CS249135B2 - Method of bicyclic compounds production with benzene ring - Google Patents

Description

The invention relates to a process for the preparation of benzene ring bicyclic compounds, in particular hive 5-hydroxy-7-substituted-3,4-dihydro-2H-benzopyranes, which are also substituted in the 4-position, by the C (R2R3) CH2OH group and their acylated derivatives and pharmaceutically acceptable cationic salts and acid addition salts. These compounds are effective as agents affecting the functioning of the nervous system, so that they can be used as analgesics, antiemetics, and anti-diarrhea agents in mammals, including humans. The compounds can be formulated in conventional manner into pharmaceutical compositions.

Although a wide range of alnalgesics are currently available, research into these substances with less and better effect is ongoing, as there is still no substance available that can be used for some types of painful conditions, while having the least side effects. The most common analgesic, aspirin, is not suitable for severe pain and, moreover, has various undesirable side effects. Other more active substances of this type, such as d-propoxyphene, code and morphine are compounds whose use leads to addiction. Obviously, it would be desirable to find analgesics with a strong effect without side effects.

U.S. Pat. 3 507 885

(+420) 636 058, 3 649 650, 3 856 821, 3 928 598,

Nos. 944,673, 3,953,603 and 4,143,139 disclose a variety of diabenzyl [b, d] pyran derivatives having ainalgesic activity, which are substituted in the 9-position, for example, by an alkyl radical, a hydroxy group or an alkoxy group. A particularly important compound of this group is dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexa-halo -9H-dibenzO '[b, d] pyran-9-one, a compound that has anti-emetic properties and is effective against anxiety states while also having analgesic properties in various animals, is now called the conventional term nalbilone.

U.S. Pat. No. 4,152,450 discloses various S-alkyl-1-hydroxytetrahydro-hexahydrodibeinzlo [b, d] pyranyl amino groups or an amido group at the 9-position, which are effective as analgesics, antidepressant and antitussive compounds, and as a blood pressure lowering agent.

Bergel et al., J. Chem. Soc., 286 (1943) investigates the substitution of the pentyl group at the 3,7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzyl [b, d] pyirane position The 1-ol group has from 4 to 8 carbon atoms and has been shown to have a hashish-like effect at a dose of 10 to 20 mg / kg, but the effect was very small.

Loev et al., J. Med. Chem., 16, 1,200-1,206 (1973) compares 7,8,9,10-tetriahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol wherein the substituent at the 3-position is -OCH (CH 3) C 5 H 11, -CH 2 CH (CH 3) 15 C 11 H 11 or -CH (CH 3) C 5 H 11. The compound containing the ether side chain was 50% less central nervous system active than the corresponding compounds in which the alkyl side chain was directly bound to the aromatic ring and five times more potent than the compound in which the oxygen atom was replaced with a methylene group.

Mechoulam and Edery in Marijuana, Machoiulam, Academic Press, New York, 1973, page 127, suggest that major structural changes in the tetrahydrocannabinol molecule appear to reduce analgesic efficacy.

U.S. Pat. No. 4,087,545 discloses the anti-emetic and anti-vomiting effect of certain 1-hydroxy-3-alkyl-6,6a, 7,8,10,10a-hexahydro-9H-dihenzp [b, d] pyran-9- onů.

Sellan et al., N. E. J. Med. 293, 795 (1975) describe the amtiemetic properties of delta-9-tetrahydrocannabinol when administered orally in patients with antitumor therapy.

.alpha.-9-Tetrahydrocannabinol is described in Shannon et al. (Life Ssiences 213, 49-54, 1978) as a non-aintiemetic agent in dogs in which apomorphine-induced emesis was induced. Borison et al., N. England J. of Med. 298, 1480 (1978) disclose the use of non-anesthetic cats in a model to determine the aintiemetic effect of the compounds, particularly in the context of emesis induced by compounds used in the treatment of malignant tumors. Pre-administration of 1-hydroxy-3- (Γ, Γ-dimethylheptyl) -6,6-dimethyl-6,6a-7,8,10,10a-hexahydro-9H-dibenzilio [b, d] pyran has been shown -9 (8H) -one (inabilon) to non-anesthetized cats protect these cats to a large extent from vomiting, which otherwise occurs following injection of compounds with antitumor activity.

The starting materials used in the preparation of the compounds mentioned below are known. They are compounds of formula IV

where

R1, M, Z and W are as defined below.

A method for producing the starting compounds is disclosed in U.S. Patent 4,143,139 of March 6, 1979 and U.S. Patent 4,235,913 of November 25, 1980.

The compounds of formula (I) are active agents which can be used in mammals as tranquillizers, antispasmodics, diuretics, anti-diarrhea, anti-cough and anti-glaucoma agents. These compounds are particularly effective in mammals, including humans, as analgesics, anti-diarrhea, and for the treatment and prevention of emesis and nausea, especially when these conditions are caused by anti-cancer agents. The compounds have no anti-narcotic effect and do not give rise to addiction.

The present invention provides a process for the preparation of a benzene ring bicyclic compound of formula (I)

where

R 1 represents a hydrogen atom or a CH 3 CO group,

R2 and R3 are hydrogen or methyl,

Z is OCH (CH 3) CH 2 CH 2 CH 2 or C (CH 3) 2 (CH 2) b and

W represents a hydrogen atom, or a phenyl group, characterized in that a compound of the general formula is reduced

where

R 2, R 3 and W are as defined above, Y 1 is hydrogen, methyl, beinzyl, benzyl or acetyl and R 7 is hydrogen, methyl or ethyl, or the cyclic ester formed when R 7 and Y 1 are hydrogen in the presence of a solvent inert to the reaction conditions with a metal hydride, preferably lithium aluminum hydride or catalytic hydrogelation using a noble metal catalyst.

Particularly preferred compounds of formula I are those in which:

Ri is a hydrogen atom or acetyl,

R 2 and R 3 are hydrogen atoms.

Compounds of formula I contain an asymmetric atom at the 4-position, another asymmetric center can be formed at the 7-position (ZWJ). Of course, the invention includes racemic mixtures of compounds of formula I mixtures of diastereomers, pure enantiomers and diastereomers. enantiomers and diastereomers are dependent on biological evaluation as described below.

As mentioned above, the compounds produced by the process of the invention are particularly valuable as analgesics, anti-diarrhea agents, antiemetics and anti-nausea agents in mammals including humans. The use of these agents induces analgesic conditions in mammals and suppresses vomiting and nausea by administering an orally or pareinterally effective amount of a pharmaceutically acceptable compound of formula (I) or a salt thereof.

The compounds of the present invention may be formulated into analgesic formulations by treating an effective amount of a compound of the present invention or a salt thereof together with a pharmaceutically acceptable carrier.

Compounds of formula (I) wherein B is hydrogen may be represented by formula (II)

Scheme A

Compounds of formula II

Rg · (M 2 = O)

OV

M ZW

BrC (R 2 R 3) Q 2, Zn or

LiC _(R2 R3) Q2

Q2 = COOR7

R 7 = H, CH 3 or C 2 H 5 zw

where

R1 to R3, Z and W are as defined above.

Scheme A illustrates a process for preparing a compound of Formula II. The starting ketones of formula IVA are described in U.S. Patent No. 4,143,139 (M 2 = O).

(Q2 = COOR7)

LAH (IX, Q2 - COOR7 ----) ► (II) or (X)

In the starting materials of formula IVA, Y 1 is a hydroxyl protecting group, for example benzyl or methyl, R 4, R 5, M 2, Z and W are as defined above. In the first step of the reaction sequence, the compound of formula IVA is reacted with an α-haloester in the presence of zinc metal according to the well-known reaction of RefOrmatsky to give the corresponding intermediate of formula VI. This step can also be carried out by modifying the Reformat reaction using a lithium acetic acid derivative, preferably a lithium ester of the general formula

L1C (R2R3) Q2 where

Q2 is COOR7 and

R2, R3 and R7 are as defined above.

For a review of the Reformat reaction, see Riatbke, Organic Reactiions, 22, 423-460 (1975).

When the above α-halo-esters are used, the brominated compound of formula (I) is the preferred reagent.

BrC (R 2 R 3) Q 2 where

R 2 and R 6 are hydrogen, methyl or ethyl, and

Q 2 is CN or, COOR 7, wherein

R2 is methyl or ethyl.

Said reagent is contacted, for example, with at least an equimolar amount of zinc metal in the presence of an organic solvent inert under the reaction conditions to form an oirganometallic intermediate of formula

BrZnC (R 2 R 3) Q 2 wherein

R2, R3 and Q2 are as defined above, and this intermediate product is then reacted with a ketone of the general, formula IVa to give the desired intermediate of formula VI ^and, after the hydrolysis reaction mixture, for example ammonium hydroxide or acetic acid. Alternatively, the zinc metal, reagent, BrC (R 2 R 3) Q 2, and the starting ketone of formula IVA are contacted simultaneously in the presence of an organic solvent inert under the reaction conditions to provide the desired intermediate of formula VI.

A preferred temperature range for the reaction between the reagent BrC (R 2 R 3) Q 2 and the starting material of formula IVA is 0 ° C to the reflux temperature of the solvent used; examples of solvents inert under the reaction conditions may be benzene, toluene, ethyl ether, tetrahydrofuran, dimethoxyethane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, trimethylborate and mixtures of these solvents. Preferred substances are benzene, tetirahydro, furan, dimethoxymethane and 1,2-dimethoxyethane. The desired intermediate (VI) is isolated by conventional means. The crude intermediates obtained are optionally purified by standard methods, for example, recrystallization or column chromatography.

When lithium derivatives of the formula LiC (R 2 R 3) Q 2 are used in the preparation of intermediates of formula VI, these can be obtained by several known methods, for example as described in Fieser "Reagents for Organic Chemistry", WileyInterscience, New York, Vol. . 3, 1972. The use of lithium dialkylamide and acetic acid nitrile or nitrile of the formula CH (R 2 R 3) Q 2 in a solvent inert to the reaction conditions is preferred. A particularly preferred type of lithium dialkylamide is lithium dicyclohexylamide. This compound is obtained, for example, from an equimolar amount of n-butyllithium and dicyctohexylamime in a reaction-inert solvent. In the tapic course of the reaction, both reagents are contacted in an anhydrous mixture and under an inert atmosphere, for example under nitrogen at -80 to -70 ° C in a solvent inert to the reaction conditions and an equimolar amount of reagent is added to the resulting suspension. of formula CH (R ₂ R ₃ ) Q 2 at the same temperature. The resulting lithium compound of formula LiC (R 2 R 3) Q 2 is then immediately reacted with the starting ketone of formula IVA in a solvent inert to the reaction conditions at -80 to -70 ° C. The reaction is usually complete within 1 to 10 hours, then the reaction mixture is treated with an equivalent amount of a weak acid, such as acetic acid, to decompose the lithium salt of the resulting product. The product is then isolated in a conventional manner and optionally purified as described above. The solvent which is inert under the reaction conditions may be one of the solvents mentioned above for the reaction using a balogen ester.

The 4-hydroxy-4- (R 2 R 3 CQ 2) -substituted compounds of formula (VI) obtained above are then subjected to hydrogenolysis followed by removal of the protecting group Y 1 on the hydroxy group to give compounds of formula (IX) or (X) or mixtures thereof. Hydrogeinolysis of compounds of formula VI wherein Q 2 is COOR 7 is typically carried out with hydrogen in the presence of a noble metal catalyst. Examples of these metals are nickel, palladium, platinum and rhodium. The catalyst is usually used in a catalytic amount, for example 0.01 to 10% by weight, preferably 0.1 to 2.5% by weight, based on the amount of the compound of the general formula (VI). It is often desirable to deposit the catalyst on an inert support, particularly preferred, the catalyst being palladium on an inert support, for example on activated carbon.

A common method of carrying out this conversion is to stir or shake a solution of a compound of formula VI in a hydrogen atmosphere in the presence of one of the above-mentioned noble metal catalysts. Suitable solvents for this hydrogenolysis are those which sufficiently dissolve the starting compound of formula (VI) but do not themselves undergo hydrogenation or hydrogenolysis. Examples of suitable solvents are lower alkanols such as methanol, ethanol, and isopropanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, low molecular weight esters such as ethyl acetate and butyl acetate, tertiary amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidoin and mixtures thereof. The hydrogen gas is usually supplied from the reaction mixture by carrying out the reaction in a closed vessel containing a compound of formula VI, a solvent, a catalyst and hydrogen. The pressure inside the reaction vessel may be between 10 and 1000 MPa. The preferred pressure range when the medium inside the reaction vessel is pure hydrogen is 20 to 50 MPa. The hydrogenolysis is usually carried out at a temperature of 0 to 60 degrees Celsius, preferably 25 to 50 ° C. Using the preferred temperature and pressure ranges, the hydrogenolysis usually takes only a few hours, for example 2 to 21 hours.

The product can then be isolated in a conventional manner, for example by filtration to remove the catalyst and evaporate the solvent, or by separating the mixture between water and a water-immiscible solvent, followed by evaporation of the dried extract.

When hydrogenolysis is carried out with a compound of formula VI in which Y 1 is hydrogen or benzyl and Q 2 is COOR 7, the resulting product is usually a mixture of the corresponding carboxylic acid or ester thereof of formula IX and a lactone of formula X, which is formed by removing the R7OH group from a compound of formula IX. The mixture thus obtained can be used as such or the substances can be separated from the mixture in a known manner, for example by crystallization and / or chromatography on silica gel.

When a compound of formula VI is used as the starting material for hydrogenolysis, wherein Y 1 is an alkyl radical, benzoyl or alkanoyl as defined above and Q 2 is COOR 7, the only resulting product obtained corresponding to Y 1 is a substituted derivative of the compound of formula IX . Removal of the protecting group Y 1 on the hydroxy group by, for example, hydrolysis when Y 1 is beinzoyl or alkanoyl as defined above, or by known cleavage of the ether group when Y 1 is alkyl as defined above, for example mixtures of hydrogen bromide and acetic acid IX or a mixture thereof with a lactone of formula X.

Compounds of formula IX in which Q 2 = COOR 7 and compounds of formula X, as well as mixtures of these compounds, are valuable intermediates for the production of the corresponding hydroxy compounds of formula II using known reagents, for example hydrides such as lithium aluminum hydride or lithium borohydride aluminum borohydride borane, aluminum hydride and lithium triethylborohydride, as well as catalytic hydrtogeination using noble metal catalysts. Preferred reducing agents are hydrides, preferably lithium aluminum hydride in terms of economy and efficiency. The reduction is conducted in the absence of water in the presence of an inert · solvent, for example ethyl, tetnahydrofuranu, 1,2-dimethoxyethainu ^ad: ethylene glycol. In typical examples, a compound of formula IX wherein Q 2 is COOR 7, a lactone of formula X or a mixture thereof is dissolved in a solvent inert to the reaction conditions and about equimolar amounts of hydride, for example 11thium aluminum hydride in the same solvent, are added. the mixture is maintained at a temperature of -50 to 50 ° C, preferably 0 to 30 ° C. Under these conditions, the reduction is substantially complete within 2 to 24 hours, then the excess reducing agent is removed, for example, by the vigorous addition of a solvent containing water or ethyl acetate, and the product isolated in a known manner, for example by washing the reaction mixture with water followed by evaporation of the dried organic phase. Optional purification can be carried out, for example, by recrystallization or column chromatography.

5-Acethoxyalcohols of formula II wherein Q = CH 2 OH, R 1 = COOCH 3 can be obtained by subjecting to selective acylation the corresponding dihydroxy compound wherein R1 is H. In a preferred embodiment of the selective acylation process, the dihydroxy compound is mixed with an equimolar amount of tertiary. an alkylamine such as triethylamine and a dialkylaminopyridine such as 4-dimethylaminopyridine in the presence of an organic solvent inert under the reaction conditions. An equimolar amount of acetic anhydride is then added at a temperature lower than room temperature, preferably at a temperature of -10 to 20 ° C, in particular 0 to 10 ° C. The mixture is maintained at this temperature for about 1-4 hours in typical examples, then allowed to warm to room temperature and the resulting product isolated, for example, by extraction followed by evaporation of the extract to give a crude product which is purified by column chromatography. A preferred solvent inert to the reaction conditions for use in the above reaction is, for example, methylene chloride, chloroform and ethyl ether.

Esters of compounds of formula II wherein R 1 is an alkannyl group can be readily prepared by reacting a compound of formula I wherein R 1 is hydrogen with an appropriate alkanoic acid in the presence of a condensing agent such as dicyclohexylcarbodiimide. Similarly, they can also be obtained by reacting a compound of formula (II) wherein R 1 is hydrogen with an appropriate chloride or acid anhydride such as acetyl chloride or acetic anhydride in the presence of a base such as pyridine.

The analgesic properties of the compounds of the present invention can be determined using experiments using the heat stimuli used to test the animals, such as the mouse tail twitch experiment, and chemical stimuli can also be used, e.g. Compounds · Suppress painful cramps after phenylbenzoquinone in mice. These experiments will be described below.

Experiments in which thermal stimuli were used

a) Experiment with hot mouse plate

In these experiments, the modified method described by Woolfe and MacDonald, J. Pharmaceol, Exp. Ther., 80, 300-307 (1944). A controlled thermal stimulus is applied to the mouse paws by means of a 3 mm thick aluminum plate. A 250 W infrared lamp is placed underneath the plate. A thermal controller that is coupled to the thermistor on the plate surface ensures that the lamp has a constant temperature of 57 ° C. Each mouse is placed in a glass cylinder about 15 cm in diameter, which is stored on a hot plate, and time starts counting as soon as the animal's limb touches the plate. Half an hour and two hours after administration of the test compound, the time at which the mouse draws one or both hind paws or a dose that provides 10 seconds without these movements is determined. Morphine in this case has an MPE 50 = -4 to 5.6 mg / kg subcutaneously.

hj Mouse tail retraction experiment

The mouse tail withdrawal experiment was performed in a modification of the method described by D‘Amour and Smith, J. Pharmacol. Exp. Ther., 72, 74-79 (1941); a high intensity controlled heat was applied and applied to the tail. Each mouse was placed in a metal cylinder from which its tail protruded from one boar. This cylinder was placed so that the tail lay above the bulb. The bulb was covered with an aluminum lampshade. At the beginning of the experiment, the lampshade is removed and the light from the bulb is passed through the slit to heat the tail end. At the same time, time is deducted. After a certain latency period, sudden tail withdrawal is observed. Untreated mice usually respond within 3 to 4 seconds. The end point of the experiment is to achieve a latency of 10 seconds. Each mouse is followed half and two hours after treatment with morphine and the test substance. Morphine has an MPE 50 of 3.2 to 5.6 mg / kg subcutaneously.

c j Tail immersion

In this experiment, a modification of the method described by Benbasset et al., Arch. int. Pharmacodyin., 122, 434 (1959). To do this, male white mice weighing 19-21 g of Charles River CD-I strain are weighed and labeled for identification. Usually, five animals are used for each test group, with each animal being its own control. Typically, the novel compounds are administered at a dose of 56 mg / kg intraperitoneally or subcutaneously as a first dose, at a dose of 10 ml / kg. After treatment, the animal is placed in a cylinder after half an hour and two hours. The control treatment is carried out before the active substance is administered. Each cylinder is perforated to provide sufficient air supply and is closed with a nylon plug through which the animal's tail passes. The cylinder is held upright so that the tail is completely immersed in a bath whose temperature is still maintained at 56 ° C. The final throw of the experiment is always a vigorous tail jolt, which is associated with the movement response of the entire animal. In some cases, after the administration of ainalgesic active substances, the response of the animal is not as pronounced. To avoid tissue damage, the experiment is always terminated and the tail is always removed from the water bath after 10 seconds. The measured latency time shall always be expressed as rounded to the nearest half second. In addition to the new active compounds, control experiments are always carried out with a solvent and with a standard active compound of known effect. If the substance is still active after a normal time of two hours, further experiments are carried out after 4 to 6 hours. The test is always terminated after 24 hours, if the potency of the test compound can be demonstrated at this time. Experiments using chemicals

Suppression of painful cramps induced by phenylbenzoquinone

Groups of five Carworth Farms CF-1 mice are pretreated subcutaneously or orally with saline, morphine, codeine or the test compound. Twenty minutes after subcutaneous treatment or 50 minutes after penoiral administration, each animal of each group is intraperitoneally administered with phenylbenzoquinone, an irritant that induces abdominal contractions. After administration of the irritant, waiting for 5 minutes, the mice are observed for 5 minutes and the presence of painful cramps is recorded. The MPE 50 value to prevent these convulsions was determined.

Experiments using pressure

Haffner's attempt to squeeze rat time

In these experiments, a modification of the procedure described in Haffner, Experimentelle Prufung Schmerzstillender was used. Dr. Mittel Deutch Med. Wschr., 55, 731-732 (1929). In this way, the ability of the active ingredients produced by the process of the invention to aggressive tail compression behavior of the tail was investigated. Male rats weighing 50-60 g Charles River (Sprague-Dawley) CD were used in the experiment. Prior to drug administration and again at 0.5, 1, 2 and 3 hours after treatment, a 7.5 centimeter clamp (Johns Hopkins) was placed on the root of the rat's tail. Morphine is effective at a dose of 17.8 mg / kg intraperitoneally.

% MPE - ^{dOt> and} P '~~ ^{time piece in} controls end time - dtoba in controls

As already mentioned, the compounds of the invention are useful as antiemetics and as nausea suppressants in mammals. In particular, they are useful as emesis-inhibiting compounds and nausea when administered with antitumor agents.

Antiemetic properties were determined on non-aesthetized cats according to Proc. Soc. Exptl. Biol. and Med., 188: 437-440 (1979).

Anti-diarrhea effect of compounds produced by the method of the invention in mice in PGE2-induced diarrhea (prostaglamdin E2)

The pro-diarrhea effect of the compounds produced by the method of the invention is determined by modification of the method described by Dajani et al., European Jour. Pharmacol. 34, 105-113 (1975). In this way, diarrhea can be induced in otherwise untreated mice within 15 minutes. Pre-treated non-diarrheal animals are considered to be protected by the active substance. The effect of these substances is evaluated only according to whether there are ¹ watery stools that are

Experiments with electric current

Defense reflex test

In these experiments, a padlock defensive reflex test was published: Tenen, Psychopharmactologia, 12, 278-285 (1968) to determine the pain threshold, male white rats weighing 175-200 g Charles River {Sprague) were used. -Dawley) CD. Before administration of the effective dose, the limbs of each rat are immersed in a sodium chloride solution of 20% glycerol. The animals are then placed in a chamber and exposed to electrical stimuli for 1 second, the intensity of these stimuli increasing at intervals of 30 seconds. The intensities used are 0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04. mA. The behavior of each animal is evaluated by the presence of a) defensive movement with withdrawal of paws, b) squeaking, and c) leaping up or forward at the start of the stimulus. A series of stimuli are applied to each rat before and at 0.5, 2, 4 and 24 hours after drug administration.

The results of the above experiments are expressed as a percentage of the maximum possible effect (% MPE). This value for each active substance is statistically evaluated in comparison to the same value for the standard substance and the pre-drug control values. This value is expressed by the following formula

X 100.

significantly different from normal mouse droppings or these stools do not occur.

Charles River CD-I white mice were used in the experiment. These mice are used for experiments one week after intake. The mice weigh 20-25 g. They are fed ad libitum within 18 hours prior to the experiment, at which time the feed is removed.

Animals are weighed and labeled for identification. Usually five mice are used for each active substance. Mice weighing 20-25 g are housed in cages in groups and are not fed overnight at night, water is ad libitum. The animals are then administered PGE2 at a dose of 0.32 mg / kg intraperitoneally in 5% ethanol for one hour after administration of the drug, and the animals are immediately placed one at a time in transparent 15 x 15 X 18 cm acrylic cages. The removable pad at the bottom of each cage is removed at the end of 15 minutes to determine whether or not diarrhea has occurred. In the control experiment, solvent + PGE 2 and another group were used to pause the solvent.

Data are analyzed using linear regression of probites using a logarithmic dose of 24,135 k, the maximum probability is determined. A computer is used to evaluate the results by analyzing linear regression including the degree of freedom, the sum of the squares, the diameter of the squares and the critical values of Fos and Chi ² . If the regression is statistically significant, ED 30, ED 50, ED 50 and ED 90 are calculated and then 95% confidence limits.

The compounds of the present invention are effective as analgesics, diarrhea, vomiting and nausea in perioral and parenteral administration and can be administered for this purpose in the form of compositions containing the active ingredient and a pharmaceutical carrier selected according to the route of administration. . Thus, it can be, for example, tablets, pills, powders or granules containing carriers such as starch, milk sugar, some types of clay and the like. It may also be a capsule containing the active ingredient a spiral with the same or similar carrier. Oral administration is also suitable for suspensions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For oral administration, tablets or capsules containing 0.01 to 100 mg of active ingredient are suitable for the vast majority of cases.

Suspensions and solutions of the active compounds, especially those in which R 1 is hydroxy, are usually prepared just prior to use in order to avoid, for example, oxidation or precipitation from the suspension or solution. In this case, a solid is supplied which can also be used for the preparation of injectables.

The physician will readily determine the dosage which will be most appropriate for each case and will vary depending on the age, weight and condition of the patient and the mode of administration. Usually, however, the initial amalgesic dose is the same as reducing or treating nausea in adults in the range of 0.01 to 500 mg per day in a single dose or in several divided doses. In many cases it is not necessary to exceed the 100 mg daily dose. For oral administration, the dose is in the range of 0.01 to 300 mg / day, preferably 0.10 to 50 mg / day. For parenteral administration, a dosage range of 0.01 to 100 mg / day is preferred, a range of 0.01 to 20 mg / deine is preferred. Example 1 dl-5-Hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-one

An anhydrous nitrogen was blown into a 1 liter three-neck flask equipped with a mechanical stirrer, thermometer, and condenser and 8.5 g (36 mmol of 1,3-dihydroxy-5- (2,2-dimethylheptyl)) were charged to the flask. benzene and 4.6 g (46.0 mmol) of 3,3-dimethylacrylic acid. The mixture is vigorously stirred while heating to 135 DEG C. The thermometer is then replaced by a funnel equipped with a condenser and 11.3 ml (107, The mixture was heated for a further 10 minutes, then allowed to cool to room temperature and stirred for a further 10 minutes, 10 ml of cold water and 40 ml of 6N sodium hydroxide were added and the resulting mixture was heated to reflux for 5 minutes. The mixture is then heated and acidified by the addition of 5 ml of concentrated hydrochloric acid and cooled to 30 DEG C., 200 ml of ethyl ether are added at this temperature, and the mixture is stirred for a further 5 minutes and the layers are separated. and v The ether phases are combined, washed successively with 2 x 80 ml of water, once with 100 ml of saturated aqueous sodium bicarbonate solution, 3 times with 50 ml of 1N sodium hydroxide, once with 100 ml of sodium chloride and once with 100 ml. water, then the solution is dried over anhydrous magnesium sulfate. The ether was evaporated in vacuo to give 11.8 g of an oily liquid which was sufficiently pure for use in the next step.

The crude product can also be chromatographed on a silica gel column eluting with ether and hexane. The fractions were monitored by thin layer chromatography on silica gel, eluting with ether: hexane (9/1, v / v) to give an _{Rf of} 0.41. Yield: 8.9 g (77.7%).

¹ H-NMR spectrum (CDCl 3) ppm:

0.80 to 0.81 (m, 3Hj)

I, 0 to 1.7 (m, 22H),

2.7 (s, 2H).

6.3 to 6.7 (m, 2H),

II, 6 (s, 1, disappears when D2O is added).

Infrared spectrum in potassium bromide has maxima at cm ^-1 :

400 (OH), 2899 (CH), 1639 (C = O). Mass spectrum (m / e): M ⁺ 318. Anal. Calcd. For C 20 H 30 O 3:

C: 75.43, H: 9.50%, found:

C: 75.40, H: 9.54%.

Example 1A dl-5-Hydroxy-2,2-dimethyl-7- (5-phenyl-2-pentyloxy) -3,4-dihydro-2H-benzopyran-4-one

A mixture of 16.4 g (100 mmol of 5-phenyl-2-pentanol, 28 ml (200 mmol of triethylamine) and 80 ml of anhydrous tetrahydroifuranine) was cooled in a water bath and crushed ice under a nitrogen atmosphere.

8.5 ml (110 mmol) of methanesulfcinyl chloride in 20 ml of anhydrous tetrahydrofuran, maintaining the temperature constant. The mixture was allowed to warm to room temperature and then filtered to remove triethylamine hydrochloride. The filter cake was washed with anhydrous tetrahydnofuran and the wash and filtrate were evaporated under reduced pressure to give an oil-like product. The product is dissolved in 100 ml of chloroform and the solution is washed twice with 100 ml of water and then once with 20 ml of saturated aqueous sodium chloride solution; Evaporation of the solvent gave 21.7 g (89.7%) of 5-phenyl-2-pentaniol mesylate which was used in the next step without further purification.

A mixture of 2.08 g (10 mmol) of 2,2-dimethyl-5,7 • dihydroxy-4-chromantone, 2.76 g (20 mmol) of potassium carbonate, 10 ml of NN-dimethylformamide and 2.61 g (11 mmol) of potassium carbonate. The 5-phenyl-2-pentaminediuesylate was heated in an oil bath at 80-82 [deg.] C. for 1.75 hours under a nitrogen atmosphere, then cooled to room temperature and poured into 100 ml of a mixture of water and ice. extracts are extracted twice with 25 ml of ethyl acetate, the extracts are discarded, washed successively with 3 times 25 ml of water and once with 25 ml of saturated sodium chloride solution, dried over magnesium sulphate, decolourised with charcoal and evaporated to give a oil which crystallizes after evaporation. adding a small amount of pure product, the product is obtained in quantitative yield and has a melting point of 83-84 ° C.

Example 2 dl-5-Benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-one

To a flask containing 3.52 g (45 mmol) of potassium hydride as a 50% suspension in oil after washing five times with pentain to remove the oil by decamation was added 50 ml of Ν, Ν-dimethylformamide, which was purified by stirring overnight. with calcium hydride and then distilled. The mixture was stirred and cooled to 0 ° C at which time 11.8 g (36 mmol) of crude 3-hydrO, xy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3 was added dropwise. 4-dihydrio-2H-benzopyran-4-one in 100 ml of purified dimethylformamide at a rate such that the temperature does not exceed 6 ° C. The addition takes approximately 20 minutes. The mixture was then allowed to warm to room temperature and stirred for 1 h, then cooled to 3 ° C and a solution of benzyl bromide (4.4 mL, 37 mmol) in DMF (50 mL) was added dropwise over 10 min. below 8 ° C. The mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction is stopped by slowly adding dropwise 10 ml of water, then the mixture is diluted

500 ml of ethyl ether, washed once with 150 ml of water, 3 times with 150 ml of 0.1 N hydrochloric acid, once with 100 ml of water, once with 150 ml of saturated aqueous solution of hydrogen carbonate, once with 150 ml of saturated sodium chloride solution and once with 150 ml of water. The washed ether solution was dried over anhydrous magnesium sulphate, the solvent was evaporated in vacuo, and 15 g of the oil thus obtained was purified by chromatography on a column containing 200 g of dicagel having a particle size of 40-63 microns, eluting with pentain and ethyl acetate. Evaporation of the product fractions yielded 8.8 g of a solid in 60% yield. Recrystallization from hexane or pentane gave crystals, m.p. 52-52.5 ^° C.

¹ H-NMR-rum, (CDCl 3 ppm (δ):

0.85 (s, 3H);

1.0-1.8 (m, 22H);

2.7 (s, 2H).

6.5 (s, 2H).

7.2-7.8 (m, 5H).

Mass spectrum (m / e): M ⁺ 408. Anal. Calcd. For C 27 H 30 O 3:

C: 79.37, H: 8.88%, found:

C: 79.22, H: 8.74%.

Example 3 dl-5-Beinzyloxy-4-ethloxycarboinylmethyl-4-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihyidrto-2H-benzopyrain

A. Dq 200 ml three neck flasks equipped with a magnetic stirrer, funnel and nitrogen inlet were charged with 11.36 ml (25 mmol) of m-butyllithl in hexane at 2,2 N at -78. Dilute the solution with 12 ml tetrahydrofuran, which has been pre-purified with sodium metal and distilled. Then, 4.42 g (25 mmol) of dicyclohexylamine in 12 ml of tetrahydrofuran, purified in the same manner, was added dropwise via a funnel. To the resulting suspension was added dropwise 2.44 mL (25 mmol) of ethyl acetate, and the resulting mixture was stirred at -78 ° C for 15 minutes. Then, 10.01 g (24.5 mmol) of 5-benzyloxy-2,2-diimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-ion in 30 ml are added dropwise. ml of tetrahydrofuran purified in the same manner. The resulting mixture was stirred at -78 ^{° C} for 3 hours, then 2 mL (35 mmol) of glacial acetic acid was added. The mixture was allowed to warm to room temperature, 50 ml of a saturated aqueous solution of sodium hydrogen carbonate was added, followed by 50 ml of ethyl ether. The layers were separated, the organic layer was washed three times with 35 ml of cold 1 N hydrochloric acid, then once with 30 ml of saturated sodium bicarbonate solution *, once with 30 ml of water, then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated to give 12.5 g of an oil. This oil is purified by chromatography on a column containing 200 g of silica gel with a particle size of 40 to 63 microns, eluting with 4 liters of a 2: 23 mixture of ethyl ether and low-pressure perchlorether and then with 2 liters of the same solvents in a 5: 5 by volume ratio. 20. The product fractions were combined and evaporated to dryness to give 9.0 g of purified product in a yield of 74.5%. This product has an _Rf of 0.22 in TLC chnomatografii siPkagelu using ether: hexane 1: 1st

1 H-NMR-SDoctruin (CDCl 3) ppm (?):

0.72 (s, 3H);

0.90 (t, 3H);

1.03 (s, 6H);

1.12 (s, 3H).

1.18 (s, 3H),

1.70 (d, 1 H),

2.05 (d, IH);

2.42 (cl, 1 H),

2.57 (d, 1 H),

3.07 (s, 1 H),

3.30 (q, 2H).

4.28 (s, 2H).

5.42 (s, 2H).

6.08 to 6.38 (m, 5H).

Infrared spectrum (film) has maxima at cm ^-1 :

560 (OH),

030 (CH, aromatic),

925 (CH, aliphatic),

710 (C0).

Mass spectrum (m / e): 496, 478 (M-18, base peak).

B. The same product can also be obtained as follows.

g (0.2 mol) of zinc metal is overlaid with a small amount of dimethoxymethane.

The mixture was heated to reflux and a solution of 16.7 g (0.1 mol) of ethyl bromoacetate in 75 ml of dimethoxymethane was added over 20 minutes, and the mixture was heated at reflux for 30 minutes, then cooled to 0. 5 ^DEG- 5 ^DEG C. and 40.85 g (0.10 mol) of dl-5-benzyloxy-2,2-dimethyl-7- (1,1-dimethyletheptyl) -3,4-dihydro-3H-beraziol are added dropwise. The mixture was stirred at 0-5 ° C for one hour, then allowed to warm to room temperature and stirred overnight, 25 ml of ammonium hydroxide was added, the mixture was extracted with ethyl ether, and the resulting product was isolated. as described above in Section A.

Example 3A

d.l-4,5-Dihydroxy-4-methoxycarbonylmethyl-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran

A mixture of 655 µg (1.37 mmol) of 5-benzyloxy-4-ethoxycarbonylmethyl-4-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H- benzopyran, 133 mg of 5% palladium on calcium carbonate and 50 ml of methanol are hydrogenated at 50 psi until hydrogen uptake is complete. The mixture was filtered. The filtrate was evaporated in vacuo and the oily residue was treated with hexane. Upon cooling, 66 mg of crystals were formed which were collected by filtration. The mother liquor was evaporated in vacuo to an oily residue, peintane was added and the mixture was stored in a refrigerator overnight. Filtration yielded an additional 178 mg of product.

¹ H-NMR spectrum (CDCl 3) ppm (s):

3.00 (dd, 2H).

3.20 (s, 2H).

3.70 (s, 3H);

4.90 (s, 1 H),

6.35 (m, 2H).

7.65 (s, 1 H).

Example 4 dl-5-Hydroxy-4-methoxycarbonylmethyl-2,2-d '^; methyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2 H -beta-py ranq corresponding lactone

A solution of 55 g (17.2 mmol) of 5-benzyloxy-4-ethoxycarbonylmethyl-4-staroxyl-2,2-diene is charged to 500 ml pressure vessels ^. methyl-7- (1,1-dimethylheptyl) -3β-dihydro-RH-benzopvran in 50 ml of rootbanol, 1 g of 5% palladium on activated carbon catalyst is added and the mixture is shaken under a hydrogen atmosphere at 0.028 MPa 17 hours. The reaction mixture was then filtered through a pad of magnesium sulfate and the solvent was evaporated in vacuo. The residue is partitioned between 100 ml of ethyl ether, 50 ml of water. the aqueous layer is extracted again with 50 ml of ether, the ether extracts are combined, washed with 30 ml of saturated sodium hydrogen carbonate solution and 30 ml of water, the ether layer is extracted with 50 ml of ether and copied with the ether extract. The ether solution was dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo to give a mixture of methyl ester and lactone, and the methyl ester crystallized on standing. After recrystallization from low boiling petrtol ether. 72 DEG-73 DEG C. is obtained.

@ 1 H-NMR Spectrum (CDCl3) ppm .delta .:

0.82 (s, 3H);

1.0-1.5 (m, 2OH)

1.53 to 2.6 (m, 4H),

3.1 to 3.6 (m, 3H),

3.68 (s, 3H);

5.8 (s, 1 H),

6.2-6.4 (m, 2H).

Infrared spectrum in potassium bromide has max ^; m at cm ':

390 (OH).

924 (CH, aliphatic),

17.5 (C = O).

Mass spectrum (m / e): M ⁺ 376, base peak 260.

Analysis for C23H56O1 calculated:

C: 73.36, H: 9.64%, found:

C: 73.38, H: 9.51%.

Purification of the mother liquor and chromatography on silica gel gave the lactone: 2,2-dimethyl-8- (1,1-dimethylheptyl) -3,3 a, 4,5-tetrahydro-2H-pyran [4,3,2-de] benzopyran -5-on.

1 H-NMR (CDCl 3) ppm (?):

0.85 (s, 3H);

1.03 to 1.83 (m, 2OH)

1.53 to 2.6 (m, 4H),

3.1 to 3.6 (m, 3H);

243135

3.68 (s, 3H);

5.8 (s, 1 H),

6.2-6.4 (m, 2H).

Infrared spectrum (film) has maxima at cm ^-1 :

025 (CH, aromatic),

925 (CH, aliphatic),

1.660 (C = O).

Mass spectrum (m / e): M ⁺ 343, base peak 260.

Analysis for C 22 H 32 O 3 calculated:

C: 76.70, II: 9.31%, found ¹ :

C: 76.38, H: 9.54%.

Example 5 dl-5-Hydroxy-4- (2-hydroxyethyl) -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyrrine

A 125 ml round-bottom flask equipped with a magnetic stirrer and flushed with nitrogen inlet was thoroughly washed with anhydrous nitrogen. 158 mg (4.2 mmol) of lithium aluminum hydride and 50 ml of anhydrous ethyl ether are added to the flask and the suspension is stirred while cooling in an ice bath. To the cooled suspension was slowly added 1.55 g (4.2 mmol) of 5-hydroxy-4-methoxycarbonylmethyl-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydrio-2H- of benziopyran in solution in 20 ml of ether. The cooling bath was removed and the reaction mixture was stirred at room temperature for 12 hours. 50 ml of ethyl acetate are then carefully added. The resulting mixture is washed successively with 50 ml of saturated aqueous sodium bicarbonate solution, sodium chloride and water, the organic layer is dried over anhydrous magnesium sulphate, the solvent is evaporated off under vacuum and 1.5 g of the crude oil thus obtained is purified by chromatography on 25 g of silica gel. 48 to 63 microns, pentane and ethyl acetate are used as solvent. TLC silica gel eluting with ether: toluene = 1: 1 in 69% yield, 1.0 g of product, _Rf 0.125 ^1.

1 H-NMR spectrum (CDCl 3) ppm:

0.83 (s, 3H);

1.0 to 1.67 (m, 23H),

1.7 to 2.1 (m, 2H);

2.7-3.3 (m, 2H)

3.83 (t, 2 H),

6.4 (s. 2H);

7.4 to 7.9 (s, broad, 1H).

Infrared spectrum (film) has maxima at cm ^-1 :

333 (OH),

545 (CH).

Mass spectrum (m / e): M ⁺ 348, 264, basic peak.

Analysis for C28H50O5 calculated:

C: 76.70, H: 9.36%, found:

C: 77.38, H: 9.67%.

When lactone is used, i.e. 5,5-dimethyl-8- (1,1-dimethylheptyl) -3,3a, 4,5-tetriahydno-2H-pyrano [4,3,2-de] benzopyran- The 2-oin or mixture thereof with the methyl ester and reduction is carried out as described above to give the same resulting product.

When 1,3-dihydroxy-5- (5-phenyl-2-pentyloxy) benzene was used instead of 1,3-dihydroxy-5- (2,2-dimethylheptyl) benzene, the procedure of Example 1 was carried out and the resulting the product was worked up as in Examples 2-5 to give dl-5-hydroxy-4- (2-hydroxyethyl) -2,2-dimethyl-7- (5-phenyl-2-pentylcxy) -3,4-dihydro -2H-benzioipyrain.

¹ H-NMR spectrum (CDCl 3) ppm:

1.2-1.5 (m, 9H)

1.52 to 2.3 (m, 8H),

2.4-2.8 (m, 2H),

2.9-3.2 (m, 1H);

3.8 (t, 2H).

4.1 to 4.5 (m, 1H);

6.0 (s, 2H).

7.2 (s. 5H).

Infrared spectrum (film) has maxima at cm ^-1 :

400 (OH)

980 (CH).

Mass Spectrum: M ⁺ 384, base peak 191.

Example 6 dl-2-Hydroxy-5,5-dimethyl-8- (1,1-dimethylheptyl) -3,3a, 4,5-tetrahydro-2H-pyrano [4,3,2-de] benzopynan

A solution of 1.80 g (5.2 mmol) of 5,5-dimethyl-8- (1,1-dimethylheptyl) -3,3a, 4,5-tetrahydro-2H-pyrano [4,3,2-de] benzoipyran The -2-one in 25 mL of anhydrous toluene was cooled to -78 degrees Celsius. To the mixture was added dropwise 5.2 mL of 1.0 M diisobutylaluminium hydride at a rate such that the temperature did not exceed -78 ^° C, which took approximately 20 minutes. The resulting mixture was stirred at -78 ^° C for 1 hour, then 4 mL of methanol was added and the mixture was allowed to warm to room temperature. Ethyl ether (75 ml) was added and the mixture was washed three times with 30 ml of sodium potassium tartrate solution, 30 ml of saturated sodium chloride solution and 30 ml of water. The organic phase is dried over magnesium sulphate and the solvent ¹ is evaporated off under vacuum to give 1.80 g of the resulting acetoacetal in 100% yield.

@ 1 H-NMR spectrum (CDCl3) ppm:

0.83 (s, 3H);

1.0 to 1.4 (m, 22H])

1.6 to 2.3 (m, 4H),

2.8-3.3 (m, 1H);

3.5 (s, broad, 1H);

5.4 to 5.8 (m, 1H);

6.4 (s, broad, 2H).

Infrared spectrum (film) has maxima at cm ^-1 :

450 [OH]

925 (CH).

Mass spectrum (m / e): M ⁺ 346, 146 base peak.

Analysis for C22H34O3 calculated:

C: 76.26, H: 9.89%, found:

C: 75.40, H: 9.45%.

When reduced as described above, 5,5-dimethyl-8- (5-phenyl-2-pentytyloxy) -3,3a, 4,5-tetrahydro-2H-pyrano [4,3,2-de] benzopyran 2-one, yielding 95% of 2-hydroxy-5,5-dimethyl-8- (5-phenyl-2-pentyloxy) -3,3a, 4,5-tetrahydro-2H-pyrano [4, 3,2-de] benzopyran in oily form. The product was identified by ¹ H-NMR, R _f 0.47, by thin layer chromatography on silica gel using cyclohexane / ethyl ether (1: 1 v / v) as a spray.

Example 7 dl-5-Hydroxy-4- (2-hydroxy-2-methylpropyl) -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran

A solution of 344 mg (1 mmol) of 2,2-dimethyl-8- (1,1-dimethylheptyl) -3,3a, 4,5-tetrahyidro-2H-pyraino [4,3,2-de] beinziopyran- The 5-one in 10 ml of ethyl ether was cooled in an ice bath for 15 minutes. To the cooled solution was slowly added 0.80 mL of 2.9 M methylmagnesium iodide in ethyl ether. The resulting mixture was allowed to warm to room temperature and stirred for 14 hours. Crystalline ammonium chloride (100 mg) was added, the mixture was stirred for 20 minutes, water (5 ml) was added and the layers were separated. The aqueous layer is extracted with 10 ml of ether, the ether layers are combined, washed with 30 ml of saturated sodium bicarbonate solution, 30 ml of saturated sodium chloride solution and 30 ml of water. The organic layer was dried over magnesium sulfate, and the solvent was evaporated in vacuo to give 348 mg of an oil which crystallized on standing. Recrystallization from pentanes gave a yield of 66.5% (250 mg) of purified piroduct, m.p. 101-103 ° C.

¹ H-NMR spectrum (CDCl 3) ppm:

0.83 (s, 3H);

1.0 to 1.5 (m, 28H),

1.53 to 2.5 (m, 5Hi,

2.9-3.2 (m, 1H);

6.3 (d, 1 H),

6.4 (d, 1 H),

7.8-8.6 (m, 1H).

Infrared spectrum in potassium bromide has maximum at cm ¹ :

333 (OH),

899 (CH).

Mass spectrum (m / e): M ⁺ 376, base peak 274.

Analysis for C24H40O3 calculated:

C: 76.55, H: 10.71%, found:

C: 76.61, H: 10.45%.

Example 8 dl-5-Hydroxy-4- (2-hydroxypropyl) -2,2-dimethyl-7 (-1,1-dimethylheptyl) -3,4-dihydrlo-2H-benzopyran

The semiacetal obtained in Example 6, i.e.

491 mg (1.42 mmol) of dl-5-hydroxy-2,2-dimethyl-8- (1,1-dimethylheptyl) -3,3a, 4,5-tetrahydro-2H-pyran 10 [4,3, 2-De] -bemzopyran is dissolved in 10 ml of diethyl ether and the mixture is cooled in an ice bath for 15 minutes. Then, 1.58 ml of 2.9 M methylmagnesium iodide is added slowly with syringe stirring. The reaction mixture was stirred for 3 hours after warming to room temperature. Ammonium chloride crystals in an amount of about 100 mg were then added to consume the non-reacted Grignard reagent, and the mixture was stirred for a further 20 minutes. Then, 75 ml of ethyl acetate and 50 ml of water were added, the mixture was stirred for a few more minutes, and then the layers were separated. The aqueous layer was extracted with 50 ml of ethyl acetate, the organic layers were combined and washed with 50 ml of water, 50 ml of saturated sodium chloride solution ¹ and again with 50 ml of water. The organic layers were dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo to give 525 mg of a crude oil. This material was chromatographed on silica gel thin layer ¹ 2 mm in thickness, employing a mixture of acetate and Pantano ethyl249133 in a volume ratio of 1 to 3. The zone of _Rf from 0.09 to 0.21 was extracted with 200 ml of ethyl acetate from 2 to 3 hours to give Yield: 300 mg (38.3%).

¹ H-NMR spectrum (CDCl 3) ppm (<S):

0.70 (s, 3H);

0.78 to 1.35 (m, 25H), 1.40 to 1.87 (m, 4H),

2.41 to 2.77 (m, 1H),

2.85-3.50 (m, 1H)

6.44 to 6.60 (m, 2H),

7.52 to 8.35 (broad 1H).

Infrared spectrum (film) has maxima at cm ^-1 :

350 (OH, very wide),

925 (CH).

Mass spectrum (m / e): M ⁺ 362, base peak 44.

Analysis calculated for C28 H5 O5:

C: 76.19, H: 10.57%, found:

C: 75.97, H: 10.16%.

Example 9

100 mg of di-5-hydroxy-4- (2-hydroxyethyl) -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzlopypan are thoroughly sieved and milled with 900 mg of starch . The resulting mixture is then stored in telescopic gelatin capsules, each capsule containing 10 mg of active ingredient and 90 mg of starch.

Example 10

The tablet matrix is prepared from the following mixture:

Ingredient parts sucrose 80.3 tapioca starch 13.2 magnesium stearate 6.5

A sufficient amount of dl-5-acetoxy-4- (2-acetoixyethyl) -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran is added to this matrix so that Tablets containing 0.1, 0.5, 1, 5, 10 and 25 medigriam of the active ingredient were formed.

Example 11

A suspension of dl-5-hydroxy-4- (4-hydroxyethyl) -2,2-dimethyl-7- (5-phenyl-2-pentyloxy) -3,4-dibydro-2H-benzopyraine can be prepared by preparing add a sufficient amount of the above compound to a 0.5% methylcellulose solution to form suspensions containing 0.05, 0.1, 0.5, 1, 5 and 10 milligrams of active ingredient per ml.

Claims (1)

A process for the preparation of a benzene ring bicyclic compound of the formula I in YN A1. e from π where R 1 represents a hydrogen atom or a group CH3CO, R 2 and R 5 are hydrogen or methyl, Z is OCH (CH 3) CH 2 CH 2 CH 2 or C (CH 3) 2 (CH 2) g a W represents a hydrogen atom or a phenyl group, characterized in that a compound of the general formula wherein R 2, R 3 and W are as defined above, Y 1 is hydrogen, methyl, benzyl, benzoyl or acetyl and R 2 is hydrogen, methyl or ethyl, or the cyclic ester formed when R 2. and Y 1 are hydrogen, in the presence of a solvent inert to the reaction conditions, a metal hydride, preferably lithium aluminum hydride or catalytic hydrogenation using a noble metal catalyst.