FI88158C - Process for the preparation of novel therapeutically useful bicyclic benzofusion compounds - Google Patents

Description

Process for the Preparation of New Therapeutically Useful Benzofused Benzocyclic Compounds 1 ^ 8153

Separated from patent application 830858 5

The invention relates to a process for the preparation of new therapeutically useful bicyclic benzofused compounds of the formula I, 10 r2 cQ3

r3 ^ OH

CH 2 F N I (I) 15 C ^ 3 —v

0 ZW

ch3 wherein R2 and R3 are each hydrogen or methyl, Q3 is -CH2OH, -CH (CH3) OH or -C (CH3) 2OH, Z is -O-CH (CH3) CH2CH2CH2 or -C (CH3) 2 (CH2) 6-, and W is hydrogen or phenyl.

The invention also relates to the preparation of pharmaceutically acceptable cationic and acid addition salts of the compounds of formula (I). The compounds are useful central nervous system drugs, especially as analgesics, antidiarrheals and antiemetics for administration to mammals, including humans.

Although numerous analgesics are available today, there is a constant effort to find new and better ones. This indicates the need for drugs that are able to relieve large-scale pain and have minimal side effects. The most commonly used drug, aspirin, is unable to relieve severe pain and is known to be associated with a variety of unwanted side effects. On the other hand, more potent analgesics such as 2 * 8158 d-propoxyphene, codeine and morphine are addictive. Thus, the need for better and more effective analgesics is obvious.

A series of analgesic dibenzo [b, d] pyrans having, for example, alkyl, hydroxy and oxo as substituents at the 59 position are described in U.S. Patents 3,507,885, 3,636,058, 3,649,650, 3,856,821, 3,928,598, 3,944,673, 3,953,603 and 4,143,139. Of particular interest is dl-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10 10,10a-Hexahydro-9H-dibenzo [b, d] pyran-9-one, an antiemetic and anxiolite with analgesic properties for animals, which is now commonly referred to as nabilone.

U.S. Patent 4,152,450 describes certain 3-15 alkyl-1-hydroxytetrahydro- and hexahydrodibenzo [b, d] pyrans having an amino or amido group at the 9-position that are useful as analgesics, antidepressants, anxiolytics, and antihypertensives. .

Bergel et al., J. Chem. Soc., 286 (1943), studied 20,8,8,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol in the 3-position replacement of the existing pentyl group with alkoxy groups having 4 to 8 carbon atoms. They found that the hashis effect of these compounds was minimal or non-existent at a dose of 10-20 mg / kg.

25 In a more recent study, Loev et al., J. Med.

Chem., 16, 1200-1206 (1973), reported 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1 in which the 3-substituent is -OCH (CH3) C5Hn, -CH2CH (CH3) CsHn or -CH (CH3) C5H11. The compound with central nervous system activity with an ether side chain was 50% less active than the corresponding compound in which the alkyl side chain is directly attached to the aromatic ring and not through an intermediate oxygen atom, and five times more active than the yh-35 compound in which oxygen is replaced by methylene.

3,881 58

Mechoulam and Edery have found ("Marijuana", edited by Mechoulam, Scademic Press, New York, 1973, p. 127) that major structural changes in the tetrahydrocannabinol molecule appear to lead to a sharp decrease in analgesic activity.

U.S. Patent 4,087,545 describes the antiemetic and nausea properties of 1-hydroxy-3-alkyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ones.

Sallan et al., N.E.J.Med., 293, 795 (1975), reported that orally administered delta-9-tetrahydrocannanabinol has antiemetic properties in patients subjected to cancer chemotherapy.

Shannon et al. (Life Sciences, 23, 49-54, 1978) reported that delta-9-tetrahydrocannabinol has no antiemetic effect in apomorphine-induced emesis in dogs. Borison et al., N. England J. of Med., 298, 1480 (1978), reported the use of anesthetized cats as an animal model to determine the antiemetic effect of compounds, particularly in emesis induced by cancer chemotherapy drugs. They found that by pretreating anesthetized cats with 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a-7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9 (8H) -one (nabilone) can clearly protect against vomiting itself after injection of anti-neoplastic drugs.

Compounds of formula (I) shall be prepared by reacting a compound of formula (IX) or (X): "^ 2 9 '" · 30 ^ ccoor7 R2' ^> r ^ s · "OU! 11 i llil or ZW 4 ·; ·: ·: 35 CH 3% (IX) (X) 4 8815a wherein Y 3 is hydrogen, methyl, benzyl, benzoyl or acetyl and R 1 is hydrogen, methyl or ethyl, is reduced in the presence of an inert solvent to a metal hydride, preferably lithium aluminum hydride, or methylmagnesium iodide, or by catalytic hydrogenation over a noble metal catalyst at a temperature of 0-60 ° C.

The starting materials of formula (IV) for the preparation of the compounds of formula (I) according to the invention are known in the art (compounds of formula IV are used in the preparation of starting materials IX and X): CH 2 O (IV) wherein ZW is as defined above. Detailed methods for preparing starting materials of formula IV are set forth in U.S. Patent 4,143,139 and U.S. Patent 4,235,913.

The compounds of formula I are effective drugs which can be administered to mammals as sedatives, anticonvulsants, diuretics, antidiarrheals, antitussives and glaucoma drugs. When administered to mammals, including humans, they are particularly effective as analgesics, antidiarrheals, and drugs for the treatment and prevention of vomiting and nausea, especially when caused by antineoplastic drugs. These compounds are non-addictive and non-addictive.

In particularly preferred compounds of formula I, R 2 and R 3 are each hydrogen.

The compounds of formula I have asymmetric centers at the 4-position. In addition, there may be 5 38158 centers of asymmetry in the 7-position substituent (ZW). The invention includes racemates of formula (I) and diastereomeric mixtures thereof, as well as pure enantiomers and diastereomers. The utility of racemic mixtures, diastereomeric mixtures, and pure enan-5 thiomers and diastereomers has been determined by the biological assays described below.

As mentioned above, the compounds of formula (I) are particularly useful as analgesics, antidiarrheals, antiemetics and antiemetics when administered to mammals, including man. The invention further provides a method of inducing analgesia in a mammal and a method of preventing and treating nausea in a mammal suffering from nausea, in each case administering orally or parenterally an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) may be formulated into pharmaceutical compositions for use as analgesics as well as compositions suitable for the prevention and treatment of nausea, which compositions comprise an effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

Flow Scheme A shows methods for obtaining compounds of formula (I). The required starting ketones of formula (IVA) are described in U.S. Patent 4,143,139.

6 88158 F2 O OY, aW30Yl

BrC (R2R3) Q2, V Ί 5 <* 14 I 4 Zn is „ΛΛ

y ^ -O '^^' ZW ^ 34 J [J

ChC L1C (R2R3) Q2 / noAs ^ azw 3, CH {(IVA) 3 (VI) 10 R n.

0H r2. I

Rj ^ - ^ ί ^ \ X ^ 0

ch ^ oA ^ zw + C "3 '> C" JT ^ L

15, IX) C? 3 ^ ^ ZW

(when Q? = C00R7) LAH * 7

(IX, Q2 - COOR,) - »(I,„ Ι = Η) (XI

In said starting materials (IVA), Y3 is a hydroxy-protecting group, e.g. benzyl or methyl, and Z and H have the same meaning as above. In the first lie of the reaction series, a compound of formula (IVA) is reacted with an alpha-haloester in the presence of a zinc metal, i.e. by a known reaction of Re-25 format, to give the corresponding intermediate of formula (VI). Alternatively, this step is performed as a variation of the Reformatsk reaction using a lithium acetic acid ester reagent of formula LiC (R 2 R 3) Q 2 wherein Q is C 10 R 7 and R 2, R 3 and R are as defined above. A recently published, extensive overview of the Reformatsky reaction can be found in Rathke, Organic Reactions, 22, 423-460 (1975).

When the above-mentioned alpha-halo ester reagents are used, the bromine compounds of the formula BrC (R2R3) Q2 are those in which R2 and R3 are each hydrogen, methyl or ethyl, Q2 is COOR7 and R7 is as defined above. The reagent BrC (R2R3) Q2 is contacted e.g. with at least an equimolar amount of zinc metal in the reaction in the presence of an inert organic solvent to give the organometallic intermediate BrZnC (R2R3) Q2, which is then reacted with the ketone of formula (IVA) to give the desired ketone of formula (VI). after hydrolysis with ammonium hydroxide or acetic acid. Alternatively, the zinc metal, the reagent BrC (R 2 R 3) Q 2 and the starting ketone (IVA) can be reacted simultaneously in the reaction in the presence of an inert organic solvent to give the desired intermediate (VI).

In the reaction of BrC (R2R3) Q2 and the starting material (IVA) described above, the preferred temperature is from about 0 ° C to the reflux temperature of said solvent. Examples of useful reaction-inert solvents include benzene, toluene, ethyl ether, tetrahydrofuran, dimethoxymethane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, trimethylborate, and mixtures thereof. Of these, benzene, tetrahydrofuran, dimethoxymethane and 1,2-dimethoxyethane are preferred. The desired intermediate of formula (VI) is isolated by standard methods known in the art and exemplified herein. If desired, the impure intermediates are purified by standard methods, e.g. by recrystallization or column chromatography.

When using the reagents LiC (R2R3) Q2 in the preparation of intermediates of formula (IV), they can be prepared using one of the many methods in the prior art, cf.

30 e.g., Fieser, "Reagents for Organic Chemistry". Wiley

Interscience, New York, vol. 3, 1972. But the preferred process exemplified herein uses lithium dialkylamide and an ethyl V ·: acid ester of formula CH (R2R3) Q2 in an reaction in an inert solvent. In particular, its preferred lithium dialkylamide is lithium dicyclohexyl β 88158 cyclamide. The latter compound is prepared, for example, from equimolar amounts of n-butyllithium and dicyclohexylamine in a reaction in an inert solvent. In a typical reaction, both reagents are brought together under anhydrous conditions and in an inert atmosphere, e.g., nitrogen, at -80 to -70 ° C in an inert solvent, and an equimolar amount of a reagent of formula CH (R 2 R 3) Q 2 is added to the resulting suspension at the same temperature. . The formed lithium reagent 10 LiC (R2R3) Q2 is then immediately reacted with the starting ketone (IVA) in an inert solvent, even now at -80 to -70 ° C. The reaction is usually completed in about one to ten hours, after which the reaction is stopped by adding an equivalent amount of a weak acid, e.g. acetic acid, to decompose the lithium salt of the desired product. The product is then isolated by standard methods and, if desired, purified as described above. Examples of useful and preferred reaction-inert solvents are those mentioned above in the reaction of the halogen ester reagent.

The 4-hydroxy-4- (R 2 R 3 CO 2) -substituted compounds of formula (VI) obtained as described above are then hydrogenolyzed and the hydroxy protecting group Y3 is removed to give compounds of formula (IX) and (X) or mixtures thereof. Hydrogenolysis of distillates of formula (VI) wherein Qz is C00R7 is usually carried out with hydrogen in the presence of a noble metal catalyst. Examples of useful precious metals include nickel, palladium, platinum and rhodium. The catalyst is usually used in conventional catalytic amounts, e.g. about 0.01 to 10% by weight, preferably about 0.1 to 2.5% by weight, based on the compound of formula (VI). It is often practical to suspend the catalyst on an inert support, and a particularly preferred catalyst is a palladium suspended on an inert support such as carbon.

One convenient way to carry out this transformation is to stir or shake a solution of the compound of formula (VI) g 88158 in a hydrogen atmosphere in the presence of one or more of the above-mentioned metal catalysts. Suitable solvents for this hydrogenolysis reaction are those which substantially dissolve the starting compound of formula (VI) but do not themselves hydrogenate or hydrogenolyze. Examples of such 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 N, N-dimethyl amide. amide, N, N-dimethylacetamide and N-methylpyrrolidone and mixtures thereof. Usually, hydrogen gas is fed to the reaction medium by carrying out the reaction in a sealed vessel containing a compound of formula (VI), a solvent, a catalyst and hydrogen. The pressure in the reaction vessel can range from about 1 to about 100 kg / cm 2. When the atmosphere in the reaction vessel is formed of substantially pure hydrogen, the preferred pressure range is from about 2 to about 5 kg / cm 2. Generally, the hydrogenolysis is performed at a temperature of about 0 to about 60 ° C, and preferably about 25 to about 50 ° C. When using the recommended temperature and pressure values, the hydrogenolysis usually takes place within a few hours, e.g. from about two hours to about 24 hours.

The product is then isolated by standard methods known in the art, e.g. by filtration to remove the catalyst and evaporation of the solvent or by partitioning between water and a water-immiscible solvent and evaporating the dried extract to dryness.

When compound-1 'was used as a starting material in hydrogenolysis. 30 te is of formula (VI) wherein Yx is hydrogen or benzyl and Q2 is C00R7, the product obtained is usually a mixture of the corresponding carboxylic acid or ester of formula (IX) and a lactone of formula (X) formed by removal of a lactone from R70H (IX). The mixture thus obtained can be used as such or can be separated into its components by known methods, e.g. by crystallization and / or chromatography on silica gel.

When the starting compound of hydrogenolysis is of formula (VI) having methyl, benzoyl or acetyl-5 as defined above, and Q 2 is COOR, the corresponding Yi-substituted derivative of the compound of formula (IX) is, of course, obtained as the only product. Removal of the hydroxy protecting group Yx, e.g. by hydrolysis (when Y2 is benzoyl or acetyl as defined above) or cleavage of ethers by methods known in the art, e.g. HBr / acetic acid (when Y1 is alkyl as defined above), gives the desired compound (IX) and its mixture lacto with (X).

The products of formulas (IX, Q2 are COOR7) and (X) and mixtures thereof are useful as intermediates for the preparation of the corresponding hydroxy compounds of formula (I) using known reducing agents, e.g. hydrides such as lithium aluminum hydride or lithium borohydride, aluminum borohydride, aluminum borohydride aluminum hydride and lithium triethyl borohydride and catalytically hydrogenated with noble metal catalysts. Preferred reducing agents are the above-mentioned hydrides and especially lithium aluminum hydride due to their economy and efficiency. The reduction is carried out under anhydrous conditions and in a suitable reaction in the presence of an inert solvent such as ethyl ether, tetrahydrofuran, 1,2 to 25 dimethoxyethane or diethylene glycol dimethyl ether. Typically, a compound of formula (IX, Qz is C00R7), a lactone (X) or a mixture thereof is dissolved in one of the above reaction inert solvents and the solution is added to a solution of about an equimolar amount of hydride, e.g. lithium aluminum hydride, in the same solvent as above. the mixture is allowed to stand at a temperature of about -50 to 50 ° C, preferably about 0 to 30 ° C. Under these conditions, the reduction is substantially complete in about 2-24 hours, after which the excess reducing agent is decomposed e.g. by careful addition of aqueous solvent or ethyl acetate and then 88158 is isolated by known methods e.g. e.g. washing the reaction mixture with water and evaporating the dried organic phase to dryness. If desired, purification is carried out, for example, by recrystallization or by column chromatography.

The analgesic properties of the compounds of this invention are determined by assays using an unpleasant thermal irritation, such as a tail-tailing mouse test, or an unpleasant chemical irritation, such as a test measuring the ability of a compound to reduce phenylbenzoquinone-induced writhing in a mouse. These tests are described below.

Test using an unpleasant chemical irritation

Reduction of torsion-15 telegramation by phenylbenzoquinone irritant.

Groups of five Carworth Farms CF-1 mice were pre-administered subcutaneously or orally with saline, morphine, codeine, or test compound. Twenty minutes (if administered subcutaneously) or fifty minutes (where administered orally), each group was injected intraperitoneally with phenylbenzoquinone, an irritant known to cause abdominal cramps. Mice are observed for five minutes for writhing or 25 absence thereof. The observation period starts five minutes after the injection of the irritant. Determine the MPE50 values of the anti-torsion premedication.

The results obtained from this test for the compounds of formula (I) are shown in the following table: 12 881 58

Table I

Reduction of Phenylbenzoquinone Irritant Twisting Using Compounds of Formula (I) 5

Q

ch2 oh 10 Xs o 10 CH3 Q ZWX (subcutaneous administration) 15 MPE50 (mg / kg) CH2OH B 0.36 CH2OH ^ A 0.65 20 * A is OCH (CH3) CH2CH2CH2C6H5 B is C (CH3) 2 (CH2) 5CH3 denotes a mixture of diastereomers The compounds of the present invention are effective as analgesics, antidiarrheals, antiemetics or antiemetics when administered orally or parenterally, and for these purposes they are administered in the form of a composition. Such compositions contain a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. They may be administered, for example, in the form of tablets, pills, powders or granules containing excipients such as starch, milk sugar, certain types of clays, etc. They may be administered as capsules in admixture with the same or similar excipients. They can also be administered orally in the form of suspensions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For oral administration of the drugs of this invention, tablets or capsules containing from about 0.01 to about 100 mg may be used in most cases.

Suspensions and solutions containing these drugs are generally prepared just prior to use, thus avoiding storage problems associated with the stability of the drug (e.g., oxidation) or the drug-containing suspension or solution (e.g., precipitation). Compositions suitable for this purpose are generally dry solid compositions which are reconstituted for injection.

The physician will be able to determine the dosage which will be most favorable to an individual patient and it will vary with the age, weight and response of the particular patient and the route of administration. But in general, the initial dose of analgesic and also the initial dose for the prevention of nausea or Hoi-20 is 0.01 to 500 mg per day in single or divided doses. In many cases, it is not necessary to exceed a daily dose of 100 mg. The recommended dosage range for oral administration is from about 0.01 to about 300 mg per day, and the recommended range is from about 0.10 to about 50 mg per day. The preferred parenteral dose is about 0.01 to about 100 mg per day, and especially about 0.01 to about 20 mg per day, f'- '; Preparation 1 dl-5-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-one (interm.) )

A 1 liter three-necked flask equipped with a mechanical stirrer, thermometer and, for ether, a vertical condenser was purged with dry nitrogen and 8.5 g (36 mmol) of 1,3-dihydroxy-5- (2,2-di-35 methylheptyl) benzene and 4.6 g were added. g (46.0 mmol) of 3.3-1488158 dimethylacrylic acid The mixture was stirred vigorously and heated to 135 ° C. The thermometer was replaced with a condenser addition funnel, which was used to rapidly add 11.3 mL (107.4 mmol) of boron-5 trifluoride etherate. Heating was continued for 10 minutes, the mixture was allowed to cool to room temperature and stirring was continued for a further 10 minutes, 10 ml of cold water and then 40 ml of 6N sodium hydroxide solution were added and the resulting mixture was heated for five minutes at 80 ° C. acidified with 5 ml of concentrated hydrochloric acid and cooled to 30 ° C, at which temperature 200 ml of After stirring for 5 minutes, the layers were separated and the aqueous phase was extracted with 2 x 50 mL of ether. The combined ether layers were washed successively with 2 x 80 mL of water, 1 x 100 mL of saturated sodium bicarbonate solution, 3 x 50 mL of 1 N sodium hydroxide solution, 1 x 100 mL of brine, and 1 x 100 mL of water, and finally dried over anhydrous magnesium sulfate. The ether was evaporated in vacuo to give 11.8 g of an oil which was sufficiently pure for the next step.

Alternatively, the crude product was chromatographed on a silica gel column eluting with hexane-ether in a volume ratio of 9: 1 (Rf <0.41) to give 8.9 g (77.7%) of the desired product.

1 H-NMR (CDCl 3) ppm (delta): 0.80-0.81 (m, 3H), 1.0-1.7 (m, 22H), 2.7 (s, 2H), 6.3- 6.7 (m, 2H), 11.6 (s, 1, disappears upon addition of D 2 O).

: 30 IR (KBr), cm-1: 3400 (OH), 2899 (CH), 1639 (00).

Mass spectrum (m / e): M * 318 Analysis for C20H3003:

Calculated: C 75.43, H 9.50 Found: C 75.40, H 9.54.

15,881 58

Preparation IA

dl-5-hydroxy-2,2-dimethyl-7- (5-phenyl-2-pentyloxy) -3,4-dihydro-2H-benzopyran-4-one (intermediate) 5 Mixture of 16.4 g (100 mmol) of 5-phenyl-2-pentanol, 28 ml (200 mmol) of triethylamine and 80 ml of dry tetrahydrofuran under nitrogen were cooled in an ice-water bath. 8.5 ml (110 mmol) of methanesulfonyl chloride in 20 ml of dry tetrahydrofuran were added dropwise at such a rate that the temperature remained almost constant. The mixture was allowed to warm to room temperature and then filtered to remove triethylamine hydrochloride. The filter cake was washed with dry tetrahydrofuran and the combined washings and filtrate were evaporated in vacuo to give the product as an oil, the oil was dissolved in 100 ml of chloroform and the solution was washed with 2 x 100 ml of water and then 1 x 20 ml of saturated brine. . Evaporation of the solvent gave 21.7 g (89.7%) of 5-phenyl-2-pentanol 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-chromanone, 3.76 g (20 mmol) of potassium carbonate, 10 ml of N, N-dimethylformamide and 2, 64 g (11 mmol) of 5-phenyl-2-pentanol mesylate were heated at 80-82 ° C in a Ö1 bath for 1.75 hours. The mixture is cooled. was brought to room temperature and then poured into 100 ml of a mixture of ice and water. The aqueous solution was extracted 2 x 25 '; ml of ethyl acetate and the combined extracts were washed successively with 3 x 25 ml of water and 1 x 25 ml of saturated: 30 saline solution. The extract was then dried over magnesium sulfate, decolorized with charcoal to give the product as an oil which crystallized on seeding with pure product, m.p. 83-84 ° C, yield quantitative.

16 88158

Preparation 2 dl-5-benzyloxy-2,2-dimethyl-7- (1,1-dimethyl-heptyl) -3,4-dihydro-2H-benzpyran-4-one (intermediate) 5 In a flask of 3, To 52 g (45 mmol) of potassium hydride as a 50% oil suspension from which the oil had been removed by washing the decanters five times with pentane was added 50 ml of Ν, Ν-dimethylformamide (DMF), which was purified by stirring overnight with calcium hydride and distillation. The mixture was stirred and cooled to 0 ° C and 11.8 g (36 mmol) of crude 5-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H were added dropwise. -benzopyran-4-one in 100 ml of purified DMF at such a rate that the temperature of the reaction mixture did not exceed 6 ° C (about 20 minutes). The mixture was then allowed to warm to room temperature and stirred for one hour. The reaction mixture was cooled to 3 ° C and a solution of 4.4 mL (37 mmol) of benzyl bromide in 50 mL of DMF was added dropwise over 10 minutes keeping the temperature of the mixture below 8 ° C. The mixture was allowed to warm to room temperature and stirred for four hours. The reaction was quenched by the slow dropwise addition of 10 mL of water, the mixture was diluted with 500 mL of ethyl ether and washed with 1 x 150 mL of water, 3 x 150 mL of 0.1 N hydrochloric acid, 1 x 100 mL of water. , 1 x 150 ml of saturated sodium bicarbonate solution, 1 x 150 ml of brine and 1 x 150 ml of water. The washed ether solution was dried over anhydrous magnesium sulfate, the solvent evaporated in vacuo to give a residue of 15 g of oil, which was purified by chromatography on 200 g of silica gel (40-63 microns) eluting with pentane and ethyl acetate. By evaporating the the product containing fractions was obtained 8.8 g (60%) of a solid. Recrystallization from hexane or pentane gave crystals, m.p. : 35 52-52.5 ° C. 1 H-NMR (CDCl 3) ppm (delta): 0.85 (s, 3H), 1.0-17,881 58 1.8 (m, 22H), 2.7 (s, 2H), 6.5 ( s, 2H), 7.2-7.8 (m. 5H). Mass spectrum (m / e): M * 408.

Analysis for C 27 H 30 O 3 Calculated: C 79.37, H 8.88 Found: C 79.22, H 8.74.

Preparation 3 dl-5-Benzyloxy-4-ethoxycarbonylmethyl-4-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran (intermediate) 10 A. In a 200 ml three-necked flask Equipped with a magnetic stirrer, a dropping funnel and a nitrogen feed tube, 11.36 ml (25 mmol) of 2.5 molar n-butyllithium in hexane was charged at -78 ° C. The solution was diluted with 12 mL of tetrahydrofuran (THF) treated with sodium metal and distilled. A solution of 4.52 g (25 mmol) of dicyclohexylamine in 12 ml of the same THF was added dropwise via addition 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. To the mixture was added 10.01 g (24.5 mmol) of 5-benzyloxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-one dissolved in 30 ml. the same THF. The resulting mixture was stirred at -78 ° C for three hours and then quenched by the addition of 2 mL (35 mmol) of glacial acetic acid. The mixture was allowed to warm to room temperature and 50 ml of saturated sodium bicarbonate solution and then 50 ml of ethyl ether were added. The layers were separated, the organic layer was washed with 3 x 35 mL of cold 1N hydrochloric acid, 1 x 30 mL of saturated sodium bicarbonate solution and 1 x 30 mL of water, and the organic layer was dried over anhydrous magnesium sulfate. Evaporate the solvent to give 12.5 g of an oil as a residue. This was purified by chromatography on 200 g of silica gel (40-35 63 microns) eluting with 4 liters of a mixture of ethyl ether and low boiling petroleum ether (2:23 by volume) and 2 liters of the same solvent mixture in a volume ratio of 5:20. The combined product fractions were evaporated to give 9.0 g (74.5%) of purified product. When thin layer chromatographed on silica gel using a 1: 1 by volume mixture of ether and hexane as the solvent system, the Rf was 0.22.

1 H-NMR (CDCl 3) ppm (delta): 0.72 (s, 3H), 0.90 (t, 3H), 1.03 (s, 6H), 1.12 (s, 3H), 1.18 (s, 3H), 1.70 (d, 1H), 2.05 (d, 1H), 2.42 (d, 1H), 2.57 (d, 1H), 3.07 (s, 1H) ), 3.30 (q, 2H), 4.28 (s, 2H), 5.42 (s, 2H), 6.08-6.38 (m, 5H).

Infrared spectrum (capillary film), cm -1: 3560 (OH), 3030 (CH, aromatic), 2925 (CH, aliphatic), 1710 (00).

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

B. Alternatively, the product can be prepared as follows: 13 g (0.2 moles) of zinc metal was covered with a pie-20 quart of dimethoxymethane. The mixture was heated under reflux and a solution of 16.7 g (0.1 mol) of ethyl bromoacetate in 75 ml of dimethoxymethane was added over 20 minutes. After heating under reflux for 30 minutes, the mixture was cooled to 0-5 ° C and: 40.85 g (0.10 moles) of dl-5-benzyloxy-2,2-dimethyl-7- (1 , 1-dimethylheptyl) -3,4-dihydro-2H-benzopyran-4-one. The mixture was stirred for 1 hour at 0-5 ° C, allowed to warm to room temperature and stirred overnight. 25 ml of ammonium hydroxide were added, the mixture was extracted with ethyl ether, isolated as described in Part A above to give the desired product.

19,881 58

Preparation 3A

dl-4,5-dihydroxy-4-methoxycarbonylmethyl-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran (interm.) 5 A mixture of 655 mg (1, 37 mmol) 5-benzyloxy-4-ethoxycarbonylmethyl-4-hydroxy-2,2-dimethyl-11-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran, 133 mg 5 % palladlum calcium carbonate and 50 ml of methanol were hydrogenated at a pressure of 2.7 kg / cm 2 until hydrogen uptake was complete. The mixture was filtered, the filtrate was evaporated in vacuo and the residual oil was taken up in hexane. Upon cooling, crystals formed which were isolated by filtration to give 66 mg. The mother liquor was evaporated in vacuo to an oil, pentane was added and the mixture was cooled overnight. Filtration gave an additional 179 mg of product.

1 H-NMR (CDCl 3) ppm (delta): 3.00 (dd, 2H), 3.20 (s, 2H), 3.70 (s, 3H), 4.90 (s, 1H), 4.90 (s, 1H), 6.35 (m, 2H), 7.65 (s, 1H).

20 881 58

Preparation 4 dl-5-hydroxy-4-methoxycarbonylmethyl-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran and the corresponding lactone (intermediate) 5 CB2C02C2H5 HO / OCH-CH - \ / | 265 cb3jT jT x 10 ctx ^ 'sn ^ c <ch,) 2 (ch2> 5ch3

f CH 2 OH Pd / C

15 CO-CH, I 2 3 ch2 oh “3> 00 ^ 20 (Ca3) 2 (CB2) 5ch3 +: 25

O

To a 500 ml pressure flask was added a solution of 8.55 g (17.2 mmol) of 5-benzyloxy-4-ethoxycarboxylate. - 2i 8815b methyl ± 4-hydroxy-2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran in 250 ml of methanol. 1 g of 5% palladium-on-carbon catalyst was added and the mixture was shaken under a hydrogen atmosphere at 2.8 kg / cm 2 for 17 hours. The reaction mixture was filtered through anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was partitioned between 100 ml of ethyl ether and 50 ml of water, the aqueous layer was re-extracted with 50 ml of ether and the combined ether extracts were washed with 30 ml of saturated sodium bicarbonate solution and 30 ml of water. The ether was dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo to give a mixture of methyl ester and lactone, from which the previous product crystallized on standing. Recrystallization from low boiling petroleum ether gave the purified methyl ester, m.p.

72-73 ° C.

2 H-NMR (CDCl 3) ppm (delta): 0.82 (s, 3H), 1.0-1.5 (m, 20H), 1.53-2.6 (m, 4H), 3.1- 3.6 (m, 3 H), 3.68 (s, 3 H), 5.8 (s, 1 H), 6.2-6.4 (m, 2 H).

Infrared spectrum (KBr), cm -1: 3390 (0H), 2924 (CH, aliphatic), 1745 (C-0).

Mass spectrum (m / e): M * 376, bottom peak 260.

Analysis for C23H3604:

Calculated: C 73.36, H 9.64. Found: C 73.38, H 9.51.

Purification of the mother liquors by silica gel chromatography gave the lactone 2,2-dimethyl-8- (1,1-dimethylheptyl) -3,3a, 4,5-tetrahydro-2H-pyrano [4,3,2-de] benzopyran. -5-one.

2 H-NMR (CDCl 3) ppm (delta): 0.85 (s, 3H), 1.03-1.83 (m, 20H), 1.87-3.17 (m, 5H), 3.2 -3.7 (m, 2H), 6.4 (s, 1H), 6.6 (S, 1H).

Infrared spectrum (capillary film), cm -1: 3025 (CH, aromatic), 2925 (CH, aliphatic), 1660 (C-0).

35 Mass spectrum (m / e): 343 M *, bottom peak 260.

22 881 58

Analysis for C22H3203:

Calculated: C 76.70, H 9.31 Found: C 76.38, H 9.54.

Example 1 5 dl-5-hydroxy-4- (2-hydroxyethyl) -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzopyran (final product) 125 ml round bottom flask , equipped with a magnetic stirrer and a nitrogen supply tube, was thoroughly purged with dry nitrogen. 158 mg (4.2 mmol) of lithium aluminum hydride and 50 ml of dry ethyl ether were added and the suspension was stirred and cooled in an ice bath. To the cooled mixture was slowly added 1.44 g (4.2 mmol) of 5-hydroxy-4-methoxycarbonylmethyl-2,2-15 d ± methyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-benzo. -pyran dissolved in 20 ml of ether. The cooling bath was removed and the reaction mixture was stirred for 12 hours at room temperature. 50 ml of ethyl acetate was carefully added to quench the reaction. The resulting mixture was washed with 50 mL of both saturated sodium bicarbonate solution, brine and water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo to give 1.5 g of a crude oil which was purified by chromatography on 25 g of silica gel 25 (48-63 microns) eluting with pentane and ethyl acetate. The amount of the desired product was 1.0 g (69%) and when chromatographed on silica gel using a 1: 1 by volume mixture of ether and toluene, its Rf value was 0.125.

1 H-NMR (CDCl 3) ppm (delta): 0.83 (s, 3H), 1.0-1.67 (m, 23H), 1.7-2.1 (m, 2H), 2.7 -3.3 (m, 2H), 3.83 (t, 2H), 6.4 (s, 2H), 7.4-7.9 (s, broad, 1H).

Infrared spectrum (capillary film), cm-1: 3333 (OH), 2545 (CH).

Mass spectrum (m / e): M * 348, 264 bottom peak.

23 8 8158

Analysis for C22H3603:

Calculated: C 76.70, H 9.36 Found: C 77.36, H 9.67.

When the lactone 5,5-dimethyl-8- (1,1-dimethylheptyl-5H) -3,3a, 4,5-tetrahydro-2H-pyrano [4,3,2, -de] benzopyran-2-one or mixtures thereof with the methyl ester used above was reduced by the method described above, the title compound was similarly obtained.

When 1,3-dihydro-10-hydroxy-5- (5-phenyl-2-pentyloxy) benzene is used in place of 1,3-dihydroxy-5- (2,2-dimethylheptyl) -benzene in the process of Preparation 1 and the resulting product is treated 2-4 and according to the methods of Example 1, dl-5-hydroxy-4- (2-hydroxyethyl) -2,2-dimethyl-7- (5-phenyl-15-2-pentyloxy) -3,4- dihydro-2H-benzopyran.

1 H-NMR (CDCl 3) ppm (delta): 1.2-1.5 (m, 9H), 1.52-2.3 (m, 8H), 2.4-2.8 (m, 2H), 2.9-3.2 (m, 1H), 3.8 (t, 2H), 4.1-4.5 (m, 1H), 6.0 (s, 2H), 7.2 (s, 5H).

Infrared spectrum (capillary film), cm -1: 3400 (OH), 2980 2 O (CH).

Mass spectrum: M + 384, bottom peak 191.

Example 2 dl-5-hydroxy-4- (2-hydroxy-2-methylpropyl) - 2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-di-: 25-hydro-2H-benzopyran (end product)

A solution of 344 mg (1 mmol) of 2,2-dimethyl-11-8- (1,1-dimethylheptyl) -3,3a, 4,5-tetrahydro-2H-pyrano [4,3,2- de] benzopyran-5-one in 10 ml of ethyl ether, cooled in an ice bath for 15 minutes. To the cold solution was added 0.80 ml of 2.9 mol of methylmagnesium iodide in ethyl ether by slow injection. The resulting mixture was allowed to warm to room temperature and stirred for 14 hours. About 100 mg of crystalline ammonium chloride was added, the mixture was stirred for 20 minutes, 5 ml of water was added and the layers were separated.

24 881 58

The aqueous layer was extracted with 10 mL of ether and the combined ether layers were washed with 30 mL of saturated sodium bicarbonate solution, 30 mL of brine and 30 mL of water. The washed organic layer was dried over magnesium sulfate, the solvent was evaporated in vacuo to give 348 mg of an oil which crystallized on standing. Recrystallization from pentane gave 250 mg (66.5%) of purified product, mp 101-103 ° C.

1 H-NMR (CDCl 3) ppm (delta): 0.83 (s, 3H), 1.0-1.5 (m, 28H), 1.53-2.5 (m, 5H), 2.9 -3.2 (m, 1H), 6.3 (d, 1H), 6.4 (d, 1H), 7.8-8.6 (m, 1H).

Infrared Spectrum (KBr), cm -1: 3333 (OH), 2899 (CH). Mass spectrum (m / e): M * 376, bottom peak 274.

Analysis for C 24 H 40 O 3: Calculated: C 76.55, H 10.71 Found: C 76.61, H 10.45.

Example 3 dl-5-hydroxy-4- (2-hydroxypropyl) -2,2-dimethyl-7- (1,1-dimethylheptyl) -3,4-dihydro-2H-Bent-20 sopyran (final product) 491 mg (1.42 mmol) of hemiacetal dl-5-hydroxy-2,2-dimethyl-8- (1,1-dimethylheptyl) -3,3a, 4,5-tetrahydro-2H-pyrano [4.3, The 2-de] -benzopyran was dissolved in 10 ml of diethyl ether and cooled in an ice bath for 15:25 minutes. 1.58 ml of 2.9 M methylmagnesium iodide was added slowly with a syringe and with stirring. The reaction mixture was allowed to warm to room temperature and stirred for three hours. About 100 mg of ammonium chloride crystals were added to consume unreacted Grignard reagent, and the mixture was stirred for 20 minutes. 75 ml of ethyl acetate and 50 ml of water were added, the mixture was stirred for a few minutes and the layers were separated. The aqueous layer was extracted with 50 mL of ethyl acetate and the combined organic layers were washed with 50 mL of water, brine and again 35 water. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo to give 525 mg of a crude oil, the oil was chromatographed on two 2 mm thick silica gel plates using a 1: 3 by volume mixture of ethyl acetate and pentane as the solvent system. The range with an Rf value of 0.09-0.21 was extracted with 200 ml of ethyl acetate for 2-3 hours to give 300 mg (58.3%) of product.

1 H-NMR (CDCl 3) ppm (delta): 0.70 (s, 3H), 0.78-1.35 (m, 25H), 1.40-1.87 (m, 4H), 2.41- 2.77 (m, 1H), 2.85-3.50 (m, 1H), 6.44-6.60 (m, 2H), 7.52-8.35 (broad 1H).

Infrared spectrum (capillary film) mp 1: 3350 (OH, very broad), 2925 (CH).

Mass spectrum (m / e): 362, bottom peak 44.

Analysis for C 23 H 38 O 3: 15 Calculated: C 76.19, H 10.57%

Found: C 75.97, H 10.16%.

The starting hemiacetal was prepared as follows:

A solution of 1.80 g (5.2 mmol) of 5,5-dimethyl-20-11-8- (1,1-dimethylhetpyl) -3,3a, 4,5-tetrahydro-2H-pyrano [4 , 3,2-de] benzopyran-2-one in 25 ml of dry toluene, was cooled with stirring to -78 ° C. Added dropwise

5.2 ml of 1.0 M diisobutylaluminum hydride at a rate such that the temperature of the mixture did not exceed -60 ° C

25 (about 20 minutes). The resulting mixture was stirred for one hour at -78 ° C, then 4 ml of methanol was added and the mixture was allowed to warm to room temperature. 75 ml of ethyl ether were added and the mixture was washed with 3 x 30 ml of sodium potassium tartrate solution, 30 ml of brine and 30 ml of water. The organic phase was dried over magnesium sulfate, the solvent was evaporated in vacuo to give 1.80 g (100%) of the desired hemiacetal.

V: 1 H-NMR (CDCl 3) ppm (delta): 0.83 (s, 3H), 1.0-1.4 (m, 22H), · 1.6-2.3 (m, 4H), 2 , 8-3.3 (m, 1H), 3.5 (s, broad, 1H), 5.4-35, 5.8 (m, 1H), 6.4 (s, broad 2H).

26 881 58

Infrared spectrum (capillary film), cm -1: 3450 (OH), 2925 (CH).

Mass spectrum (m / e): M * 346, 146 bottom peak.

Analysis for C 22 H 34 O 3: 5 Calculated: C 76.26, H 9.89 Found: C 75.40, H 9.45.

Claims (2)

A process for the preparation of new therapeutically useful bicyclic benzofused compounds of formula (1), R 2, J 2, c 3 R 3 OH HOn. ch3 wherein R2 and R3 are hydrogen atoms or methyl groups, Q3 is -CH2OH, -CH (CH3) OH or -C (CH3) 2OH, Z is -O-CH (CH3) CH2CH2CH2- or -C (CH3) 2 (CH2) 6-, and W is hydrogen or phenyl, characterized in that the compound of formula (IX) 20 or (X) Ro0 \ Ro__1 ccoor7 25 or 3ΓΧ | ι ^ Ί CH3 / \ R4 A0 / CH 3 R 5 (IX) 00 30 wherein Y 2 is hydrogen, methyl, benzyl, benzoyl or acetyl and R 1 is hydrogen, methyl or ethyl, is reduced in the presence of an inert solvent with a metal hydride, preferably lithium aluminum hydride, or methylmagnesium iodide, or by catalytic hydrogenation with a noble metal catalyst at a temperature of 0-60 ° C. 28 881 58 Förfarande för framställning av nya therapeutiskt användbara bicykliska benzofueionerade föreningar med 5 formeIn I, r2. R3 oh 10 Ti J ZW ch3 15. A compound of formula R2 and R3 is a hydrogen atom or a methyl group, Q3 ttr -CH2OH, -CH (CH3) OH or -C (CH3) 2OH Z? -O-CH (CH3) CH2CH2CHa- or -C ( CH3) 2 (CH2) 6-, and W is the same as phenyl, the same is used to give for -20 minutes (IX) or (X) ^ ccoor7 .25 Γ ^ τΓ ^ ι eiier R3rVS CH -, __ I [ I τ> Λ_ II / o ^ zw / 0 zw CH3 R5 (IX) (X). en metal hydrides, ferrous 11-thium aluminum hydrides, or methylmagnesium iodides, or genomic catalytic hydrogens with a metal catalyst 35 at a temperature of 0-60 ° C.