Preferred solvents are lower alcohols such as methanol, ethanol, isopropanol or tert-butanol. The reaction is expediently brought to an end by heating for several hours.

If phenolic hydroxyl groups are present in protected form, they can already be under the conditions set free of condensation. So you can find compounds in which hydroxyl groups present protected as tetrahydropyranyl ether, cyclize in an acidic or alkaline medium; in the case of an alkaline cyclization, the hydroxyl group can then be briefly boiled be set free with acid. Compounds with a hydroxyl group protected as an ester can likewise be condensed in an acidic or alkaline medium, whereby the ester group can be saponified.

Ether groups, such as benzyl ethers or methyl ethers, are also suitable as protective groups. The split Such an ether can take place, for example, if one uses hydrobromic acid as the cyclizing agent such conditions are used under which phenolic ethers are known to be cleaved.

If the process product still contains protected hydroxyl groups, these are known per se Methods by treatment with hydrolyzing or hydrogenolyzing agents in the wild set. For example, an esterified hydroxy group is hydrolyzed with basic or acidic agents.

The optionally to be carried out esterification of the hydroxyl group in the 6-position can, for. B. by Heating done with the anhydride or a halide of acetic acid or nicotinic acid. The esterification takes place advantageously in the presence of a base such as pyridine or an alkali metal salt of the corresponding Acid or a small amount of mineral acid such as sulfuric acid or hydrochloric acid.

To prepare the sulfuric acid esters of the compounds of the general formula I, these are used

with sulfuric acid or a derivative of this acid suitable for esterification, with one after Usual methods known from the literature works (see, for example, Houben-Weyl, methods der Organischen Chemie, Vol. VI / 2, pp. 452 to 464 [1963], and Vol. XII / 2, pp. 143 to 210 [1964], Georg-Thieme-Verlag, Stuttgart).

It is also possible to carry out the reaction with a sulfuric acid derivative in which a hydroxy group blocks -.- is to be carried out, and then the protective group present in the esters obtained in this way to be removed hydrolytically or hydrogenolytically.

Preferably compounds according to the invention and optionally corresponding esters and acid addition salts are those of the general formula I in which R ^{1 is} methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-amyl, isoamyl, means n-hexyl or isohexyl group.

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 which are suitable for parenteral, enteral or topical application and which do not react with the new compounds, such as water, vegetable oils, polyethylene glycols, Gelatin, milk sugar, starch, magnesium stearate, talc, petroleum jelly, cholesterol. For parenteral In particular, solutions, preferably oily or aqueous solutions and suspensions, are used for application or emulsions. For enteral application, tablets or coated tablets are also suitable for the topical application of ointments or creams, which may be sterilized or with excipients, such as Preservatives, stabilizers or wetting agents or salts for influencing the osmotic pressure or are mixed with buffer substances.

The 3-alkyl flavanones according to the invention are preferably administered in a dosage of 1 to 500 mg per dosage unit.

Example 1 ,

a) 1 g of benzaldehyde and 1.6 g of 2,5-dihydroxypropiophenone are in 3 ml of dry piperidine and 14 ml absolute ethanol refluxed for 15 hours, then stirred into ice water, with hydrochloric acid acidified and extracted with chloroform. The organic phase is washed over with water Dried sodium sulfate and evaporated to dryness. The residue is recrystallized from benzene, the 3-methyl-6-hydroxyflavanone having a melting point of 174 ° to 176 ° C. is obtained in a yield of 2.2 g.

In an analogous manner, the following are obtained from the corresponding 2,5-dihydroxyphenyl alkyl ketones:

S-ethyl-o-hydroxy-flavanon, m.p. 147 to 149 ° C,
3-n-propyl-6-hydroxy-flavanone, m.p. 145 to 146 ° C,

b) A solution of 1 g of the 3-methyl-6-hydroxy-flavanone obtained according to a) in 6 ml of pyridine is at 90 ° C. with 1.1 g of sulfamic acid and more Stirred for 3 hours at this temperature. The reaction mixture is cooled with 30 ml of ether added and mixed well. The ether phase is separated and discarded. The pyridine phase is with 17 ml Π% sodium hydroxide solution and 12 ml pyridine are good mixed, '' separated and 3 times with 10 ml of ether each time

ίο shaken out. The pyridine solution is evaporated. The sodium salt of 3-methyl-6-hydroxyflavanone-6-sulfuric acid ester crystallizes from ethanol M.p. 173 to 180 ° C. The yield is 0.72 g.

Example2

1 g of 3-n-propyl-6-hydroxyflavanone obtained analogously to Example 1 a) is in a mixture of 5 ml dry pyridine and 5 ml nicotinic acid chloride heated on the steam bath for 30 minutes. Man pours then the whole thing in water, sucks off the solid part, dries it, dissolves the product in a little ethanol and the hydrochloride of S-n-propyl-o-nicotinoyloxy-flavanons precipitates with ethereal hydrochloric acid. the Compound melts at 163 to 170 ° C.

The free base is obtained from the hydrochloride with sodium hydroxide solution and by fractional crystallization from methanol in ice- (mp. 131 to 133 ° C) and trans-S-n-propyl-o-nicotinoyloxy-flavanone (mp. 90 to 92 ° C) separately.

Example ^

1 g of 2-hydroxy-5-benzyloxy-propiophenone and 0.5 g of benzaldehyde are dissolved in 10 ml of ethanol, with 5 g 50% potassium hydroxide solution added and shaken for 5 minutes.

The mixture is then mixed with water, the precipitate is filtered off with suction, it is carefully washed with water, 3-methyl-6-benzyloxy-flavanone is obtained which, without further purification, is dissolved in 40 ml with hydrogen chloride saturated ethyl acetate in 5% palladium carbon at 35 ° C until the calculated Amount of hydrogen is hydrogenolyzed. The catalyst is filtered off and the solvent is removed and recrystallizes the 3-methyl-6-hydroxyflavanone obtained from benzene. F. 174 to 176 ° C. The

booty is 1.1 g. ■■ .. ■.: ■ ..

Example 4

2 g of 2-hydroxy-5- (tetrahydropyranyl-2-oxy) propiophenone are added analogously to Example 3 with benzaldehyde and the crude 3-methyl-6- (tetrahydropyranyl-2-oxy) -flavanone obtained is boiled 2 hours with 5% aqueous-ethanolic hydrochloric acid. The reaction mixture is stirred into water and as in Example 1 a) described worked up. The 3-methyl-6-hydroxy-flavanone is obtained with a melting point of 174 bis 176 ° C in a yield of 1.6 g.

Claims (5)

1 2 The invention relates to 3-alkylflavanones of the general claims: my formula I 1. 3-Alkylflavanones of the general formula I / OCX ^{(I) HO} HO JR ¹ ίο O in which R ^{1 is} an alkyl group with 1 to 6 carbon: ty, '\ Y' ^. '/ ■■'-; ■ 'atoms, and their sulfuric acid, nicoin of R ^{1 is} an alkyl group with 1 to 6 carbon tinsäure- or acetic acid ester and physiologically veratomen, as well as their sulfuric acid, inert ester salts and a process to their nicotinic acid or. Acetic acid esters and physiolo- 15 production as well as drugs containing them, gisch tolerable ester salts. These 3-alkylflavanones have valuable pharmaceutical 2. 3-methyl-6-hydroxy-flavanone. · Ecological properties. In particular, they show one 3. Sodium salt of 3-methyl-6-hydroxy-flava- cholesterol lowering effect.
non-6-sulfuric acid ester. The cholesterol lowering effect was on 4. S-n-propyl-o-nicotinoyloxy-flavanon and des- 20 rats according to the methodology of C o u η s e 11 and sen hydrochloride. Employees, J. med. pharm. Chem., Vol. 5, pp. 724ff. 5. Process for the preparation of 3-alkyl-flava- and 1224ff. (1962), determined. In the following table Nonene of the general formula I is the lowering of the cholesterol level in the serum of rats given in percent after oral administration. C ₆ H ₅ 25 The dosage in mg / kg rat is given in brackets. give.