CS214888B2 - Method of preparation of the new hexahydrobenzopyranoxanoxanthenons - Google Patents

Description

The invention relates to a process for the preparation of novel hexahydrobenzopyranoxanthenones useful as antiandogens. Androgens are substances that are effective as stimulators of secondary sexual characteristics in males. Although these substances appear to be of great physiological importance, they may cause certain undesirable side effects and it would be highly beneficial to prophylactically or therapeutically eliminate or minimize these effects. For example, the stimulatory effects of androgens on the prostate have been known for many decades. Pathogenesis of benign prostate hypertrophy (BPH) and / or prostate cancer (PC is not fully elucidated, however, both of these syndromes are thought to be influenced by androgens. In addition, acne, an inflammatory disease affecting the adipose glands, mainly found in adolescents. , is believed to be dependent on and is dependent on androgen action, and androgen-dependent diseases are hirsutism and certain cancers, including breast cancers.

Androgens are steroid hormones. For some time, it has been customary to try to regulate the effect of androgen by administering other steroids. However, although the administration of these steroids may be effective in reducing the effect of androgens, it is usually associated with other undesirable side effects that reduce their usefulness. For example, cyproterone acetate is a potent steroid antiandrogen. Although its clinical efficacy has been demonstrated against both benign prostatic hypertrophy and prostate cancer, it is not commonly used in human medicine for its hormonal side effects. It has been reported to suppress adrenal function and to have strong progestational side effects.

It is therefore highly desirable to find non-steroidal structures having a potent antlandrogenic effect. The invention relates to such a class of compounds. To date, only a very small number of non-steroidal antiandrogens are known. U.S. Patent No. 3,857,953 discloses a class of arylidecyclanone compounds. These substances have no steroid structure and have an antiandrogenic effect. The invention relates to a new class of non-steroidal antiandrogens.

The present invention provides a process for the preparation of novel hexahydrobenzopyranoxanthenone compounds of formula I,

213 8 8 8

'where each symbol represents

R is hydrogen, C1-C4 alkyl, -, C1-C4 alkoxy, hydroxy, cyano, or halogen, both R being identical and located symmetrically,

R1 is C1-C3 alkyl;

R2 is methyl, or

R 1 and R 2 together represent a group (CH 2 _n ) wherein n represents an integer from 4 to 6, and

Xa, Xb, Xc, Xd, Ya, and Yb represent hydrogen atoms, with the proviso that both Xc and Xd are in the ' -configuration, both Xa and Xb are in the a- or β-configuration and R1 when C1 is -C3 alkyl is in the n-configuration characterized in that the compound of formula V is reduced,

where

R1, R2, R, Xc and Xd are as defined above, by catalytic hydrogenation at 25 to 50 ° C or electrolytically at 5 to 80 ° C in an organic or aqueous-organic mercury cathode environment in the presence of a proton source and an electrolyte selected From the group consisting of alkali metal salts, quaternary ammonium salts of 10 to 28 carbon atoms in the cation and salts of tertiary amines having a total of 7 to 21 carbon atoms in the cation, whereby the reduction product is further treated with pyridinium chlorochromate when the reduction is carried out , neh _of sodium dichromate, potassium dichromate.

The starting compounds of the formula V are prepared by reacting 2-hydroxybenzaldehyde of the formula II,

O

kde _ __

Ra is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, cyano or halogen, reacted with 2,5-cyclohexadiene of formula III,

O

Ri Rz mi) where

R1 and R2 are as defined above, in the presence of a pyrrolidine or pyrrolidine mono- or disubstituted with chlorine, bromine or C1-C3 alkyl groups, and a C1-C7 carboxylic acid in an inert solvent at 0 to 65 ° C to form the dihydrobenzopyranoxanthenone of formula IV

where

Ra, R 1 and R a are as defined above, and X c and X d are either in the "," -, or in the "-" configuration, and when the reaction of the compounds of formulas II and III was carried out at a temperature below ambient. a compound of formula IV at a temperature of from 0 to 100 ° C to give the corresponding compound of formula V wherein R is Ra and Xc and Xd are in the "," configuration, and when the compound of formula I is to be obtained, wherein R is hydroxy, treating a compound of formula V wherein Ra is C 1 -C 4 alkoxy with boron tribromide in an inert solvent to give the corresponding compound of formula V wherein R is hydroxy.

In the compounds of Formula I, the carbon atom at the 6-position of the C5-C7 complements the spiro ring or is substituted by both methyl (R2) and R1, which is CUC3 alkyl-. The term "C 1 -C 3 alkyl" refers to methyl, ethyl, n-propyl or isopropyl. Preferably R 1 is methyl and, if so, it is of course a 6,6-dimethyl compound.

However, when R 1 is a C 1 -C 3 alkyl group other than a methyl group, the substituents on the 6-carbon atom are different and therefore more than one isomer may exist.

In these cases, the compounds of the invention are those in which the methyl group (R 2J is in a position generally axial to the ring, while the R 1 group is in a position generally equatorial to the ring.

In the preceding formulas, R is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, cyano, or halo. The term "C 1 -C 4 alkyl" refers to methyl, ethyl, η-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. The term "C 1 -C 4 alkoxy" as used herein refers to methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy, isobutoxy, sec-butoxy and t-butoxy. The term "halogen" as used herein refers to chlorine, fluorine and bromine. Among the above, R is preferably hydrogen, methoxy, ethoxy or cyano.

In each of the compounds of this invention, the R group occurs at two sites. For all compounds of the invention, these groups are identical at both sites of the molecule and represent the same group. In addition, for all compounds of the invention, these groups are located symmetrically and are therefore in positions 2 and 10, 3 and 9 or 4 and 8.

The dihydrobenzopyranoxanthenones of formula IV in which the 5a and 6a hydrogens have a trans configuration, i.e., those compounds in which one hydrogen is in the α-position and the other in the (S-position), can be easily epimerized to the dihydrobenzopyranoxanthenones of formula V by heating temperature above room temperature.

The hexahydrobenzopyranoxanthenones of formula (I) differ from the dihydro compounds in that they have hydrogenated double bonds at the 12- and 13a-carbon atoms. The resulting hydrogenated products of formula VI contain hydrogen atoms at the 5α, 6α, 12α, 12α, 13α and 14-carbon atoms. An important factor in the definition of the compounds of the invention is a certain mutual stereoconfiguration of the hydrogen at the 5a, 5a, 1.2 and 13a positions. Of the various possible stereochemical combinations for these 4 hydrogen atoms, two combinations represent a compound of the invention. Hexahydrobenzopyranoxanthenones containing the following two groupings 1 and 2 are included in the definition of the compounds of the invention:

Η Η Η H

R, ^r i

11) 12)

Accordingly, the hexahydrobenzopyranoxanthenones of formula I include those compounds in which they have hydrogen atoms on the

The 5α and 6α carbon atoms both have a cis configuration relative to the other hydrogen atoms (Formula Ij, and those compounds in which the hydrogen atoms at the 12α and 13α carbon atoms have both a cis configuration relative to the other hydrogen atoms.

In addition to the above limitations relating to the stereoconfiguration of compounds of formula I, there are other limitations. R 1 may be C 1 -C 3 alkyl. When R 1 is methyl, it is a 6,6-dimethyl compound and there is no further variation with respect to stereoconfiguration. However, when R 1 is other than methyl, it is a 6-methyl-6-ethyl-, 6-methyl-6-n-propyl- or 6-methyl-6-iso-propyl compound. All of these compounds have a structure corresponding to formula I, but only those compounds having a stereoconfiguration such that R 1 is in a position equatorial to the ring structure and a methyl group (R 2J in the position axial to the ring structure) are within the definition of the compounds of Formula I. of the compounds in which R 1 is a C 1 -C 3 alkyl group other than methyl, the compounds of the invention are those in which the 5α-and 6α-hydrogens and the R1 group are all in the α-position.

The first step of the synthesis of the starting compounds involves the reaction of compounds of formulas II and III. When the reaction is carried out at or below ambient temperature, the resulting product is predominantly a mixture of 5α -, 6α / 3 - and 5α / 3, 6α - optical isomers of formula IV. These are useful intermediates. When heated to a temperature above room temperature, the rearrangement occurs to the 5aa, 6aa-isomer of Formula V.

When the condensation of 2-hydroxybenzaldehyde with 4-substituted 2,5-cyclohexadienone is carried out at a temperature above ambient temperature, usually at 55 to 65 ° C, the 5aa, 6aa-isomer is isolated directly from the reaction mixture.

As can be seen, 2-hydroxybenzaldehyde and 4-substituted 2,5-cyclohexadienone in a molar ratio of at least 2: 1 must be used to obtain the reaction products in the above condensation.

The condensation can usually be carried out in any solvent which is inert to the reactants and in which the reactants are sufficiently soluble. In the event of epimerization also permitting direct isolation of the 5aa, 6a-isomer, solvents having a boiling point sufficiently high to allow epimerization to be carried out, i.e. a boiling point above room temperature, must be used, when working at normal pressure. Examples of typical solvents that may be used are aromatic hydrocarbons such as benzene, toluene and the like, and ethers such as tetrahydrofuran.

The C 1 -C 7 carboxylic acid is usually used in an amount at least molar equivalent to the amount of aldehyde used. Typical carboxylic acids that can be used after 218888 are acetic, propionic, butyric, and benzoic acids. The preferred acid is acetic acid. In addition, pyrrolidine or substituted pyrrolidine is used. Examples of substituted pyrrolidines include 2-methylpyrrolidine, 3-chloropyrrolidine,

2,3-dibromopyrrolidine and 3-propylpyrrolidine. A preferred amine is pyrrolidine.

To conduct the condensation, the reactants are mixed in the selected solvent. The order of addition of the reactants is not critical, but cyclohexadiene is usually added last. The mixture is then allowed to react at the selected reaction temperature and the product is isolated in a conventional manner.

The starting materials are salicylaldehyde or substituted salicylaldehyde of formula II and 4-substituted-2,5-cyclohexadienone of formula III.

Salicylaldehyde as well as 3-, 4-, or

5-substituted salicylaldehydes are available by well known technologies. They can be prepared, for example, by the Reimer-Tieman reaction, which is carried out by treating a suitably substituted phenol with chloroform and an alkali metal hydroxide, in particular sodium hydroxide.

Dienon is available from one of two relatively complex reaction sequences. The formation of 4-substituted-cyclohexanones from methyl vinyl ketone and the appropriate aldehyde is well known from E. L. Eliel and C. Lukách, J. Am. Chem. Soc. 79, 5986 (1957), Y. Khan and W.W. Epstein, Org. Son. 53, 48 (1973), C. H. Heathcock et al. Tetrahedron Letters, 4995 (1971).

The condensation of methyl vinyl ketone with aldehyde is easily controlled. Usually, equimolar amounts of methyl vinyl ketone and aldehyde, or a slight excess, up to about 10% of the aldehyde are used, and are preferably operated under acidic conditions. Condensation is exothermic.

Conversion of the 4-substituted cyclohexenone to the desired product can be accomplished by one of two methods. Direct conversion involves dehydrogenation using dichlorodicyanquinone, Η. E. Zimmerman et al; J. Am. Chem. Soc. 93, 3653 (1971). Alternatively, the conversion can be performed indirectly using the reaction sequence described by H. Plicninger et al., Chem. Ber. 94, 2115 (1961). In this reaction sequence, the 4-substituted cyclohexenone is treated with propan-2-ylacetate under acidic conditions to give 2-acetoxy-5-substituted-1,3-cyclohexadiene which is treated with N-bromosuccinimide to give 4-substituted-6- bromocyclohex-3-enone, which is then dehydrobromated to the desired cyclohexadienone using hexamethylphosphoric triamide.

Compounds of formula V wherein R is hydroxy are prepared by demethylating the corresponding compounds wherein R (or Raj is methoxy) Demethylaee is accomplished by treating the dimethoxy compound with boron tribromide, typically 3 molar equivalents of boron tribromide are added to the mixture. The addition is carried out as quickly as possible while maintaining the temperature of the reaction mixture at 0 DEG C. After the addition is complete, the mixture is allowed to warm to room temperature and held at room temperature for 4 to 1Θ hours. by adding the mixture to ice water and extracting the product into a suitable solvent such as methylene chloride or ethyl acetate.

Compounds of formula V in which R is alkoxy are also available from compounds in which R is hydroxy. Hydroxy compounds are treated with a large excess of potassium carbonate and a suitable alkyl bromide in the presence of hexamethylphosphoric triamide, which itself can serve as a solvent. The reaction is carried out at an elevated temperature of 50 to 400 ° C for 1 to 20 hours.

The hexahydrobenzopyranoxanthenones of formula VI are prepared by reduction of dihydrobenzopyranoxanthenones. The reduction can be carried out catalytically. For example, it can be carried out in a suitable solvent using standard catalysts such as Raney nickel, palladium on carbon, platinum oxide, platinum on carbon, and the like. The reduction is usually carried out at room temperature or at a slightly elevated temperature, 25 to 50 ° C, and at a pressure of 206 to 412 kPa. Catalytic reduction is usually compound after 4 to 48 hours and mostly after 24 hours. The reduction can be carried out at atmospheric pressure, but the reaction time is thereby greatly extended.

The reduction is carried out in the presence of a solvent. Typical suitable solvents are ethers such as tetrahydrofuran, esters such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene, and alcohols such as methanol and ethanol. Ethers are particularly preferred, especially tetrahydrofuran is a particularly preferred solvent.

The amount of catalyst generally ranges from 10 to 109% by weight based on dihydrobenzopyranoxanthenone. When Raney nickel catalyst is used, the amount is usually higher than the amount of platinum or palladium catalyst used.

By reduction, a mixture of epimeric ketones can be obtained. Although the relative positions of the hydrogen atoms delivered to the 12α-and 13α-position are cis, both of these hydrogens can be in the α or β configuration with respect to the 5α and 6α-position hydrogen atoms. Raney nickel or palladium to afford a mixture of about 80: ¹ 20 epimers in which prevails 12ačř, 13aa isomer. When platinum is used as the catalyst, the product is essentially exclusively the 12aa, 13a-isomer.

The catalytic reduction is at least in part almost always accompanied by a reduction of the keto group at the 13-position to give the corresponding hydroxy compound. Thus, different amounts of the corresponding alcohol are obtained. Using Raney 214888 in nickel and palladium as catalyst, the keto group is reduced by 30-50%. The reduction of the keto group is higher using a platinum catalyst and is almost complete using platinum oxide.

The alcoholic portion of the product in the reaction mixture can be re-oxidized to the desired hexahydro-product of formula I by treatment with at least one equivalent of pyridinium chlorochromate, sodium dichromate or potassium dichromate. Such re-oxidation is necessary when platinum oxide is used for reduction. Prior to re-oxidation, the alcohol is preferably isolated, but this is not critical, even the entire reaction mixture may undergo treatment under oxidizing conditions. The oxidation is carried out at room temperature in a solvent such as methylene chloride or any of the above solvents. When pyridinium chlorochromate is used, the oxidation is complete in 24 hours. Using dichromate, oxidation is quicker and is complete after 1 to 4 hours.

Dihydrobenzopyranoxanthenones can also be converted to the corresponding hexahydrobenzopyranoxanthenones by electrolytic reduction. This method is sufficiently selective so that the re-reduction described above does not occur.

The electrolytic reduction is carried out by dissolving or suspending the dihydrobenzopyranoxanthenone in an organic medium or in a medium containing an aqueous-organic mixture. The aqueous-crganic mixture may be present in the form of an emulsion or in the form of a solution. Typical suitable organic media are amides such as N, N-dimethylformamide and Ν, Ν-dimethylacetamide, nitriles such as acetonitrile, alcohols such as methanol. and ethanol, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as methylene chloride and chloroform. Of the organic electrolysis media of the present invention, amides, nitriles and alcohols are most preferred. Particularly suitable media are Ν, Ν-dimethylformamide, acetonitrile and methanol, especially methanol.

In addition, an electrolyte is added to the mixture. Suitable electrolytes are salts, for example, alkali metal halides, tosylates and chlorates such as lithium, sodium and potassium. Other useful electrolytes are quaternary ammonium salts such as halides and perchlorates. Examples are tetraalkylammonium, trialkylaralkylammonium, dialkyldiaralkylammonium or alkyltriaralkylammonium, each containing a total of 10 to 28 carbon atoms in the cation. A preferred salt is the tetrabutylammonium salt.

Another class of electrolytes is the tertiary amine sol, such as halides, tosylates and perchlorates, trialkylamines, dialkylaralkylamines, alkyldiaralkylamines and triaralkylamines, each containing a total of 7 to 21 carbon atoms. A preferred tertiary amine salt is a tributylanrine salt, especially a salt derived from p-toluenesulfonic acid.

Examples of typical electrolytes include:

lithium perchlorate, potassium perchlorate, sodium perchlorate, lithium chloride, lithium bromide, potassium fluoride, sodium iodide, lithium iodide, tricaprylylmethylammonium chloride, benzyltributylammonium, benzyltriethylamoniumbromld, benzyltriethylammonium chloride, benzyltrimethylamoniumbromid, cetyltrimethylarooniumbromid, methyltributylamonium iodide, myristyl, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, ^dibenzyld: ethylamoniumchlorid , dibenzyldipropylammonium bromide, phenethyltributylammonium chloride, diphenethyldipentylammonium bromide, tribenzylethylammonium chloride, tripropylphenethylammonium iodide, tributylphenethylammonium chloride,

N, N-diisopropyl-N-ethylamine perchlorate, tri-n-hexylamine bromide,

N-benzyl-N, N-diethylamine-p-toluenesulfonate,

N-benzyl-N, N-dibutylamine bromide,

N N-dibenzyl-N-butylamine perchlorate,

N, N-benzyl-N-ethylamine chloride, trisynane-p-toluenesulfonate and tributylamine chloride.

In addition, a proton source is added to the reaction medium. Best results are obtained with relatively weak acids having a pKa of 2 to 6, such as benzoic acid and acetic acid.

In the electrolytic reduction, the dihydrobenzopyranoxanthenone of formula V is usually present in the reducing medium in an amount of 1 to 15 mg / ml. The electrolyte is usually present in an amount of from 0.01 mol to 1.0 mol and the acid is present in an amount of 1 to 5 percent by weight based on the volume of the medium. The electrolytic reduction is usually carried out at a temperature of from 5 to 80 ° C, preferably 20 to 30 ° C.

The resulting mixture containing dihydrobenzopyranexanthenone, a proton source, an electrolyte and an organic or aqueous-organic medium is placed in contact with the cathode of the electrolyzer. The potential of the corresponding point at which; the background is starting to drain. This potential is determined by constructing a current curve against the potential for the working electrode in the environment used prior to electrolysis. The current is then passed through the electrolyzer at a certain potential until the amount of current corresponding to one to two times the number of Faradays needed to reduce the four electrons passes through the electrolyzer. Electrolysis is a particularly suitable cathode reduction process that is readily performed in electrolysers of conventional design. For example, the method can be performed using conventional electrolytic cells, such as those described in MJ Allen, Organic Electrode Processes, Reinhold Publishing Corporation, New York, 1958. These conventional electrolytic cells are described on page 33 of the publication and include a suitable cathode and anode which are separated by a bridge. Mercury cathodes are used as the cathode in this process. Platinum and carbon can be used as anode materials. The metal platinum is the preferred anode material and preferably forms the platinum anode platinum in the form of a fine mesh or wire mesh. Another preferred anode is the carbon anode for its cheapness.

As a bridge connecting the cathode and anode, a conventional salt bridge, such as a 4% aqueous mixture saturated with potassium chloride, can be used. The bridge may also be a suitable porous membrane, such as an ion exchange membrane, a ceramic membrane, or a glass frit membrane with a small to medium porosity. Any of the membranes described and discussed in M. J. Allen, cited above, may also be used.

A typical electrolyzer consists of a cylindrical cathode space formed by a jacketed glass vessel. In the cathode compartment there is an anode compartment formed from a glass container comprising a glass frit. The cathode is usually a ring-shaped layer of mercury. The anode space is usually formed by a glass frit cylinder or a double-walled glass tube of circular cross-section, to whose lower end a circular glass frit is fused. The anode is typically a platinum wire immersed in the same mixture of organic or aqueous organic medium and electrolyte as used in the cathode space. The electrolyser is usually sealed with a cap in which a vent frit, a reference probe, and a thermometer are inserted. The reference electrode probe is formed by a glass tube containing a fiber joint into which a saturated calomel electrode is inserted.

In practice, a suitable mixture comprising an organic or aqueous-organic medium, an electrolyte and a proton donor is placed in the cathode space. A predetermined amount (about 1 to 15 mg / ml dihydrobenzopyranoxanthenone) is added to this mixture while stirring, and a circular anode space containing a mixture of organic or aqueous-organic medium and electrolyte is placed with the electrolyzer cap suitably relative to the cathode. At the end of the vent (about 15 minutes), the vent frit is raised above the surface of the cathode solution and the argon continues to be introduced throughout the electrolysis period, then a predetermined potential is applied to the electrolyzer and electrolysis is performed. until the amount of current passed corresponds to approximately twice the Faradays required to reduce 12 or 4 electrons The counting of coulombs passed through the system can be performed by a coulombmeter and the state of the system can also be monitored by thin layer chromatography or * high pressure liquid chromatography Any of these methods are useful for monitoring the extent of the reaction: Upon completion of the electrolysis, the catalyst solution is removed from the cell and subjected to further processing.

The reaction mixture is worked up by conventional techniques. Usually, most of the organic or aqueous-organic medium is first removed under vacuum. The resulting syrupy residue was then dissolved in ethyl acetate. The ethyl acetate solution was washed several times with approximately equal volumes of water to remove the electrolyte and the proton donor. The ethyl acetate phase is then dried with a suitable desiccant, such as anhydrous magnesium sulfate, and then filtered. The ethyl acetate was evaporated and the residue was dried in a vacuum oven at about 45 ° C for several hours. The desired hexahydrobenzopyranoxanthenone product is then obtained by crystallizing the residue from a suitable solvent system.

Electrolyte cation is a very important factor in the electrolytic reaction. It has been found that the stereoconfiguration of the hexahydrobenzopyranoxantherion of formula VI is largely dependent on the particular electrolyte used. When a salt is used as the electrolyte, the cation forms a strongly associated ion pair, such as lithium, sodium or potassium, to give a product containing predominantly hexahydrobenzopyranoxanenone with a 5azK, 6aia, 12a / 3,13a, * 3 configuration. Conversely, the caftane electrolyte, which forms a weak ion pair, such as a quaternary ammonium cation or a tertiary amine salt cation, directs the electrolytic reduction so that the product contains predominantly 5-aa, 6aa, 12ate, 12aa. Since the α, α, β, α-isomer is usually a more potent antiandrogen than the corresponding α, α, β-isomer, it is preferable to use a quaternary ammonium salt or a tertiary amine salt as the electrolyte.

Examples of the dihydrobenzopyranoxanthenones of formula IV which are useful intermediates in the preparation of antiandrogens include:

(5aa, 6aS) -8,6a-dihydro-6,6-dimethyl-5aH, 13H- (1J benzopyrano (3,2-bJ xanthene-13-o * n, (5aa, 6a, 6 ')) -6,6a-dihydro-4,8-dimethyl-6,6-dimethyl-5aH, 12H- (i) benzopyrano (3,2-b) xanthen-13-one, (a, 6a) - 6,6a-dihydro-3,9-diethyl-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6a (3) -6,6a) -dihydro-2,10-di-n-propyl-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3,2-b) xanthen-13-one, (5aa, Bap) -Q, 6a-dihydro -2,10-dl-t-butyl-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3,2-b) xanthen-13-one, (5a, 6a) -1,6,6a- dihydro-3,9-diinethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3,2-b) xanthen-13-one, (5aa, 8a / i) -6,6a-dihydro-4, 8-diethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3,2-b) xanthen-13-one, (5aa, 6a _, 13) -6,6a-dihydro-4,8-diisopropyl opoxy-6,6-dimethyl-5aH, 13H- (1 (benzopyranof 3,2-b) xanthen-13-one, (5a, 6a, 3 ') - 6,6a-dihydro-3,9-di- n-butoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aS) -6,6a-dihydro-3,9-dicyano- 6,6-dimethyl-5aH, 13H- (1 (benzopyrano (3,2-b) xanen-13-one), (Saaea-β-α-dihydro-β-dichloro-β-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6a ')) -6,6a-dihydro-4,8-difluoro-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3,2-b) xanthen-13-one, (5aa, 6a / 3) -6,6a -dihydro-2,10-dibromo-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (δβα, δβ, ό (-6,6α-dihydrospiro [ 5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'-cyclopentan] -13-one, (5aa, 6a (3) -6,6a-dihydro-4,8-dimethylsplro [5aH] 13H- (1 (benzopyrano! 3,2-b (xanthene-6,1'-cyclohexane J-13-one, (5aa, 6a (3) -6,6a-dihydro-3,9-diethylsplro [5aH, 13H- (1) benzopyrano (3)) 2-b) xanthene-6,1'-cycloheptan] -13-one, (5aa, 6a (S) -6,6a-dihydro-2,10-di-n-propylspiro [5aH, 13H- ( 1 (benzopyrano (3,2-b) xanthene-6 ' -cyclopentane] -13-one (5aa, 6 ₁ d) -6,6-dihydro-3,9-dimethoxyspiro [5aH, 13H- (1 Benzopyrano-3,2-b (xanthene-6,1'-cyclohexane) -13-one, (5aa, 6a (S) -6, .alpha.-dihydro-4,8-diethoxyspiro [5aH, 13H- (1) benzopyrano) 1,3-b) xanthene-6,1'-cyclopentan] -13-one, (5aa, 6a / 3) -6,6a-dihydro-4,8-dihydroxyspiro [5aH, 13H- (1 (benzopyranof)) 3,2-b) xanthen-6,1'-cyclohexane] -13-one;

Examples of dihydrobenzopyranoxanthenones of general formula V which are useful Antiandrogens include:

{5aw, 6aa] -6,6a-dihydro-8,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one.

(5aa, 6aa (-6,6a-dihydro-6H-methyl-6'-ethyl) -5aH, 13H- (1 (benzopyrano (3,2-b (xanthen-13-one, (5aia, 6aa)) 6,8a-dihydro-6H-methyl-6a-n-propyl-5aI, 13H- (1 (benzopyranof 3,2-b (xanthen-13-one, (5aa, 6a, a)) -6), 6α-dihydro-6β-methyl-6α-isopropyl-5αH, 13H- (1} benzopyrano (3,2-b (xanthen-13-one), (5α.a, 6αa (-6,6α-dihydro-4,8a)) -dimethyl-6,6-dimethyl-5α, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5α, 6α-6,6α-dihydro-3,9-diethyl-6) 6-diinethyl-5aH, 13H- (1 (benzopyranol 3,2-b (xanthene-13-osn, (5a, 6aa)) -6,6a-dihydro-2,10-di-n-propyl-6a) 6-dimethyl-5aH, 13'H- (1) benzopyranof 3,2-b) xanthien-13-one, (5aa, 6aa (-6,6a-dihydro-2,10-di-t-butyl-6)) (S) -methyl-6a-ethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa) -6,6a-dihydro-3,9-dimethoxy-6, 6-dimethyl-5α, H, 13H- (1) benzopyranol 3,2-b) xanthen-13-one, (5αa, 6α- (-6,6α-dihydro-4,8-diethoxy-6 / 3-) methyl 6a-isopropyl-5aH, 13H- (1) benzopyrano (3,2-b (xanthen-13-one, (5aia, 6aa)) -6,6a-dihydro-4,8-dlisopropoxy-6,6-dimethyl -5aH, 13H- (1 (benzopyranol 3,2b) xanthe) n-13-one, (5aa, 6a, a) -6,6a-dihydro-3,9-di-n-butoxy-6H-methyl-6a-n-propyl ^: 5aH, 13H- (1) benzopyrano (3,2-b (xanthen-13-one, (5aa, 6aa)) -6,6a-dihydro-4,8-dihydro-6,6-dimethyl-5aH, 13H- (1) benzopyranol; 3,2-b) xanthen-13-one, (5aor, 6aa) -6,6a-dihydro-3,9-dicyano-6'-methyl-6of-ethyl-5aH, 13H- (1 (benzopyrano (3, 6, 6a, 6a, 6a)) 2-b) xanthene-13one, (5a, 6aa) -6,6a-dihydro-4,8-dichloro-6,3-methyl-6a-isopropyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa) -6,6a-dihydro-4,8-difluoro-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b (xanthene-13) -one, (5aa, 6aa) -6,6a-dihydrospir o214888 (5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'-cyclohexane] -13-one, (5ace, 6a ') ) -6,6a-dihydro-4,8-dimethylspiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'-cyclopentan] -13-one, (a, 6aa) - 6,6a-dihydro-3,9-diethylspiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthanen-6,1'-cyclohexane] -13-one, (5aa, 6aa) -6,6a-dihydro-3,9-dimethoxyspiro [5a H, 13 H- (1) benzopyrano (3,2-b) xanthfen-6,1'-cyclohexane] -13-one, (5aa, 6aa) -6, 6a-di'hydro-4,8-diethoxyspiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'-cyclopentan] -13-one, (5aa, 6a, a) -6 ₁ , 6a-Dihydro-4,8-dihydroxyspiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'-cyclohexane] -13-o n, (5a, 6a) -6,6a-dihydro-2,10-dibromo-6,6-dimethyl-5aH, 13H- (1'-benzopyrano (3,2-b) xanthanen-13-one) as examples of hexahydrobenzopyranoxanthenes of formula I include (5aa, 6aa, 12aa, 13aa j -6.6a, 12a, 12a, 13a, 14-hexahydro-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3)). 2-b) xanthen-13-one, (5aa, 6aa, 12aa, 13: aa) -6,6a, 12,1,2a, 13a, 14-hexahydro-6 (3-methyl-6o) - ethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa, 12a ', 13aa] -6,6a, 12,, 12a, 13a, 14-biphexahydro- 6'-methyl-6'-n-propyl-5aH, 13H- (1'-benzopyrano (3,2-b) xanthen-13-one, (5a, 6aa, 12aa, 13aa) -6,6a, 12) ^; , 12a, 13a, 14-hexahydro-6'4-methyl-6'-isopropyl-5aH, 13H- (1'-benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa, 12a) aa, 13aa) - 6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethyl-6,6-dimethyl-5aH, 13H- (1-benzopyrano (3,2-b) xanthene) -13-one, (5aa, 6aa, 12aa, 13aa) ^ 6,63,121,12 ^ 138,14-hexahydro-3,9-diethyl-6,6-dimethyl-5aH, 13H- (1-benzopyrano (3,2-a) -b J xanthen-13-one, (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-2,1-dl-n-propyl-6,6,6-dimethyl- 5aH, 13, H- (1-benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa, 12aa, 13aa) -6.6a, 12.12a, 13a, 14-hexahydro-2.10 -di-t-butyl-6/3-methyl-6a-ethyl1S

-5.31, 1311- (1) benzopyrano (3,2-b) xanthen-13-one, (caa, 6aa, 12aa, 13aa) -6,6a, 12, 12a, 13a, 14hexahydro-3,9-dimethoxy- 6,6-dimethyl-5aH, 13H- (1'-benzopyrano (3,2-b) xa-then-13-one), (5aa, 6aa, 12aa, 13a ') -6,6a, 12,12a, 13 a, 14-hexahydro-4,8-diethoxy-6S-methyl-5-ethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (3aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-diisopropoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa, 12aa, 13a (S) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-di-n-butoxy-6/5-methyl-6a-isopropyl-5aH, 13H- (1'-benzopyrano (3,2-b) xanthen-13-one, (~ aa ', 6aa, 12aa, 13aa) -6.6a, 12.12a, 13a, 14-bexahydro-4.8 - dihydroxy-6,6-dimethyl-5aH, 13H- (1'-benzopyrano (3,2-bj xanthen-13-one), (5301,680: 1230, 1330 :) -6,6 and 12,12a, 13a, 14-hexahydro-3,9-dicyano-6,3-methyl-6a-ethyl-5aH, 13, H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa, 12aa) , 13AA) -6,6, 12,12a, and 13, _{14-hexahydro-4,8-dichloro-6} and 3-methyl-6 «-isopropyl-5aH, 13H- (1) benzopyrano (3,2-b ) xanthen-13-one (5acr, 6aa, 12th) aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-difluoro-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-bJ xanthene) -13-one, (5a.or, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14hexahydro-2,10-dibromo-6,6-dimethyl-5aH, 13 ^l H- (1) benzopyrano (3,2-b) xanthein-13-one, (5α.o:, 6αo:, 12a, δ-, 13a4) -6,6a, 12,12a, 13a, 14-hexahydro-6,6-dimethyl -5aH, 13H- (1J benzopyrano (3,2-b) xanthen-13-one, (5aa, 6ax, 12aft13a ') - 6,6, a, 12,1.2a, 13a, 14-hexahydro-6., CH 2 -ethyl-6.alpha.-ethyl-5.alpha., 13H- (1benzopyrano (3,2-b) xanen-13-one), (5aoj, 8aa, 12a, 13a / S) -6,6a, 12,12a, 13a, 14-hexahydro-6'-3-methyl-6'-n-propyl-5aH, 13H- (1'-benzopyrano (3,2-bj xanthen-13-one, (53'-6aa, 12aft13a / 3)) -6.6a, 12.12a, 13a, 1417

-hexabydro-4,8-diethyl-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa, 12a / i, i3a / ij) -6,6a, 12,12a, 13a, 14-bexahydro-4,8-dimethyl-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa) , 32, x, 12afl, 13afl) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-diethyl-6,6-dimethyl-5a.Hl 3H- (1) benzopyrano 2-b) xantlien-13-one, (5aa ', 6aa, 12ap, 13ad) -6,6a, 12,12a, 13a, 14-hexahydro-2,10-dl-n-propyl-6,6-dimethyl- 5aH, 13H- (1J benzopyrano (3,2-b) xanthen-13-one, (5aa, 6aa, 12ad, 13adJ-6,6a, 12,12a, 13a, 14-bexahydro-2,1-di) - t -butyl-6'-methyl-6'-ethyl-5aH, 13H- (1J benzopyranof 3,2-b) xanthen-13-one, (5a ', 6aa, 12a <3,13a.S] - 6,6a, 12,12a, 13a, 14-bexahydro-3,9-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5aa) Saa, 12a-13ad) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-diethoxy-6- (3-methyl-6a-ethyl-5aH, 13H- (1) benzopyrano (3)); 2-b) xanthen-13-one, (5a, 6aa, 12aft13a, β) -6,6a, 12,12a, 13a, 14-hexahydro-4i, 8-diiscpropoxy-6,6-dimethyl-5aH 13H- (1J benzopyrano (3,2-b) xanthen-13-one, (5aa) 6aa, 12a _, 3,13a, or 6,6.a, 12,12a, 13a, 14-hexahydro-3,9-di-n-butoxy-6 (3-methyl-6a-isopropyl-5aH), 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (5a, 8a, 12a, d, 13a, S) -6,6a, 12,12a, 13a, 14-hexahydro- 4,8-dihydroxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-bJ xanthen-13-one, (53α, 68α, 12α, 13α6) -6,6η, 12,123,133, 14-hexahydro-3,9-dicyano-O (? -Methyl-6.? -Ethyl-5? H, 13H- (1) benzopyrano (3,2-b) xanthen-13-one, (~ aa, 6aa, 12aa) 13aa) -6,6a, 12,12a, 13a, 14-hexahydrospiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'-cyclohexen] -13-one, (5aa ') , 6aa, 12aw, 13aaJ -6.6a, 12.12a, 13a, 14-hexahydrospir [5a.H, 13H- (1) -benzopyrano (3,2-b) xanthene-6,1'-cyclopentane] -13-one, (5aor, 6aa, 12aa, 13aaJ -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethylspiro 214888 [5aH, 13H- (1benzopyrano (3,2-bJ xanthene-6)) , 1'-cyclohexane] -13-one, (3aa.6aa, 12aa, 13a ') - 6,6a, 12,12a, 13a, 14'-hexahydro-3,9-dimethoxyspiro [5aH, 13H- (1) benzopyrano (3,2-bJ xanthene-6,1'-cyclohexane) -13-one, (5aa, 6aa, 12aa, 13aa J-8,6a, 12,12a, 13a, 14-hexahydro-4,9 -diethoxy spiro [5aH, 13H- (1J benzopyrano (3,2-bJ xanthene-6''-cycloheptan-13-one), (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14- Hexahydro-4,8-di, hydroxysplro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'-cyclohexane] -13-one, (otfiaa, 12 act, 13 aa) -6 6a, 12,12a, 13a, 14'-hexahydro-4,8-dichloro-spiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'-cyclopentan-13-one, (Saa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14 -hexabydro-2,10-dibromospiro [5aH, 13H- (1J benzopyranof 3,2-b) xanlene-8.1'-cyclopentane] -13-one, (5aa, 6aa, 12ad, 13ad) -6,6a, 12,12a, 13a, 14 -hexahydrospiro (5aH, 13H- (1'-benzopyrano (3,2-b) x-inthen-6), l'-cyclopentane] -13-an, (5aa, 6a, 12a _and ai, 13a ₁ z3] 6,6a, 12,12a, 13 and 14 -hexahydrospiro [5aH, 13H- (1) benzopyrano 3 2-b) xanthen-6,1'-cyclliobexane] -13-one, (5aa, 6aa, 12a / S, 13a / S) -6,6a, 12,12a: 13a, 14-hexahydro- 4,8-dimetb.ylspiro [5aH, 13H- (1) benzopyrano 3,2-b xantben J-6 &apos; cycloalkyl ehexan] -13-one (5aa, 6a, 12a, ₁ d, 13a / 3 ) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-diethylspiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'- cyclopentane] -13-cin, (5aa, 6aa, 12a, 6a, 13a: d) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-dimetboxyspiro [5aH, 13H- (1) benzopyranof 3,2b J xanthene-6 &apos; -cyclopentane] -13-one (5aa, 6a, and _also, 12ad, 13aej-6,6a, 12,12a, 13a, 14

hexahydro-4,8-diethoxyspiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-8 &apos; cyklchexan] -13-one (5a _and! 6a, x, 12ad, 13a! , -) - 6,6a, 12,12a, 13, a, 14-hexahydro-4,8-dihydroxyspiro [5aH, 13H- (1'-benzopyrano (3,2-b) xanthene-6,1'-cycloheptane] - 13-one, (5aa _, 6aa, 12a _and 3,13ad) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-dicyanospiro [5aH, 13H- (1J benzopyranof 3,2-b) xanthen-6,1'-cyclopentane] -13-one,

14 8 8 8 (5a ·, Saa, 12a ·, 6,13a / 3) -6,6a, 12,12a, 13a, 14-ihexahydro-4,8-dichlorospiro [5aH, 13H- (1) benzopyrancif 3 2-b) xantlien-6,1'-cyclchexan] -13-one, (5a, 6a, 12a / S, 13a (16S) -6,6a, 12,12a, 13a, 14-hexahydro-4, 8-Dichloro-6H-methyl-6a-iso, propyl-5aH, 13H- (1) benzopyrano (3,2-b) xantheh-13-one, (5aa ', 6aa, 12aap, 13a ^) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-difluoro-6,6-dimethyl-5aH, 13H- (1) belzopyrano (3,2-b) xanthen-13-one, (5a) 6aia, 12a (3,13a) (3) -6,6a, 12,12a, 13a, 14-hexahydro-2,10-dibromo-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3) 2-b) xanthen-13-one.

The hexahydropyranoxanthenones of formula I exhibit an antiandrogenic response when administered at a dosage of from 0.05 to 100 mg / kg body weight. They are therefore useful in the treatment or amelioration of conditions caused by androgens or androgen dependent, such as benign prostatic hyperfrophy, acne, prostate cancer and the like.

The compounds of the invention may be administered orally in the form of tablets, capsules, elixirs and the like. They may also be administered in the form of parenteral injections. In addition, they can be administered in the form of suppositories and lotions. When formulated as tablets, the active ingredients may be mixed with inert pharmaceutical carriers which optionally contain suitable binders, such as resins, starches and sugars. They can also be incorporated into gelatin capsules or processed into elixirs which have the advantage that they can be flavored by the addition of standard natural or synthetic flavors. The compounds may also be administered in the form of aqueous parenteral suspensions.

The compounds of the invention exhibit anti-antigegein activity at a daily dose of 0.05 mg to 100 mg / kg body weight. The dosage forms are adjusted so that the unit dosage form contains 1 to 500 mg of active compound. Particularly preferred unit dosage forms contain 50 to 250 mg of active ingredient. Preferably, the compounds are administered orally.

The antiandrogenic effect of the compounds of the invention can be demonstrated by a standard in vivo rat test using castrated juvenile male rats. The standard test is performed on juvenile male rats, usually 21 days old, who have been neutered and left untreated for 3 days. This time is sufficient for the metabolism of endogenous androgens and for the start of atrophy of the secondary genital organs. The castrated rats are then divided into at least three treatment groups. Ten rats were injected subcutaneously once daily with 0.02 mg of teslosterone propionate (TP), suspended in corn oil. These rats serve as a control androgen stimulated group. Another group of five rats were injected subcutaneously once daily with corn oil vehicle and this group served as a control group of castrated rats. The five rats forming the third group receive daily 0.02 mg TP subcutaneously and the test compound once daily either orally or subcutaneously. A separate group of rats is used for each compound and dose tested. All animals are treated for seven consecutive days. On the eighth day, all rats, now 28 days old, are killed and dissected. At autopsy, the seminal vesicles (SV) and ventral prostate (VP) are removed and weighed.

The SV and VP weights of the control group of castrated rats are subtracted from the glands of the androgen-stimulated group to determine androgen stimulation achieved by exogenous administration of TP. Subsequently, the SV and VP gland weights of each of the experimental groups (rats receiving both TP and test substance) are subtracted from the rat gland weights of the androgen-stimulated group, and the difference is divided by the organ weight gain achieved with only TP administration. These differences are expressed as · percent inbibico.

The effect of the administered compounds on the stimulatory effect of exogenous TP is positive when the weight of the endocrine-weighted endocrine glands does not increase to the extent that in TP-stimulated TP rats that receive no test compound.

The androgenin inhibitory effect of the compounds of the invention is shown in the following table.

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1. The number indicates compounds tested in one particular experiment. Since the sensitivity of this assay varies from experiment to experiment, the potency of each compound should be compared to that of other compounds in the same experiment. For this reason, 6 6aa, 12,12ao5,13aa, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aaH, 13H- (1) -benzopyrano (3,2-hexahydro-4,8-dimethyl-5aa) are used as standard in each test group. (b) xanthene-13-one.

2. s.c. = subcutaneous.

3. A mixture of hexahydroepimers (a) 5aa, 6aa, 12a, or, 1.3aa and (b) 5aa, 6aa, 12, and / 3,13a / 3.

The following examples illustrate the preparation of starting compounds and compounds of Formula I.

Example A

4.4-Dimethyl-2-cyclohexenone

A mixture of 743 ml (630 g, 8 mol) of freshly distilled methylenedetone and 1250 ml (940 g, 13.7 mol) of isohutyraldehyde in a 3 L flask was prepared. 9 ml of concentrated sulfuric acid are added to the mixture over two minutes. The mixture was stirred with a magnetic stirrer and cooled with an ice-water bath to maintain the temperature inside the flask at 45-50 degrees Celsius. After one hour, the bath was removed and the mixture was refluxed with a Dean-Stark water trap for 3 hours. The mixture was then distilled through a short Vigreux column at 2 kPa. The main fraction boiling at 70 to 77 ° C at 20 mbar is a substantially pure product, possibly containing a small amount of isobutyraldehyde. Yield: 751 g (67%). After distillation, a product with a sharper boiling point (bp 74-79 ° C at 10 mbar) is obtained which is free of isobutyraldehyde.

Example 1 a d B

4,4-Dimethyl-2,5-cyclohexadienone

Method a): Using 2,3-dichloro-5,6-dicyanobenzoquinone

To 1.5 L of toluene was added 134.9 g (1.1 mol)

4,4-dimethyl-2-cyclohexanone and 249 g (1.21 mol) of 2,3-dichloro-4,5-dicyanobenzoquinone (DDQ). The resulting mixture was refluxed for 3.5 hours under nitrogen. During this time, a precipitate of 2,3-dichloro-4,5-dicyarihydroquinone (DDH) settles from the initially dark red solution. The reaction mixture was cooled and the DDH was filtered off. The bulk of the toluene was evaporated in a rotary evaporator and the resulting residue was dissolved in ether. The ether solution was washed several times with 1 N sodium hydroxide until the washings were clear and then with water. After drying, the ethereal solution is concentrated to give the crude title compound. Distillation of the product yields 8.2.6 g of the pure title compound, b.p. 58-61 ° C under 1 mm Hg.

Method b): Indirect reaction sequence

1. 2-Acetoxy-5,5-dimethyl-1,3-cyclohexadiene

To a solution of 465 g (3.75 mol) of 4,4-dimethyl-2-cyclohexanone in 1.5 L of isopropenyl acetate was added 6 g of p-toluenesulfonic acid. Acetone was distilled from the mixture overnight (about 16 hours) through a 355 mm Vigreux column. The temperature was then raised to distill off most of the remaining isopropenyl acetate. The resulting mixture was distilled under reduced pressure. 484 g of crude title compound of b.p. 45-65 ° C / 533 Pa are obtained. The product is purified by distillation. The pure title compound is obtained with a boiling point of 80-84 ° C / 933 Pa.

2. 6-Bromo-4,4-dimethyl-2-cyclohexanone

To a solution of 484 g (2.92 mol) of 2-acetoxy-5,5-dimethyl-1,3-cyclohexadiene in 4 L of carbon tetrachloride was added 421 g (2.92 mol) of N-bromosuccinimide (NBS) and then 0.5 g of azo-bis-isobutyronitrile (AIBN). The resulting mixture was stirred and refluxed for 2 hours. After cooling, the major part of the tetrachloride was distilled off under vacuum. The residue was then dissolved in ether and the ethereal solution was washed twice with an aqueous solution of sodium bicarbonate. The ethereal solution was then dried over sodium sulfate and the solvent was distilled off in vacuo. The resulting residue was distilled to give 396 g (68%) of the title compound, bp 90-102 ° C / 0.2 mm Hg.

3. 4,4-Dimethyl-2,5-cyclohexadienone

A solution of 218 g (1.0-9 mol) of 6-bromo-4,4-dimethyl-2-cyclohexanone in 1000 mL of dry hexamethylphosphoric triamide (HMPT) was heated at 80 ° C under nitrogen for 5 hours. The product is extracted with 4 portions of ether, the ether extracts are washed twice with saturated sodium chloride solution, the ether is distilled off in vacuo and the product is distilled, boiling at 2 kPa, 83-87 [deg.] C. Yield 88 g. (65%) Example

4-Ethyl-4-methyl-2-cyclohexenone

To 200 ml of benzene was added 35.0 ml (30.8 grams) of methyl vinyl ketone (freshly distilled at 40 ° C / 20.66 kPa) and 50.0 ml (40.1 g) of α-methylbutyraldehyde. The mixture is slowly heated to reflux for one hour and then refluxed for 3 hours in a system containing a Dean-Stark water separator. The ethereal extract was separated and washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate, and the ether was removed by rotary evaporation and the residue was distilled under reduced pressure (800 Pa) to give 38.5. g (64.6%) of the title compound having a boiling point of 73-78 ° C / 933 Pa.

IC (CHCl3) 1668 cm @ ¹ (C = O),

Λ _max (MeOH) 228 nm (ε 16,050),

NMR (CDCl3) δ

Οι, 92 (t, J = 7 Hz, 3 H, Et),

1.12 (s, 3H, CH 3),

1.51 (qt, J = 7Hz, 2H, Et);

1.85 (mult, 2H, [beta] -CH2),

2.45 (t, J = 7 Hz, 2H, [alpha] -CH2),

5.84 (d, J = 10 Hz, 1-H, α-CH),

6.68 (d, J = 10 Hz, 1H, [alpha] -CH).

Analysis for C9H14O:

calculated:

C 78.21, H 10 ', 21%;

found:

C 77.97, H 9.95%.

Example D

4-Ethyl-4-methyl-2,5-cyclohexadienoin

To 300 mL of toluene was added 35.0 g (0.25 mol) of the product of Example C and 62.4 g (0.275 mol) of 2,3-dichloro-4,5-dicyanobenzoquinone (DDQ). The resulting mixture was refluxed under nitrogen for 4 hours. The mixture was cooled and the 2,3-dichloro-4,5-dicyanohydroquinone (DDH) formed was filtered off. The filtrate is worked up in a rotary evaporator to remove the bulk of the toluene. The resulting residue was then dissolved in ether and the ether solution was washed several times with 1 N sodium hydroxide and then water. The ether layer was then dried over sodium sulfate and the ether removed using a rotary evaporator. The remainder was distilled. 23.5 g (69% of the title compound, b.p. 86-93 ° C) were obtained.

IR (CHCl3) 1667 (C = O), 1627 cm ^-1 (C = C), A _max (MeOH) 237 nm (ε 13,900)

NMR (CDCl 3) δ

0.61 (t, J = 7 Hz, 3H, Et);

1.25 (s, 3H, CH 3),

1.69 (qt, J = 7Hz, 2H, Et);

6.28 (d, J = 10Hz, 2Ή, β-CH),

6.80 (d, J = 10 Hz, 2H, [alpha] -CH).

Analysis for C9H12O:

calculated:

C 79.37, H 8.88%;

found:

C 79.65, H 8.66%.

Example 1 E

4-Cyclohexanebiro-2-cyclohexanone

A solution of 54.3 ml (0.5 mol) of cyclohexanecarboxaldehyde and 40.5 ml (0.5 mol) of freshly distilled methyl vinyl ketone in 200 ml of benzene is stirred at room temperature and carefully treated with 0.5 ml of concentrated sulfuric acid. The resulting mixture was gradually heated to reflux for 1 hour. The mixture was refluxed for 3 hours and water was collected in a Dean-Stark trap. The mixture was allowed to cool and washed with dilute sodium bicarbonate solution. The washings were extracted with ether and the combined organic mixture was dried over sodium sulfate. The solvents were removed under reduced pressure and the remaining oil was distilled. 46.8 g of the title compound are obtained (56%), b.p. 122-1.26 ° C / 1 mm Hg. IC (CHCl 3) 1670 cm ^-1 (C = O),

NMR (CDCl 3) δ

1.42 [s, 10H, (CH2) s,

1.90 (t, J = 7 Hz, 2H, [beta] -CH2),

2.44 (t, J = 7Hz, 2H, [alpha] -CH2), 5.89 (d, J = 10Hz, 1H, [beta] -CH), 6.87 (d, J = 10Hz, 1H, [alpha] -CH) ).

Analysis for · CnHieO:

calculated:

C 80.44, H 9.82%;

found:

C, 80.18. H, 9.99%.

Example F

4-Cyclohexanebiro-2,5-cyclohexadienone

A mixture of 16.4 g (0.1 mol) of the product of Example E and 25 g (0.12 mol) of DDQ in 150 ml of toluene was refluxed for 6 hours. The resulting mixture was cooled and filtered. The bulk of the toluene was removed from the filtrate under reduced pressure. The resulting residue was dissolved in ether. The solution was washed twice with 1 N sodium hydroxide, once with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was removed and the residue crystallized from hexane. 9.9 g (61%) of the title compound are obtained as a pale yellow solid, mp 86-88 ° C.

IR (CHCl), 1663 (C = O), 1622 ^cm-1 (C = O), A _max (MeOH) 242 nm (ε 14,800)

NMR (CDCl3) δ

1.60 [S, 1GH, (CHsjs)]

6.27 (d, J = 10 Hz, 2H, [beta] -CH),

7.98 (d, J = 10 Hz, 2H, [alpha] -CH).

Analysis for C11H14O:

calculated:

C 81.44, H 8.70%;

found:

C 80.50, H 8.32%.

The following examples serve to illustrate the preparation of certain compounds of the general formula (1) in more detail.

He did.

(5αa, 0aa) -6,6a-dlhydro-6,6-dimethyl-5aH, 13H- (1} biszopyrano (3,2-b) xanthen-13-one)

To a solution of 30 g (0.25 mol) of salicylaldehyde in 150 ml of benzene was added 26.25 g (0.37 mol) of pyrrolidine and then 15 ml (0.25 mol) of acetic acid while cooling under nitrogen. After 15 minutes at room temperature, 15 g (0.1,12 mol) of 4,4-dimethyl-2,5-cyclohexadienone are added and the mixture is heated at 60 ° C overnight. After cooling, the mixture was poured into a large volume of ice water. The organic layer was separated and washed twice with 1% aqueous acetic acid and then three times with 1 M sodium hydroxide solution. After the last wash with a saturated sodium chloride solution, the organic solution is dried over sodium sulfate. The solvent was removed and the product was recrystallized from benzene-hexane. The yield after two recrystallizations was 18.6 g (46%), mp 211-213 ° C.

IR (CHCl 3) 1670 '(C = O), 1623 cm ^-1 (C = C),

Λ _max (EtOH) 253 (ε 12400), 119 (ε 13,300), 378 nm (ε 10,300),

NMR (CDCl3) δ

1.19 (s, 3H, 6H-CH3),

1.49 (s, 3 (m, 6/3-CH3)),

4.89 (d, j = 2.3Hz, 2Η, 5a-H and 6a-H),

7.07 (m, 8H, Ar-H);

7.60 (d, J = 2.3 Hz, 2H, 12H and 14H).

Analysis for C22H18O3:

calculated:

C 79.98, H 5.49%;

found:

C 79.76, H 5.69%.

Example I (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthene- 13-on

A solution of 4.0 g (12.1 mmol) of the product of Example 1 in 500 ml of ethyl acetate was hydrogenated with 4 g of Raney nickel [prepared by AW Burgstahler, see L. Fieser and M. Fieser, Reagents for Organic Synthesls 1, p. 729, John Wiley and Sons, Inc. (1967)] at 40 to 60 ° C and 412 Pa for 5 to 12 hours. After filtration, the solvent was separated. The product was recrystallized from ethanol-water. Yield: 2.4 g (61%), mp 205-207 ° C.

iC (CHCl3) 1732 cm ^-1 (C = O),

A _max (EtOH) 275 (ε 4,300), 283 inflection nm (ε 3,500),

NMR (CDCl3) δ

1.37 (s, 3H, 6a-OH 3),

1.56 (s, 3H, 61 S-CH 3),

2.67 (extended qt, J = 7 and 17Hz, 2Ή, 12 / 3H, and 14- / 3-H),

3.24 (broad qt, 2H, 12a-H and 13a-H),

3.34 (broad d, J = 17 Hz, 2H, 12α-H and 14x-H),

4.18 (d, J = 2.8 Hz, 2H, 5a-H and 6a-H),

6.87 (m, 8H, Ar-H).

Analysis for G22H22O3:

calculated:

C 79.02, H 6.63%;

found:

C 78.76, H 6.63 ° / o.

Example 2 (5aa, 6aa) -8,6a-dihydro-2,10-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3,2-b) xanthen-13-one

To a solution of 12.5 g (82 mmol) of 5-methoxysalicylaldehyde in 100 ml of benzene was added, with cooling, 8.73 g (123 mmol) of pyrrolidine and then 4.92 g (82 mmol) of acetic acid. The reaction mixture was stirred at room temperature for several minutes and 5.0 g (41 mmol) was added.

4,4-dimethyl-2,5-cyclohexadienone. The mixture was heated to 60 ° C under nitrogen overnight and then added to ice water and the resulting organic layer was separated. The organic layer was washed successively with dilute acetic acid, several times with dilute sodium hydroxide and then brine. The organic layer was dried over sodium sulfate and the solvent was removed. The residue was recrystallized twice from a mixture of benzene and hexane. 3.75 g (23%) of the title compound of melting point 219 DEG-220 DEG C. are obtained.

IC (CHCl 3) 1663 (C = O), 1620 cm ^-1 (C = C),

A _max (EtOH) 221 (ε 36,200), 336 (ε 20,400), 472 (ε 11,600), 453 inflection nm (ε 11,400), NMR (CDCh) δ

1.18 (s, 3H, 6'-CH 3),

1.48 (s, 3H, 6/3-CH3),

3.76 (s, 6H, OCH 3),

4.83 (cl, J = 2.1Hz, 2H, 5a-H and 6a-H),

6.78 (m, 6H, Ar-H);

7.55 (d, J = 2.1 Hz, 12-H and 14-H). Analysis for C24H22O3:

calculated ·:

C 73.83, H 5.68%;

found:

C 73.95, H 5.88%.

Example 3 (5aia, 6a) -6,6a-dihydro-3,9-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

A solution of 14.35 g (94.4 mmol) of 4-methoxysalicylaldehyde in 100 ml of benzene is prepared. The solution was cooled and 10 g (141 mmol) of pyrrolidine and 5.66 g (94.4 mmol) of acetic acid were added. After a few minutes, 5 g (41 mmol) of 4,4-dimethyl-2,5-cyclohexadiene are added. The solution was then heated to 55 ° C under nitrogen overnight. The resulting reaction mixture was added to ice water and the organic layer was separated. The organic layer was washed successively with dilute acetic acid, several times with dilute sodium hydroxide and then brine. The organic layer was dried over sodium sulfate and the solvent was removed. The residue was recrystallized from benzene / hexane and chromatographed on magnesium silicate. Elution is carried out with benzene. 1.5 g of the title compound of melting point 220-221 ° C is obtained.

IR (CHCl3) 1660 (C == O), 1608 cm ^-1 (C = C)

A _max (EtOH) 213 (ε 38,400), 276 (ε 16,900), 460 (ε 23,900), 446 inflection nm (ε 22,800), NMR (CDCl3) δ

1.18 (s, 3H, 6a-CH 3),

1.49 (s, 3H, [delta] -J-CH3),

3.82 (s, 6Ή, OCH 3),

4.88 (d, J = 2.1 Hz, 2H, 5a-H and 6a-H),

6.44 (m, 4H, Ar-H);

7.10 (m, 2H, Ar-H);

7.55 (d, J = 2.1 Hz, 2H, 12-H and 14-H). Analysis for C24H22O5:

calculated:

C 73.83, H 5.68%;

found ·:

C 73.79, H 5.78%.

Example 4 (5aa; 6aa) -6,6a-dihydroc-4,8-dimethoxy-6,6dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

To a solution of 3-methoxysalicylaldehyde (ICO g, 0.66 mol) in benzene (800 ml) was added pyrrolidine (80 g, 1.15 mmol) followed by acetic acid (60 g, 1.0 mol) while cooling under nitrogen. After 15 minutes at room temperature, 40 g (0.33 mol) of 4,4-dimethyl-2,5-cyclohexadienone are added and the mixture is heated at 55-60 ° C overnight. P _by cooling the mixture was poured into a large volume of ice water ·. The organic layer was washed twice with 1% aqueous acetic acid and then three times with 1 M sodium hydroxide solution. After the last wash with a saturated sodium chloride solution, the organic solution is dried over sodium sulfate. The solvent was evaporated and the product was recrystallized from a mixture of benzene and hexane. This gave 43 g (33%) of the title compound, mp 239-241 ° C.

IC (CHCl 3) 1664 (C = O), 1619 cm ^-1 (C = C),

A _max (EtOH) 225 (ε 35,400), 358 (ε 18,300), 436 (ε 8,300), 454 inflection nm (ε 6,500),

NMR (CDCl 3) δ

26 (s, 3H, 6a-CH 3),

1.61 (s, 3H, 6-CH 3),

3.88 (s, 6H, OCH 3),

4.94 (d, J = 2.3Hz, 2Ή, 5a-H and 6a-G),

6.86 (s, 6H, Ar-H);

7.59 (d, J = 2.3 Hz, 2H, 12-H and 14-H). Analysis for C24H22O5:

calculated:

C 73.83, H 5.68 ° / o, found:

C 73.79, H 5.62%.

Examples (5aa, 6aa, 12iaa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-2,10-dimethoxy-6,6214888

-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

A solution of 1.0 g (2.56 mmol) of the product of Example 3 in ethyl acetate was hydrogenated with Raney nickel for 24 hours. The mixture is filtered and the filtrate is freed from the solvent by evaporation. The resulting residue was recrystallized twice from methanol / water. 174-178 ° C, 0.59 g (58%).

Analysis of the product. NMR shows that it is a mixture of epimers of the title compound which contains a certain amount of product that has been reduced to the corresponding alcohol.

A portion of this product (0.35 g) was stirred under nitrogen overnight in 10 ml of methylene chloride containing 0.3 g of pyridinium chlorochromate. 10 ml of benzene are then added and the mixture is stirred for a further 1 hour. The mixture was filtered and the solid which separated was washed extensively with benzene, which was added to the filtrate. The solvent was removed from the filtrate and the residue was dissolved in ethyl acetate. The ethyl acetate solution is then passed through a short column of magnesium silicate. The solvent is removed from the filtrate and the residue is recrystallized from a mixture of benzene and hexane. 0.18 g (51%) of dry, slightly contaminated title compound was obtained.

A high pressure liquid chromatography column having a length of 183 cm and a diameter of 15.9 mm is packed with about 150 g of dry silica gel having a particle size of 10 'to 20 μηα. The column was equilibrated with a 20:80 mixture of tetrahydrofuran (THF) and isooctane. About 30 mg of the above slightly contaminated product in methylene chloride was applied to the column. A total of 173 mg of product was passed through the column in seven runs. After crystallization of the product from hexane, a total of 137 mg of purified dry title compound (yield 30%) was obtained, m.p. 207-207.5 ° C.

IR (CHCl3) 1727 cm @ ^-1 (C = O),

_Λm (MeOH) 229 nm (ε 13,800),

NMR (CDCl3) δ

1.37 (s, 3Ή, 6a-CH3j,

1.52 (s, 3H, 6-CH 3),

2.68 (extended qt, J = 7Hz, a

17Hz, 2H, 12, (3-H and 14/3-H),

3.23 (broad qt, 2H, 12a-H and 13a-H),

3.30 (broad d, J = 17 Hz, 2H,

12a-H and 14ior-H),

3.67 (s, 6H, OCH 3),

4.12 (d, J = 2.7 Hz, 2H, 5a-H and 6a-H),

6.57 (m, 6H, Ar-H).

Analysis for C24H26O5:

calculated:.

C 73.08, H 6.64%, found:

C 72.84, H 6.70%.

Example III (5aa, 6a, 12a _when S, 13a | S) -6,6, 12,12a, 13a, 14-hexahydro-3,9-d'metboxy-6,6-dimethyl-5aH, 13H- ( (1) benzopyrano (3,2-b) xanthen-13-one and (5aa, 6aa, 12aai, 13aa) -6,6.a, 12,12a, 13a, 14-hexabydro-3,9-dimethoxy-6; 6-Dimethyl-5a.H, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

Using the hydrogenation procedure described in Example II, 0.5 g (12.8 mol) of (5a and 6a) -6,6a-dihydro-3,9-dimethoxy-6,6-dimethylmethyl-5aH is used. 13H- (1) benzopyranof 3,2-b-xanthen-13-one is reduced in the presence of Raney nickel in ethyl acetate. The mixture was filtered and the solvent was removed in vacuo. The resulting yellowish residue was recrystallized twice from a mixture of ethanol and water. The yield of the product having a melting point of 217 degrees Celsius is 0.31 g (61%). NMR analysis of the dried product indicated a 1: 4 mixture of the title compounds.

Analysis for C24H26O5:

calculated:

C 73.0 · 3, H 6.64%, found:

C 73.23, H 6.40%.

A high pressure liquid chromatography column having a length of 183 cm and a diameter of 15.9 millimeters is packed with about 150 g of dry silica gel of 10 to 20 microns in size. using this system, at a flow rate of 5 to 6 ml / min at an overpressure of about 20 kPa. The mixture is applied to the column in about 10-15 mg portions dissolved in about 0.75 mL of THF. A total of 70 mg was processed six times. The two purified components were recrystallized from hexane, collected and dried. 15 mg (total yield 13%) of the title compound are obtained, m.p. 219 DEG C., and 44 mg (38% overall yield) of the α, α, α, α compounds, m.p. 230-231. Deň: 32 ° C. 'a, and β, β-compound:

IR (CHCl), 1727 cm ^"1 (C = O)

A _mnx (MeOH) 283 (ε 7,800), 289 nm (ε 7,400), NMR (CDCl 3) δ

1.32 (s, 3H, 6 '- CH 3),

1.47 (s, 3H, 6.3-CH 3),

2.90 (m, 6H, H at 12, 12a, 13a and 14),

3.54 (m, 2H, 5α-H and 6α-H),

214388

3.77 (s, 6H, OCR);

6.45 (d, J = 2.5 Hz, 2H, 4-H and 8-H),

6.48 (qt, J = 2.5Hz and 9Hz, 2H, 2-H and 10-H),

7.02 (d, J = 9 Hz, 2H, 1H and 11H). ce, .a, and, ce-compound:

IR (CHCl₃) 1727 cm ^"1 (C = 0)

Λ _max (MeOH) 284 (ε 6,500), 291 nm (ε 6,000), NMR (CDCl ₃ ) δ

1.39 (s, 3H, Ba-CR 5),

1.55 (s, 3H, 6β'-CR}),

2.63 (extended qt, J = 7 and 16Hz,

2H, 12β-H and 14 (S-H),

3.23 (broad qt, 2H, 12a-H and 13a-H),

3.26 (broad d, J = 16 Hz, 2H, 12a-H a

14 «-H],

3.69 (s, 6H, _OCH3);

4.78 (d, J = 2.8 Hz, 2H, 5a-H and 6a-H),

6.27 (d, J = 2.5 Hz, 2H, 4-H and 8-H),

6.36 (qt, J = 2.5 and 8 Hz, 2H, 2-H and 10-H);

6.91 (d, J = 811), 2H, 1-H and 11-H).

Example 5 (5aa, 6a) -6,6a-dihydro-4,8-dihydroxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

A solution of 5.0 g (12.8 mmol) of (5aa, 6aa-6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthene) Example 4 in 100 ml of methylene chloride was stirred under nitrogen with ice-cooling in methanol, a solution of 5 ml of boron tribromide was added dropwise over 10 minutes, the bath was removed and the resulting intense violet-colored mixture was stirred overnight. The organic layer was separated and the aqueous phase was extracted twice with fresh ethyl acetate, the extracts were filtered and dried over sodium sulfate, the solvents were removed and the crude product was recrystallized from acetone and ethyl acetate. Yield: 3.59 g (77%), mp 230 ° C (dec.).

IR (KBr) 1660 (C = O), 1613 cm ^-1 (C = O),

A _max (MeOH) 223 (ε 41,600), 363 (ε 24,050), 433 inflection (ε 10,100), 455 inflection nm (ε 8,000),

NMR (DMSO-d 6) (?

1.14 (s, 3H, _6-CH3);

1.61 (s, 3H, 6d-CH3l,

4.98 (d, J = 2, 6 Hz, 2H, 5aH and 6a-H)

6.88 (s, 6H, Ar-H);

7.57 (d, J = 2.0 Hz, 2H, 12-H and 14-HJ,

9.27 (s, 2H, OH).

Analysis for CziHieOs:

calculated:

C 72.92, H 5.01%, found:

C 72.66, H 5.23%.

Example IV (53α, 63α ·, 123α, 133α) β-6,63,12,12η, 133,14-hexahydro-4,8-dihydroxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano ( 3,2-b) xanthen-13-one

A solution of 1.0 g of the product of Example 5 was dissolved in ethyl acetate and hydrogenated in the presence of 1 g of freshly prepared Raney nickel. The hydrogenation is carried out at room temperature under a pressure of 40 mbar for 1 hour. The mixture was filtered and the filtrate was evaporated to remove the solvent. The resulting residue was crystallized from a mixture of benzene and ethyl acetate. The product was separated and recrystallized again from benzene-ethyl acetate. 0.15 g (about 15% yield) of the title compound of melting point 194-198 ° C is obtained.

IR (mull) 3520 (OH), 1720 cm ^"1 (C = O)

Λ _max (MeOH) 277 (ε 3,400), 283 nm (ε 3,300), NMR (DMSO-d 6) δ

1.48 (s, 3H, 6 '- CH 3),

1.66 (s, 3H, 63-CH 3),

2.86 (expanded qt, J = 7?, 13Hz, 12 / T-H and?)

14I / 3-H),

3.36 (s, OH).

3.52 (broad m, 4H, 1H-alpha and 13a-H), - 4.26 (d, 2H, 5a-H and 6a-H),

6.59 (m, 6H, Ar-H).

Analysis for C-22H22O5:

calculated:

C 72.12, H 6.05%, found:

C 71.91, H 5.86%.

Example 6 (5aa _; 6aa) -6,6a-Dihydro-4,8-diethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrrole (3,2-b) xanthen-13-one

To a solution of 1.0 g (2.76 mmol) of (5aa, 6aa ·) -6,6a-dihydro-4,8-dihydroxy-6,6-dimethyl5aH, 13H- (1) benzopyrano (3,2-bxanthene) -13-one in 25 ml of dry hexamethylphosphoric triamide (HMPT) was treated with 1 g (7.25 mmol) of potassium carbonate and 2 ml (2.9 g, 27 mmol) of ethyl bromide and heated at 70 ° C under nitrogen overnight. After cooling, the mixture was poured into 200 ml of cold water and the resulting product collected and recrystallized twice from ethanol-water to give 0.54 g (47% yield) of the title compound, bp 211-213 ° C.

IR (CHCl3) 1680 (C = O, 1635 cm @ -1 ⁾ (C = C),

A _lnax (MeOHj 224 (ε 41,200), 356 (ε 19,800), 434 (ε 9,100), 456 inflection nm (ε 7,200),

NMR (CDC1 ₃₎ 8

1.28 (s, 3H, 6a-CH 3),

1.42 (t, J = 7 Hz, 6 H, OEt),

1.59 (s, 3H, O 6 -CH 2),

4.06 (qt, J = 7Hz, 4H, OEt);

4.90 (d, J = 2.3 Hz, 2H, 5a-H and 6a-H),

6.87 (ni, 6H, Ar-H),

7.58 (d, J = 2.3 Hz, 2H, 12-H and 14-H). Analysis for CžeHzeOO:

calculated:

C 74 62, H 6.26%, found:

C 74.92, H 6.51%.

Example V (5aa, 6aia, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-diethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyr yes (3,2-b) xanthene-13-one

A solution of 0.45 g of the product of Example 6 in ethyl acetate was hydrogenated in the presence of Raney nickel for 24 h. The resulting mixture was filtered and the filtrate was evaporated to a light yellow solid residue. The resulting crude product was dissolved in methylene chloride and then 0.3 g of pyridine chlorochromate was added and the mixture was stirred under nitrogen overnight. The resulting mixture was then diluted with 10 mL of benzene, stirred for one hour and decanted. The solvents were removed and the residue dissolved in ethyl acetate was filtered through a short column of magnesium silicate. Thin Layer Chromatography (TLC) revealed one major spot with very weak traces of two other substances. The product was recrystallized from a mixture of benzene and hexane. The resulting product was collected and dried. 0.23 g (51%) of the title compound is obtained, m.p. 219-221 ° C.

IR (in suspension) 1735 cm ^-1 (G = O),

A _mnx (MsOH) 277 (ε 3,300), 282 nm (ε 3,300), NMR (CDCl ₃ ) δ

1.28 (t, J = 7 Hz, 6 H, OEt),

1.45 (s, 3H, 6'-CH 3),

1.67 (s, 3H, 6 / I-CH 3),

2.73 (qt, J = 8 and 17 Hz, 2H, 12 [beta] -H and 140-H),

3.32 (qt, J = 2.8 and 8 Hz, 2H, 12a-H and

13a-H),

3.40 (d, J = 17 Hz, 2H, 12a-H and 14'-H),

4.03 (m, 4H, OE d),

4.16 (d, J = 2.8 Hz, 2H, 5a-H and 6a-H),

6.68 (m, 6H, Ar-H).

Analysis for C26H30O5:

calculated:

C 73.91, H 7.16%, found:

C 73.98, H 7.10%.

Example VI (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano 2-b) xanthene-13-one

A mixture of 200 g of (5aa, 6aa) -6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1-benzopyrano (3,2-b) xanthen-13-one in 3,7 Tetrahydrofuran (THF) is hydrogenated under an initial hydrogen pressure of 50 to 60 ° C for 24 hours in the presence of 100 g PtO 2, then the reaction mixture is cooled, the catalyst is filtered off and washed well with methylene chloride. The filtrate was concentrated in vacuo to a residue which was triturated with hexane to give a hexahydric compound in which the carbonyl group at the 13-position was reduced to a hydroxy group and the product was obtained as a crude colorless solid, mp 180-181 ° C.

IR (CHCl 3) 3550 cm -1 (OH),

NMR (CDCl 3) δ

1.12 (s, 3H, Ba - CH3),

1.66 (s, 3H, 6/3-CH 3),

2.35 (extended qt, J = 2 and 8Hz, 2H,

I2.a-H and 13a-H),

2.89 (d, J = 17 Hz, 2H, 12 &apos; -H and 14a-H),

3.19 (extended qt, J = 8 and 17Hz, 2H,

12/3-H and 14 (3-H),

3.80 (broad s, 9H, OCH3, 5a-H, 6a-H and

13-Hj,

6.70 (mult, 6H, Ar-H).

Analysis for C24H28O5:

calculated:

C 72.89, H 6.88%, found:

C 73.01, H 6.71%.

To. In a twelve liter flask containing 3 L of methylene chloride is added 250 g (0.16 mol) of pyridinium chlorochromate. The resulting slurry of 214888 was stirred vigorously and 250 g (0.63 mol) of the above product in 4 liters of methylene chloride was added rapidly under nitrogen at room temperature. The mixture was stirred for 24 hours and then toluene (3 L) and 300 g of decolorizing charcoal were added. The resulting mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the concentrate was passed through a column (30X55 cm) containing 1 kg of silica gel in methylene chloride. methylene chloride / hexane to give colorless needles (6.2% yield), mp 203-209 ° C.

IC (in suspension) 1718 cm ¹ (C = O), λ _πκ . _χ (EtOH) 275 (ε 3,660), 280 nm (ε 3,630).

NMR (CDCl3) δ

1.34 fs, 3H, Oa-CI-b),

1.65 (s, 3J, Be-Crb),

2.68 (extended qt, J = 7 and 17Hz,

2H, 12.0-11 and 14111),

3.26 (broad qt, 2H, 12a-H and 13a-H),

3.37 (broad d, J = 17 Hz, 2H, 1,2a-H and 14a-H),

3.77 (s, 6H, OCH 3),

4.15 (d, J = 2.8 Hz, 2H, 5a-H and 6a-H),

6.68 (s, 6H, Ar-H).

Analysis for CziHteOg:

calculated:

C 73.03, H 6.64%.

found ·:

C 72.83, H 6.81. %.

Ex 1 to 1 and cl. VII (5aa, 6a ', 12aa, 13a') -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1'-benzopyrano (3,2-b) ) xanthene-13-οπ

A solution of 10 g (25.6 mmol) of the product of Example 4 in 1 liter of ethyl acetate was hydrogenated in the presence of 10 g of Raney nickel at 60 degrees Celsius and a pressure of 412 Pa for 2 hours. After filtration, the solvent was removed. The residue was dissolved in 200 ml of methylene chloride and the solution was stirred under nitrogen overnight in the presence of 6.0 g of pyridinium chlorochromate. The mixture was diluted with 200 mL of benzene. After stirring for minutes, the mixture was aspirated through a pad of diatomaceous earth. The solvents were removed and the residue was passed through a short column of magnesium silicate and eluted with benzene. Crystallization of the product from benzene-heptane gives 7.1 g of a mixture which, according to high pressure liquid chromatography (HPCl 3), consists of 70% (5aa, 6aa, 12aa, 13aa) -6,6a, 12,36

12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1J benzopyrano (3,2-b) xanthene-13-ene (1), 19% (5aa, 6aa, 12a / J, 13a1S) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1J benzopyrano (3,2-b) xanthene-13) -one (2) and 11% (5aa, 6aa, 12aa, 13a / 3) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xa-thien-13-one (3) Further recrystallizations gave a mixture containing 50% (1j and 10% (2)), mp 206-2010 ° C.

Example VIII (5α, 6α, 12α, β, 13α, β) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- ( 1) benzopyrano (3,2-bxanthan-13-one)

The mother liquor obtained from the purification of the product of Example VII and enriched with the compounds 2 and 3 of Example VII is purified by high pressure liquid chromatography (HPLC). A high-pressure chromatography column of 183 cm length and 15.9 mm diameter is packed with about 150 g of silica gel. The mixture of products {µt (mg) was chromatographed in 6 portions using a mixture of tetrahydrofuran and isooctane 30:70 as eluent to remove residual title compound of Example VII and other trace materials. Compounds 2 and 3 were chromatographed again using tetrahydrofuran-isooctane 10: S0 and the fractions containing the title compound were collected and evaporated and the residue was washed with hexane and dried overnight in vacuo to give 30 mg of the title compound, m.p. Deň: 32 ° C.

IR (KBr) 1720 cm ^-1 (C = O)

Mmax (MeOHJ 275 (ε 3 500), 280 Inflection nm (ε 3 300),

NMR (CDCl3) δ

1.40 (s, 3H, 6'-CH 3),

1.57 (s, 3H, 6 ₍ d-CH 3))

2.97 (m, 6H, H at 12.1 2a, 13a and 14),

3.54 (m, 2H, 5α-H and 6α-H),

3.85 (s, 6H, OCH 3),

6.76 (m, 6H, Ar-H).

Analysis for C24H26O5:

calculated:

C 73.08, H 6.64%, found:

C 73.34, H 6.33%.

Example 7 (5aa, 6aa, 6,6a-dihydro-60-methyl-6a-ethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one)

Κ 220 ml of benzene was added with 18.2 g (149 mmol) of salicylaldehyde, 13.3 g of pyrrolidine and 8.9 g of acetic acid while cooling in an ice bath. To the resulting solution was added 4-ethyl-4-methyl-2,5-cyclohexadienone (10.0 g, 73.5 mmol). The resulting mixture was stirred under nitrogen at 55 ° C for 5 days. The mixture was cooled and poured into a large volume of ice water. The resulting organic layer was separated, washed twice with 1% defective acetic acid, three times with 1 N sodium hydroxide and once with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and the benzene solvent was removed by rotary evaporation. The residue was filtered from a mixture of benzene and hexane. 4.6 g (18.2%) of the title compound of melting point 189 DEG-10 DEG C. are obtained.

IR (in suspension) 1665 (C = O), 1622 cm ^J (C = C), λ, _ΙΧΙΧ (εεΟΗ) 217 (ε 35,800), 257 (ε 11700), 324 (ε 13,800), 430 nm (ε 11,800),

NMR (CDCH) 0 '

1.03 (t, p = 7Hz, 3 °, Et),

1.20 (s, 3H, CH 3),

2.01 (qt, J = 7Hz, 2H, Et);

5.07 (d, J = 2Hz, 2.H, 5α-H and 6α-H),

7.08 (m, 8H, Ar-H);

7.60 (d, J = 2 Hz, 2H, 12-H and 14-H).

Analysis for C23H18O3:

calculated:

C 80.21, H 5.85%, found:

C 80.43, 1-1 6.13%.

Example IX (5a → 6a → 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-6/3-methyl-6a-ethyl-5aH, 13H- (1) benzopyrano (3, 6a-ethyl) 2-b) xanthene-13-one

A solution of 1.0 g (0.29 mmol) of the product of Example 7 in 49 ml of tetrahydrofuran was hydrogenated in the presence of 0.5 g of platinum oxide under a pressure of 343 kPa for 32 hours at room temperature. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using benzene as eluent. Recrystallization from ether gave 0.28 g (27%) of the hexahydrosulfate whose carbonyl group at the 13-position was reduced to the hydroxy group. The product is a colorless solid, m.p. 161-162 ° C.

Analysis for C23H26O3:

calculated:

C 78.83, H 7.40%, found:

C 78.61, H 7.27%.

The title product (0.27 g, 0.76 mmol) was dissolved in 5 mL of acetic acid and cooled. A mixture of 20 mg (0.5 mmol) of sodium dichromate dihydrate in 10 ml of acetic acid 33 was cooled in an ice bath and then added to the mixture. The resulting mixture was stirred at room temperature for 4.5 hours. The mixture was then poured into 100 ml of ice water. The resulting precipitate was filtered off and the aqueous filtrate was extracted with methylene chloride to extract any product residue. The product was separated and purified by silica gel chromatography using benzene as eluent. After recrystallization from a mixture of benzene and hexane, it is obtained

55.7 mg (21%) of the title compound, mp 133-140 ° C.

IR (CI-ICl 3) 1730 cm ^-1 (C = O),

Λ _max (MeOH) 276 (ε 3,500), 283 nm (ε 3,140), NMR (CDCl 3) δ '

1.07 (t, J = 7 Hz, 311, Et),

1.52 (3, 3H, CH 3),

1.84 (qt, J = 7Hz, 2 °, Et),

2.71 (extended qt, j = 7 and 17Hz, 2H,

12/3-H and 14C-H),

3.21 (extended qt, J - 2.5 and 7Hz,

2H, 12a-H and 13a-H),

3.35 (broad d, J = 17 Hz, 2H, 12a-H a

14 (-H),

4.26 (d, J = 2.5 Hz, 2H, 5a-H and 6a-H),

6.88 (m, 8H, Ar-H).

Analysis for C23H22O3:

calculated:

C 79.28, H 6.94%, found:

C 79.22, H 6.70%.

Example 8 (53 ', 6a') -6,6a-dihydro-4,8-dimethoxy-66 'methyl-6'-ethyl-5aH, 13H (1) benzopyrano (3,2-b) xanthen-13-one

180 ml of benzene are added with cooling

18.10 g (119 mmol) of 3-msthoxysalicylaldehyde, 10.64 g of pyrrolidine and 7.12 g of acetic acid. To the resulting solution was added 4-ethyl-4-methyl-2,5-cyclohexadienone (8.00 g, 58.6 mmol). The resulting mixture was stirred at 53 ° C under nitrogen for two days. The mixture was cooled and poured into a large volume of ice water. The organic layer was separated and washed twice with 1% aqueous acetic acid, three times with 1N sodium hydroxide and then with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and the benzene was evaporated in a rotary evaporator.

The residue is chromatographed on silica gel. The product obtained is recrystallized from a mixture of chloroform and methanol. 2.18 g ^(9.2;%) of the title compound, mp 203-205 ° C.

IR (CHCl) 1668 (C = O), 1622 cm ^"1 (C = C)

A _max (MeOH) 225 (ε 40,800), 356 (ε 20,400), 430 inflection nm (ε 9 340),

NMR (CDCl3) δ

1.12 (t, J = 7 Hz, 3 H, Et),

1.25 (s, 3H, CH 3),

2.11 (qt, J = 7Hz, 2H, Et).

3.85 (s, 6H, OCH 3),

5.05 (d, J = 2 Hz, 2H, 5a-H and 6a-H),

6.86 (s, 6H, Ar-H);

7.58 (d, J = 2 Hz, 2H, 12-H and 14-H). Analysis for · C25H24O5:

calculated:

C 74.2.4, H 5.98%, found:

C 74.46, H 5.97%.

Example X (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-6-dimethoxy-6S-methyl-6a-ethyl-5aH, 13H- (1) benzopyrano ( 3,2-b] xanthen-13-one

A solution of 1.0 g (2.5 mmol) of the product of Example 8 in 49 ml of tetrahydrofuran was hydrogenated in the presence of 0.5 g of platinum oxide at 343 kPa for 16 hours at room temperature. The catalyst was filtered off, the filtrate was evaporated in vacuo and The product was recrystallized from benzene / hexane to give 0.41 grams (40%) of the hexahydro compound whose carbonyl group at the 13-position was reduced to the hydroxy group, m.p. 222-223 ° C.

IR (CHCl3) 3550 cm @ ^-1 (OH),

Λ _max (MeOH) 274 nm (ε 2,760).

Analysis for · C25H30O5:

calculated:

C 73.15, H 7.37%;

found:

C 72.91, H 7.53%.

To 6 ml of acetic acid was added 40 (0 mg (0.98 mmol) of this alcohol. The mixture was cooled in an ice bath and then treated with a pre-cooled solution of 258 mg of sodium dichromate dihydrate in 13 ml of acetic acid. The mixture was allowed to stand for 4 hours and then poured into 150 ml of ice water, and the resulting precipitate was too fine to separate, so it was extracted with several portions of methylene chloride, the methylene chloride extract was dried over sodium sulfate and the solvent was evaporated. The product was collected but could not be crystallized and the product was chromatographed on silica gel using benzene as eluent to give the title compound as a benzene / hexane mixture to give the title compound as a white solid. colorless crystals, m.p. 191-192 ° C.

IR (CHCl) 1733 cm ^-1 (C = O)

A _max (MeOH) 276 (ε 3,070), 281 inflection nm (ε 3,030),

NMR (CDCl3) δ

1.11 (t, J = 7 Hz, 3H, Et);

1.64 (s, 3H, _CH3);

1.90 (qt, J = 7Hz, 2H, Et);

2.75 (extended qt, J = 8 and 17Hz, 2H, 12/3-H and 14, / 3-H),

3.31 (extended qt, J = 8 and 2.5Hz, 2H, 12a-H and 13a-H),

3.39 (broad d, J = 17 Hz, 2H, 12'-H and

14a-H),

3.78 (s, 6H, OCH 3),

4.29 (d, J = 2.5 Hz, 2H, 5α-H and 6α-H),

6.68 (m, 6H, Ar-H).

Analysis for C25H28O5:

calculated:

C 73.51, H 6.91%;

found:

C 73.28, H 7.00%.

Example 9 (5aa, 6a, a) -6,6a-dihydrospiro [5aH, 13H- (1) benzopyrrole (3,2-b) xanthene-6, Γ-cyclohexane] -13-one

To 85 ml of benzene was added 7.52 g (61.6 mmol) of salicylaldehyde, 5.5 g of pyrrolidine and 3.7 g of acetic acid. The mixture was cooled and 4-cyclohexanspiro-2,5-cyclohexadienone (5.00 g, 30.8 mmol) was added. The mixture was stirred under nitrogen at 55 ° C for 2 days, then cooled and poured into a large volume of ice water. The resulting organic layer was separated and washed twice with 1% aqueous acetic acid, three times with 1 N sodium hydroxide and then with a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and the benzene was evaporated in a rotary evaporator. The residue is recrystallized from methanol, but a considerable amount of product remains in the mother liquor. The mother liquor is therefore concentrated and the residue is chromatographed on silica gel using benzene as eluent. The combined product (recrystallized and chromatographed) was recrystallized from a mixture of chloroform and methanol. 3.62 g (32%) of the title compound of q, melting point 162 DEG-163 DEG C. are obtained.

IR (CHCl ₃ ) 1671 (C = -C), 1622 cm ^-1 (C = C),

A _III ( _xOH ) 218 (ε 35,800), 256 (ε 9900), 322 (ε _13,100 ), 388 nm (ε 12,900),

NMR (CDCl 3) δ

1.8 (broad m, IOH, CH 2),

5.03 (d, J = 2 Hz, 2H, 5a-H and 6a-H),

7.1 (m, 8H, Ar-H);

7.53 (d, J = 2 Hz, 2H, 12-H and 14-H).

Analysis for G25H22O3:

calculated:

G 81.06, H 5.99%;

found:

C 31.13, II 6.12 P / o.

Example XI (5aa, 6aa, 1.2aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydrospiro [5aH, 13H- (1) benzopyrano (3,2-b) xanthene-6,1'- cyclohexane] -13-one

A solution of 2.0 g (0.55 mmol) of the product of Example 9 in 97 ml of tetrahydrofuran was hydrogenated in the presence of 1.0 g of platinum (IV) oxide at 50 psi for 16 hours at room temperature. The catalyst was filtered off, the filtrate was evaporated in vacuo and the residue was recrystallized from benzene / hexane. 1.10 g (54%) of the hexahydro compound are obtained, the carbonyl of which in position 13 has been reduced to a hydroxyl group, m.p. 236-238 ° C.

IR (CHCl 3) 3580 cm ^-1 (OH),

Λ _max (MeOH) 277 nm (ε 4 150).

Analysis for · C25H28O3:

calculated ·:

C 79.76, H 7.50%;

found:

C 79.40, H 7.63%.

To 20 ml of acetic acid was added 1.00 g (2666 mmol) of this alcohol. The mixture is cooled in an ice bath and a cooled solution of 0.70 g (1.75 mmol) of sodium dichromate dihydrate in 3.5 ml of acetic acid is added. The mixture was kept at room temperature for 4 hours and then poured slowly into 500 ml of ice water. The resulting precipitate was filtered off. The material was then dissolved in a small amount of ethyl acetate and chromatographed on magnesium silicate using ethyl acetate as eluent. The ethyl acetate fraction was evaporated and the residue was recrystallized from benzene / hexane. 385 mg (38%) of the title compound of melting point 228 DEG C. are obtained.

IR (in suspension) 1720 cm ^-1 (C = 0),

_{Λ max} (MeOH) 274 (ε 3,450), 282 nm (ε 3,450). Analysis for C25H24O3:

calculated:

C 80.18, H 7.00%;

found:

C 80.43, H 6.77%.

Example 10 (5aa, 6ad) -6,6a-dihydro-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

A solution of stilicylaldehyde (8.72 g, 71.4 mmol) in benzene (60 ml) was cooled and treated with pyrrolidine (8.2 g, 115 mmol) and then

4.7 g (77 mmol) of acetic acid. After stirring for 15 minutes, 4.36 g (35.7 mmol) are added.

4,4-dimethyl-2,5-cyclohexadienone and the solution was stirred under nitrogen at 50 ° C overnight. After cooling, the mixture was poured into ice water and extracted with benzene. The extracts were washed with dilute sodium hydroxide solution and then brine. After the extract was dried with sodium sulfate, the solvent was removed in vacuo. The crude product was crystallized from benzene-hexane to give a total of two portions of the 5aa, 6aa-isomer having a total weight of 4.43 g. The mother liquor was evaporated to dryness and chromatographed on a 100 g silica gel of activity grade I column. Three main fractions were obtained from the column. The first fraction contained an additional 0.18 g of pure 5aa, 8aa-isomer. The second fraction contained 0.97 g of a 1: 2 mixture of the 5aa, 6aa-isomer and the title compound. The third fraction contained 0.66 g of pure title compound. The product is crystallized from hexane, m.p. 121-123 ° C.

IR (CHCl 3) 1670 (CO), 1622 cm ^-1 (C = C), NMR (CDCl 3) δ

1.32 (s, 6H, CH 3),

4.79 (d, J = 2Hz, 2H, 5a-H and 6a-H),

7.11 (m, 6H, Ar-H);

7.50 · (d, J = 2 Hz, 2H, 12-H and 14-H). Analysis for C12H18O3:

calculated:

C 79.88, H 5.49%;

found:

C 80.24, H 5.61%.

214883

Example 11 (5aa, 6aa-6,6a-dihydro-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one)

A solution of 50 mg of (5aa, 6aa) -6,6a-dihydro-6,6-dimethyl-5aH, 13H- (1 (benzopyrano (3,2-b) xanthen-13-one) in 5 ml of toluene is boiled under nitrogen over TLC analysis of the sample indicated complete conversion to the title compound, the solvent was removed and the residue chromatographed on a short silica gel column eluting with benzene 48 mg of the product was isolated from the benzene eluate. The residue was recrystallized from benzene-hexane to give 45 mg of (5aa, 6aa) -6,6a-dihydro-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-bxanthen-13-one). · m.p. about 183-184 ° C. the product was recrystallized again from a mixture of benzene and ^hexane; typist pure compound, mp 211-212 ° C.

Example 12 (5a-6aS) -6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

A solution of 3-methoxycalicylaldehyde (100 g, 0.66 mol) in toluene (800 ml) was cooled and treated with pyrrolidine (60 g, 0.85 mol) followed by acetic acid (39.4 g, 0.68 mol). to 0 ° C and 40 g (0.33 mol) of 4,4-dimethyl-2,5-cyclohexadienone are added. The mixture was stirred under nitrogen overnight and then allowed to warm gradually to room temperature. The mixture was poured into ice water. The organic layer was washed successively with two portions of 1% acetic acid, three portions of 1 M sodium hydroxide solution, several portions of 1 M hydrochloric acid (until a small amount of color was extracted), three more portions of 1 M sodium hydroxide, and one portion of saturated sodium chloride solution. After drying the organic solution with sodium sulfate, the solvent was evaporated in vacuo, and the obtained crystalline residue was weighed after washing with hexane and air dried 14 g (11%) and had a melting point of 175-180 ° C (m.p. Spectral analysis revealed that the product was an almost pure title compound contaminated with less than 5% of the 5aa, 6a-isomer, and attempts to remove this impurity by careful recrystallization from benzene-hexane failed.

IR (CPICh) 1665 (C = O), 1620 cm @ ^-1 (C = C),

Λ _max (EtOH) 223 (ε 45,400), 350 nm nm (ε 24,400),

NMR (CDCl 3)

1.39 (s, 6H, CH 3),

3.86 (s, 6H, OCH 3),

4.82 (d, J = 2Hz, 2H, 5a-H and 6a-H),

6, £ 0 (s, 6H, Ar-H);

7.51 (d, J = 2 Hz, 2H, 12-H and 14-H). Analysis for C21H22O5:

calculated:

C 73.83, H 5.68%;

found:

C 73.97, H 5.76%.

Example 13 (5α, 6α) -6,6α-dihydro-4,8-dimethoxy-6,6-dimethyl-3αH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

ICO solution (5aa, 6a, e) -6,6a-dihydro-4,8-dimethyl-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one TLC analysis of the sample showed complete reaction, the solvent was removed and the residue was chromatographed on a short silica gel column using 10% ethyl acetate in benzene as eluent. The product (89 mg) was isolated from the eluate and recrystallized twice from benzene-hexane to give (5aa, 6aa) -6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano) 3,2-banthanthen-13-one, m.p. 237-239 ° C.

EXAMPLE 1 (5aa, 6aa, 12aa, 13aaj-6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano) (3,2-b) xanthene-13-one

To 75 ml of acetonitrile containing 5% water was added 15.0 g of tributylamine p-toluenesulfonate and 4.0 g of benzoic acid. To the resulting mixture was added 1.0 g of (5aa, 6a) -6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl5aH, 13H- (1J benzopyrano (3,2-b) xanthene-13). The solubility of the substrate at 25 [deg.] C. is about 4-5 mg / ml, so that the substrate remains in the slurry form and is placed in the cathode space of an electrolyzer containing a layer of mercury as a cathode and a platinum anode. -1.6 V compared to a reference electrode, which is a saturated calomel electrode, until electrolysis is performed until thin layer chromatography analysis indicates that the reaction is complete, the reaction mixture is removed from the electrolyser and the solvent is removed. ethyl acetate and the resulting solution was washed successively three times with 1 N hydrochloric acid, three times with saturated aqueous sodium bicarbonate, three times with 1 N hydrochloric acid, twice with saturated aqueous sodium carbonate solution and once with water. HPLC analysis showed that about 65% (5aa, 6aa, 12aia, 13aa) -6.6a, 12.12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH was formed 13H- (1) benzopyranof 3,2-b] xanthen-13-one. The ethyl acetate was removed and the product was dried. The product is crystallized from a mixture of methanol and chloroform. The title compound is obtained in about 50% yield, which is about 90% pure.

EXAMPLE XIII (5aa, 6aia 12a / ^l S, _{13a; ii)} -6,6, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-bj xanthen-13-one

The procedure described in Example XII is followed. A mixture of 0.8 g of lithium perchlorate and 4/0 ml of glacial acetic acid in 75 ml of acetonitrile containing 5% water is prepared. To the resulting mixture was added 1 g of (5aa, 6aa) -6,6a-dihydro-4,8-dimethoxy-6,6-d ^; methyl-5aH, 13H- (1) benzopyrano (3,2-bj xanthen-13-one) The resulting mixture is subjected to an electrolytic reduction in an electrolytic cell containing a mercury layer and a platinum anode. at a constant potential versus a saturated calomel reference electrode of 1.5V. After treatment and crystallization from a chloroform-methanol mixture, 5aa, 6a, 12a, 3.13a / 3) -6.6a, 12.12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1J benzopyranof 3,2-b) xanthen-13-one in the form of white to cream colored plates. The yield was about 65%. The product has a purity of about 92%. Melting point: 235-245 ° C (estimated).

Example XIV '(5', 6'PiX, 12aa, 13 '') - 6,6a, 12,12a, 13a, 14-hexahydro-1,8-dimethoxy-6,8-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

The procedure described in Example XII is followed. To 50 ml of N, N-dimethylforman containing 5% water was added 2 g of benzoic acid and amounts of tetrabutylammonium perchlorate to a concentration of 0.2. To the resulting mixture was then added 100 mg of (5a.a, 6a-1-6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1benzopyrano (3,2-bj xanthene-13)). The resulting mixture is subjected to an electrolytic reduction in an electrolyzer containing a mercury layer as a cathode.The electrolysis is carried out at 25 ° C and at a constant potential relative to a saturated calomel reference electrode of 1.6 V. After processing and crystallization from the mixture, (5aa) is obtained. 6aa, 12aa, 13aa] -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3,2b) xa. 13-one, in about 70% yield.

Example XV (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexa-46 hydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano 2-b) xanthene-13-one

The procedure is as described in Example XII. To a mixture of 60 ml of methanol and 4.8 ml of glacial acetic acid was added tetrabutylammonium umchloxide in an amount such that a concentration of 0 M was reached. 100 mg of (5aa, 6a * a) -6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3,2-b) are then added to the resulting mixture. xanthen-13-one. The resulting mixture is subjected to an electrolytic reduction in an electrolyzer containing a mercury layer as a cathode. Electrolysis is performed at 25 ° C and at a constant potential versus a saturated calomel reference electrode of - 1.4V. After treatment and crystallization from the mixture, (5a, 6aa, 12aa, 13aa) -6,6a, 12,12.a is obtained. 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1J benzopyranof 3,2-b) xanthen-13-one, about 85% yield.

Example XVI (5a-6e / 6, 12a-13aa) -8,6a, 12,12.a, 13a, 14-hexahydro-4,8-d ^: methoxy-8,6-dimethyl-5aH _; 13H- (1) benzopyranof 3,2b) xanthen-13-one

Following the procedure described in Example XII, a mixture of 2.57 g of tetrabutylamomumperchlorate and 2.5 g of benzoic acid in 50 ml of toluene and 25 ml of methanol was prepared. To the resulting mixture was added 309 mg of (5a, 6a * a) -6,6a-1'-hydro-4,8-dimethoxy 6,6-dmethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthene-13-ooiu. The resulting mixture is subjected to an electrolytic reduction in an electrolyzer containing a mercury layer as a cathode. Electrolysis is performed at 25 ° C and at a constant potential versus a saturated calomel reference electrode of 1.6 V. After processing and crystallization from the mixture, (5a * ύ 6ax, 12aa, 13aa) -6.6a, 12.12a, 13a is obtained. 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1J benzopyrano (3,2-b) xanthan-13-one), in about 65% yield.

Example XVII (5 ', 8a'a, 12aia, 13aa) -6,6a, 12,12a, 13a, 14'-hexahydro-4 _; 8-D'-methoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

The procedure is as described in Example XII. To 75 ml of acetonitrile containing 5% acetic acid and 5% water was added tetra-n-hexylammonium chloride in an amount to achieve a 0.1 M concentration. To the resulting mixture was then added 200 mg of (5aa, 6a ') - 6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1'-benzopyrano (3,2-b) xanthene-13). The resulting mixture is subjected to an electrolytic reduction in an electrolyzer containing a mercury layer as a cathode.The electrolysis is carried out at 25 ° C and at a constant potential against a saturated calomel reference electrode of 1.7 V. High pressure liquid chromatography shows the presence of (5aK ₍ 6aa, 12aa) (13aa) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-bxanthen-13-one), in about 65 to 70% yield.

Example XVIII (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12'a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1J benzopyrano (3, 6a, 12a) 2-b) xanthene-13-one

The procedure is as described in Example XII. To 75 ml of acetonitrile containing 5% acetic acid was added methyltrioctylammonium chloride (aliquot 336) in an amount to achieve a 0.1 M concentration. To the resulting mixture was then added 200 mg of (5aa, 6aa) -6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthene-13. -onu. The resulting mixture is subjected to an electrolytic reduction in an electrolyzer containing a mercury layer as a cathode. Electrolysis is performed at 25 ° C and at a constant potential against a saturated calomel reference electrode of 1.6V. High pressure liquid chromatography shows the presence of (5aa, 6aa, 12aa, 13aa) -6.6a, 12.12a, 13a, 14- hexahydro-4,8-dimethyloxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-bantanen-13-one) in about 65 to 70% yield.

Example XIX (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5a, H, 13H- (1) benzopyrano ( 3,2-b} xanthen-13-one

The procedure is as described in Example XII. To 67 ml of acetonitrile containing 5% water and 1.5% acetic acid was added Ν, Ν-diisopropylethylamin tosylate in an amount sufficient to achieve a 0.1 M concentration. To the resulting mixture was then added 100 mg of (5aa, 6aa) -6,6a-dihydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-bj xanthene-13-). The resulting mixture is subjected to an electrolytic reduction in an electrolyzer containing a mercury layer as a cathode.The electrolysis is carried out at 25 ° C and at a constant potential against a saturated calomel reference electrode of 1.5 V. High pressure liquid chromatography shows the presence of (5aa, 6a «, 12aa). 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-4,8-dimethoxy-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-bxanthen-13-one) in about 60 to 65% yield.

Example 14 (5aa, 6aa-6,6a-dihydro-3,9-dlcyan-6,6-dimethyl-5aH, 13H- (1'-benzopyrano (3,2-bxanthen-13-one))

The sequence of reactions described in Example 1 is followed and 4-cyansalicylaldehyde is reacted with 4,4-dimethyl-2,5-cyclohexadienone in the presence of pyrrolidine and acetic acid. The product is purified as described in Example 1. The desired product is obtained in good yield.

Example 15 (5aa, 6aa) -6,6a-dihydro-3,9-diethyl-6,6-diniethyl-5aH, 13H- (1'-benzopyrano (3,2-b) xanthen-13-one)

Following the sequence of reactions described in Example 1, 4-ethylsalicylaldehyde and 4,4-dimethyl-2 ', 5-cyclohexadiene nonem are reacted in the presence of pyrrolidine and acetic acid under a nitrogen atmosphere. The product is isolated and the crude product is recrystallized by the general method described in Example 1. A decent yield of the desired product is obtained.

Example 16 (5aa, 6a) -6,6a-dihydro-2,10'-dichloro-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2-b) xanthen-13-one

The 5-chlorosalicylaldehyde solution is treated with pyrrolidine and acetic acid and then reacted with 4,4-dimethyl-2,5-cyclohexadienone, as generally described in Example 1. After isolation and purification according to Example 1, the desired product is obtained. in good yield.

Example XX (5aa, 6aa, 12aG1, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-dicyano-6,6-dimethyl-5aH, 13H- (1) benzopyranof 3.2 (b) xanthen-13-one

The product of Example 14 was reduced by the methods described in the preceding Examples. (5aa, 6a ', 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-dicyano-6,6-dimethyl-5aH, 13H- (1'-benzopyrano) 2-b) xanthen-13-one

Example XXI (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-diethyl-6,6-dimethyl-5aH, 13H- (1) benzopyrano (3,2) (b) xanthen-13-one

The product of Example 15 was reduced by the methods described in the above Examples. In good yield, (5aa, 6aa, 12aa, 13aa) -6,6a, 12,12a, 13a, 14-hexahydro-3,9-diethyl-6,6-dimethyl-5a.H, 13H- ( 1 j benzopyrano (3,2-b) xanthen-13-one.

Example XXII (5aa, 6aa, 12aa, 13aa ') - 6,6a, 12,12a, 13a, 14-hexahydro-2,10-dichloro-6,6-dimethyl-5aH, 13H- (1J benzopyrano (3, 6a, 12aa)) 2-b) xanthene-13-one

214 888

Using the methods described in the above examples, the product of the example is reduced

16. (5aa, 6aa, 12aa, 13a-16a) -66a, 12,12a, 13a, 14-hexahydro-2,1-dichloro-6,6-dimethyl-5aH, 13H- (1) benzopyrano was obtained in good yield (3,2-b Jxanthen-13-one.

Claims (9)

A process for the preparation of the new hexahydrobenzopyranoxanthenone compounds of the general formula I, wherein each represents a symbol R is hydrogen, C1-C1 alkyl- C1-C4-alkoxy-, hydroxy-, cyano- or halogen, both R being identical and positioned symmetrically, R1 is C1-C3 alkyl; R 2 is methyl, or R 1 and R 2 together represent (CH 2) _n wherein n is an integer from 4 to 6, and Xa, Xb, Xc, Xd, Ya, and Yb are hydrogen atoms, with the proviso that both Xc and Xd are in the «-configuration, both Xa and Xb are in the α- or β-configuration, and R 1 when The C 1 -C 3 alkyl group is in the «-configuration characterized in that the compound of formula V wherein ynAleze is reduced by catalytic hydrogenation at 25 to 50 ° C or electrolytically at 5 to 80 ° C in organic or aqueous-organic is reduced a mercury cathode medium in the presence of a proton source and an electrolyte selected from the group consisting of alkali metal salts, quaternary ammonium salts of 10 to 28 carbon atoms in the cation, and tertiary amine salts containing a total of 7 to 21 carbon atoms in the cation; in the presence of platinum oxide, the reduction product is further treated with pyridinium chlorochromate, sodium dichromate or potassium dichromate. 2. The process according to claim 1, wherein the catalytic hydrogenation is carried out in the presence of Raney nickel. 3. A process according to claim 1, wherein the catalytic hydrogenation is carried out in the presence of platinum oxide and the catalytic hydrogenation product is further reacted with pyridinium chlorochromate, sodium dichromate or potassium dichromate. 4. The process of claim 1 wherein the electrolytic reduction is an alkali metal salt. 5. The process of claim 1, wherein the electrolytic reduction is based on the quaternary ammonium or tertiary amine salts defined in 1. 6. A process according to claim 5 wherein the electrolyte is tetrabutylammonium salt. 7. The process of claim 5, wherein the electrolyte is a salt of tributylamine. 8. The method of claims 1 and 4 to 7, characterized in that an acid having a pKa of 2-4 is used as the proton source in the electrolytic reduction. 9. Process according to claim 8, characterized in that it is operated at a temperature of 20 to 30 ° C. R, R 1, R 2, X c and X d have the aforementioned