FI63568C - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC THERAPEUTIC MEASURES I 7-STATIONARY SUBSTITUTES OF 8-AMINOMETHYLSOPHLAVONDERIVAT - Google Patents

Description

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S & 6 ** utlAggninosskrift o «5 boo C Patent granted 11 07 1933 V? V ^ Petent oeddelat ^ 1 ^ (51) Kv.ik? /Int.a.3 C 07 D 311/36 FINLAND — FINLAND (21) PKonttlhakomu · - Put «Mam6kntn (751272 (22) HakwntapUvt —AMBknktc ^ ag 28.0U.75 * '(23) AlkupIM-GlMghottdai 28.0U.75 (41) Tulkit JulklMkH - HMt eNuntNg 0U .11.75

Patent and RakirtarihallitiM _, „nrh - (44) Nlhtlvlkilponcn | a kotiLJulkotoun fnrm.— o- PMint- OCR njIlUrityrilNn An * 6ktA utltfd och \ ni * krtttm puMtemd 31 · 03 * 03

(32) (33) (31) i’yydMtr ocuoikoua —tegii * priority 03.05.7U

Hungary-Hungary (HU) CI-1U7U

(71) Chinoin Gygyszer Is Vegylszeti Termlkek Gyara RT., Τδ u. 1-5, Budapest IV, Hungary-Hungary (HU) (72) Laszlo Feuer, Budapest, Istvan Dory, Budapest, Lorand Farkas, Budapest, Mihaly Nogradi, Budapest, Maria Polgär, Monor, Hungary-Hungary (HU) (7U) Oy Kolster Ab (5U) Process for the preparation of new, therapeutically useful, 7-substituted 8-aminomethylisoflavone derivatives

The invention relates to a process for the preparation of new therapeutically useful 7-substituted 8-aminomethylisoflavone derivatives of the general formula (I) (I) 0 CH, I 2

OF

/ ^ \!

R R

63568 wherein R is an alkyl group having 1 to 16 carbon atoms, R 1 is an alkyl group having 1 to 4 carbon atoms, R is a hydroxyethyl group or an O-picolyl group, or R and R together with an adjacent nitrogen atom form a morpholino, piperidino or a pyrrolidino ring, and salts of these compounds with inorganic or organic acids.

It is known from Finnish Patent Publication 57,406 (corresponding to Hungarian Patent Publication 162,377) that 7-alkoxy isoflavones are used as feed additives because they have an effect on metabolism.

7-Alkoxyisoflavones are naturally occurring compounds with high biological activity. They play an important role in regulating the metabolism of cells in plant and animal organisms. When allowed to act on a living organism, a significant vitamin-like effect can be observed. In practice, however, the use of these compounds for this purpose is hampered by the fact that these compounds are completely insoluble in water and aqueous solvents and their solubility in organic solvents is also very limited.

Preferred compounds of general formula (I) are those in which R is a methyl, isopropyl or cetyl group * R 1 is a methyl or butyl group and R is * (- picolyl or β-hydroxy-12 ethyl group) or R and R form together with an adjacent nitrogen atom a morpholino, pyrrolidino or piperidino ring.

Particularly preferred compounds of general formula (I) are the following derivatives: 7-methoxy-8- (methyl-β-hydroxyethylamino) methylisoflavone, 7-methoxy-8-morpholinomethylisoflavone, 7-isopropoxy-8-morpholinomethylisoflavone , 7-isopropoxy-8- (methyl-N-hydroxyethylaminomethyl) -isoflavone, 7-fisopropoxy-8-piperidinomethyl-isoflavone, 7-isopropoxy-8- [n-butyl-2 '- (n-picolyl) - aminomethyl] isoflavone, 7-isopropoxy-8-pyrrolidinomethylisoflavone 7-cetyloxy-8-morpholinomethylisoflavone and salts thereof.

The compounds of general formula (I) form salts with inorganic and organic acids. Preferred salts include hydrochlorides and hydrogen sulfates, as well as nicotinates, bitartrates, citrates, gluconates and lactates.

The salts formed with the compounds of general formula (I) with organic or inorganic acids crystallize from aqueous solvents while taking up water of crystallization.

Hydrochlorides prepared in this way can be prepared in 4-5% aqueous solutions, while salts prepared using organic acids can be prepared in 0.5-1% solutions. By adding 5-10% alcohol, Gly-serine and 4-5% glucose to the aqueous solvent, more concentrated solutions can also be prepared.

The process according to the invention for the preparation of 7-substituted 8-aminomethylisoflavone derivatives of the general formula (I) is characterized in that the compounds of the general formula (II)

Jl / ° 6H5 rrj

RO

wherein R is as defined above, chloromethylated and the resulting compounds of general formula (III) O / C6H5 iff (III) RO '[

CH

tl2 wherein R is as defined above, is reacted with secondary amines of general formula (IV) wherein R and R are as defined above, and the resulting compounds of general formula (I) are subjected to if desired, react with organic or inorganic acids to give the corresponding salts.

4,63568

The compounds of general formula (II) used as starting materials in the process are known (see, for example, Finnish Patent Publication 57,406).

In the first step of the process, the compounds of general formula (II) are chloromethylated. This reaction is carried out in the presence of para-formaldehyde with dry hydrochloric acid gas or in the presence of formaldehyde with a concentrated aqueous solution of hydrochloric acid. The chloromethylation is preferably carried out in the presence of a Lewis acid, suitably in the presence of zinc chloride, aluminum chloride or stannous chloride. For example, acetic acid or propionic acid can be used as the reaction medium. The reaction is carried out at temperatures between 60 and 100 ° C, preferably between 85 and 95 ° C.

The obtained compounds of general formula (III) can be isolated in a manner known per se by evaporating the reaction mixture and precipitating with concentrated hydrochloric acid.

Compounds of general formula (III) are converted into the desired compounds of general formula (I) by reacting them with secondary amines of general formula (IV). As the amines of the general formula (IV), p-methylaminoethanol, morpholine, piperidine, pyrrolidine or o (-n-butylamino-N-picoline) are preferably used, and the reaction is carried out by heating, preferably at the boiling point of the reaction mixture.

Suitable reaction media are preferably lower alkanols, for example methanol, ethanol or propanol, or also an excess of the amine of the general formula (IV). At the same time, the excess amine acts as an acid scavenger to scavenge the resulting hydrochloric acid.

The compounds of general formula (I) are isolated in a manner known per se, for example by pouring the reaction mixture into water, removing the solvent and, if necessary, precipitating.

The compound of general formula (I) can be prepared in a manner known per se in a solvent medium, for example alkanols, such as methanol or ethanol, by adding the desired acid addition salts by treating the acid added with a suitable stoichiometric amount.

The compounds of general formula (I) and their salts can be used for the treatment of various bone defects (osteopathy) and for the treatment of heart and lung diseases in which oxygen deprivation and (blood) hyperacidity are the main causes of symptoms, such as pulmonary heart disease, 5 6 8 for the treatment of flatulence and connective tissue of the lungs, as well as for the treatment of disorders of the peripheral circulation. The compounds have a beneficial effect on oxidative phosphorusation and energy storage processes within the meaning of the term "oxygen conservation", in part on the energy-consuming ion translocation processes within pot cells (potassium economy, calcium mineralization).

The 7-substituted 8-aminomethylisoflavone derivatives of the invention significantly increase the enzyme activity of mycocrine cytochrome C.

Compared to the known 7-alkoxy isoflavones, the 7-substituted 8-aminomethylisoflavone derivatives according to the invention have the advantageous property of their water solubility.

Compounds of general formula (I) or their salts and inert, solid or liquid diluents. The pharmaceutical preparations are prepared in ways known per se.

Preparations containing compounds of general formula (I) or their salts may, if desired, contain other additives, for example biologically active substances. As such, vitamins, amino acids and choline chloride come into play. The preparations may also contain mineral salts, trace elements and other biologically important substances. Tablets prepared with common diluents and carriers such as talc, starch, magnesium stearate, etc. preferably contain 100 to 200 mg of active ingredient. The daily dose depends on the patient's condition and the doctor can easily determine the dose based on his professional skills.

The potency of the compounds of the invention is as follows:

Pharmacological and clinical effects 7-Isopropoxy-8-morpholinomethyl-isoflovan-nicotinate caused significant nitrogen retention in rats at a daily dose of 10 mg / kg for 5 weeks (orally). In a swimming experiment in male rats, rats treated with 5 mg / kg of compound showed a significant improvement in swimming performance in a 45-day experiment.

In addition, the compound significantly reduced the oxygen demand of resting animals, as observed in a 4-week experiment of 6,63568 rats given 1 mg / 100 g body weight daily.

The compound significantly increases the retention of calcium, potassium and phosphate. In this case, no estrogenic or androgenic side effects occur and no effect on the thyroid gland or the adrenal cortex is observed. The compound increases the activity of the glycolytic enzyme system. NAD-dependent substrates were found to have such an effect on oxidation that the intensity of oxidation at rest was lower and, in the active state, higher than otherwise. The degree of oxidation is improved by the effect on the Shuttle mechanism (the energy-consuming swelling of the rods is increased and, in addition, the activity of β-glycerophosphate is increased.

The invention is further illustrated by the following examples:

Example 1 7-Methoxy-8- (methyl- [3-hydroxyethylamino) -methyl-isoflavone 50.4 g of 7-methoxy-isoflavone are suspended in 500 ml of glacial acetic acid and, after addition of 24.9 g of paraformaldehyde, it is heated to 90 ° C. To the resulting clear solution is added dropwise a solution containing 1.5 g of zinc chloride in 150 ml of concentrated hydrochloric acid. The reaction mixture is kept at 90-95 ° C for a further 2 hours, then clarified with 1 g of activated carbon and filtered. The filtrate is evaporated under reduced pressure to 100 ml. To this residue is added 20 ml of concentrated hydrochloric acid and, after cooling with ice, filtered. The precipitate is washed with 80% acetic acid and then dried in vacuo. The crude product obtained (51.8 g) is recrystallized from boiling methanol. 7-Methoxy-8-chloromethylisoflavone is obtained, melting at 146-148 ° C 15.0 g of 7-methoxy-8-chloromethylisoflavone are suspended in 150 ml of methanol, 8 ml of p-methylaminoethanol are added to the suspension, and the mixture is boiled for 3 hours. The reactants are completely soluble. The solution is poured into 450 ml of water and, after cooling, the separated product is filtered off. It is washed with 20% methanol and dried. 15.2 g of 7-methoxy-8- (methyl-β-hydroxyethylamino) methylisoflavone are obtained, which, after recrystallization from methanol, melts at 72-74 ° C.

Example 2 7-Methoxy-8-morpholinomethylisoflavone A. To a suspension of 60.0 g of 7-methoxy-8-chloromethylisoflavone in 600 ml of methanol is added 35 ml of morpholine and the mixture is heated to reflux with stirring. . A clear solution is obtained within 20 minutes. The solution is boiled for 3 hours. The resulting slightly yellow solution is drained into 2400 ml of water while stirring. After cooling, the precipitate formed is filtered off, washed with 20% aqueous methanol and finally dried. This gives 67.1 g of 7-methoxy-8-morpholinomethylisoflavone, which melts at 179-18 ° C after recrystallization from methanol.

B. Salts of 7-methoxy-8-morpholinomethyl-isoflavone: a) 7-Methoxy-8-morpholinomethyl-isoflavone hydrochloride 17.5 g of 7-methoxy-8-morpholinomethyl-isoflavone are suspended in 160 ml of absolute methanol and the suspension bring to the boil while stirring. To the mixture is added 5 ml of concentrated hydrochloric acid in 15 ml of methanol, whereby the substance is completely soluble. After boiling for 15 minutes, the solution is clarified with activated carbon at reflux temperature and filtered. 15 ml of benzene are added to the filtrate, after which 2/3 of the solvent is distilled off at atmospheric pressure. The hydrochloride salt is crystallized by cooling the remaining solution to -10 ° C, the cooled solution is filtered, the crystals are washed with methanol and dried. 16.9 g of the title hydrochloride are obtained, melting at 240-242 ° C b) 7-methoxy-8-morpholinomethyl isoflavone nicotinate 14.0 g of 7-methoxy-8-morpholinomethyl isoflavone are dissolved in 140 ml of boiling water. absolute isopropanol. A suspension of 5.0 g of nicotinic acid in 15 ml of isopropanol is passed into the solution. The slightly yellow solution is boiled for 15 minutes and then cooled, whereupon the product separates on crystallization. After cooling to -10 ° C, the product is filtered and washed with isopropanol. After drying, 18.3 g of 6,3568 nicotinate are obtained, which, after recrystallization from isopropanol, melts at 157-158 ° C.

Example 3 7-Isopropoxy-8-morpholinomethyl-isoflavone 56.0 g of 7-isopropoxy-isoflavone are dissolved in 560 ml of acetic acid with gentle stirring. 24 g of paraformaldehyde are added to the solution and the solution is heated to 90 ° C. 150 ml of concentrated hydrochloric acid containing 1.5 g of zinc chloride are added to the solution over 2 hours with stirring. After heating for a further hour, the solution is clarified at 90-95 ° C with activated carbon, filtered hot and evaporated under reduced pressure to 150-160 ml. The residue thus obtained is diluted with 20 ml of concentrated hydrochloric acid and crystallized with stirring and cooling. After cooling with ice, the crystals are filtered off and washed with 80% acetic acid. After drying, 50.6 g of 7-isopropoxy-8-chloromethylisoflavone are obtained, melting at 125-126 ° C.

The 7-isopropoxy-8-chloromethyl-isoflavone obtained is converted into 7-isopropoxy-8-morpholinomethyl-isoflavone as follows: 32.8 g of 7-isopropoxy-8-chloromethyl-isoflavone are dissolved in 164 ml of warm absolute alcohol while adding 20 ml of morpholine and the mixture is boiled for 3 hours. hours. The boiling solution is drained, while stirring, very slowly into 700 ml of water. After cooling, the separated crystals are filtered off and washed with 20% aqueous alcohol solution. This gives 37.7 g of 7-isopropoxy-8-morpholinomethylisoflavone, which, after recrystallization from methanol, melts at 126-128 ° C.

B. Salts of 7-isopropoxy-8-morpholinomethyl-isoflavone: a) 7-Isopropoxy-8-morpholinomethyl-isoflavone hydrochloride monohydrate 10.0 g of 7-isopropoxy-8-morpholinomethyl-isoflavone are dissolved in 50 ml of boiling absolute alcohol. A mixture of 2.8 ml of concentrated hydrochloric acid and 10 ml of absolute alcohol is added to the solution. After boiling for 30 minutes, the solution is clarified with activated carbon, filtered and crystallized by cooling. After filtration, the hydrochloride obtained is washed with 96% alcohol. 10.1 g of the title hydrochloride monohydrate are obtained, melting at 223-224 ° C.

(b) 7-Isopropoxy-8-morpholinomethyl-isoflavone hydrogen sulphate To a warm solution containing 10.0 g of 7-isopropoxy-63568 8-morpholinomethyl-isoflavone in 40 ml of methanol is added 145 ml of concentrated 1N-SO 2 ( specific gravity 1.84) and 10 ml of methanol. The mixture is boiled for 15 minutes. Already during cooking, the product begins to separate. The mixture is cooled with stirring, then cooled with ice, filtered and the product separated by filtration is washed with absolute methanol. After drying at 60 ° C, 9.9 g of the title hydrogen sulphate are obtained, melting at 228-23 ° C.

o) 7-Isopropoxy-8-morpholinomethyl-isoflavone nicotinate 10.0 g of 7-isopropoxy-8-morpholinomethyl-isoflavone are dissolved in 40 ml of hot isopropanol. To this solution is added a solution containing 3.5 g of nicotinic acid in 10 ml of isopropanol. After boiling for 15 minutes, the solution is clarified with activated carbon at boiling temperature for 30 minutes and filtered. After cooling to -10 ° C, the crystallized product is filtered off and washed with isopropanol. After drying in a vacuum desiccator, 11.5 g of the title nicotinate are obtained, melting at 133-134 ° C.

If the nicotinate of 7-isopropoxy-8-morpholinomethyl-isoflavone is recrystallized from a four-fold amount of 85% isopropyl alcohol, the compound binds one mole of water of crystallization and also retains it during drying in a desiccator. The melting point of 7-isopropoxy-8-morpholinomethyl isoflavone nicotinate monohydrate is 106-108 ° C.

d) 7-Isopropoxy-8-morpholinoisoflavone bitartrate hydrate 10.0 g of 7-isopropoxy-8-morpholinomethylisoflavone are dissolved in 40 ml of hot isopropanol. A suspension of 4.0 g of tartaric acid and 10 ml of isopropanol is added to the solution with stirring. After only a few seconds, the product begins to crystallize vigorously. After boiling for 15 minutes, the mixture is cooled and filtered and the crystals are washed with isopropanol. This gives 13.3 g of the title bitartrate, melting at 184-186 ° C.

e) 7-Isopropoxy-8-morpholinomethyl isoflavone citrate hydrate 10.0 g of 7-isopropoxy-8-morpholinomethyl isoflavone are dissolved in 50 ml of 85% boiling isopropanol. A suspension of 6.5 g of citric acid in 15 ml of 85% isopropanol is passed into the solution. After boiling for 15 minutes, 10 ml of anhydrous benzene are added to the completely clear solution. 20 ml of 10 63568 distillate are distilled off at atmospheric pressure. The remaining solution is clarified with activated carbon, filtered and crystallized with stirring. After cooling with ice, the separated product is filtered off, washed with anhydrous isopropanol and finally dried. This gives 14.1 g of the title salt, melting at 151-153 ° C.

f) 7-Isopropoxy-8-morpholinomethyl-isoflavone-gluconate 10.0 g of 7-isopropoxy-8-morpholinomethyl-isoflavone are dissolved in 50 ml of warm anhydrous isopropanol. 10 ml of 50% gluconic acid solution are poured into the solution and the mixture is then boiled for 1/2 hour. After thorough cooling, the product is filtered and washed with ice-cold isopropanol. After drying at 60 ° C, 15.5 g of the title salt are obtained in the form of snow-white crystals melting at 131-133 ° C.

Example 4 7-Isopropoxy-8- (methyl-β-hydroxyethylaminomethyl) -isoflavone A. 20.0 g of 7-isopropoxy-8-chloromethyl-isoflavone and 16 ml of β-methylaminoethanol are refluxed in 100 ml of absolute ethanol. 6 hours. The pale yellow solution is then clarified with activated carbon, filtered and evaporated to dryness in vacuo. This leaves 31.0 g of a viscous mass which is mixed with 31 ml of acetone. The pH of the mixture is adjusted to 8 with concentrated hydrochloric acid and the product is crystallized by cooling. After cooling to -10 ° C, the mixture is filtered. The product is washed with 50% aqueous acetone and dried in a desiccator. 21.7 g of 7-isopropoxy-8- (methyl-β-hydroxyethylaminomethyl) -isoflavone are obtained, melting at 80-81 ° C.

B. Salts of 7-isopropoxy-8-methyl-p-hydroxyethylaminomethyl) isoflavone: a) 7-Isopropoxy-8- (methyl- (3-hydroxyethylaminomethyl) isoflavone hydrochloride monohydrate 10.0 g 7-isopropoxy -8-Chloromethyl isoflavone is reacted as described in Example 3A in 50 mL of absolute ethanol with 8 mL of N, N-methylaminoethanol. The tough mass (15 g) obtained after evaporation to dryness is dissolved in 10 ml of hot 1N hydrochloric acid and the product is precipitated by adding 12.0 g of common salt. The crystals separate on cooling. These are filtered off, dried and recrystallized from twice the amount of methanol. 6.4 g of the title salt are obtained, melting at 164-166 ° C.

b) 7-Isopropoxy-8- (methyl-p-hydroxyethylaminomethyl) isoflavone isonicotinate 30.0 g of 7-isopropoxy-8- (methyl-p-hydroxyethylaminomethyl) isoflavone are dissolved in 90 ml of warm isopropanol. The solution is run into a suspension containing 10.2 g of nicotinic acid in 32 ml of isopropanol. The mixture is boiled for 15 minutes and then cooled with stirring. The salt separated by crystallization is filtered off at -10 ° C and dried in a vacuum desiccator. This gives 26.0 g of the title product, melting at 120-121 ° C.

o) 7-Isopropoxy-8- (methyl-p-hydroxyethylaminomethyl) -isoflavone bitartrate hydrate 10.0 g of 7-isopropoxy-8- (methyl-β-hydroxyethylaminomethyl) -isoflavone are dissolved in 40 ml. hot isopropanol. A suspension of 4.1 g of tartaric acid in 10 ml of isopropanol is passed into the solution. The mixture is boiled for 15 minutes. Crystallization begins in the already boiling solution. After cooling, the product is filtered off, washed with isopropanol and finally dried. 12.6 g of the title salt are obtained, melting at 134-136 ° C.

Example 5 A. 7-Isopropoxy-8-piperidinomethylisoflavone To 10 g of 7-isopropoxy-8-piperidinomethylisoflavone are added 50 ml of absolute alcohol and 10 ml of piperidine and the mixture is refluxed for b hours. After clarification with activated carbon, the mixture is filtered and the base is crystallized from the filtrate under efficient cooling. At -10 ° C, filtration is performed, the product is washed with absolute ethanol and finally dried at 60 ° C. This gives 9.06 g of crystalline 7-iso-propoxy-8-piperidinomethyl-isoflavone, melting at 138 ° C.

B. 7-Isopropoxy-8-piperidinomethyl-isoflavone salt: a) 7-Isopropoxy-8-piperidinomethyl-isoflavone-nicotinate 3.8 g of 7-isopropoxy-8-piperidinomethyl-isoflavone are dissolved by boiling in 15 ml of isopropanol. 1.3 g of nicotinic acid suspended in 5 ml of 12 6 3568 85% isopropanol are added to the solution with stirring. The mixture is boiled for 1/2 hour and then cooled. The crystals obtained are filtered off, washed with 85% isopropanol and dried in a desiccator. This gives a yield of 4.4 g of the title salt containing one mole of water of crystallization. It melts at 133-134 ° C.

Example 6 7-Isopropoxy-8-t-butyl-21- (° C-picolyl) -aminomethyl] -isoflavone hydrochloride 10 g of 7-isopropoxy-8-chloromethyl-isoflavone and 50 ml of absolute alcohol and 6 ml of butylamino-N'-picoline is mixed together. The mixture is refluxed for 2 hours. It is then clarified with activated carbon, filtered and the filtrate evaporated to dryness in vacuo. 16.7 g of a viscous mass remain, which is dissolved in 33 ml of acetone. The solution is made strongly acidic with concentrated hydrochloric acid and the product is precipitated by adding water. After efficient cooling, the precipitate is filtered off, washed with aqueous acetone solution and dried in vacuum desiccators. This gives 8.6 g of 7-isopropoxy-8-tert-butyl-2 '- (-picolyl) aminomethyl-7-isoflavone hydrochloride, which, after recrystallization from methanol, melts at 108-110 ° C.

Example 7 A. 7-Isopropoxy-8-pyrrolidinomethyl-isoflavone 10.0 g of 7-isopropoxy-8-chloromethyl-isoflavone are suspended in 50 ml of absolute ethanol. 5 ml of pyrrolidine are added to the suspension and the mixture is refluxed for 3 hours. The substance begins to dissolve already at 50 ° C. The orange solution is clarified with activated carbon, filtered and run while still warm in 100 ml of water. The mixture is worked up as described in Example 3A. This gives 10.5 g of 7-isopropoxy-8-pyrrolidinomethyl isoflavone, melting at 115-116 ° C.

B. Salts of 7-isopropoxy-8-pyrrolidinomethyl-isoflavone: a) 7-Isopropoxy-8-pyrrolidinomethyl-isoflavone hydrochloride 10.0 g of 7-isopropoxy-8-pyrrolidinomethyl-isoflavone are dissolved in 38 ml of warm absolute methanol. A mixture of 2.5 ml of concentrated hydrochloric acid (specific gravity 1.19) and 10 ml of absolute ethanol is added to the solution, followed by boiling for 15 minutes. Upon cooling, the separated crystals are isolated as described in Example 3Ba). 10.25 g of the hydrochloride hydrate of the title 13,63568 are obtained, melting at 218-220 ° C.

b) 7-Isopropoxy-8-pyrrolidinomethyl isoflavone nicotinate 10.0 g of 7-isopropoxy-8-pyrrolidinomethyl isoflavone are dissolved in 30 ml of warm anhydrous isopropanol. A suspension of 3.4 g of nicotinic acid in 10 ml of anhydrous isopropanol is added to the solution and the mixture is boiled for 15 minutes. Thereafter, further processing is performed as described in Example 3Bc). 12.60 g of the title nicotinate are obtained, melting at 156-158 ° C.

c) 7-Isopropoxy-8-pyrrolidinomethyl-isoflavone bitrate hydrate 10.0 g of 7-isopropoxy-8-pyrrolidinomethyl-isoflavone are dissolved in 40 ml of isopropanol by boiling. The boiling solution is stirred in a suspension of 4.0 g of tartaric acid in 10 ml of anhydrous isopropanol. Crystallization begins immediately. After boiling for 1/2 hour, the mixture is cooled, filtered and the separated crystalline product is washed with cold 85% isopropanol. The product is dried at atmospheric pressure at 60 ° C. 14.30 g of crystalline title salt are obtained, melting at 166-168 ° C.

Example 8 A. 7-Cetyloxy-8-morpholinomethyl-isoflavone 23.0 g of 7-cetyloxy-isoflavone and 6.0 g of paraformaldehyde are dissolved in 460 ml of warm glacial acetic acid. 40 ml of concentrated hydrochloric acid containing 0.4 g of zinc chloride are added to the solution at 90-95 ° C over a period of 2 hours. After the addition is complete, the mixture is stirred for an additional 2 hours at 90-95 ° C. While still warm, the mixture is clarified with activated carbon, filtered and crystallized by cooling. The silky, greasy product is filtered off, washed with 80% acetic acid and dried in a vacuum desiccator. After recrystallization from absolute alcohol, 19.0 g of 7-cetyloxy-8-chloromethylisoflavone are obtained.

A mixture of 15.6 g of 7-cetyloxy-8-chloromethylisoflavone, 50 ml of absolute ethanol and 10 ml of morpholine is refluxed for 6 hours. The solid dissolves slowly. The dark red solution is clarified hot with activated carbon, filtered and finally cooled. After cooling with ice-salt-cold mixture, the crystalline product is filtered off, washed with absolute ethanol and dried in a vacuum desiccator. 15.5 g of 7-cetyloxy-8-morpholinomethyl-1463568 isoflavone are obtained, melting at 93-94 ° C.

B. Salts of 7-cetyloxy-8-morpholinomethyl-isoflavone: a) 7-Cetyloxy-8-morpholinomethyl-isoflavone hydrochloride 11.0 g of 7-cetyloxy-8-morpholinomethyl-isoflavone are dissolved in 20 ml of hot absolute alcohol and in solution a mixture of 1 ml of concentrated hydrochloric acid and 3 ml of absolute alcohol is added. The clear solution is boiled for 15 minutes and then cooled. The separated hydrochloride is filtered and washed with 96% alcohol. After drying, 6.3 g of hydrochloride are obtained, melting at 187-189 ° C.

b) 7-Cetyloxy-8-morpholinomethyl isoflavone 1-nicotinate 5.6 g of 7-cetyloxy-8-morpholinomethyl isoflavone are dissolved in 28 ml of hot isopropanol. The solution is mixed with a suspension of 1.3 g of nicotinic acid in 5 ml of isopropyl alcohol and boiled for 15 minutes. The product crystallizes on cooling. After cooling with ice, the product is filtered off, washed with isopropanol and dried in vacuo. This gives 4.8 g of the title nicotinate, melting at 97 ° C.

Claims (1)

A process for the preparation of novel, therapeutically useful, 7-substituted 8-aminomethylisoflavone derivatives of the general formula (I) P c H .Φ ", CH, I 2 / sr R wherein R is an alkyl group, having 1 to 16 carbon atoms, R 1 is an alkyl group having 1 to 4 carbon atoms, R is a hydroxyethyl group or a J 12 R picolyl group, or R and R together with an adjacent nitrogen atom form a morpholino, piperidino or pyrrolidino ring, and for the preparation of salts of these compounds with inorganic or organic acids, characterized in that the compounds of general formula (II) Mr - in which R is as defined above are chloromethylated and the resulting compounds of general formula (III) CfiHp <ΓΙΙ> fYY 6 5 Ro / Ύ "0" CH- i2 Cl where R is as defined above is reacted with secondary amines of general formula (IV) 16 6 35 6 8 / r1 HV, (IV) 1 2 where R and R denote s as above, and the resulting compounds of general formula (I) are, if desired, reacted with organic or inorganic acids to give the corresponding salts. For the preparation of therapeutically active compounds, 7-substituted substituents of the 8-aminomethyl isoflavone derivatives with the formula (I) RO ^ V ^ »^ (I) CH i 2 ^ \ l R R-1 · color R är en alkylgrupp with 1-16 cholatomers, R1 is an alkyl group with 1-4 cholatomers, R is a hydroxyethyl group or a "> (.- picolyl group, or R1 and R2 is a bridging atom with a negative quaternary atom of morpholino, piperidino or pyrrolidination, and obtained from organic or organic syringes in the form of a mixture of chlorine-methylated compounds having the same formulation (II) 0 Γ T Γ UI) RO color R III)