DE2222926A1 - Substituted benzopyran derivatives, processes for their preparation and medicinal preparations containing these compounds - Google Patents

Description

"Substituted Benzopyran Derivatives, Processes for Their Production and Medicinal Preparations Containing Dier · ⁰ " Orbonds ^!

Priority: May 11th. 1971, Great Britain, IJr. 14 226/71

The invention relates to new substituted benzopyran derivatives which contain an optionally substituted phenyl group in the 4-position of the benzopyran ring, processes for their preparation and medicinal preparations containing these compounds.

From British Patent No. 1,169,784 are among others Benzopyran derivatives of the general formula (I) known,

(D

^ L

1 2

in U ₁ a lower alkyl group and R-. is a non-aromatic carbon fiber group with 1 to 20 carbon atoms. Corresponding compounds in which the pyridyl group through

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.- 2 - 2222326

other heterocyclic groups are replaced, are subject ■;. "■ · older German patent application No. P 21 ^ 5 319.0. These compounds have an activity on the central nervous system.

Originally it was thought that the presence of a heterocyclic Ring in the 4-position of the benzopyran ring is necessary for pharmaceutical activity. It has now been found that the heterocyclic ring can be replaced with a carbocyclic aromatic group without loss of activity. aside from that the spectrum of pharmaceutical activity of these compounds differs somewhat from that of the compounds described so far, so that the new benzopyran derivatives could be used where no appropriate treatment was previously possible was.

Accordingly, the invention relates to substituted benzopyran derivatives te of the following general formula (II) and their salts

¹ I ' ^{w R} 5

in the R ,. and R _{0 are} identical or different and are each a carbon; A hydrogen group with 1 to 6 carbon atoms, R denotes a non-aromatic hydrocarbon group with 1 to 12 carbon atoms, R / denotes an optionally substituted phenyl group and A denotes a hydrogen atom or a salt, acyl or inorganic ester group derived therefrom.

8AD ORIGINAL

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Suitable groups for R ₁ and R ₂ are the methyl, isopropyl, butyl, allyl and phenyl groups.

The methyl group is preferred for R ₁ and R _2.

Suitable groups for R- are the methyl, ethyl, allyl, pentyl, heptyl, nonyl, dodecyl, cyclohexyl, methylcyclopentyl and cyclopentylmethyl groups.

Preferred for R are alkyl groups with 5 "to 9 carbon atoms, especially those closest to the ring. Carbon atom are branched, e.g. the 2-octyl and 3-methyl-2-octyl groups.

Suitable for R ^ is the phenyl group, optionally with one or more halogen atoms, one or more alkyl or alkoxy groups. or with a cyano, amino, hydroxyl, Hydroxyalkyl, carboxyl, acyloxy, acylamino, carboalkoxy or dialkylamino group is substituted.

Preferred for R ^ is phenyl, fluorophenyl, chlorophenyl, Bromophenyl-, Tolvl-, Methoxyphenyl-, Dimethylphenyl-, Hydroxymethy! Phenyl-, Carboxyphenyl, dimethylaminophenyl and hydroxyphenyl groups.

An H, Li, Na, K, Ca, Mg and Al ion or an acetyl, benzoyl, propionyl, 3-diethylaminopropionyl, h -diinethylamiiiobutyryl or " a phosphate group.

Preferred for X is H or an alkali metal.

Among the benzopyric derivatives of the general formula (II) according to the invention, the compounds of the formula (III.) And their ", fjfilz'ci" are preferred,

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ι Ο

ίί Ί

in which Rc is an alkyl group having 5 "to 9 carbon atoms and Rg a hydrogen or halogen atom, a hydroxyl, methoxy, methyl, hydroxylmethyl, carboxyl or dimethylamino group "means.

The invention also relates to processes for the preparation of the substituted benzopyran derivatives of the general formula (II).

Procedure A

The compounds of the general formula II according to the invention , is obtained by reacting a chromanone of the general formula (IV) or its salts

(IV)

in which FL, Rp, R ^ and X are as defined in formula (II), with an organometallic compound R ^ Y, in the R- as in formula (II) defines and Y is an alkali metal or a magnesium halide is. The intermediate product is converted into a compound of the formula (V) with a proton donor

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HO R ,. OX

(ν)

Dehydration

This compound (ν) gives the benzopyran derivatives of the general formula (II) according to the invention _; in which one can optionally convert the radical R. into another radical R ^ and / or the radical X into another radical X by methods known per se.

Preferred for R ^ Y is R ^ Li, R ^ MgCl, R ^ MgBr or R ^ MgJ.

If RfY is a lithium derivative, v / ground depending on the stability of the connection RrY uses low room or higher temperatures. Temperatures between -40 C and -80 C are beneficial, although higher temperatures can be used. To with enough To react quickly, Grignard reagents generally require higher temperatures, e.g. those of the boiling point Tetrahydrofurans or higher.

Suitable solvents for the process according to the invention are solvents such as are usually used in reactions of organometallic Compounds are used, for example, ether for both lithium and magnesium compounds or Ether or /. Hydrocarbons, such as hexane, for lithium compounds. The reaction takes place via an intermediate compound of the formula (VI)

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(VI)

which then in situ in an aqueous reaction medium to the desired Hydroxy compound of formula (V) is decomposed. Suitable decomposition reagents for this are e.g. 1 η sulfuric acid, aqueous ammonium chloride or other agents, as they are commonly used for such decomposition reactions.

If the hydroxy compound (V) is unstable, spontaneous elimination of water takes place with formation of the compound (Tl), especially if the decomposition conditions for the intermediate (VI) are strong enough. If appropriate, the compound can be obtained directly by treating the compound (VI) with dilute hydrochloric acid (II) obtained. However, it can occasionally be advantageous to isolate the compound (V) and the elimination of water in one carry out further reaction stage. Besides, it is occasional necessary to change the reaction medium for the dehydration stage.

The elimination of water can be carried out using customary methods, for example by heating the compound (V) alone or in a solvent or by treating with a water-releasing agent, like a strong acid.

Depending on the nature of the residue Ra, temperatures of, for example, 25 to 250 ^° C. are used. In some cases the elimination of water is facilitated by finely dividing the chromanol of the formula (V)

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divides and / or heated in vacuo.

Inert solvents suitable for splitting off water are hydrocarbons, alcohols, halogenated compounds or Similar solvents in which the chromanol of the formula (V) is soluble and which boils higher than the corresponding temperature, in which the chromanol (V) is dehydrated ".

If an acid catalyst is used, the water is split off at much lower temperatures than without acid. E.g. can the water atis most of the chromanols of the formula (V) in the presence of ■ sulphuric acid or p-toluenesulphonic acid easily split off at temperatures of 100 G or less. at When p-toluenesulfonic acid is used in benzene, the water is split off easily and quickly at 80 C.

If the radical R «contains a substituent that is associated with the formation of a derivative R ^ Y is incompatible, this 3ub ~ introduce substituents after the reaction by methods known per se. For example, the following reaction steps can be performed after Preparation of the compound of formula (II) can be carried out.

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R-

Soil in the compound of the formula (II) the radical X is an acyl group mean, this compound can be formed from a corresponding compound in which X is a hydrogen atom or a salt is, according to the German Offenlegungsschrift 2 122 643 and 2 135 521 described methods are produced.

Compounds of the formula (IV) can according to Fahrenholz and coworkers in J. Amer. Chem. Soc., 89, p. 5934 (1967) will.

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Procedure B

Compounds of the general formula (II) in which IL · and Rp are the same can be obtained by reacting an organometallic compound R ^ Y in which Y is an alkali metal or a magnesium halide is to be prepared with a coumarin of the formula (VII). ...

(VII)

The intermediate product obtained is converted into a compound of the formula (VIII) with a proton donor.

OX

(VIII) HO (R ₁ ) ₂ C

By splitting off water from this compound (VIII), the compound of the formula (II) is obtained, which is optionally used the radical R ^ into another radical R ^ or the radical X into one can convert another radical X by methods known per se,

Preferred derivatives R ^ Y are CHzLl ₉ CH ₃ MgCl, CH ₃ MgBr and CH ₃ MgI.

The reaction with R ₁ Li is generally carried out at low temperature, for example below -2Q ⁰ C, in an inert solvent, such as an ether or a hydrocarbon.

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For a Grignard reaction is used depending on the type of Grignard reagent is not extremely low, Raun "or high temperatures, normal / else between -20 to 120 ⁰ C, preferably between 0 and 100 ⁰ C, for example room temperature.

The solvents which are usually suitable for this process are used ether.

The hydroxy compound of the formula (VIII) is obtained by hydrolysis the corresponding salt in a conventional manner, e.g. by adding water / water, which may be ammonium chloride, contains a dilute mineral or organic acid.

The desired compound of the formula (II) is obtained from the compound (VIII) by elimination of Waoser. This splitting off of water can take place spontaneously under the reaction conditions for the preparation of the compound of the formula (VIII). In some cases, v / ith the elimination of water achieved by conventional methods, such as heating the compound (VIII) either alone or with an acid _y as hydrochloric or sulfuric acid or glacial acetic acid.

Changes in R ^ and / or X are made as for the procedure A described, carried out.

The new coumarins of the formula (VIl) are made by implementation of a ß-benzoylacetate of the formula (IX), in which Rc is an ester-forming Group is made with a resorcinol of formula (X) in the presence of a Xondensation agent:

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OH
. CO. CH ₀ . COpR,; - f if ^^ ·. —— · ——- ^ (VII)

(ix)

HO

(X)

Suitable condensation agents are acids and / or Lewis acids, such as sulfuric acid, occasionally with phosphorus oxychloride, aluminum chloride, Hydrochloric acid and polyphosphoric acid.

A preferred condensing agent is a mixture of concentrated Sulfuric acid and phosphorus oxychloride.

The benzopyran derivatives according to the invention of the general formula (il) have an activity on the central nervous system, above all they change the mood.

Accordingly, the invention also relates to medicinal preparations which contain a benzopyran derivative of the formula (II) marked in combination with 'a conventional carrier material are.

These medicinal preparations can be administered in single doses, such as tablets or capsules. The daily dosage is generally 5 to 300 mg and can be in the form of several single dosages

administered. The single doses contain 5 to 50 mg, generally 7 to 30 mg, especially 10 to 20 mg.

The examples illustrate the invention.

SAD ORfGiNAL 209848/1240

example 1

From 0.80 g (0.03 * 'mol / uride 4.71 g (0.03 mol) of bromobenzene in 30 ml of dried ether is a solution of Pheny! Magnesium-

bromide (0.03 mol). To this stirred Grignard solution 3.18 g (0.01 mol) of 2,2-dimethyl-5-hydroxy-7- (3-methyl-2-octyl) -chroman-4-one are added dropwise over 20 minutes added in 10 ml of dried ether. The solution is stirred for an additional 3 hours, then with aqueous ammonium chloride decomposed. 4.37 g of 2,2-DimethyV ^ ~ (3-methyl-2-octyl) -4-phenylchromane-4,5-diol are separated from the aqueous solution away.

4.37 g of this crude chromanediol and 1.80 g of p-toluenesulfonic acid are dissolved in 100 ml of dried benzene. The solution is refluxed for 1 l / h hour, then poured into water. The organic phase is evaporated; 4.02 g of an oil are obtained which is chromatographed on silica gel with 1: 4 benzene / light gasoline. 1.97 g (52 percent) of 2,2-dimethyl-7- (3-methyl-2-octyl) -4-phenyl-2H-chromen-5-ol are obtained as a colorless oil which turns dark in air colors.

C ₂₆ H ₃₄ O ₂ calc .: 82.5 9.0 found: 82.9 9.5.

In gas-liquid chromatography, the product is 9k.5 percent pure.

SAD ORiGiHAL 209848/1240

Example2

2.2 » Dimethyl - ^ - (4-N, N -dlmethylaminophenyl) -7- (3-methyl-2-octyl) -2H-chronene- 5-ol

To a solution of n-butyllithium, prepared from 0.76 g (0.11 mol) of lithium and 6.1 g (0.045 mol) of n-butyl bromide in 27 ml of dried ether, a solution is added dropwise with stirring over the course of 15 minutes 4.65 g (0.14 mol) of N, N, N, N-tetrainethylethylenediamine in 10 ml of dried ether were added. The solution is stirred for a further 15 minutes and a solution of 8.0 g (0.04 mol) of 4-bromo-N, N-dimethylaniline in 16 ml of milk + oil ether is added over the course of 10 minutes and then for 30 minutes stirred for a long time. To this solution of 4-N, N-dimethylaminophenyllithium, a solution of 3.18 g (0.01 mol) of 2,2-dimethyl-5-hydroxy-7- (3-methyl -2-octyl) -chroman-4-one added in 5 ml of dried ether. This solution is stirred at room temperature for 4 hours. After neutralization with 5 η sulfuric acid, the organic phase is separated off, washed with water and extracted with 50 ml 5 η hydrochloric acid. You get three phases. The middle phase is separated off, neutralized with sodium bicarbonate, extracted with ether and dried over magnesium sulfate. After distilling off the Lö'sungs ^ means in vacuo gives a braunas oil, which is heated in vacuum at 100 ⁰ C in order to remove any existing N, N-dimethylaniline and unreacted 4-bromo-N, N ~ diraethylanilin. The remaining oil (1.36 g) is chromatographed on silica gel with 2: 3 benzene / light gasoline. 0.83 g (19 percent) of 2,2-dimethyl-4- (4-N, N-dimethylaminopheriyl) -7- (3-methyl-2-octyl) -2H-chromene-5-ol are obtained as brown oil that is in the

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Gaw Blüssig Chromatography is 92 percent pure.

C% E% NJO

C ₂₈ H ₃₉ NO ₂ ; calc .: 79.8 9.3 3.3

Found: 79.2 x 9.6 3.2. .

Example 3 2,2-Dimethyl-4- (4-fluorophenyl) -7- (3-methyl-2-octyl ) -2H- chromen-5-ol

magnesium
A solution of 4-fluorophenylmagnesium bromide (0.03 mol) is prepared from 0.86 g (0.035 mol) and 5.57 g (0.03 mol) of 4-bromofluorobenzoi in 30 ml of dried ether. To the stirred solution of the Grignard reagent add dropwise 3.18 g (0.01 mol) of 2,2-dimethyl-5-hydroxy-7- (3-methyl-2-octyl) over the course of 20 minutes. -chroman-4-one added in 15 ml of dried ether. After a further 3 hours, the reaction mixture is decomposed with hydrochloric acid, the organic phase is separated off, washed with water and dried over magnesium sulfate. After the solvent has been distilled off, a brown oil is obtained which is heated to 160 ° C. in vacuo for 1 hour in order to split off the water from the chromanediol formed. The remaining oil is chromatographed on silica gel with 1: 4 benzene / light gasoline. First traces of a pale yellow solid are obtained, then 2.27 g (57 percent) of 2,2-dimethyl-4- (4-fluorophenyl) -7- (3-methyl-2-octyl) -2H-chromen-5-ol as a pale yellow oil that is 94 percent pure in gas-liquid chromatography.

^C 26 ^H 33 ^F0 2 ^: calc .: 78.8 8.3

found: 78.5 8.6.

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Example 4 2 j g-Dimethyl-A - (4 ~ chlorophenyl) -7 ~ (3-ethyl-2-octyl) -2H-

This compound is obtained according to Example 3 by reacting 2,2-dimethyl-5-hydroxy-7- (3-methyl-2-octyl) -chroman-4-one with 4-chlorophenyl magnesium bromide in 73 percent yield as a pale yellow, gummy product which in gas-E-liquid chromatography 97 percent is pure.

C% E% C156

C ₂₆ H ₃₃ ClO ₂ : calc .: 75.65 8.0 8.6

found: 74.9 8.1 8.3.

Example5

2,2-Dimethyl-4- ( 3- fluorophenyl) -7- (3-methyl-2-octyl) -21I-ora e n- 5 - oil

This compound is obtained according to Example 3 by reacting 2,2-dimethyl-5-hydroxy-7- (3-methyl-2-octyl) -chroman-4-one with 3-fluorophenylmagnesium broraide using tetrahydrofuran instead of dried ether in 58 percent Yield as a pale yellow, gummy product that is found in the Gas-liquid chromatography is 100 percent pure.

C ₂₆ H ₃₃ FO ₂ :

Example 6

2,2-dimethyl-4- (4-methoxyphenyl) -7- (3-methyl-2-octvl) -2H-chromen-5-ol

This compound is obtained according to Example 3 from 2,2-dimethyl-5-hydroxy-7- (3-methyl-2-octyl) -chroman-4-one and 4-methoxy-

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C% H% ber .: 78.8 8.3 found: 78.7 8.4.

phenylmagnesium bromide in 42 percent yield as a pale brown, rubbery product, which in the gas-blüssig-Chroraato- graphics is 95 percent pure.

C% U%

^C 27 ^H 36 ° 3 ^: calc .: 79.4 8.8

found: 79.2 8.9 '

Example7

2 _t 2-dimethyl-4- (4-tolvl) ~ 7- (3-methyl- »2-octyl) -2H-chromene -5-ol This compound is obtained according to Example 3 by reacting 2,2 ~ dimethyl -5-hydroxy-7- (3-methyl-2-octyi) -chroman-4-one and 4-tolylmagnesium bromide using tetrahydrofuran instead of ether in 71 percent yield as a pale yellow oil, which in gas-liquid chromatography 95 Percent is pure.

ber .: C% H% ^C 27 ^H 36 ° 2 found: 82.7 9.2 82.7 9.4

Example 8

■ 2,2-Dimethyl-4- (3,4-dimethylphenyl) -7- (3-methyl-2-octyl) -2H-chromen-5-ol

This compound is obtained according to Example 3 by reacting 2,2-dimethyl-5-hydroxy-7- (3-methyl-2-octyl) -chroman-4-one with 3/4-dimethylphenylmagnesium bromide in 50 percent yield.

Example 9

2,2-dimethyl-4- (4-trifluoromethylphenyl) -7- (3-methyl-2-octyl) -; .-i chromene-5-ol

This compound is obtained according to Example 3 by reacting 2,2-dimethyl-5-hydroxy-7- (3-methyl-2-octyl) -4-chromanone with 4-trifluoromethylphenylmagnesium bromide in 69prozentiger yield as a pale yellow gummy product.

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Example 10

2 _> 2-Dimethvl-4-T) hgnyl-7- (2-octvl) -2H-chromen-5-ol To a mixture of 22.2 g (0.1 hol) 5- (2-0cty! ') Resorcinol and 19.2 g (0.1 Hol) of ethyl benzoylacetate are added dropwise to 50 ml of concentrated sulfuric acid at 0 ° C. while stirring. 30 ml of phosphorus oxychloride are added all at once and the mixture is stirred at room temperature for 24 hours, then poured into a saturated aqueous sodium bicarbonate solution and extracted with chloroform. After removal of the chloroform, 28 g of a solid are obtained which crystallizes from aqueous ethanol. 7.3 g (21 percent) of 5-hydroxy-7- (2-octyl) -4-phenylcoumarin are obtained.

C ₂₃ H ₂₆ O-, calc .: 78.85 7.4 '
found: 78.6 7.6.

7.0 g (0.02 mol) of this coumarin in 100 ml of dried benzene are added dropwise to a stirred mixture over 30 minutes Solution of 0.2 mol of methyl magnesium iodide in 100 ml of dried Ether added. The solution is stirred for 1 hour at room temperature, then with aqueous ammonium chloride decomposed. The organic phase is separated off and dried over magnesium sulfate. After removing the solvent 4- / 2,6-dihydroxy-4- (2-octyl) -phenyl_7-2-methyl-4-phenylbut-3-en-2-ol is obtained, which is dissolved in 20 ml of glacial acetic acid, refluxed for 1 hour, then poured into water. After extraction with ether, the organic phase is washed with an aqueous sodium bicarbonate solution and with water dried over magnesium sulfate. After removing-

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of the solvent, 7.8 g of an oil are obtained, which is chromatographed on silica gel with 1: 4 benzene / light gasoline. Man yields 4.62 g (63 percent) 2,2-dimethyl-4-phenyl-7- (2-octyl) ~ 2H-chromen-5-ol as a colorless oil.

^C 25 ^H 32 ° 2 "calc .: 82.4 8.8

found: 82.1 9.0

Example 11

2,2-Dimethyl-4- (2-fluorophenvl) -7 - (3-methyl-2- octyl) -2H-chromen-5-ol

A mixture of 2.1 g (0.01 mol) of ethyl o-fluorobenzyl acetate, 2.36 g (0.01 mol) of 5- (3-methyl-2-octyl) resorcinol and 10 ml of 80 percent sulfuric acid is at room temperature for 72 hours stirred for a long time, poured into water and extracted with ethyl acetate. The organic extract is chromatographed on silica gel with 10 percent ether / 90 percent light gasoline. 2.26 g (59 percent) 4- (2-fluorophenyl) -5-hydro; ey-7- (3-methyl-2-octyl) are obtained ) -coumarin, m.p. 85 to 95 ° C from light gasoline at 0 ⁰ C.

1.53 g of this coumarin v / earth according to Example 3 in tetrahydro-

Excess
furan with a 10-fold / of methyl magnesium iodide, then decomposed with acetic acid. 1.5 g of a black oil are obtained, which is chromatographed on silica gel using light gasoline. 0.35 g (22 percent) of 2,2-dimethyl-4- (2-fluorophenyl) -7- (3-methyl-2-octyl) -2K-chromen-5-ol are obtained as a pale yellow oil.

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Example-12

2,2-Dim ethyl-A- (4-carb oxyphene yl) -7- (5-methyl - 2-octyl) -2H-chrpmen-5-ol

A mixture of 0.27 g (0.0011 mol) of ethyl 4-carboxybenzoyl acetate, 0.27 g (0.0011 mol) of 5-O-methyl ^ -octyl) resorcinol and 5 ml of 80% sulfuric acid is stirred at room temperature for 112 hours , then poured into Yfasser and extracted with ethyl acetate. After removing the solvent, 0.42 g of an almost colorless solid is obtained, which is recrystallized from ethyl acetate. 0.2 g (42 percent) of 4- (4-carboxyphenyl) -5-hydroxy-7- (3- methyl-2-octyl) -coumarin are obtained _; Mp. 263-267 ° C

0.2 g (0.0005 mol) of the coumarin are suspended in 10 ml of dried ether and added to a methylmagnesium iodide solution, made from 0.12 g (0.005 mole) magnesium and 0.71 "g (0.005 mole) methyl iodide in 8 ml of dried ether, added. The mixture is refluxed with stirring for 1 hour 25 minutes. The reaction mixture is made with ammonium chloride decomposed, extracted with ethyl acetate. 0.19 g of a black oil is obtained, which is dissolved in 5 ml of dried benzene and 0.1 g of p-toluenesulfonic acid is added. The resulting Solution is refluxed for 1 hour. After removal of the benzene, an oil is obtained, which on silica gel with 1: 4 ether / light gasoline is chromatographed. 0.15 g (72 percent) of 2,2-dimethyl-4- (4-carboxyphenyl) -7 - ^ -raethyl-2-octyl) -2H-chromen-5-ol are obtained from light gasoline as a colorless solid which melts at about 95 ° C. but does not have a clear melting point.

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Example 13

a) 2,2-Dimethyl-4- (4-fluorophenyl) »? - (3 ~ methyl-2 ~ octyl) ~ 2H-chromen-5-ol affects the behavior of the mails at 30 mg / kg. orally and in a simple toxicity test is up to 900 mg / kg orally not fatal.

This compound increased the hypnotic effect of Hexabarbiton at 15 mg / kg orally and pa ¹ shows anticonvulsant activity against metrazol-induced convulsions in 10 mg / kg per oral. These results suggest that this compound is a central nervous system depressant with some anticonvulsant activity.

b) 2,2-dimethyl-4-phenyl-7- (3-methyl-2-octyl) -2H-chromen-5-ol influences the behavior of the mouse, especially depressive, at 9 and 30 mg / kg orally. The mouse shows increased Passivity and decreased spontaneous activity. At 300 mg / kg

No harmful side effects orally are observed. This connection clearly antagonizes the hypothermia caused by reserpine at 10 and 30 mg / kg orally; this suggests that the compound is an antidepressant agent.

c) 2,2-Dimethyl-4- (4-tolyl) -7- (3-methyl-2-octyl) -2H-chromene-5-O.1 causes depression at 90 mg / kg orally. The compound also shows activity against aggression caused by catapresan at 30 mg / kg (effective dose EDc ₀ ) and inhibition of fights caused by metrazol at 20 mg / kg orally. These results suggest that this compound is a depressant agent with some anticonvulsant and anti-aggressive activity.

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Example l4

This compound is obtained according to Example 3 from the corresponding the initial holdings in 25 percent yield in the form of a brown t3ls.

• Example 15 2,2-D: imethyl ~ 4 ~ (4-bromophenyl) -7- (? -Methyl-2-ootyl) -2H-

This compound is obtained according to Example 3 from the corresponding Auygangslcoiiiponenteri in YO percent yield in the form a brown rubber-like substance.

Example 16

^ ■ », 2 - D: ime thy 1 - 4 - phenyl -7- (2z2IQÜ_Ir. ^ Ir chrome n-5-ol This compound is obtained according to Example 10 via 7-amyl-5-hydroxy-4-phenylcoumarin ( 24 percent weakly colored solid, melting point 173 to 175 ° C) in 56 percent yield in the form of a weakly colored rubbery substance.

C ₂₂ H ₂₆ O ₂ calc.! 82.0 8.1

found: 82.2 8.4

209848/1240

Claims (1)

11.j Substituted benzopyran derivatives of the following. ·! "! General formula (II) , 0X in which IL · and Rp are identical or different and each have a hydrocarbon group with 1 to 6 carbon atoms, R _v a non-aromatic hydrocarbon group with 1 to 12 carbon atoms, R ^ an optionally substituted phenyl group »and X a hydrogen atom or a salt derived therefrom , Acyl or inorganic ester group. 2. Substituted benzopyran derivatives according to claim 1, formula II, in which R ^ and Rp each a methyl group, R ^ an alkyl group having 5 to 9 carbon atoms and X is a hydrogen atom or a salt derived therefrom. 3. Substituted benzopyran derivatives according to claim 1 and 2, in which R ^ is optionally one with one or more halogen atoms, one or more alkyl or alkoxy groups, a cyano, amino, hydroxyl, hydroxyalkyl, carboxyl, Acyloxy, acylamino, carboalkoxy or dialkylamino group means substituted phenyl group. 209848/1240 4. Substituted benzopyran derivatives according to Claims 1 to 3 of the following formula (III) and their salts ^R 6 (III) Oh in which R ₁ - denotes an alkyl group with 5 to 9 carbon atoms and R ^ denotes a hydrogen or halogen atom, a hydroxyl, methoxy, methyl, hydroxymethyl, carboxyl or dimethylamino group. 5. 2,2-Dimethyl-7- (3-methyl-2-octyl) ^ -phenyl ^ H-chromene-5-Ql. 6. 2,2-Dimethyl-4- (4-N, N-dimethylaminophenyl) -7- (3-methyl-2-octyl) -2H-cliromen-5-ol. 7. 2,2-Dimethyl-4- (4-fluorophenyl) -7- (3-methyl-2-octyl) -2H-chromen-5-ol. 8. 2,2-Dimethyl-4- (4-chlorophenyl) -7- (3-methyl-2-octyl) -2H-chroraen-5-ο1. 9 «2,2-dimethyl-4- (3-fluorophenyl) -7- (3-methyl-2-octyl) -2H-chroinen-5-ol. 10. 2,2-Dimethyl-4- (4-methoxyphenyl) -7- (3-methyl-2-octyl) -2H-chromen-5-ol 11. 2,2-Dimethyl-4- (4-tolyl) -7- (3-methyl-2-octyl) -2H-chromene- 209848 / Ί2Α0 12. 2,2-Dimethyl-A- (3,4-dimethylphenyl) -7- (3-methyl-2-octyl) · 2H-chrdinen-5-ol. 13. 2,2-Dimethyl-4- (4-trifluoromethylphenyl) -7- (3-methyl-2-octyl) -2H-ohromen-5-ol. 14. 2,2-Direthyl-4-phenyl-7- (2-octyl) -2H-ClIrOmGn-5-ol. 15. 2,2-Dimethyl-4- (2-fluorophenyl) -7- (3-methyl-2-octyl) -2H-chromen-5-ol. 16. 2,2-Dimethyl-4- (4-carboxyphenyl) -7- (3-methyl-2-octyl) -2H-chromen-5-ol. 17. 2,2-Dimethyl-7- (3-methyl-2-οαtyl) -4-pentafluorophenyl-2H- chromene-5-ol. 18. 2,2-Dimethyl 1-4- (4-bromophenyl) -7- (3-methy1-2-octyl) -2H-chromene-5-ol. 19. 2,2-Dimethyl-4-phenyl-7- (n-amyl) -2H-chromen-5-ol. 209848/1240 20th Substituted benzopyran derivatives of the following formula (V) HO (V) in which R>, _r Rp, R ^, R /, and X are defined according to claim 1. 21. ' Substituted benzopyran derivatives according to Claim · 20, in where R ^ and R2 each have the methyl group, R ^ an alkyl group 5 to 9 carbon atoms, R ^ a para-substituted phenyl group and X represents a hydrogen atom. . 22. Substituted. Benzopyran derivatives of the following formula (VII) 209848/1240 / 6 (VII) in which R ₇ , R ^ and X are defined according to claim 1. 23. Substituted benzopyran derivatives according to claim 22, in which R _{7 is} an alkyl group having 5 to 9 carbon atoms, Rj is a para-substituted phenyl group and X is a hydrogen atom. 24. Substituted benzopyran derivatives of the formula below (VIII) (VIII) HIGH in which R ^ is an alkyl group having 5 to 9 carbon atoms
and R ^ is a para-substituted phenyl group. 25. A method for producing the Benz.opyran derivatives according to claim 1, characterized in that nan
(a) a compound of the formula (IV) (IV) in which R ^, Rp, R _v and X are defined according to claim 1, with a compound R. Y, in which R. according to claim 1 o. ". ln 209848 / 1-240 BATH and Y is an alkali metal or a magnesium halide, or (b) a compound of the formula (VII) R ₁ , (VII) in which FiU, R / and X are defined according to claim 1, with a compound R ₁ Y, in which R ,. defined according to claim 1 and Y is an alkali metal or a magnesium halide, converts the intermediate products with a proton donor into a compound of formula (V) or (VIII), R ₄ .0X (V) (VIII) serve to form a benzopyran derivative by splitting off water of the formula (II) and optionally the radical R ^ into another radical R ^ and / or the radical X into another Remainder X is converted by methods known per se. Process according to Claim 25 for the preparation of substituted benzopyran derivatives according to Claim 4, formula (III), characterized in that
a) a compound of the formula (IVa) or its salt .209 8 A 87-1-24 2222925 (IVa) in which R, - is defined according to claim 4, with a compound R ^ Li, R ^ MgCl, R ^ MgBr or R-MgJ, in which R, is a para-substituted phenyl group, or
(b) a compound of the formula (VII) or its salt (VII) in which R ^ is a hydrocarbon group with 5 to 9 carbon atoms and R ^ is a para-substituted phenyl group, _{reacts with CH 3} Li, CH ₃ MgCl, CH ₃ MgBr or CH ₃ MgJ, the intermediate products with a proton donor into a compound of the formula ( Va) or (Villa) converts HO (CH ₇ ) ₂ C HO (Va) (villa) and this with elimination of water in a substituted benzo pyran-Derivac of the formula (ill) transferred. 209848/1240 ' 27 · Medicinal product, characterized by a content of a substituted benzopyran derivative according to claim 1 in combination with a pharmaceutically acceptable carrier. 209848/1240