HUT68558A - Method for preparing isoflavon derivatives - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to isoflavone-I-isoflavan-4-one and its isoflavan derivatives, their salts, pharmaceutical compositions containing the compounds of the formula I and processes for their preparation.

A narrower range of compounds of Formula I is the

I isoflavone of general formula

Isoflavan-4-οπ and IB

Isoflavans of Formula IC.

In the general formula I

R 1 is when n = 0 and taken together is an oxo group and the dotted line represents a double bond with alkylcarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, morpholino or pyridino; or (C.- _The alalkil) (CHpj ^ OCO (CHP) - y ^ alkyl-N ^ T ^ CCHPmCOCClT csUportfal''heiyetteSLxett C g alkyl group, a C3-6 cycloalkyl or cycloalkenyl, or

· R ³ represents where η = 1, R ⁵ and R ^she together represent an oxo group and the dotted line represents a double bond, optionally substituted alkylcarbonyl, alkoxycarbonyl, carboxyl, sulfonic acid, hydroxy, phenoxy, piperidino , morpholino or piridinocsoporttal or (C alkyl.) ~ N- (CH _o) CO (CH) - group - 4 £ £ £ μ substituted ΓΠ

C 1 -C 6 cycloalkyl or cycloalkenyl or C 2 -C 6 alkenyl, or

R 1 is when n = □ or 1, the dashed line does not represent a valence line and together represents an oxo group or a separate hydrogen atom;

phenyl, phenoxy, piperidino, morpholino or pyridino optionally substituted with alkylcarbonyl, alkoxycarbonyl, carboxy, succinic acid, hydroxy, alkoxy, optionally halogen, or alkyl-N- (CH ₂ ) _m CO _(CH2) p - szénatomas substituted alkyl group, C3-6 cycloalkyl or C2-6 alkenyl group, is C, _Q-alkyl, halogen, C i-V2-5 acrlcft'i ínetil- j is a ¹ -alkoxymethyl or hydroxymethyl group,

R * is hydrogen or (C 1 -C 4) -alkyl and is hydrogen or (C 1 -C 6) -alkoxy, and R 4 together represent an oxo group or a hydrogen atom separately, the dotted line represents an optional double bond, n 0 or 1 m is an integer from 1 to 4 p is an integer from 1 to 4.

The compounds of formula I are useful in the prevention and treatment of osteoporosis.

According to the present invention, compounds of formula IA can be prepared by reacting ketones of formula III (wherein R, n, R, R and R are as defined in formula I).

the. ) with an ortho-formic acid alkyl ester in the presence of a basic catalyst, or

b. ) with hydrogen cyanide and / or cyanide salts in the presence of a hydrohalic acid, or

c. ) with a formic acid alkyl ester in the presence of an alkali metal, or

d. ) with an alkyloxalyl halide, the isoflavone ester thus obtained is optionally saponified and / or decarboxylated, or

e. ) with organic carboxylic anhydride, or!

f. ) With N, N-dialkyl acid amide in the presence of phosphorus chloride, or

g. ) (IV) 2-hydroxy-Isoflav _non derivatives but is hydrated and, if desired, an R ^ group is converted, or the compound of formula I containing R as hydrogen to form the group R and, if desired, a compound (I a different group of the formula ) to form a salt or liberate a salt thereof.

In carrying out variant (a) of the process according to the invention, it is preferable to react the appropriately substituted ketone with an alkyl octohionic acid, preferably ethyl ester, in a higher boiling aprotic solvent. Pyrrolidine, dimethylformamide or diethylene glycol dimethyl ether may be used as the solvent. Preferred basic catalysts are piperidine, morpholine, pyrrolidine and other secondary amines.

In variant (b) of our process, the ketones can be reacted with hydrogen cyanide in an aprotic solvent in the presence of dry hydrochloric acid or other halogen acids or Lewis acids. The reaction may be carried out using a non-basic aprotic solvent, preferably diethyl ether or other dialkyl ethers. The catalyst may be zinc chloride or other Lewis acids.

/

The reaction is carried out with hydrogen cyanide or a suitable salt thereof, preferably zinc cyanide. The mixture can be saturated with dry hydrochloric acid gas and finally the resulting substituted N-formimino-2-hydroxyphenylbenzyl ketone hydrochloride hydrates are quenched by aqueous treatment.

In variant c), the ketones of formula III are reacted with alkyl esters of formic acid in the presence of an alkali metal.

• ·· · · ♦

Preferably, the appropriately substituted 2-hydroxyphenylbenzyl ketone, dissolved in ethyl formic acid, is added dropwise to powdered sodium hydroxide, and the reaction mixture is quenched with water and the resulting isoflavone is prepared. In variant (d) of our process, the appropriately substituted 2-hydroxyphenylbenzyl ketones are reacted with alkyl oxalyl halides. This produces a 2-alkoxycarbonyl isoflavone derivative which, if desired, can be converted to the 2-unsubstituted isoflavone by hydrolysis of the ester group followed by decarboxylation. This process can advantageously be carried out with methyl or ethyl oxalyl chloride in the presence of a basic acid acceptor in a suitable aprotic solvent. Preferably, the acid-binding property is pyridine or other tertiary amine.

Variant e) of the process comprises reacting the appropriately substituted 2-hydroxyphenylbenzyl ketone with organic acid anhydrides in the presence of a basic catalyst. Organic anhydrides include acetic, propionic, and benzoic anhydrides. The anhydride is heated in the presence of a basic catalyst, suitably the alkali metal salt of the acid component of the acid anhydride, or in the presence of tertiary amines, in a solvent or in a higher aprotic solvent such as pyridine, dimethylformamide.

In variant (f) of the process, the ketone is suitably reacted with N, N-dialkyl acid amides 1 in the presence of phosphorus oxychloride by reacting the appropriately substituted 2-hydroxyphenylbenzyl ketone with N, N-dialkyl acid amide (dimethylformamide, dimethylacetamide) and phosphorus oxychloride.

And the solvent used is Ν, Ν-dialkyl acid amide itself. In variant (g) of our process, the 2-hydroxyisoflavonones of formula (IV) are dehydrated by heating or heating in an acidic medium in a polar solvent.

In the first step of the process of the present invention, compounds of formula (III) or (IV) may be formed which have the substituents R ^{1 being} hydrogen or not the desired R 1 group in the final product.

In these cases, the group is replaced by introducing the group into a hydrogen atom or converting one group into another group.

This operation can be accomplished by partial or total alkylation of mono and polyhydroxyisoflavones, which alkylation is preferably carried out by reaction with alkyl or substituted alkyl halides, alkyl sulfonic acid lactones, alkyl sulfates, olefins or epoxides, preferably by in suitable solvents, ketones, dimethylformamide, or higher ethers, the alkylation isoflavones are preferably heated in the presence of halogen compounds, preferably in the presence of an acid acceptor such as an alkali carbonate, and in the case of alkyl bromides and alkyl chlorides.

This operation may be carried out on partial or complete deaciles of acyloxy and polyacyloxy, alkyloxy, and polyalkyloxy isoflows. ·································•

- or by partial or total dealkylation.

Acyloxy and polyacyloxy isoflavones are formed when the process of variant e) is carried out with di- and polyhydroxyphenylbenzyl ketones having a hydroxy group in the 2-position. The deacylation is preferably carried out in an acidic or basic medium in the presence of a polar solvent.

The procedure may be carried out by decarboxylation of iso-lavon-2-carboxylic acids. Isoflavone-2-carboxylic acids are formed in process variant d) and are preferably decarboxylated by heating in the presence or absence of catalysts, both in the presence of copper powder.

3

Compounds of formula IB (wherein R, n, R, R, R x

and R is as defined in Formula (I) may be prepared by reduction of compounds of Formula IA (wherein R, n, R ¹ , R ² , R 1 and R 4 are as defined in Formula I). The reduction is carried out by catalytic hydrogenation or by using metal hydrides.

In the catalytic hydrogenation, a noble metal catalyst, preferably palladium on charcoal catalyst, is used and the reduction is carried out in an organic solvent, preferably acetone.

Preferably, the complex metal hydride is diisobutylaluminum hydride with reduction at low temperature (-70 ° C).

• · · · · · · · · · · · · · · · · · · · · · ·

4 «··

123

Compounds of formula IC (wherein R, n, R, R, R and R ⁴ are as defined in formula I) are IB

The compounds of Formula 34 (wherein R, n, R, R, R and R are as defined in Formula I) may be prepared by catalytic hydrogenation in the presence of a noble metal or nickel catalyst. The reduction is preferably carried out in a polar solvent, preferably acetic acid or ethyl acetate.

That r! The compounds of formula (I) wherein the alkyl is substituted with a carboxy group may be prepared by hydrolysis of an ester group of a compound containing an alkyl group substituted with an alkoxycarbonyl group. The hydrolysis is preferably carried out in an acidic medium, preferably with lower organic acids in the presence of a strong acid catalyst.

The compounds of formula (IA) containing the 6-position methyl group may be prepared by reduction / halomethylisoflavones obtained from the 6-positioned hydrogen (IA) compounds by halomethylation. The reduction is preferably carried out in the presence of metals, preferably zinc.

Compounds of general formula (I) having an alkoxy or hydroxymethyl group at the 6-position can be obtained by replacing the halogen atom of the halomethyl isoflavones obtained by the above process with alcohols or by converting sodium acetate to O-acetyl group and converting the acetoxy group to OH. live.

The compounds of formula (I) are active in medicine and are inert, non-toxic, pharmaceutically acceptable. ····················································

It may be used in the form of compositions containing a solid or liquid diluent or carrier. The compositions may, if desired, contain known biologically active substances (e.g., vitamins, amino acids, choline chloride, salts of mineral acids, trace elements, etc.). As a carrier, e.g. talc, gelatin, calcium carbonate, magnesium stearate, starch, water, polyalkylene glycols and the like. It can be used. The compositions may be in solid (e.g., tablet, dragee, capsule, suppository) or liquid (e.g., solution, suspension or emulsion) form.

I · The present invention is illustrated by the following examples.

* ·· «··«

·· ···· • ·

- 11 Examples:

First

10 g of 7-hydroxyisoflavone, 10 ml of chloroacetone and 8 g of potassium carbonate were stirred in 120 ml of acetone and refluxed for 5 hours.

The reaction mixture was diluted with water, the precipitate was filtered off and recrystallized from acetic acid. 8.5 g of 7- (2-oxopropyl) isoflavone, m.p. 174-175 ° C.

Similarly prepared from 7-hydroxyisoflavone and the corresponding alkyl halide or m.p. 7- (2,3-dihydroxy-1-propyloxy) -isoflavone (FL 230) using a substituted alkyl halide, m.p. 164-165 ° C, 7- (3-ethoxycarbonylpropyloxy) isoflavone (FL 283), m.p. 124-125 ° C, 7- (2-phenoxyethoxy) isoflavone (FL 273), m.p. 195-197 ° C, 7- (1-ethoxycarbonyl-1-decyloxy) -isoflavone, (FL 279), m.p. 97-99 ° C, from 7-hydroxy-3 ', 4'-dimethoxyisoflavone using 3-methyl-1-butyl bromide to give 7- (3-methyl-1-butyloxy) isoflavone, (FL 191) p.p. 107-108 ° C, and 7-ethoxy-8-methylisoflavone (FL 315) from 7-hydroxy-8-methyl isoflavone, m.p. 129-130 ° C, and 7- (carbethoxymethoxy) -8-methylisoflavone (FL 316), m.p. 137-139 ° C. And 7- (4-oxo-1-pentyloxy) isoflavone (FL 501), m.p. 143-145 ° C.

··················································································································································· Receiving ·

Second

A mixture of 6-n-hexyl-7-hydroxyisoflavone (14 g), isopropyl bromide (14 ml) and dimethylformamide (ml) was stirred at 90 ° C for 16 hours in the presence of potassium carbonate (16 g). The reaction mixture was poured into 500 mL of water, the product was separated and crystallized from 8.0% aqueous methanol. 15 g of 6-n-hexyl-7- (1-methylethoxy) isoflavone are obtained, m.p. 37-39 ° C.

Similarly, 6-n-hexyl-7-ethoxyisoflavone (FL 319), m.p. 57-59 ° C, and a

6-n-hexyl-7- (2-methyl-1-propyloxy) -isoflavone (FL 321), m.p.

65-67 ° C, as well as the reaction of 6-chloro-7-hydroxyisoflavone with alkyl halides, 7-ethoxy-6-chloroisoflavone (FL 322), m.p. 162-164 ° C, 7- (1-methylethoxy) -6-chloroisoflavone (FL 323), op-156-158 ° C, 7- (2-methyl-1-propyloxy) -6- chloroisoflavone (FL 324), op.

170-172 ° C, 7- (2-propen-1-yloxy) -isoflavan-4-one (FL 238), m.p. 76-7 ° C, 7- (4-nitro-benzyloxy) -isoflavan-4-one (FL 239), m.p. Mp 100-102 ° C.

Third

6.5 g of 7-n-hexadecyloxy isoflavone are hydrogenated in 1200 ml of acetone in the presence of 3.0 g of palladium on charcoal up to 1.2 molar equivalents of hydrogen. The catalyst was filtered off and the solution was evaporated. The residue was recrystallized from methanol-acetone to give 5.3 g of 7-n-hexadecyloxyisoflavon-4-one, m.p. 90-92 ° C.

• · · ··· ·· £ · «* * · · *« ·· ···· 999 ·· ··

In a similar manner, 7-ethoxy-5-methylisoflavan-4-one (FL 299) was prepared from 7-ethoxy-5-methylisoflavone, m.p. 97-98 ° C, and 7-cyclohexylisoflavan-4-one (FL 312) is obtained by absorption of 2.2 equivalents of hydrogen from 7- (1-cyclohex-2-enyloxy) isoflavone (FL 286), m.p. 119-120 ° C.

.

A solution of 7-isopropyloxyisoflavone (g) in acetic acid (160 ml) was hydrogenated to 5 molar equivalents of hydrogen in the presence of 5% palladium on carbon. The catalyst is filtered off, the solvent is evaporated and the residue is recrystallized from methanol. 10 g of 7- (1-methylethoxy) isoflavan (FL 199) are obtained, m.p. 93-95 ° C.

Similarly prepared from the corresponding isoflavones

7- (2-methyl-1-propyloxy) isaflavan (FL'248), m.p. 97-99 ° C, 7- (n-hexadecyloxy) isoflavane (FL 314), m.p. 90-92 ° C, and absorbing 4 molar equivalents of 7- (1-cyclohex-2-enyloxy) isoflavone to give 7-cyclohexyl isoflavan (FL 314) p.p. 90-92 ° £.

5th

2.38 g of 7-hydroxyisoflavone and 1.94 g of propanesulfone are dissolved in 25 ml of methanolic sodium methylate. After 48 hours, the precipitated product is filtered off with suction and recrystallized from water.

3.0 g of sodium salt of 7- (3-sulfonyl-1-propyloxy) -isofl avon are obtained, which does not melt to 350 ° C.

· ♦ ··· ··· * * · ··· ·· ··

- 14 -. · ... ·· .. · · ..

from the corresponding 7-hydroxy-isolavone derivatives, the corresponding 7- (3-sulfonyl-1-prapyloxy) -8-methyl-isoflavone sodium salt (FL 318), m.p. Above 350 ° C, and? -Chloro-7- (3-sulfone-11-propyloxy) -isoflavone (FL 346), m.p. Above 20 ° C, 5-methyl-7-C3-sulfo-1-propyloxy) -isoflavone sodium salt (FL'5O2), m.p. Above 32 ° C; and 7- (3-sul: o-1-propyloxy) -2-methylisoflavone sodium salt (PL-291), which does not melt up to J 50 ° C.

□ 9

7- (3-Carbomethoxy-1-propyloxy) -isoflavone (16.5 g) in glacial acetic acid (165 ml), water (0.5 ml) and concentrated sulfuric acid (1.0 ml) was heated at reflux for 9 hours. After cooling, the free acid (Op 108-190 ^a C) precipitates, which is filtered off, dissolved in 300 ml of methanol and neutralized to pH 8 with 1N sodium methylate solution. The precipitated 7- (3-carboxy-1-propyloxy) -isoflavone sodium salt was filtered off with suction, yielding 13.1 g of op. In a similar manner, 7- (1-carboxy-1-propyloxy) -isoflavone (m.p. 197-200 ° C) and its sodium salt (FL 282), 7- (1-carboyl-1-decyloxy) are prepared from the corresponding esters. ) -isoflavone (m.p. 124-126 ° C) and its sodium salt (FL 280).

7th

7 g of 7-isopropyloxyisoflavone and 3.2 g of pacaformaldehyde were stirred for 3 hours at 70 ° C in a mixture of 80 ml of glacial acetic acid and 40 ml of concentrated hydrochloric acid with continuous addition of dry hydrogen chloride gas. The next day, the solution was partially evaporated and the precipitate was filtered off with suction and recrystallized from methanol. The thus obtained 7-isopropoxy-8-chloromethylisoflavone (m.p. 123-124 ° C) was obtained. · ·

To a solution of 15 ml of benzene was added boiling an equivalent amount of IN sodium methylate. The cooled solution is shaken several times with water and evaporated. The residue was recrystallized from methanol to give 7 g of 7-isopropoxy-8-methoxymethylisoflavone, m.p. 92-95 ° C. Similarly, 7-methoxy-8-methoxymethylisoflavone (FL 308) is obtained from 7-methoxyisoflavone.

8th

To a suspension of 7.5 g of 7-methoxy-8-chloromethylisofluorine in 45 ml of glacial acetic acid was added 3.0 g of zinc powder over 3 hours. After stirring for a further 8 hours, the reaction mixture was diluted with warm water, the precipitate formed was filtered off with suction and recrystallized from ethanol. 5.1 g of 7-methoxy-8-methylisoflavone are obtained, m.p.

133-135 ° C.

.

36.2 g of 2-hydroxy-4- (3-phenoxy-1-propyloxy) phenylbenzyl ketone, g of ethyl ortho-formic acid and 5 g of morpholine are refluxed in 200 ml of dimethylformamide for 8 hours. The ethyl alcohol formed during the reaction is removed via a fractionation pad. Most of the solvent was then evaporated in vacuo and the residue diluted with dilute aqueous hydrochloric acid.

The crude product is filtered off and recrystallized from acetone to give 32 g of 7- (3-phenoxy-1-propyloxy) isoflavone.

(FL 230), mp 123-125 ° C.

• ♦ ······· ···· ·· • · · · · · · · · ····· ···· ·· ·· ··

- 16 10.

9.8 g of 7- (3-chloro-1-propyloxy) isoflavone with 4.1 ml of piperidine in 2 ml of 2-butanone are 5.5 g of potassium carbonate and 0.5 g of potassium iodide. in the presence of boiling for 14 hours. The inorganic salts are filtered off hot, and after cooling, an excellent product is filtered off with suction and crystallized from methanol. 7- (3- (1-piperidinyl) propyloxy) isoflavone (FL 118) is obtained. Yield 6.0 g, m.p. 138-139 ° C.

In a similar manner, 7- (3- (1-morpholinyl) propyloxy)} isoflavone (FL 117) was prepared, m.p. 162-163 ° C.

11th

18.5 g of 7- (10-ethoxycarbonyl-1-decyloxy) isoflavone are heated in a mixture of 180 ml of glacial acetic acid, 10 ml of water and 3 ml of concentrated sulfuric acid for 4 hours. The next day, the precipitated 7- (10-carboxy-1-decyloxy) -isoflavone (m.p. 118-120 ° C) is suctioned off, dissolved in 180 ml of 4: 1 acetone-methanol and the solution is made up to pH 8 with 10% sodium hydroxide solution. set it up. The precipitated salt is suctioned off and washed with the solvent mixture. 7- (10-carboxy-1-decyloxy) -isoflavone -!

sodium salt (PL 295) is obtained. Yield: 10.6 g of product

Does not melt up to 360 ° C.

In a similar manner, 7- (5-carboxy-1-pentyloxy) -isoflavone was prepared from 7- (5-carboxy-1-pentyloxy) -isoflavone (m.p. 146-148 ° C), followed by the corresponding sodium salt (FL 302). which does not melt to 360 ° C.

12th

Dissolve 3.0 g of 7-methoxyisoflavone in 30 ml of chloroform and add to it · · · · · ······················································································· · · ···· ······ · · ·

17 g of 2.0 g of sulfuryl chloride were added. The mixture was refluxed for 1 hour, evaporated and the residue was crystallized from chloroform-ethanol (1: 1). 8-Chloro-7-methoxyisoflavone (FL 501) is obtained. Yield 22.5 g, m.p. 181-182 ° C.

Similarly, 7-ethoxy-8-chloro-isoflavone (m.p. 144-145 ° C) is prepared from 7-ethoxy-isoflavone, and S-chloro-7- (2-propyloxy) is obtained from 7- (2-propyloxy) -isoflavone. ) -isoflavone (m.p. 167-169 ° C) and from 2-methyl-7-methoxyisoflavone 8-chloro-2-methyl-7-methoxyisoflavone (FL 517) (m.p. 176-178 ° C).

13th

2.0 g of 7- (carbethoxymethoxy) isoflavone are dissolved in 10 ml of diethylaminoethanol, 2.0 g of potassium carbonate are added and the mixture is stirred for 5 hours and then poured into a mixture of ice and 2% hydrochloric acid. The product was filtered off with suction and recrystallized from methanol-acetone. 7- (N, N-diethylaminoethoxycarbonylmethoxy) isoflavone (FL 105) is obtained. Yield: 1.5 g, m.p. 227-228 ° C.

In a similar manner, 7- (N, N-diethylaminoethoxycarbonylmethoxy) -2-methylisoflavone (FL 104) is prepared from 7- (carbethoxy, methoxy) -2-methylisoflavone (FL 104) p.p. 190-192 ° C.

14th

8-Chloromethyl-7-methoxyisoflavone (16.0 g) and anhydrous sodium acetate (11.4 g) were boiled in acetic anhydride (80 ml) for 4 hours.

The reaction mixture was poured into water, the precipitated product was filtered off and recrystallized from acetic acid. 8-Acetoxymethyl-7-methoxyisoflavone (FL 509) is obtained. Yield: 11.7 g, m.p. 195-197 ° C.

Similarly, 8-acetoxymethyl-7- (2-propyloxy) -isoflavone (FL 521) was prepared from 8-chloromethyl-7- (2-propyloxy) -isoflavone, m.p. Mp 107-109 ° C.

A process for the preparation of compounds of the formula I and their salts

Claims (9)

Patent claims - where in the formula R 4 · represents when η = o and R 4 together represents an oxo group and the dashed line represents a double bond, alkylcarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino. morpholino or pyridino (C, _z1 alkyl) _? 1ί- _(CH?) ... OCOJ C? L) j bowl or (C ^ substituted ^C l-C18 alkyl group, C 3-6. cycloalkyl or cycloalkenyl; or R 4, when η = 1, R 4 and R 4 together represent an oxo group and the dotted line represents a double bond, optionally alkylcarbonyl, alkoxycarbonyl, carboxy, sulfonic acid, hydroxy, phenoxy, piperidino, C 1-6 alkyl, C 3-6 cycloalkyl or cycloalkenyl substituted with morpholino or pyridino or alkyl) ₂ N- (CH ₂ ) _m CO (CH ₂ ) -, or C 2-6 alkenyl; or R 4, when η = o or 1, the dashed line does not represent a valence line, R 4 and taken together represent an oxo group or a hydrogen atom; optionally substituted alkylcarbonyl, alkoxycarbonyl, carboxyl, sulfonic acid, hydroxy, alkoxy, optionally substituted phenyl, phenoxy, piperidino, morpholino, or pyridine group, or (C ^ _ ^ ₄ alkyl) 2 "halogen • · · - C 20 -alkyl, C 3-6 -cycloalkyl or C 2-6 -alkenyl substituted with 20 N- (CH ₂ ) _m CO (CH ₂ ) p -, R is C ₁ -C 4 -alkyl, halogen, ^1- acyloxymethyl- ¹ -alkoxymethyl-4-hydroxy-methyl, R is hydrogen or C 1-4 alkyl, 2 3 R and R are hydrogen or C 1-6 alkoxy, R 4 and together an oxo group or a hydrogen atom, respectively, the dotted line represents an optional double bond, n is 0 or 1 m is an integer from 1 to 4 p is an integer from 1 to 4 . characterized in that 1.) forming a narrower class of compounds of formula I For the preparation of compounds of formula IA wherein R, n, 12 3 A R ¹ , R ² , and R ⁴ are the ketones of Formula (III) (wherein R, n, R, R and R are as defined in Formula (I)) as defined herein. the. ) ortho-anhydrous ester 1 is reacted in the presence of a basic catalyst, or b. ) with hydrogen cyanide and / or cyanide salts in the presence of hydrochloric acid, or »· • · · c. ) with a formic acid reactant in the presence of an alkali metal, or d. ) with an alkyl oxalyl halide, the isoflavone ester thus obtained is optionally saponified and / or decarboxylated, or e. ) with an organic carboxylic acid anhydride, or f. ) With M-N, dialkyl acid amide in the presence of phosphorus chloride, or g. ) Dehydrating the 2-hydroxyisoflavonone derivatives of formula (IV), or 2.) a narrower range of compounds of formula I IB The compounds of general formula - wherein R, n, r \ r 2, r ³ and R ⁴ are as defined above for formula 1 2 IA Compounds of general formula - wherein R η, R ', R, R3 and ^R4 have the meanings given - reduced, desire 3.) a narrower range of compounds of formula I For the preparation of compounds of formula IC - wherein R, n, r ¹ , R ² , R ^3, and R ⁴ are as defined in the foregoing Compounds of formula IB - wherein R, n, R, R, 3 4 R and R are as defined in the disclosure by catalytic hydrogenation and, if desired, R ^{1 is} converted to another R 1 within the scope of the disclosure or R is hydrogen in the compound of formula I wherein R is hydrogen. »· · · · · · · · · · · · · · · · · · · · · · · · · ··· · The compound of formula (22) (I) is converted into a salt or liberated therefrom. 2. A process according to any one of claims 1 a) to f) wherein the starting material of formula III is 2-hydroxy-4-alkoxyphenylbenzyl ketone. 3. A process according to claim 2 wherein the starting material of formula (III) is 2-hydroxy-4-isopropoxyphenylbenzyl ketone. 4. Azl. a) wherein the basic catalyst used is piperidine, morpholine or pyrrolidine. / 5. The process according to 1b), wherein the reaction is carried out in an aprotic solvent, preferably diethyl ether or other dialkyl ether. / Process according to claim 5, characterized in that the reaction is carried out in the presence of Lewis acids, preferably zinc chloride. 7. The process of claim 1 c) wherein the alkali metal is sodium. I · »· * e« * · · · · · · · · · ·············································································································· Management ·· -t 8. The process of claim 1 e) wherein the organic acid anhydride is acetic anhydride, propionic anhydride or benzoic anhydride. 9. The process according to claim 8, wherein the reaction is carried out in the presence of a basic catalyst, preferably an alkali metal salt of the acid component of the acid anhydride or a tertiary amine. The process of claim 1 f) wherein the N, Ν-dialkyl acid amide is dimethylformamide or dimethylacetarone. 1. Method of carrying out the process according to g. characterized in that the dehydration is carried out in an acidic medium. - The process of claim 1, wherein the group R The compound of formula I containing a hydrogen atom is introduced by alkylation with alkyl halides, alkyl sulfates, alkyl sulfonic acids with lactones, olefins or epoxides. The process according to claim 1, claim 2, wherein the reduction is carried out by catalytic hydrogenation using 24 or metal hydrides. . The process according to claim 1, claim 3, wherein the catalyst is nickel or noble metal catalyst. i. Process for the preparation of pharmaceutical compositions. characterized in that according to a Claim 1-1-23 produced compound of the general formula - wherein R, R, R, R, R ^4, R ^5, R ^h, n, m, p and the dotted line represents the 1 The compound of claim 1 - or a salt thereof in admixture with an inert, non-toxic, solid or liquid diluent or carrier for pharmaceutical use and other excipients and preparing it in a pharmaceutical composition. 6. Compounds of the formula I and their salts. .7. Pharmaceutical compositions containing compounds of formula I.