DE2434659A1 - CHROMAN AND CHROME COMPOUNDS, THEIR SALT, METHOD OF MANUFACTURING THEREOF AND MEDICINAL PRODUCTS - Google Patents

Description

uZ: K 871 (Vo / su / ko)
Case: Bender-Loev Case 1
SmithKline Corporation
Philadelphia, Penna. (V.St.A.)

¹¹ Chroman and Chrorae compounds, their salts, processes for their production and medicinal products "

Priority: July 18, 1973, V.St.A., No. 380 kk6

The invention relates to the subject matter characterized in the claims.

The term "lower alkyl" and "lower alkoxy" refers to radicals having from 1 to 6, preferably 1 to h carbon atoms. The term "lower alkanoyl radical" denotes radicals with 2 to 6, preferably 2 to k, carbon atoms.

The method according to the invention is carried out by the following Reaction scheme explained.

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(ID.

OH

R ₂ CCH ₂ COR ¹ +

HO

R ₁

(III)

and R4
R ₁ , R ₀ and Ri / have the meaning given above, R ¹ is a lower alkyl radical and X is a halogen atom,

The lower 3-cycloalkyl or 3-cycloalkenyl-3-oxopropionic acid alkyl ester of the general formula II is reacted with the Rk ₁ -substituted dihydroxybenzene in the presence of an acid such as phosphorus oxychloride or sulfuric acid. The resulting hydroxycoumarin of the general formula III is _{reacted with a lower alkylmagnesium halide of the general formula R 1} MgX, in which R ₁ and X have the meanings given above.

To prepare the compounds of general formula I in which R. is a lower alkoxy radical, the 3 ^ cycloalkyl or 3-cycloalkenyl-3-oxopropionsäurealkyi-

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ester of the general formula II reacted with trihydroxybenzene to form dihydroxycoumarin, which is then reacted with the alkylmagnesium _{halide of the general formula R 1} MgX to form dihydroxychromene. The resulting dihydroxychromene is alkylated with an equimolar amount of an alkylating agent such as an alkyl halide in the presence of a base. A chromene compound of the general formula I is obtained in which R. is a lower alkoxy radical.

The hydroxychromane compounds of the general formula I are prepared by the corresponding Hydroxychromes are catalytically hydrogenated using e.g. palladium-on-carbon as a catalyst or chemically reduced using e.g. sodium and ethanol.

The alkali metal salts of the hydroxychromene and -chromane compounds of the general formula I are prepared by reacting the hydroxy compound with an alkali metal hydroxide, -hydride or alkoxide converts.

The hydroxychromene and -chroman compounds are described in usually esterified and etherified to the compounds of general formula I in which R_ is lower Denotes alkanoyl or alkyl radical. So z. B. the compounds in which R_ is a lower alkanoyl radical, prepared by reacting the hydroxy compounds or their alkali metal salts with a lower alkanoyl halide

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or a lower alkanecarboxylic anhydride, preferably in the presence of a base. The compounds in which R_ is a lower alkyl radical are z « B, prepared by using an alkali metal derivative a hydroxy compound with a lower alkyl halide implements.

The 3-cycloalkyl and used according to the process 3-Cycloalkenyl-3-oxopropionic acid alkyl esters are either known or become known per se by reacting a R_COO- lower alkyl ester with a lower one Acetic acid alkyl ester or by reacting an acid chloride of the general formula R COCl with a lower one Acetoacetic acid alkyl ester produced.

The Ri / -substituted dihydroxybenzene compounds are either known or are produced in a manner known per se.

The compounds of the invention are valuable drugs. You have e.g. B. a "dampening effect on the central nervous system and are therefore valuable sedatives and tranquillizers. Furthermore, the compounds of the invention an analgesic, antihypertensive, anti-inflammatory and diuretic effect.

The effect on the central nervous system is evident when administered orally at a dose of about 10 mg / kg

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in rats due to reduced spontaneous motility.

The compounds of the invention can be mixed with conventional carriers- substances and / or diluents and / or auxiliaries are combined.

As carriers, for. B. solid or liquid substances can be used, such as lactose, magnesium stearate, Terra alba, sucrose, talc, stearic acid, gelatin, agar-agar, pectin, gum arabic, syrup, peanut oil, olive oil, sesame oil, Propylene glycol, polyethylene glycol (molecular weight 200 - 400) and water. The carrier or diluent can be a known agent with delayed drug release such. B. glyceryl monostearate or glyceryl distearate, optionally together with a wax.

Administration can be in the form of tablets, capsules, powder, suppositories, lozenges, lozenges, syrup, Emulsions, sterile liquids for injection or liquid Suspensions or solutions.

The medicinal preparations are produced in a known manner, for. B, by mixing, granulating and compressing, or Dissolving the components.

The examples illustrate the preparation of the compounds according to the invention.

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example 1

A mixture of 8.3 S (0.042 mol) of ethyl 3-cyclohexyl-3-oxopropionate and 10.0 g (0.042 mol) of 5- (i, 2-dimethylheptyl) resorcinol is initially mixed with 45 ml of sulfuric acid and then with stirring and cooling 31.5 g (0.26 mol) of phosphorus oxychloride were added. The mixture is stirred at room temperature for 98 hours, neutralized with aqueous potassium carbonate solution and the separated aqueous phase extracted with ethyl acetate. The ethyl acetate extract and the organic phases are combined, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue is recrystallized from nitromethane. 4-Cyclohexyl-7- (1 »2-dimethylheptyl) -5-hydroxycoumarin is obtained.

A solution of 32.0 g (0.276 mol) of methyl magnesium bromide in 97 "nil of a mixture of benzene and tetrahydrofuran is added dropwise and with stirring with a solution of 15»! S (0.014 mol) of 4-cyclohexyl-7- (i, 2 dimethylheptyl) -5-hydroxycoumarin in 150 ml of a mixture of benzene and tetrahydrofuran is added under nitrogen. The mixture is refluxed for 23 hours, then allowed to cool and treated with saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate, the ethyl acetate extract and the The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and evaporated. The residue is dissolved in diethyl ether, a solution of hydrogen chloride in diethyl ether is added and the mixture is refluxed for two hours.

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river boiled. The solution is made with an aqueous solution neutralized by sodium carbonate, washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is chromatographed on a column filled with silica gel, 110 cm long and eluted with benzene. the first fraction is evaporated and the residue is distilled. 4-Cyclohexyl-7- (1,2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene is obtained of bp 200 ° C / 3 Torr.

Example 2

Example 1 is repeated, but 5-pentylresorcinol used instead of 5- (1 »2-dimethylheptyl) resorcinol. ^ Cyclohexyl-S-hydroxy ^^ - dimethyl-Y-pentyl- is obtained. 2H-chrome. 5-Hexylresorcinol is obtained in the same way the fy-cyclohexyl ^ -hexyl-S-hydr 2H-chrome and from 5-nonylresorcinol the ^ - hydroxy-2,2-dimethyl-7-nonyl-2H-chromene.

Example 3

Example 1 is repeated, but 5- (1,1,2-trimethyl octyl) resorcinol instead of 5- (1,2-dimethylheptyl) resorcinol used. 4-Cyclohexyl-5-hydroxy-2,2-dimethyl-7- (1 »1,2-trimethyloctyl) -2H-chromene is obtained.

The output connection is established as follows:

A two-fold excess of methyl magnesium bromide in Diethyl ether is slowly mixed with 26 g of 3j5-dimethoxyphenyl

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o (., · Χ. — added dimethylacetonitrile in diethyl ether that the Mixture refluxes gently. The mixture is then refluxed for an additional 18 hours and thereafter poured into cold 2N sulfuric acid. The solvent will distilled off and the residue heated to 95 ° C for one hour. After cooling, diethyl ether is added Phases separated from one another and the aqueous phase extracted with diethyl ether. The organic phase and the extracts are combined, washed with water, dried over magnesium sulfate and evaporated. The residue is in Distilled under high vacuum. 3 »5-dimethoxy-'i, vC-dime are obtained thyIb enzylme thyIke t on.

A solution of n-Hexylmagie siumbromid in anhydrous Diethyl ether is treated with 3 »5-dimethoxy-t, $ - dimethylbenzyl methyl ketone added dropwise in anhydrous diethyl ether. The mixture is refluxed for 15 hours and then saturated ammonium chloride solution is added dropwise. The individual phases are separated, and the aqueous phase is extracted with diethyl ether. The organic phase and the extracts are combined, washed with water, dried over magnesium sulfate and evaporated. 1,3-Dimethoxy-5- (2-hydroxy-1,1,2-trimethyloctyl) benzene is obtained.

A solution of 6.2 g (0.02 mole) 1,3-dimethoxy-5- (2-hydroxy-1,1,2-trimethyloctyi) benzene in diethyl ether is dried over magnesium sulfate, filtered and six

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Hours with a suspension of 0.8 g (0.02 mol) of potassium reacted in 60 ml of diethyl ether, then with 1.5 g (0 »02 mol) Carbon disulfide was added and the mixture was stirred for 30 minutes. That obtained mixture is mixed with 2.8 g of methyl iodide, refluxed for six hours, 16 to 18 hours left to stand at room temperature and filtered. The filtrate is evaporated and the residue under reduced pressure Distilled pressure. The distillate is refluxed in ethanol with Raney nickel, boiled and distilled.

10 percent
Using / palladium-on-charcoal

the product is 30 minutes at a pressure of 3 »5 at hydrogenated. 1,3-Dimethoxy-5- (1 »Ί, 2-trimethyloctyl) benzene is obtained, .The 1,3-dimethoxy compound obtained is heated under reflux for 16 to 18 hours in a mixture of glacial acetic acid and 48 percent hydrobromic acid and thereby demethylated. The reaction mixture is poured into ice water, extracted with benzene, concentrated and distilled. 5- (1 »1,2-trimethyloctyl) resorcinol is obtained,

Example k

Example 1 is repeated, but 5— (1 »2 — dimethyl— decyl) -resorein is used. ^ -Cyclohexyl-7- (1,2-dimethyldecyl) -5-hydroxy-2,2-dimethyl-2H-chromene.

The output connection is established as follows:

According to Example 3, 3 »becomes 5-dimethoxyph. Enyl-t-methylacetonitrile the 3 t 5-dimethoxy-vji, -niethyrbenzylmethylketon

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produced, which is reacted with n-octyl magnesium bromide. The obtained 1,3-dimethoxy-5- (2-hydroxy-1,2-dimethyldecyl) benzene is dehydrated and reduced and the methoxy groups are split off. 5- (1 »2-dimethyldecyl) resorcinol is obtained.

Example 5

A mixture of 3.0 g of 4-cyclohexyl-7- (i, 2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene in 100 ml of anhydrous ethanol and 10 percent palladium-on-carbon one hour at 25 C and a pressure: from 3 »4 a-t hydrogenated. Then 20 ml of chloroform are added.

The mixture is filtered and the filtrate is evaporated. Of the residue obtained is distilled. 4 — Cyclohexyl - ^ - is obtained (1f2-dimethylheptyl) -5-hydroxy-2,2-dimethylchroman.

Example6

Example 1 is repeated, but using ethyl 3-cyclopentyl-3-oxopropionate instead of 3 — cyclohexyl — 3— ethyl oxopropionate used. 4-Cyclopentyl-7- (1,2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene is obtained,

The output connection is established as follows:

A mixture of 55 g of magnesium and 5 ml of carbon tetrachloride is gently heated, with 200 ml of methanol and

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- ¹¹ - 2A34659

then added a solution of 285 g of ethyl acetoacetate in 125O ml of methanol and 150 ml of tetrahydrofuran. The mixture is refluxed for 5 hours until the magnesium is dissolved. The solvent is then evaporated under reduced pressure. The residue is dissolved in refluxing tetrahydrofuran, and 270 g of cyclopentanecarbonyl chloride are added over the course of 30 minutes. The mixture is refluxed for a further hour, half of the solvent is distilled off at normal pressure and the mixture is poured into 5 kg of ice containing 250 ml of concentrated hydrochloric acid. The aqueous phase is separated off and extracted twice with diethyl ether, the combined organic phases are washed with ₅ % strength aqueous sodium bicarbonate solution and water, a mixture of 1 5 5 liters of a concentrated aqueous ammonia solution and 500 ml of water is added and the mixture is kept at 30 for two hours C stirred. The separated diethyl ether phase is mixed with a mixture of 200 ml of concentrated hydrochloric acid and 1 liter of water and stirred for one hour. The mixture is washed with 5 percent aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. The residue is distilled at 20 torr. Ethyl 3-cyclopentyl-3-oxopropionate is obtained.

In the same way, but using 1-cyclo-

one receives
penten-1-carbonyl chloric!; / the k ~ ( 1-cyclopentenyl) -7- (1,2-.

dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene, or from 3-cyclopentene-1-carbonyl chloride the ^ - (3-cyclopentenyl) -

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7- (1,2-dimethyllieptyl) -5-hydiOxy-2, 2-dimethyl-2H-chroraeii, from i-cyclohexene-i-carbonyilehlorid the 4- (i-cyclohexenyl) -7- (i, 2- dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene _r and from 3-cyclohexene-1-carbonyl chloride the 4- (3-cyclohexenyl) -7- (1,2-dimethylheptyl) -5-hydroxy- 2,2-dimethyl-2H-chromene.

Example 7

A solution of 2.0 g of 4-cyclohexyl-7- (i, 2-dimethylheptyl) -5-hydroxy-2 _t 2-dimethyl-2H-chromen in 40 ml of acetic anhydride containing 1.0 g sodium acetate, is five hours heated to reflux. The excess acetic anhydride is evaporated under reduced pressure, the residue is dissolved in barrels and extracted with diethyl ether. The extract is washed neutral with water, dried, evaporated and chromatographed. The eluate is evaporated and the residue is distilled. 5-Acetoxy-4-cyclohexyl-7- (1,2-dimethylheptyl) -2,2-dimethyl-2H-chromene is obtained.

In the same way, one obtains when using propionic anhydride instead of acetic anhydride, 4-cyclohexyl-7- (1,2-dimethylheptyl) -2,2-dimethyl-5-propionyloxy-2H-ehromen.

Likewise, when using n-butyric anhydride, one obtains the corresponding 5-n-butyryloxy compound, in the case of n-valeric anhydride the corresponding 5-n-valeryloxy compound, and for n-caproic anhydride the corresponding 5-n-hexanoyl

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oxy compound.

Example 8

A solution of 2.0 g of 4-cyclohexyl-7- (i, 2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-ehromen in 50 ml of anhydrous dimethyl sulfoxide, 0.75 g of potassium tert, butoxide, then 2.0 g of dimethyl sulfate in 2.5 ml of dimethyl sulfoxide are added dropwise. The mixture becomes 30 Heated to 100 ° C. for minutes, stirred at room temperature for 10 hours, then poured into ice water with dilute hydrochloric acid acidified and extracted with diethyl ether. The extracts are combined, washed with water, dried and concentrated and distilled. 4-Cyclohexyl-7- (i, 2-dimethylheptyl) -5-methoxy-2,2-dimethyl-2H-chromene is obtained.

In the same way one obtains when using ethyl bromide instead of dimethyl sulfate, 4-cyclohexyl-7- (1,2-dimethylheptyl ) -5 -? - thoxy-2,2-dimethyl-2H-chromene, from propyl bromide 4-cyclohexyl-7- (1,2-dimethylheptyl) -2,2-dimethyl-5-propoxy-2H-chromene, from butyl bromide the 5-butoxy-4-cyclo- hexyl-7- (i, 2-dimethylheptyl) -2,2-dimethyl-2H-chromene, and 4 — Cyclohexyl — 7— (1,2-dimethylheptyl) —5— from hexyl bromide hexyloxy-2,2-dimethyl-2H-ehr omen '.

Example 9

Example 1 is repeated, but using ethyl 3- (2-cyclohexenyl) -3-oxopropionate and 5- (1-methylheptyl) resorcinol used. The 4- (2-cyclohexenyl) -5-hydroxy-

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2,2-dimethyl-7- (1-methylheptyl) -2H-chromene.

The output connection is established as follows:

21g (0.1 mol) of finely powdered phosphorus pentachloride is mixed with 15.4 g (θ, 1 mol) of 1-carbethoxycyclohex-2-ene while stirring. The mixture is stirred for three days at 95 ° ± 100 ° C., then the phosphorus oxychloride is distilled off under reduced pressure. The residue is heated to 95 ° C. with 5 mg of palladium black until the development of ethyl chloride has subsided. Distillation under reduced pressure gives 2-cyclohexene-i-carbonyl chloride, which is converted according to Example 6 to ethyl 3- (2-cyclohexenyl) -3-oxopropionate.

In the same way, 1-carbethoxycyclopent-2-ene is obtained instead of 1-carbethoxycyclohex-2-ene 4- (2-cyclopentenyl) -5-hydroxy-2,2-dimethyl-7- (1-methylheptyl) -2H-chromene.

Example 10

3.0 g (0.008 mol) of 4-cyclopentyl-7- (i, 2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene in 100 ml of ethanol, 1.84 g (0.08 mol) of sodium are added within 30 minutes. After cooling, the solution is mixed with 10 ml of water, neutralized with dilute hydrochloric acid and the The resulting mixture is evaporated to dryness under reduced pressure. The residue is extracted with water,

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dries and distilled. ^ -Cyclopentyl-7- ( 1,2-dimethylheptyl) -5-hydroxy-2,2-dimethylchroman.

In the same way, k- ( 1-cyclopentenyl) -7- (1,2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene and h- (3-cyclohexenyl) -7- ( 1,2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-ehromen reduced to the corresponding chroman compounds.

Example 11 Example 1 is repeated, but ethyl magnesium

bromide used instead of methyl magnesium bromide. Man receives if-cyclohexyl-7- (1,2-dimethylheptyl) -5-hydroxy-2,2-dimethyl ^ H-chrome,

Propylmagnesiuiribromid is obtained in the same way and butyl magnesium bromide, the corresponding 2,2-dipropyl and 2,2-dibutyl compounds.

Example 12

2.0 g of if-cyclohexyl-7- (1,2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene are refluxed for one hour with a solution of sodium hydroxide in methanol. Then the solution is evaporated. The sodium salt of A ^ -cyclohexyl-7. ~ (1 »2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene is obtained.

In the same way, ^ -Cyclohexyl - ^ - i1 »2-dimethylheptyl) -

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5-hydroxy-2,2-dimethylchromane with a solution of potassium hydroxide refluxed in methanol. After evaporation, the potassium salt of ^ -cyclohexyl-T- (1,2-dimethylheptyl) -5-hydroxy-2,2-dimethylchroman remains.

Example 13

Example 1 is repeated, but 5- (1-ethylheptyl) resorcinol is used used instead of 5- (i, 2-dimethylheptyl) resorcinol. 4-Cyclohexyl-7- (1-ethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene is obtained,

The output connection is established as follows:

3,5-Dimethoxybenzamide is first mixed with ethylmagnesium bromide implemented, the obtained 3 »5-Dimethoxyphenyläthylketon is reacted with n-hexyl magnesium bromide and dehydrated. The 1,3-dimethoxy-5- (i-hydroxy-1-ethylheptyl) obtained Benzene is reduced and the methoxy groups of the 1,3-dimethoxy-5- (1-ethylheptyl) benzene obtained are split "

Example 1 4

Example 1 is repeated, but instead of 5- (i, 2-dimethylheptyl) resorcinol, the following are used 5-substituted resorcinol uses:

5- (i, 1-dimethylheptyl) resorcinol, 5- (111-dimethylbutyl) resorcinol,

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5- (1,2-dimethylpentyl) resorcinol, 5- (1-methylpentyl) resorcinol.

You get

^ -Cyclohexyl -? - (1,1-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene

it-cyclohexyl-7- (1,1-dimethylbutyl) -5-hydroxy-2,2-. dimethyl-2H-chromene

^ -Cyclohexyl-7- (1,2-dimethylpentyl) -5-hydroxy-2,2-dimethyl-2H-chromene

or «4-Cyclohexyl-5-hydroxy-2,2-dimethyl-7- (1-methylpentyl) -2H-chromene,

Example 15

According to Example 1, 5- (1-methylhexyloxy) resorcinol is reacted with ethyl 3-cyclohexyl-3-oxopropionate in the presence of sulfuric acid and phosphorus oxychloride. Obtained h- Cyclohexyl-7- (1-methylhexyloxy) -5-hydroxycoumarin.

The coumarin obtained is in a mixture of benzene and Tetrahydrofuran with methyl magnesium bromide according to Example 1

implemented. ^ -Cyclohexyl-5-hydroxy-2,2-dimethyl-7- (1-methylhexyloxy) -2H-chromene is obtained.

The output connection is established as follows:

A solution of 126 g (1.0 mole) of phloroglucinol and 19.0 g j (0.3 ^ mol) potassium hydroxide in dimethylformamide is mixed with 186 g (1.04 mol) of 2-bromoheptane were added. The mixture will , Heated to 100 ° C for 16 hours, treated with 250 ml of acetic acid

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sets and filtered. The filtrate is evaporated, the residue dissolved in diethyl ether, washed with a barrel and washed with 10 percent sodium hydroxide solution extracted. The alkaline solution is washed with diethyl ether with dilute hydrochloric acid acidified and extracted with diethyl ether. The ether extract is dried over magnesium sulfate with activated charcoal added and filtered. The solution is evaporated and. the Distilled residue. 5- (1-methylhexyloxy) resorcinol is obtained from bp I65 to 170 ° C, 0.15 Torr.

Example 16

Example 15 is repeated, but the following compounds are used instead of 2-bromoheptane:

1 — bromopentane

1-bromohexane

1 — bromoheptane

1-bromooctane

1 - bromodecane -

2-bromooctane

2-bromo-3-methyloctane "
You get

4-Cyclohexyl-5-hydroxy-2,2-dimethyl-7-pentyloxy-2H-chromene

4-Cyclohexyl-7-hexyloxy-5-hydroxy-2,2-dimethyl-2H-chromene

4-Cyclohexyl-7-heptyloxy-5-hydroxy-2,2-dimethyl-2H-chromene

4-Cyclohexyl-5-hydroxy-2,2-dimethyl-7-octyloxy-2H-chromene

4-Cyclohexyl-7-decyloxy-5-hydroxy-2,2-dimethyl-2H-chromene

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Jf-Cyclohexyl-S-hydroxy ^, 2-dimethyl-7- (1-methylheptyloxy ) - 2H ~ chrome

or ^ -Cycloiiexyl-T-ii, 2-dimethylheptyloxy) -5 - hydroxy 2,2-dimethyl-2H-cliromen.

example

Example 1 is repeated, but 2,4-dihydroxy-1- (1,2-dimethylheptyloxy) benzene is used instead of 5- (1,2-dimethylheptyl) resorcinol used. Maxi receives

4-Cyclohexyl-8- (i, 2-dimethylheptyloxy) -5-hydroxy-2,2-dimethyl-2H- * chromene

4-Cyclohexyl-6- (1 _i 2-dimethylheptyloxy) -5-hydroxy-2,2-dimethyl-2H-chromene

4-cyclohexyl-6- (1,2-dimethylheptyloxy) -7-hydroxy-2 , 2-diπlethyl-2H-chromene.

The connections are on a filled with silica gel Column separated from each other

Using 1,4 ~ dihydroxy-2- (1,2-dimethylheptyloxy) benzene instead of 5- (1,2-dimethylheptyl) resorcinol according to Example 1 gives the following compounds:

4-Cyclohexyl-8- (1 "2-dimethylheptyloxy) -6-hydroxy-2 j- 2-dimethyl-2H-chromene

4-Cyclohexyl-7- (1,2 <-dimethylheptyloxy) -6-hydroxy-2,2-dimethyl-2H-chromene

4-Cyclohexyl-5- (1 $ 2-dimethylheptyloxy -) - 6 "-hydroxy-2,2-dimethyl-2H-chromene.

Using 1 _s 2-dihydroxy-4- (1 ₉ 2-dimethylheptyloxy) -benzene instead of 5 ~ (1> 2-dimethylheptyl) resorcinol in accordance with Example 1, the following compounds;

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4-cyclohexyl-6- (1,2-dimethylheptyloxy) -8-hydroxy-2,2-dimethyl-2H-chromene,

4-cyclohexyl-5- (1,2-dimethylheptyloxy) -8-hydroxy-2 , 2-dimethyl-2H-cli: romeii.

The output connections are made as follows:

According to Example 15, 1,2,4-trihydroxybenzene is reacted with 2-bromo-3-methyloctane in the presence of potassium hydroxide. A mixture of 2,4-dihydroxy-1- (1,2-dimethylheptyloxy) benzene, 1,4-dihydroxy-2- (1,2-dimethylheptyloxy) benzene and 1 _{t of} 2-dihydroxy-4- ( i, 2-dimethylheptyloxy) benzene. The compounds are separated from one another on a column filled with silica gel.

Example 18

Using 2,3-dihydroxy-i- (i-methylhexyloxy) benzene instead of 5-0,2-dimethylheptyl) resorcinol according to Example 1 gives 4-cyclohexyl-8-hydroxy-2,2-dimethyl-7- (1-methylhexyloxy) -2H-chromene.

The output connection is established as follows:

1,2,3-trihydroxybenzene is used with an equimolar amount of Reacted 2-bromoheptane in the presence of potassium hydroxide according to Example 15. 2,3-Dihydroxy-1- (methylhexyloxy) benzene is obtained.

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Example 19

1,2,3-Trihydroxybenzene is treated with ethyl 3-cyclohexyl-3-oxopropionate reacted according to Example 1 in the presence of phosphorus oxychloride. 4-Cyclohexyl-7,8-dihydroxy- 2,2-dimethyl-2H-chromene.

The chromene obtained is reacted with 2-bromo-3-methyloctane in the presence of potassium hydroxide according to Example 15. A mixture of 4-cyclohexyl-8- (1,2-dimethylheptyloxy) -7-hydroxy-2,2-dimethyl-2H-chromene and 4-cyclohexyl-7- (1 _t 2-dimethylheptyloxy) -8-hydroxy is obtained -2,2-dimethyl-2H-chromene,

The compounds are separated from each other on a column filled with silica gel,

Example 20

According to Example 1, using 1,3 »5-trihydroxybenzene instead of 5- (1,2-dimethylheptyl) resorcinol that 4-Cyclohexyl-5> 7-dihydroxy-2,2-dimethyl-2H-chromene prepared.

The chromene obtained is reacted with 2-bromoheptane in the presence of potassium hydroxide according to Example 15. You get a mixture of 4-cyclohexyl-7-hydroxy-2,2-dimethyl-5- (1-methylhexyloxy) -2H-chromene and 4-cyclohexyl-57hydroxy-2,2-dimethyl-7- (i-methylhexyloxy) -2H-chromene. The compounds are separated from one another on a column filled with silica gel.

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Example 2 1

According to Example j> 4-Cyclohexyl-5-hydroxy-2 _f 2-dimethyl-7- (1-methylhexyloxy) -2H-chromene is hydrogenated in anhydrous ethanol with palladium-on-carbon. 4-Cyclohexyl-5-hydroxy-2,2-dimethyl-7- (1-methylhexyloxy) -chromane is obtained.

40 9886 / U59

Claims (5)

Claims 1. ί Chroman and chromene compounds of the general Formula I. (I) in which the 3, h position optionally has a double bond, R _{1 is} a lower alkyl radical, R _? a cycloalkyl or cycloalkenyl radical with 5 or 6 carbon atoms, R "a lower alkoxy or alkanoyloxy radical, a hydroxyl group or its alkali metal Isalζ and R. a straight or branched alkyl or alkoxy radical with 5 to 12 carbon atoms 2. Compounds according to claim 1 of the general formula I, in which R "is in the 5-position and R ^ in the 7-position. 3. Compounds according to claim 1 of the general formula I, in which the 3,4-position has a double bond, R " a hydroxyl group in the 5-position and R. an unbranched one or branched alkyl radical with 5 to 12 carbon atoms in the 7-position, 4. Compounds according to claim 1 and 3 of the general formula I ₉ in dor · R _? represents a cyclohexyl group. 409886/1459 5. ^ -Cyclohexyl -? - (1,2-dimethylheptyl) -5-hydroxy-2,2-dimethyl-2H-chromene. 6, process for the preparation of the compounds according to claim 1, characterized in that a lower 3 — cycloalkyl or 3-cycloalkenyl — 3 — oxopropionic acid alkyl ester of the general formula II 0 0 in which R 'and R «have the meaning given in claim 1 have, with a Ri '-substituted dihydroxybenzene, where R. 'an' unbranched or branched alkyl or Alkoxy group having 5 to 12 carbon atoms or a hydroxyl group means, in the presence of an acid, to form a hydroxycoumarin of the general formula III (III) in which R_ has the meaning given in claim 1 and R. has the meaning given above, converts the hydroxycoumarin obtained with a lower _{alkyl magnesium halide of the general formula R 1} MgX, in which R _{1 has} the meaning given in claim 1 and X represents a halogen atom, converts, and, if R. 'is a hydroxyl group, the hydroxychromene obtained is alkylated to a compound of the general formula I in which R. is a lower alkoxy radical 409886/1459 represents, and optionally the hydroxychromene catalytically hydrogenated to the hydroxychromane, and optionally the Hydroxychromene or hydroxychroman compound of the general formula I in which R "denotes a hydroxyl group, esterified or etherified to the compound in which R “one represents lower alkanoyl or alkyl radical. 7 · Medicament containing a compound according to claim 1 and customary carriers and / or diluents and / or auxiliaries. 409 8 86/1459