GB1593643A - Antiandrogen hydrobenzo-pyranoxanthenones - Google Patents

Description

(54) ANTI-ANDROGEN HYDROBENZO PYRANOXANTHENONES (71) We, ELI LILLY AND COMPANY, a corporation of the State of Indiana, United States of America, having a principal place of business at 307 East McCarty Street, City of Indianapolis, State of Indiana, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention provides novel dihydro- and hexahydrobenzopyranoxanthenones which are useful as anti-androgens.

This invention relates to a novel class of compounds having antiandrogen activity. Androgens are substances which are active in stimulating secondary sex characteristics in males. Although such substances obviously are of great physiological significance, they can produce certain undesirable side effects, and it would be highly advantageous to prophylactically or therapeutically eliminate or minimize these effects. For example, the stimulatory effects of androgens upon the prostate gland have been known for many decades. The pathogenesis of benign prostatic hypertrophy (BPH) and/or prostatic cancer (PC) is not fully understood; however, it is thought that both of these syndromes are subject to the influence of androgens. In addition, acne, an inflammatory disease involving the sebaceous glands and found chiefly in adolescents, is thought to be dependent upon sebum secretion which, in turn, is dependent upon androgen action. Other androgen-dependent conditions include hirsutism and certain types of cancer. including types of breast cancer.

Androgens are steroidal hormonal agents. For some time, it has been customary to attempt control of androgen activity by administration of other steroids. However, although administration of these steroids may be effective in diminishing androgen action, their administration in general results in other unwanted side effects which limit their usefulness. For example, cyproterone acetate is a potent steroidal anti-androgen. However, although it has demonstrated clinical effectiveness against both benign prostatic hypertrophy and prostatic cancer, it is not routinely used in humans because of its hormonal side effects. It has beenreported to cause suppression of adrenal gland function as well as to exert potent progestational side effects.

It is highly desirable, therefore, to discover substances which are nonsteroidal in structure and which exhibit potent anti-androgen activity. It is to such a class of compounds that this invention is directed. Only a very limited number of non-steroidal anti-androgens are recognized in the art. U.S. Patent No. 3,857,953 discloses a class of arylidene cyclanones. These compounds are non-steroidal, and they exhibit antiandrogen activity. It is to a new class of non-steroidal antiandrogens that this invention is directed.

The novel benzopyranoxanthenone compounds of this invention are of the formula

wherein each R is hydrogen, C,-C4 alkyl, Cl-C4 alkoxy, hydroxy, cyano, or halo, and both R groups are identical and are symmetrically located; R, is C,-C3 alkyl and R2 is methyl, or R, and R2 taken together are (CH2)n in which n is an integer from 4 to 6; and (1) Xc and Xd are hydrogen, and the combination of Xa and Y8 and of Xb and Yb each represents a double bond, subject to the limitation that, when R1 is Cl-C3 alkyl and is other than methyl, Xc, Xd, and R1 are all in an aconfiguration; or (2) Xa, Xb, Xc, Xd, Ya, and Yb are hydrogen, subject to the limitation that both Xc and Xd are in an a-configuration, both Xa and Xb are in an a-configuration or in a p-configuration, and, Rl, when it is Cl-C3 alkyl, is in an aconfiguration.

The compounds of Formula I are prepared by a novel process which comprises reacting a 2-hydroxybenzaldehyde of the formula

wherein Ra is hydrogen, C,-C4 alkyl, C,-C4 alkoxy, cyano or halo, with a 2,5cyclohexadiene of the formula

in the presence of pyrrolidine or a pyrrolidine mono- or disubstituted with chloro, bromo or C,-C3 alkyl groups, and a Cl-C, carboxylic acid, in an inert solvent, at a temperature from 0 C. to 650C., to form a dihydrobenzo-pyranoxanthenone of Formula I of the formula

wherein Ra, R1 and R2 are as defined above, and Xc and Xd are in either the α,α or a,-configuration, and, if a biologically active dihydrobenzopyranoxanthenone of Formula I is desired, and the reaction of the compounds of Formulae II and III was at a temperature below the ambient temperature, heating the compound of Formula IV to a temperature between the ambient temperature t 1000C. to prepare the corresponding compound of Formulae I and IV of the formula

wherein Ra, Rl and R2 are as defined above, and Xc and Xd are in the a configuration; and, if a compound of Formula I wherein R is hydroxy is desired, reacting a compound of Formula V wherein Ra is Cl-C4 alkoxy with boron tribromide in an inert solvent to prepare the corresponding compound of Formula V wherein Ra is R; and, if a hexahydrobenzopyranoxanthenone of Formula I, wherein X Xb Y and Yb are hydrogen, of the formula

is desired wherein R, Rl and R2 are as defined above, reducing a compound of Formula V wherein Ra is R; provided that, if the reduction is in the presence of platinum dioxide, the reduction product is further reacted with pyridinium chlorochromate, sodium dichromate or potassium dichromate.

It will be understood that the compounds of Formulae IV, V and VI are included within the definition of the compounds of Formula I.

In the compounds of Formula I, the carbon in the 6-position completes a C5- C, spiro ring or is substituted both with a methyl (R2) and with the group Rl which is C,-C3 alkyl. As used herein, the term "C,-C3 alkyl" refers to methyl, ethyl, npropyl, or isopropyl. Preferably, R, is methyl, and when this is the case, a 6,6dimethyl compound of course is defined.

However, when R, is C,-C3 alkyl and is other than methyl, the substituents at the carbon in the 6-position are dissimilar, and, therefore, more than one isomer is possible. In those cases, the compounds of this invention are those in which the methyl group (R2) is in the position generally axial to the ring while the group R1 is in a position generally equatorial to the ring.

In the foregoing formulae, the group R represents hydrogen, C,-C4 alkyl, C1 C4 alkoxy, hydroxy, cyano, or halo. As used herein, the term "C,-C4 alkyl" refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. The term "C1-C4 alkoxy" as used herein refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and t-butoxy. As used herein, the term "halo" refers to chloro, fluoro, and bromo. Of the above groups, R preferably represents any of hydrogen, methoxy, ethoxy, or cyano.

In each of the compounds of this invention, the group R (or Ra) appears at two points. In any particular compound of this invention, the group at both points in the molecule represents the same moiety. Furthermore, the groups in any particular compound of this invention are located symmetrically, and, thus, are at the 2- and 10- positions, the 3- and 9-positions, or the 4- and 8-positions.

In the dihydrobenzopyranoxanthenones of Formula IV and V, a hydrogen atom appears in both the 5a- and the 6a-positions. In order for the compound to exhibit anit-androgen activity, it is essential that the stereoconfiguration of these hydrogen atoms be such that they are cis to each other, that is, that both are located on the same side relative to the major plane of the molecule. In other words, both hydrogens must be in the a-position.

The dihydrobenzopyranoxanthenones of Formula IV in which the 5a- and 6ahydrogens are trans to each other, that is, those in which one hydrogen is in the aposition and the other is in the p-position, are not active as anti-androgens.

However, they are readily epimerized to the active dihydrobenzopyranoxanthenones by simply warming them to a temperature above room temperature. Therefore, these compounds are intermediates to the biologically active dihydrobenzopyranoxanthenones.

The hexahydrobenzopyranoxanthenones of Formula VI differ from the dihydro compounds by hydrogenation of the double bonds at the 12- and 13acarbons. The resulting hydrogenated products of Formula VI contain hydrogens at the Sa, 6a, 12, 12a, 13a, and 14-carbons. The particular stereoconfiguration of the hydrogens at the 5a, 6a, 12a, and 13a-carbons relative to each other is an essential factor in the definition of this invention. Of the various stereo-chemical combinations which are possible from these four hydrogens, two combinations represent compounds of this invention. The following two moieties of the hexahydrobenzopyranoxanthenones are included within the definition of this invention.

From the above, it is apparent that the hexahydrobenzopyranoxanthenones of Formula VI and Formula I comprise those in which (1) the hydrogens at the 5aand the 6a-carbons are each cis to the other and (2) the hydrogens at the 12a- and the 13a-carbons are each cis to the other.

In addition to the above limitations pertaining to the stereoconfiguration of the compounds of Formula I, a further limitation exists. The group Rl can be a C1- C, alkyl group. In those instances in which R, is methyl, a 6,6-dimethyl compound is defined, and no further stereo-configuration considerations arise. However, when Rl is other than methyl, a 6 - methyl - 6 - ethyl, a 6 - methyl - 6 - n propyl, or a 6 - methyl - 6 - isopropyl compound is defined. All of these represent compounds of Formula I; however, the stereoconfigurational aspects are such that the compounds of Formula I are restricted to those in which Rl is in a position equatorial to the ring structure, and the methyl group (R2) is in a position axial to the ring structure. In other words, the compounds of this invention in which Rl is C1-C, alkyl and is other than methyl are those in which the 5a and 6a hydrogens and the Rl group are all in the a-position.

The first step of the synthesis of these compounds is the reaction of the compounds of Formula II and III. When the reaction is carried out at ambient temperature or below, the product which results is predominantly a mixture of the 5aa, 6ap- and the 5ap, 6acu-optical isomers of Formula IV. These are useful intermediates and are compounds of this invention. This product, upon being subjected to a temperature above ambient temperature, rearranges to the Saa 6aa-isomer of Formula V, a potent anti-androgen.

When the condensation of the 2-hydroxybenzaldehyde with a 4 substituted - 2,5 - cyclohexadienone is carried out at a temperature above ambient temperature, and generally from 550C to 650C., the Sacs, 6aa-isomer product is isolated directly from the reaction mixture.

As is evident from the products obtained from the above reaction, at least a 2:1 molar ratio of the 2 - hydroxy - benzaldehyde to the 4 - substituted - 2,5 cyclohexadienone is required.

The condensation customarily can be carried out in any solvent which is inert to the reactants and which affords sufficient solubility for the reactants. In the event that epimerization affording direct isolation of the 5aa, 6aa-isomer is desired, the boiling point of the solvent must be high enough to achieve this result, that is, the boiling point must be in excess of room temperature, if ambient pressure is to be used. Typical solvents which are employed include aromatic hydrocarbons, including benzene, toluene, and ethers such as tetrahydrofuran.

A Cl-C, carboxylic acid is employed, generally in an amount at least equivalent on a molar basis to the amount of the aldehyde which is employed.

Typical carboxylic acids such as acetic acid, propionic acid, butyric acid, and benzoic acid are used. The preferred acid is acetic acid. In addition, pyrrolidine or substituted pyrrolidine is used. Such pyrrolidines as 2-methylpyrrolidine, 3chloropyrrolidine, 2,3-dibromopyrrolidine, and 3-propylpyrrolidine are useful.

The preferred amine is pyrrolidine.

In carrying out the condensation, the reactants are mixed in the solvent of choice. The order of addition of the reactants is not critical; normally, however, the cyclohexadienone is added last. The mixture then is permitted to react at the selected temperature of reaction, and the product is recovered by customary techniques.

The starting materials for the compounds of this invention are salicylaldehyde or a substituted salicylaldehyde of Formula II and a 4substituted - 2,5 - cyclohexadienone of Formula III.

Salicylaldehyde as well as the 3-, 4-, or 5-substituted salicylaldehydes are available by techniques well recognized in the art. They, for example, can be prepared by the Reimer-Tiemann reaction which involves treatment of the appropriately substituted phenol with chloroform and an alkali metal hydroxide, particularly sodium hydroxide.

The dienone is available by either of two relatively complex reaction sequences. The formation of 4 - substituted - cyclohexenones from methyl vinyl ketone and the appropriate aldehyde is well known from E. L. Eliel and C.

Lukach, J. Am. Chem. Soc. 79, 5986 (1957); Y. Chan and W. W. Epstein, Org. Syn.

53, 48 (1973); C. H. Heathcock et al., Tetrahedron Letters, 4995 (1971).

The condensation of methyl vinyl ketone with the aldehyde is readily controlled. Equimolar quantities of methyl vinyl ketone and the aldehyde or a moderate excess of up to about 10 percent of the aldehyde generally are employed, preferably under acidic conditions. The condensation is exothermic.

Conversion of the 4 - substituted - cyclohexenone to the desired product can be accomplished by either of two routes. The direct conversion involves a dehydrogenation using dichlorodicyanoquinone; H. E. Zimmerman et awl., J. Am.

Chem. Soc. 93, 3653 (1971). Alternatively, the conversion can be achieved indirectly by the sequence described in H. Plieninger et al., Chem. Ber. 94 2115 (1961). This sequence involves treating the 4 - substituted - cyclohexanone with propen - 2 - yl acetate under acidic conditions to produce a 2 - acetoxy - 5 substituted - 1,3 - cyclohexadiene, which is treated with N-bromosuccinimide to produce a 4 - substituted - 6 - bromo - cyclohex - 2 - enone which then is dehydrobrominated to the desired cyclohexadienone using hexamethylphosphoric triamide.

The compounds of Formula I in which the group R is hydroxy are prepared by demethylation of the corresponding compounds in which R (or Ra) is methoxy.

Demethylation is accomplished by treating the dimethoxy compound with boron tribromide. Typically, three molar equivalents of boron tribromide are added to a mixture of the dimethoxy compound in an inert solvent. The addition is carried out as rapidly as possible while retaining the temperature of the reaction mixture at OOC. Upon completion of the addition, the mixture is allowed to warm to room temperature and is maintained at room temperature for 4 to 16 hours. The product is recovered by adding the mixture to ice water and extracting the product into an appropriate solvent, for example, methylene chloride or ethyl acetate.

The compounds of Formula I in which R is alkoxy are also available from those compounds in which R is hydroxy. The hydroxy compounds are treated with a large excess of potassium carbonate and the appropriate alkyl bromide in the presence of hexamethylphosphoric triamide which itself can serve as solvent. The reaction is carried out at a elevated temperature of 50"C. to 1000C. for 1 hour to 20 hours.

The hexahydrobenzopyranoxanthenones of Formula VI are prepared by reduction of the dihydrobenzopyranoxanthenones. The reduction can be accomplished catalytically. For example, it can be carried out in an appropriate solvent over standard catalysts such as Raney nickel, palladium on carbon, platinum dioxide, and platinum on carbon. The reduction generally is carried out at room temperature or at a moderately elevated temperature of 25"C. to 50"C. and at a pressure of 30 to 60 p.s.i. The catalytic reduction usually is complete after 4 to 48 hours, and, more likely, after 24 hours. The reduction can be carried out at atmospheric pressure; however, the reaction time thereby is greatly extended.

The reaction is carried out in the presence of a solvent. Typical solvents include ethers such as tetrahydrofuran; esters, such as ethyl acetate; aromatic hydrocarbons, such as benzene and toluene; and alcohols, such s methanol and ethanol. An ether, especially tetrahydrofuran, is highly preferred as solvent.

The amount of catalyst ranges generally from 10% to 100% on a weight basis relative to the dihydrobenzo - pyranoxanthenone. In general, relative to each other, the amount of Raney nickel which is used is greater than that of a platinum or palladium catalyst.

The reduction may produce a mixture of epimeric ketones. Although the positions of the hydrogens added to the 12a- and 13a-positions are cis to each other, they may be both a and relative to the hydrogens located in the 5a- and 6a-positions. When Raney nickel or palladium are employed, approximately an 80:20 mixture of the epimers is obtained, the 12ain, 13aa isomer predominating.

When platinum is used as catalyst, the product is virtually entirely the 12acre, 13aa isomer.

The catalytic reduction tends to be accompanied at least in part by reduction of the keto group in the 13-position, producing the corresponding hydroxyl compound. Thus, varying amounts of the corresponding alcohol are obtained.

The Raney nickel and palladium catalysts produce about 30--50: overreduction. Over-reduction is greater with a platinum catalyst and is virtually complete with platinum dioxide.

The alcohol portion of the product mixture may be back-oxidized to the desired hexahydro product of Formula Vl by treatment with at least one equivalent of pyridinium chlorochromate, sodium dichromate, or potassium dichromate. Such back-oxidation is necessary when platinum dioxide catalyst is used for the reduction. It is preferred that the alcohol be isolated prior to backoxidation; however, this is not essential, and the product mixture itself can be treated under oxidizing conditions. The oxidation is carried out at room temperature in a solvent, such as methylene chloride or any of the aforedescribed solvents. When pyridinium chlorochromate is used, the oxidation is complete after 24 hours. It is faster using a dichromate, being complete after 1--4 hours.

The dihydrobenzopyranoxanthenones also can be converted to their corresponding hexahydrobenzopyranoxanthenones by electrolytic reduction.

This method is sufficiently selective so that none of the aforedescribed overreduction occurs.

The electrolytic reduction is carried out by dissolving or suspending the dihydrobenzopyranoxanthenone in an organic medium or in a medium comprising an aqueous-organic mixture. The aqueous-organic mixture itself can be present as an emulsion or as a miscible combination. Typical useful organic media include amides, for example, N,N - dimethylformamide and N,N dimethylacetamide; nitriles, such as acetonitrile; alcohols, for example, methanol and ethanol; aromatic hydrocarbons, such as benzene and toluene; halogenated hydrocarbons, such as methylene chloride and chloroform. Organic media which are preferred for use in the electrolysis process of this invention are amides, nitriles, and alcohols. Specifically preferred media include N,N dimethylformamide, acetonitrile, and methanol. An especially preferred organic medium is methanol.

In addition, an electrolyte is added to the mixture. Useful electrolytes are salts including halides, tosylates and perchlorates of the alkali metals, such as lithium, sodium, and potassium. Other useful electrolytes are quaternary ammonium salts, such as halides and perchlorates. These include, for example, tetraalkylammonium, trialkylaralkylammonium, dialkyldiaralkylammonium, or alkyltriaralkylammonium, any of which have a total of 10 to 28 carbon atoms in the cation moiety. A preferred such salt is the tetrabutylammonium salt.

A further class of electrolytes are tertiary amine salts, including halides, tosylates and perchlorates, of trialkylamines, dialkylaralkylamines, alkyldiaralkylamines, and triaralkylamines, any of which have a total of from 7 to 21 carbon atoms in the cation moiety. A preferred tertiary amine salt is a salt of tributylamine, and in particular, the p-toluenesulfonic acid salt.

Examples of typical electrolytes include lithium perchlorate, potassium perchlorate, sodium perchlorate, lithium chloride, potassium bromide, sodium fluoride, sodium iodide, lithium iodide, tricaprylylmethylammonium chloride, benzyltributylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium bromide, cetyltrimethylammonium bromide, methyltributylammonium iodide, myristyltrimethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, dibenzyldiethylammonium chloride, dibenzyldipropylammonium bromide, phenethyltributylammonium chloride, diphenethyldipentylammonium bromide, tribenzylethylammonium chloride, tetrahexylammonium chloride, triheptylbenzylammonium bromide, 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- dibenzyl - N - ethylamine chloride, tribenzylamine p - toluenesulfonate andlributylamine chloride.

Furthermore, a source of protons is included in the reaction medium.

Relatively weak acids having pKa values of from 2 to 6, such a benzoic acid and acetic acid, produce best results.

In the electrolytic reduction, the dihydrobenzopyranoxanthenone of Formula V is usually present in an amount of from 1 to 15 mg. per ml. of medium.

The electrolyte, in general, is present in an amount of from 0.01 M to 1.0 M, and, generally, the acid is present in an amount of 1-5% by weight based upon the volume of the medium. The electrolytic reduction, in general, is carried out at a temperature of from 5"C. to 800C., and, conveniently at 200 C. to 300C.

The resulting mixture, containing the dihydrobenzopyranoxanthenone, proton source, electrolyte, and organic or organic-aqueous medium, is placed in contact with the cathode of an electrolytic cell. A potential corresponding to a point at the foot of background discharge is applied. The potential is determined by preparing a current vs. potential curve at the working electrode on the medium prior to electrolysis. Current at the determined potential then is allowed to pass through the cell until an amount of current corresponding to between one and two times the number of Faradays required for a four-electron reduction has passed.

The electrolysis is an especially convenient cathode reduction process which occurs with ease in commonly constructed electrolysis apparatus. For example, the process can be carried out using a conventional electrolytic cell, such as any of those described by M. J. Allen, Organic Electrode Processes, Reinhold Publishing Corporation, New York, 1958. These conventional electrolytic cells are described at page 33 of the publication and comprise a suitable cathode and anode separated by a bridge. The cathode used in this process is mercury. Anodic materials which can be used include platinum and carbon. Platinum metal is a preferred anode and particularly when it is in the form of a fine gauze or a wire mesh. Carbon, due to its low cost, represents another preferred anode.

The bridge connecting the cathode and anode can be a conventional salt bridge such as, for example, a 4 percent aqueous mixture saturated with potassium chloride. It can also be a suitable porous membrane such as, for example, an ion exchange membrane, a ceramic membrane, or a sintered glass membrane of small to medium porosity. Any of those membranes described and discussed by M. J.

Allen, supra, can as well be employed.

A typical electrolytic cell comprises a jacketed glass cylindrical cathode compartment in which a glass anode compartment, part of which is a glass frit, is suspended. In general, the cathode is present as a ring-shaped pool of mercury.

The anode compartment generally is a fritted glass cylinder or a circular double walled glass tube having a circular glass frit sealed into its lower end. In general, the anode comprises a platinum wire immersed in the same mixture of the organic or organic-aqueous medium and electrolyte as is used in the cathode compartment. Normally, the electrolysis cell is stoppered with a cap through which a deaerating frit, a reference probe, and a thermometer are inserted. The reference electrode probe comprises a glass tube containing a fiber-junction in which a saturated calomel electrode is inserted.

In practice, the appropriate mixture containing the organic or organic aqueous medium, electrolyte, and proton donor, is placed into the cathode compartment. A predetermined quantity (about 1--15 mg/ml.) of the dihydrobenzopyranoxanthenone is added to the stirred mixture, and the circular anode compartment containing the mixture of organic or organic-aqueous medium and electrolyte together with the electrolysis cell cap is properly positioned relative to the cathode. Argon then is introduced through the deaerating frit and into the stirred cathode mixture. Upon completion of deaeration (about 15 minutes), the deaerating frit is raised to a position above the surface of the cathode solution, and the flow of argon is continued throughout the electrolysis. A predetermined potential then is applied to the cell until an amount of current has passed which corresponds to approximately twice the number of Faradays required for a four electron reduction. Calculation of the coulombs which have passed through the system can be determined by a coulometer, and the system can also be monitored by means of thin-layer chromatography or high pressure liquid chromatography. Any of these methods are useful in determining the extent of reaction. Upon completion of the electrolysis, the catholyte solution is collected.

Workup of the reaction mixture is accomplished by routine techniques. In general, the majority of the organic or aqueous-organic medium first is removed in vacuo. The resulting syrupy residue then is dissolved in ethyl acetate. The ethyl acetate solution is washed several times with generally equal volume amounts of water to remove electrolyte and proton donor. The ethyl acetate phase then is dried over a suitable drying agent, such as anhydrous magnesium sulfate, and is filtered. The ethyl acetate solvent is removed, and the residue is dried for several hours in a vacuum oven at about 45 C. The desired hexahydrobenzopyranoxanthenone product then is obtained by crystallization of the residue from an appropriate solvent system.

The cation of the electrolyte is a highly significant factor in the electrolysis reaction. It has been discovered that the stereoconfiguration of the hexahydrobenzopyranoxanthenone of Formula VI is to a great degree dependent upon the particular electrolyte which is used. When the electrolyte is a salt having a cation which forms a strongly associated ion pair, such as a lithium, sodium, or potassium cation, a product comprising predominantly the hexahydrobenzopyranoxanthenone having a 5aa, 6aa, 12c < , 13ap configuration results. Conversely, an electrolyte having a cation which forms a weak ion pair, such as a quaternary ammonium salt or a tertiary amine salt, directs (I)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexanl - 13 - one; (5a&alpha;,6ass) - 6,6a - dihydro - 3,9 - diethylspiro[5aH,13H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cycloheptan] - 13 - one; (5a&alpha;,6ass) 6,6a - dihydro - 2,10 - di - n - propylspiro - [5aH,13H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cyclopentan] - 13 - one; (5a&alpha;,6ass) - 6,6a - dihydro - 3,9 - dimethoxyspiro[5aH,13H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexanl - 13 - one; (5a&alpha;,6ass) - 6,6a - dihydro - 4,8 - diethoxyspiro[5aH,13H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cyclopentan] - 13 - one; (5a&alpha;, 6ass) - 6,6a - dihydro - 4,8 - dihydroxyspiro[5aH,13H (1)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexan] - 13 - one.

Examples of dihydrobenzopyranoxanthenones of Formula V which are useful as anti-androgens are (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 6ss - methyl - 6a - ethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one; (5aa,6aa) - 6,6a - dihydro - 6ss - methyl - 6a - n - propyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 6ss - methyl - 6a - isopropyl - 5aH,13H (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 4,8 - dimethyl - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one; (Saa,6aa) - 6,6a - dihydro - 3,9 - diethyl - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one; (5aa,6aa) - 6,6a - dihydro - 2,10 - di - n - propyl - 6,6 - dimethyl 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one; (Saa,6aa) - 6,6a - dihydro -2,10 - di - t - butyl - 6ss - methyl - 6a - ethyl 5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (Saa,6aa) - 6,6a - dihydro - 3,9 - dimethoxy - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one; (Saa,6aa) - 6,6a - dihydro - 4,8 - diethoxy - 6ss - methyl - 6a - isopropyl 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 4,8 - diisopropoxy - 6,6 - dimethyl 5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 3,9 - di - n - butoxy - 6ss - methyl - 6&alpha; - n propyl - 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one; (5aa,6aa) - 6,6a - dihydro - 4,8 - dihydroxy - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one; (Saa,6aa) - 6,6a - dihydro - 3,9 - dicyano - 6ss - methyl - 6a - ethyl 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one; (Saa,6aa) - 6,6a - dihydro - 4,8 - dichloro - 6ss - methyl - 6a - isopropyl 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one; (Saa,6aa) - 6,6a - dihydro - 4,8 - difluoro - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one; (5aa,6aa) - 6,6a - dihydrospiro[5aH,13H - (I)benzopyrano(3,2 b)xanthene - 6,1' - cyclohexan] - 13 - one; (5aa,6aa) - 6,6a - dihydro - 4,8 - dimethylspiro[5aH,l3H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cyclopentan] - 13 - one; (5aa,6aa) - 6,6a - dihydro - 3,9 - diethylspiro[5aH,13H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cycloheptan] - 13 - one; (5aa,6aa) - 6,6a - dihydro - 3,9 - dimethoxyspiro[5aH,13H (1)benzopyrano(3,2 - b)xanthene - 6,1 ' - cyclohexanl - 13 - one; (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 3,9 - dimethoxyspiro[5aH,13H (I)benzopynano(3,2 - b)xanthene - 6,1' - cyclohexan] - 13 - one; (5aa,6aa) - 6,6a - dihydro - 4,8 - diethoxyspiro[5aH,13H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cyclopentan] - 13 - one; (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 4,8 - dihydroxyspiro[5aH,13H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexan] - 13 - one; (Saa,6aa) - 6,6a - dihydro - 2,10 - dibromo - 6,6 - dimethyl - 5aH,13H (1)benzopyrano(3,2 - b)xanthen - 13 - one.

Examples of hexahydrobenzopyranoxanthenones of Formula VI are (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 6,6 - dimethyl 5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12,12a,13a,14 -hexahydro -6ss - methyl -6&alpha; - ethyl -5aH,13H - (1)benzopyrano(3,2 -b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 6ss - methyl - 6&alpha; - n - propyl -5aH,13H -(1)benzopyrano(3,2 -b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 6ss - methyl - 6&alpha; isopropyl - 5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethyl 6,6 - dimethyl - 5aH,13H - (1)benzopyrano(3,2 - b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 - diethyl - 6,6 dimethyl - 5aH,13H - (1)benzopyrano(3,2 - b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 2,10 - di - n propyl - 6,6 - dimethyl - 5aHm13H - (1)benzopyrano(3,2 -b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 2,10 - di - t butyl - 6ss - methyl - 6&alpha; - ethyl - 5aH,13H - (1)benzopyrano - (3,2 b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 - dimethoxy 6,6 - dimethyl - 5aH,13H - (1)benzopyrano(3,2 - b)xanthen -13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - diemthoxy 6ss - methyl -6&alpha; - ethyl -5aH,13H - (1)benzopyrano(3,2 -b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14-hexahydro - 4,8 - diisopropyl 6,6 - dimethyl -5aH,13H - (1)benzopyrano(3,2 -b)xanthen -13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 - di - n butoxy - 6ss - methyl - 6&alpha; - isopropyl - 5aH,13H - (1)benzopyrano(3,2 b)xanthen -13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dihydroxy 6,6 - dimethyl - 5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 - dicyano - 6ss methyl -6&alpha; - ethyl -5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dichloro - 6ss methyl - 6ss - isopropyl - 5aH,13H - (1)benzopyrano - (3,2 -b)xanthen - 13 one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - difluoro 6,6 - dimethyl -5aH,13H, (1)benzopyrano(3,2 -b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 2,10 - dibromo 6,6 - dimethyl -5aH,13H, (1)benzopyrano(3,2 -b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 6,6 - dimethyl 5aH,13H - (1)benzopyrano(3,2 - b)xanthen -13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - 6ss - methyl -6&alpha; - ethyl -5aH,13H -(1)benzopyrano(3,2 -b)xanthen -13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - 6ss - methyl -6&alpha; n - propyl - 5aH,13H - (1)benzopyrano(3,2 -b)xanthen - 1 3 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - diethyl - 6,6 dimethyl - 5aH,13H, (1)benzopyrano(3,2 -b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - diethyl - 6,6 6,6 - dimethyl - 5aH,13H, (1)benzopyrano(3,2 -b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 - diethyl - 6,6 dimethyl - 5aH,13H - (1)benzopyrano(3,2 - b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 2,10 - di - n propyl - 6,6 - dimethyl -5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 2,10 - di - n butyl - 6ss - methyl - 6&alpha; - ethyl -5aH,13H - (1)benzopyrano - (3,2 b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 2,10 - di - n 6,6 - dimethyl - 5aH,13H, (1)benzopyrano(3,2 -b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - diethoxy - 6ss methyl -6&alpha; - ethyl -5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - diisopropoxy 6,6 - dimethyl - 5aH,13H, (1)benzopyrano(3,2 -b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - diisopropoxy butoxy - 6ss - methyl -6&alpha; - isopropyl - 5aH,13H - (1)benzopyrano(3,2 b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dihydroxy 6,6 - dimethyl - 5aH,13H, (1)benzopyrano(3,2 -b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - didicyano - 6ss methyl -6&alpha; - ethyl -5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - spiro[5aH,13H (1)benzopyrano(3,2 -b)xanthene -6,1' - cyclohexan] - 13 - one; (5a,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - spiro[5aH,13H (I)benzopyrano(3,2 - b)xanthene - 6,1' - cyclopentan] - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dimethylspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexan] 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 dimethoxyspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' cyclohexyn] - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,9 diethoxyspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' cycloheptan - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dihydroxyspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' cyclohexan] - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;,) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dichlorospiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' cyclopentan] - 13 - one; (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 2,10 dibromospiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' cyclopentan] - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - spiro[5aH,13H (1)benzopyrano(3,2 - b)xanthene - 6,1' - cyclopentan] - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - spiro[5aH,13H (1)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexan] - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dimethylspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexan] 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 diethylspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' - cycloheptan] 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 dimethoxyspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 diethoxyspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexan] 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dihydroxyspiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' cycloheptan] - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 dicyanopsiro[5aH,13H - (1)benzopyrano(3,2 - b(xanthene - 6,1' - cycloheptan] 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dichlorospiro[5aH,13H - (1)benzopyrano(3,2 - b)xanthene - 6,1' - cyclohexan] 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dichloror - 6ss methyl - 6&alpha; - isopropyl - 5aH,13H - (1)benzopyrano - (3,2 - b)xanthen - 13 one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - difluoro - 6,6 dimethyl - 5aHm13H - (1)benzopyrano(3,2 - b) - xanthen - 13 - one; (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 2.10 - dibromo 6,6 - dimethyl - 5aH,13H - (1)benzopyrano(3,2 - b) xanthen - 13 - one.

The Saa,6aa - dihydropyranoxanthenones of Formula V and the hexahydropyranoxanthenones of Formula VI possess the characteristics of exerting an anti-androgenic response when administered at a dose range from 0.05 mg. to 100 mg. per kg. of body weight. They therefore are useful in treating or alleviating androgen-caused or androgen-dependent conditions such as benign prostatic hypertrophy, acne and prostatic cancer.

The compounds of this invention can be administered orally in the form of tablets, capsules, elixirs, and the like. They can also be administered by parenteral injection. In addition, they can be administered in the form of suppositories and lotions. In tablet form, they are compounded with an inert pharmaceutical carrier which may contain a suitable binder such as, for example, gums, starches, and sugars. They may also be incorporated into gelatin capsules or formulated into elixirs which have the advantage of being susceptible to flavoring by the addition of standard natural or synthetic flavoring agents. Administration may also be achieved in the form of aqueous parenteral suspensions.

Compounds of this invention effectively produce an anti-androgenic effect at 0.05 mg. to 100 mg./kg body weight on a daily basis. Preferably, these formulations are so proportioned as to afford a unit dosage of from 1 to 500 mg. of active compound. Particularly preferred unit dosages are those ranging from 50 to 250 mg. Preferably, the compounds are administered orally.

The anti-androgen activity of the compounds of this invention is demonstrated by a standard in vivo rat assay utilizing castrate immature male rats.

The assay is routinely conducted using immature male rats, usually 21 days old, which have been bi-laterally castrated and left untreated for three days. This provides adequate time for metabolism of endogenous androgens and for atrophy of the secondary sex organs to begin. The castrate rats then are divided into at least three treatment groups. Ten rats are injected subcutaneously once each day with 0.02 mg. of testosterone propionate (TP) suspended in corn oil. These rats serve as an androgen-stimulated control group. Another group of five rats is injected subcutaneously once each day with the corn oil vehicle, and these serve as a castrate control group. The third treatment group consists of five rats, each of which receives 0.02 mg. of TP subcutaneously and an experimental compound either orally or subcutaneously once each day. A separate experimental group is used for each compound and for each dose level tested. All animals are treated for seven consecutive days. On the eighth day, all rats, usually now 28 days old, are sacrificed and autopsied. At autopsy, the seminal vesicles (SV) and ventral prostate (VP) glands are removed and weighed.

The weights of the SV and VP of the castrate control group are subtracted from those of the androgen-stimulated group to determine the androgen stimulation resulting from exogenous TP administration. The SV and VP weights of each experimental group are subtracted from those of the androgen-stimulated group, and the difference is divided by the increase in organ weight resulting from TP treatment alone. These differences are expressed as percent inhibition.

The effect of the adminstered compound upon the stimulatory effect of exogenous TP is evidenced by the failure of the weighed endocrine glands to increase in weight at the rate indicated for the TP stimulated rats which do not receive any of the experimental compound.

The Table following demonstrates the androgen-inhibiting activity of the compounds of this invention.

TABLE Anti-Androgen Activity

Test Compound Change, % Group R R1 R2 Stereoconfiguration Dose, mg/day VP SV 1 H CH3 CH3 Dihydro; 5a&alpha;,6a&alpha; 0.03(s.c.) -62 -75 1 2,10-Di-OCH3 CH3 CH3 Dihydro; 5a&alpha;,6a&alpha; 0.03 (s.c.) - 68 -64 1 3,9-Di-OCH3 CH3 CH3 Dihydro; 5a&alpha;,6a&alpha; 0.03(s.c.) -71 -82 1 4,8-Di-OCH3 CH3 CH3 Dihydro; 5a&alpha;,6a&alpha; 0.03(s.c.) -69 -70 1 4,8-Di-OH CH3 CH3 Dihydro; 5a&alpha;,6a&alpha; 0.10(s.c.) -45 -56 1 H CH3 CH3 Hexahydro; 5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(s.c.) -80 -86 1 2,10-DI-OPCH3 CH3 CH3 Hexahydro 0.03(s.c.) -78 -87 1 3,9-Di-OCH3 CH3 CH3 Hexahydro 0.03(s.c.) -83 -73 1 4,8-Di-OCH3 CH3 CH3 Hexahydro; 5a&alpha;,6a&alpha;,12ass,13ass 0.10(s.c.) -47 -44 1 4,8-Di-OH CH3 CH3 Hexahydro; 5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.10(s.c.) -26 -50 1 4,8-Di-OCH3 CH3 CH3 Hexahydro; 5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(s.c.) -77 -74 2 2,10-Di-OCH3 CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -14 -17 2 3,9-Di-OCH3 CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -14 -18 2 3,9-Di-OCH3 CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12ass,12ass 0.03(oral) -20 -18 2 4,8-Di-OCH3 CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) +6 +10 2 4,8-Di-OCH3 CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -49 -40 3 4,8-Di-OH CH3 CH3 Dihydro;5a&alpha;,6a&alpha; 0.03(oral) -54 -63 3 4,8-Di-OH CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -58 -60 3 4,8-Di-OCH3 CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -56 -49 4 4,8-Di-OC2H5 CH3 CH3 Dihydro;5a&alpha;,6a&alpha; 0.03(oral) -45 -55 4 4,8-Di-OC2H5 CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -40 -44 4 4,8-Di-OCH3 CH3 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -49 -50 5 H C2H5 CH3 Dihydro;5a&alpha;,6a&alpha; 0.03(oral) -61 -63 5 H C2H5 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -50 -34 5 4,8-Di-OCH3 C2H5 CH3 Dihydro;5a&alpha;,6a&alpha; 0.03(oral) -57 -60 5 4,8-Di-OCH3 C2H5 CH3 Hexahydro;5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -66 -63 5 H -C5H10- Dihydro;5a&alpha;,6a&alpha; 0.03(oral) -53 -56 5 H -C5H10- Hexahydro; 5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -58 -45 5 4,8-Di-OCH3 CH3 CH3 Hexahydro; 5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; 0.03(oral) -72 -71 Footnotes.

1. Designates those compounds tested during a particular run. Since the sensitivity of this assay varies from one run to another, the potency of a given compound should be compared to that of others in the same run. For this purpose, 6,6a&alpha;,12,12a&alpha;,13a&alpha;,14 - hexahydro - 4,8 - dimethoxy 6,6 - dimethyl - 5a&alpha;H,13H - (1)benzopyrano(3,2 - b)xanthen - 13 - one is employed as standard and appears in each test group.

2. s.c.-subcutaneous.

3. Mixture of Hexahydro epimers (a) 6a&alpha;,6a&alpha;,12a&alpha;,13a&alpha; and (b) 5a&alpha;,6a&alpha;,12ass,13ass.

The following are provided to illustrate preparations of starting compounds.

Preparation A. 4,4-Dimethyl-2-cyclohexenone A mixture of 743 ml (630 g, 8 moles) of freshly distilled methyl vinyl ketone and 1250 ml (940 g, 13.7 moles) of isobutyraldehyde was prepared in a 3 L. flask.

Over a period of two minutes 9 ml. of conc. sulfuric acid were added to the mixture. The mixture was stirred magnetically and was cooled with an ice water bath to maintain an intertnal temperature of 45-50 C. After one hour the bath was removed, and the mixture was refluxed through a Dean-Stark trap for three hours. The mixture then was distilled through a short Vigreaux column at 15 mm. pressure. The main fraction, b13 70-77 C., was fairly pure product, possibly containing a small amount of isobutyraldehyde. Yield: 751 g (67%). Redistillation gave a sharper boiling product (bl5 74--79"C.), free of isobutyraldehyde.

Preparation B. 4,4-Dimethyl-2,5-cyclohexadienone Method a. Using 2,3-dichloro-5,6-dicyanobenzoquinone.

To 1.5 liters of toluene were added 134.9 g (1.1 moles) of 4,4 - dimethyl - 2 cyclohexenone and 249 g (1.21 moles) of 2,3 - dichloro - 4,5 dicyanobenzoquinone (DDQ). The resulting mixture was refluxed under nitrogen for 3.5 hours. During this time a precipitate of 2,3 - dichloro - 4,5 dicyanohydroquinone (DDH) was deposited from the initially dark red solution.

The reaction mixture then was cooled, and the DDH was collected by filtration. A major portion of the toluene was removed by rotary evaporation, and the resulting residue was dissolved in ether. The ether solution was washed with IN sodium hydroxide several times until the washings were clear and then was washed with water. After drying, the ether solution was concentrated to provide the crude title compound. Distillation of the product provided 82.6 g of pure title compound, b.p. 58dl"C./5 mm.

Method b. Indirect Sequence 1. 2-Acetoxy-5,5-dimethyl- 1 ,3-cyclohexadiene To a solution of 465 g (3.75 moles) of 4,4 - di - methyl - 2 - cyclohexenone in 1.5 liters of isopropenyl acetate were added 6 g of p-toluenesulfonic acid. Acetone slowly was distilled from the mixture overnight (about 16 hours) through a 14 inch Vigreaux column. The temperature then was increased to remove by distillation the bulk of the remaining isopropenyl acetate. The resulting mixture then was distilled at reduced pressure to yield 484 g of crude title compound, b.p.

45--65"C./4 mm. The product was purified by redistillation to obtain pure title compound, b.p. 8840C./7 mm.

2. 6-Bromo-4,4-dimethyl-2-cyclohexenone To a solution of 484 g (2.92 moles) of 2 - acetoxy - 5,5 - dimethyl - 1,3 cyclohexadiene in 4 liters of carbon tetrachloride were added 421 g (2.92 moles) of N - bromosuccinimide (NBS) followed by 0.5 grams of azo-bis-isobutyronitrile (AIBN). The resulting mixture was stirred and refluxed for 2 hours. After cooling, the major portion of the carbon tetrachloride was removed in vacuo. The residue then was dissolved in ether, and the ether solution was washed twice with aqueous sodium bicarbonate solution. The ether solution then was dried over sodium sulfate, and the solvent was removed in vacuo. The resulting residue was distilled to give 396 g (68%) of the title compound, b.p. 9l020C./2mm.

3. 4,4-dimethyl-2,5-cyclohexadienone A solution of 218 g (1.09 moles) of 6 - bromo - 4,4 - dimethyl - 2 cyclohexenone in 1000 ml of dry hexamethylphosphoric triamide (HMPT) was heated at 800C. under nitrogen for 5 hours. After cooling, the mixture was added to 3 liters of NaCI solution. The product was extracted using four portions of ether. The ether extracts were washed twice with saturated NaCI solution. The ether was removed under vacuum, and the product was distilled, b,5 83--87"C.

Yield: 86 g (65%).

Preparation C. 4-Ethyl-4-methyl-2-cyclohexenone To 200 ml. of benzene were added 35.0 ml. (30.8 grams) of methyl vinyl ketone (freshly distilled at 400C./155 mm.) and 50.0 ml. (40.1 grams) of amethylbutyraldehyde. The mixture was cooled in an ice bath, and 0.5 ml. of concentrated sulfuric acid was added. The mixture slowly was brought to reflux over a one hour period and then was refluxed for three hours in a system containing a Dean-Stark water trap. The mixture then was added to an ice cold saturated sodium bicarbonate solution, and the total was extracted with ether.

The ether extract was separated and was washed with saturated aqueous sodium chloride and then was dried over sodium sulfate. The ether was removed using a rotary evaporator, and the residue was distilled at reduced pressure (6 mm.) to obtain 38.5 grams (64.6%) ofthe title compound, boiling point 73--78"C./7 mm. ir (CHCl3) 1668 cm-' (C=O); Amax (MeOH) 228 nm (E 16,050); nmr (CDCL3) a 0.92 (t, J=7Hz, 3H, Et), 1.12 (s, 3H, CH3), 1.51 (qt, J=7Hz, 2H, Et), 1.85 (mult, 2H, ss-CH2), 2.45 (t, J=7Hz, 2H, a-CH2), 5.84 (d, J=lOHz, 1H, p-CH), 6.68 (d, J=10Hz, 1H, &alpha;-CH).

Analysis, Calculated forC9R14O: C, 78.21; H, 10.21 Found: C, 77.97; H, 9.95 Preparation D. 4-Ethyl-4-methyl-2,5-cyclohexadienone To 300 ml. of toluene were added 35.0 grams (0.25 moles) of the product from Preparation C and 62.4 grams (0.275 moles) of 2,3 - dichloro - 4,5 dicyanobenzoquinone (DDQ). The resulting mixture was refluxed under nitrogen for four hours. The mixture then was cooled, and the 2,3 - dichloro - 4,5 dicyanohydroquinone (DDH) which was formed was collected by filtration. The filtrate was treated in a rotary evaporator to remove the major portion of the toluene. The resulting residue then was dissolved in ether, and the ether solution was washed several times with IN sodium hydroxide and then with

Example I (5&alpha;,6a&alpha;)-6,6a-Dihydro-6,6-dimethyl-5aH,13H-(1H)benzopyrano(3,2-b)xanthen-13- one A solution of 30 g (0.25 mole) of salicylaldehyde in 150 ml of benzene was cooled under nitrogen as it was treated first with 26.25 g (0.37 mole) of pyrrolidine, and then with 15 ml (0.25 mole) of acetic acid. After 15 min. at room temperature, 15 g (0.125 mole) of 4,4 - dimethyl - 2,5 - cyclohexadienone was added, and the mixture was 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 1M NaOH solution. After a final wash with saturated NaCl solution, the organic solution was dried over sodium sulfate. The solvent was removed, and the product was recrystallized from benzene-hexane. Yield after two recrystallizations: 18.6 g (46%), m.p. 211-213 C. ir (CHCl3) 1670 (C=O), 1623 cm-1 (C=O); #max (EtOH) 253 (# 12,400), 119 (# 13,300), 378 nm, (# 10,300), nmr (CDCl3) # 1.19 (s, 3H, 6&alpha;-CH3), 1.49 (s, 3H, 6ss CH3), 4.89 (d, J=2.3 Hz, 2H, 5a-H and 6a-H), 7.07 (m, 8H, Ar-H), 7.60 (d, J=2.3 Hz, 2H, 12-H and 14-H).

Analysis, Calculated for C22H1O3: C, 79.98; H, 5.49.

Found: C, 79.76; H, 5.69.

Example 2 (5a&alpha;,6a&alpha;, 12a&alpha;,13a&alpha;)-6,6a,12a,13a,14-Hexahydro-6,6-dimethyl-5aH,13H- (1)benzopyrano(3,2-b)xanthen-13-one A solution of 4.0 g (12.1 mmoles) of the product of Example I in 500 ml. of ethyl acetate was hydrogenated over 4 g of Raney nickel [prepared according to the procedure of A.W. Burgstahler reported in L. Fieser and M. Fieser, Reagents for Organic Synthesis I, p. 729, John Wiley & Sons, Inc. (1967)] at 4(w600C. and at 60 p.s.i. for 5-12 hours. After filtering, the solvent was removed. The product was recrystallized from ethanol-water. Yield: 2.45 g (61%), m.p. 205-207 C. ir (CHCl3) 1732 cm-1 (C=O); #max (EtOH) 275 (# 4,300), 283 sh nm (# 3,500); nmr (CDCl3) # 1.37 (s, 3H, 6&alpha;-CH3), 1.56 (s, 3H, 6ss-CH3), 2.67 (broadended qt, J's=7 and 17 Hz, 2H, 12ss-H and 14ss-H), 3.24 (broadened qt. 2H, 12a-H and 13a-H), 3,34 (broadened d, J=17 Hz, 2H, 12&alpha;-H and 14&alpha;-H), 4.18 (d, J=2.8 Hz, 2H, 5a-H and 6a-H), 6.87 (m, 8H, Ar-H).

Analysis, Calculated for C22H22O3: C, 79.02; H, 6.63.

Found: C, 78.76; H, 6.63.

Example 3 (5a&alpha;-6a&alpha;)-6,6a-Dihydro-2,10-dimethoxy-6,6-dimethyl-5aH,13H- (1)benzopyrano(3,2-b)xanthen-13-one A solution of 12.5 g (82 mmoles) of 5-methoxysalicylaldehyde in 100 ml of benzene was cooled as 8.73 g (123 mmoles) of pyrrolidine followed by 4.92 g (82 mmoles) of acetic acid were added. After stirring the mixture at room temperature for several minutes, 5.0 g (41 mmoles) of 4,4 - dim ethyl - 2,5 cyclohexadienone were added. The mixture then was heated under nitrogen at 600C. overnight after which it was added to ice water, and the resulting organic layer was separated. The organic layer then was washed successively with dilute acetic acid, several times with dilute sodium hydroxide, and then with sodium chloride solution. 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 to afford 3.75 g (23%) of the title compound, m.p. 219-220 C. ir (CHCl3) 1663 (C=O), 1620 cm-1 (C=C); #max (EtOH) 221 (# 36,200), 336 (# 20,400), 472 (# 11,600), 453 sh nm (# 11,400); nmr (CDCl3) # 1.18 (s, 3H, 6&alpha;- CH3), 1.48 (s, 3H, 6ss-CH3), 3.76 (s, 6H, OCH3), 4.83 (d,J=2.1 Hz, 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, Calculated forC241122O5: C, 73.83; H, 5.68.

Found: C, 73.95; H, 5.88.

Example 4 (5a&alpha;,6a&alpha;)-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 mmoles) of 4 - methoxysalicylaldehyde in 100 ml of benzene was prepared. The solution was cooled, and 10 g (141 mmoles) of pyrrolidine and 5.66 g (94.4 mmoles) of acetic acid were added. After several minutes, 5 g (41 mmoles) of 4,4 - dimethyl - 2,5 - cyclohexadienone were added.

The solution then was warmed under nitrogen at 550C. overnight. The resulting reaction mixture then was added to ice water, and the organic layer was separated. The organic layer then was washed successively with dilute acetic acid, several times with dilute sodium hydroxide, and then with sodium chloride solution. The organic layer was dried over sodium sulfate, and the solvent was removed. The residue was recrystallized from a mixture of benzene and hexane and chromatographed on magnesium silicate, eluting with benzene, to obtain 1.5 g of the title compound, m.p. 222210C. ir (CHCl3) 1660 (C=O), 1608 cm-l (C=C); Amax (EtOH) 213 (E 38,400), 276 (r 16,900), 460 (E 23,900), 446 sh nm (E 22,800); nmr (CDCl3) a 1.18 (s, 3H, 6a-CH3), 1.49 (s, 3H, 6p-CH3), 3.82 (s, 6H, 0CM3), 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, 12-H and 14-H).

Analysis, Calculated for C24H22O5: C, 73.83; H, 5.68.

Found: C, 73.79; H, 5.78.

Example 5 (5a&alpha;,6a&alpha;)-6,6a-Dihydro-4,8-dimethoxy-6,6-dimethyl-5aH,13H- (1)benzopyrano(3,2-b)xanthen-13-one A solution of 100 g (0.66 mole) of 3-methoxysalicylaldehyde in 800 ml. of benzene was cooled under nitrogen as it was treated first with 80 g (1.15 mmoles) of pyrrolidine, and then with 60 g (1.0 mole) of acetic acid. After 15 minutes at room temperature, 40 g (0.33 mole) of 4,4 - dimethyl - 2,5 - cyclohexadienone were added, and the mixture was heated at 55--600C. overnight. After 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 1M sodium hydroxide solution. After a final wash with saturated sodium chloride solution, the organic solution was dried over sodium sulfate. The solvent was removed, and the product was recrystallized from a mixture of benzene and hexane to afford 43 g (33%) of the title compound, m.p. 239--241"C. ir (CHCl3) 1664 (C=O), 1619 cm-' (C=C); Amax (EtOH) 225 (E 35,400), 358 (E 18,300), 436 (E 8,300), 454 sh nm (E 6,500); nmr (CDCl3) a 1.26 (s, 3H, 6a-CH3, 1.61 (s, 3H, 6ss-CH3), 3.88 (s, 6H, 0CM3), 4.94 (d, J=2.3 Hz, 2H, 5a-H and 6a-H), 6.86 (s, 6H, Ar-H), 7.59 (d, J=2.3 Hz, 2H, 12-H and 14-H).

Analysis, Calculated for C24H22O5: C, 73.83; H, 5.68.

Found: C, 73.79; H, 5.62.

Example 6 (5acz,6acr, 1 2aa, I 3a)-6,6a, 12,1 2a, 1 3a, 14-Hexahydro-2, 1 0-dimethoxy-6,6 dimethyl-5aH,1 3H-( 1 )benzopyrano(3,2-b)xanthen- 13-one A solution of 1.0 g (2.56 mmoles) of the product of Example 3 in ethyl acetate was hydrogenated over Raney nickel for 24 hours. The mixture was filtered, and the filtrate was evaporated to accomplish removal of the solvent. The resulting residue was recrystallized twice from a mixture of methanol and water. The dried product, m.p. 174-178 C., weighed 0.59 g (58%). Analysis of the product by NMR indicated that it was a mixture of epimers of the title compound as well as some product which had been over-reduced to the corresponding alcohol.

A portion of the above product (0.35 g) was stirred overnight in 10 ml. of methylene chloride containing 0.3 g of pyridinium chlorochromate under nitrogen. To the mixture then were added 10 ml. of benzene, and the mixture was stirred for an additional 1 hour. The mixture then was filtered, and the solid which was collected was thoroughly washed with benzene which was added to the filtrate. The solvent in the filtrate was removed, and the resulting residue was dissolved in ethyl acetate. The ethyl acetate solution then was passed through a short magnesium silicate column. The effluent solvent was removed, and the resulting residue was recrystallized from a mixture of benzene and hexane to obtain 0.18 g (51%) of dried, slightly impure title compound.

A six foot long, 5/8" diameter high pressure liquid chromatography (HPLC) column was packed dry with about 150 grams of 10-20 silica gel. The column was ewuilibrated with a 20:80 mixture of tetrahydrofuran (THF) and issoctane.

Portions (about 30 mg.) of the above, slightly impure product in methylene chloride were added to the column. A total of 173 mg. of the product was passed through the column in 7 runs. A total of 137 mg., representing an overall yield of 30%, of dried, purified title compound was collected after crystallization of the product from hexane, m.p. 207-207.5 C. ir (CHCl3) 1727 cm-1 (C=O); #max (MeOH) 229 nm (# 13,800); nmr (CDCl3), #1.37 (s, 3H, 6&alpha;-CH3), 1.52 (s, 3H, 6ss-CH3), 2.68 (broadened qt, J's=7 and 17 Hz, 2H, 12ss-H and 14ss-H), 3.23 (broadened qt, 2H-H and 13a-H), 3.30 (broadened d, J=17 Hz, 2H, 12&alpha;-H and 14&alpha;-H), 3.67 (s, 6H, OCH3), 4.12 (d, J=2.7 Hz, 2H, 5a-H and 6a-H), 6.57 (m, 6H, Ar-H).

Analysis, Calculated forC24H26O5: C, 73.08; H, 6.64.

Found: C, 72.84; H, 6.70.

Example 7 (5a&alpha;,6a&alpha;,12ass,13ass)-6,6a,12,12a,13a,14-Hexahydro-3,9-dimethoxy-6,6-dimethyl- 5aH,13H-(1) benzopyrano(3,2-b)xanthen-13-one and (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)- 6,6a,12,12a,13a,14-Hexahydro-3,9-dimethoxy-6,6-dimethyl-5aH,13H (1)benzopyrano(3,2-b)xanthen-13-one Employing the hydrogentaion procedure of Example 6, 0.5 g (12.8 mmoles) of (5a&alpha;,6a&alpha;) - 6,6a-dihydro - 3,9 - dimethoxy - 6,6 - dimethyl - 5aH,12H - (1) benzopyrano(3,2 - b)xanthen - 13 - one was reduced over Raney nickel in ethyl acetate. The mixture was filtered, and the solvent was removed in vacuo. The resulting yellowisch residue was recrystallized twice from a mixture of ethanol and water. The yield of dried product, m.p. 217 C, was 0.31 g (61%). NMR analysis of the dried product indicated that it was a mixture of the above titel compounds in a ratio of about 1:4, respectively.

Analysis, Calculated for C24H26O5; C, 73.08; H, 6.64.

Found: C, 73.23; H, 6.40.

A six foot long, 5/8" diameter HPLC column was packed dry with about 150 grams of 10-20 silica gel. The column then was equilibrated with a 30:70 mixture of THF and isooctane. Using the system at a flow rate of 5-6 ml./min. at about 300 psig. the above mixture was separated. The mixture was placed on the column in portions of about 10-15mg. dissolved in about 0.75 ml. of THF. In all, six runs made totalling about 70 mg. The two purified components were crystallized from hexane, collected, and dried. There was obtained 15 mg. (13% yield overall) of the &alpha;,&alpha;,ss,ss compound, m.p. 219 C., and 44 mg. (38% yield overall) of the &alpha;,&alpha;,,&alpha;,&alpha; compound, m.p. 230-231 C.

&alpha;,&alpha;,ss,ss compound-ir (CHCl3) 1727 cm-1 (C=O); #max (MeOH) 283 (# 7,800), 289 nm (# 7,400); nmr (CDCl3), # 1.32 (s, 3H, 6&alpha;-CH3), 1.47 (s, 3H, 6ss-CH3), 2.90 (m, 6H, H's at 12, 12a, 13a and 14), 3.54 (m, 2H, 5a-H and 6a-H). 3.77 (s, 6H, OCH3), 6,45 (d, J=2.5 Hz, 2H, 4-H and 8-H), 6.48 (qt, J's=2.5 and 9 Hz, 2H, 2-H and 10-H), 7.02 (d, J=9 Hz, 1-H and 11-H).

&alpha;,&alpha;,&alpha;,&alpha; compound-ir (CHCl3) 1727 cm-1(C=O); #max(MeOHJ) 284 (#, 6,500).

291 nm (# 6,000); nmr (CDCl3) # 1.39 (s, 3H, 6&alpha;-CH3), 1.55 (s, 3H, 6ss-CH3), 2.63 (broadened qt, J's=7 and 16 Hz, 2H, 12ss-H and 14ss-H), 3.23 (broadened qt, 2H, 12a-H and 13a-H), 3.26 (broadened d, J=16 Hz, 2H, 12&alpha;-H and 14&alpha;-H), 3.69 (s, 6H, OCH3), 4.18 (d, J=2.8, 2H, 5a-H and 6a-H), 6.27 (d, J=2.5 Hz, 2H, 4-H and 8-H), 6.36 (qt, J's=2.5 and 8 Hz, 2H, 2-H and 10-H), 6.91 (d, J=8 Hz, 2H, I-H and Il-H).

Example 8 (5a&alpha;,6a&alpha;)-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. mmoles) of (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 4,8 dimethoxy - 6,6 - dimethyl - 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 one from Example 5 in 100 ml of methylene chloride was stirred under nitrogen with ice-methanol cooling. A solution of 5 ml of boron tribromide was added dropwise over a 10 minute period. The bath then was removed, and the resulting intense violet mixture was stirred overnight: The mixture was added to ice water. Ethyl acetate was added, and the two phases were vigorously stirred for about one hour. The organic layer was separated. 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 water to obtain the title compound.

Yield: 3.59 g (77%), m.p. > 230 C. dec. ir(KBr) 1660(C=O), 1613 cm-1 (C=C); #max (MeOH) 223 (# 41,600), 363 (# 24,050), 433 sh (# 10,100), 455 sh nm (# 8,000); nmr (DMSO-d6) # 1.14 (s, 3H, 6&alpha;- CH3), 1.61 (s, 311, 6p-CH3), 4.98 (d, J=2.0 Hz, 2H, 5a-H and 6a-H), 6.88 (s, 6H, Ar H), 7.57 (d, J=2.0 Hz, 211, 12-H and 14-11), 9.27 (s, 2H; OH).

Analysis, Calculated for C22H18O5: C, 72.92; H, 5.01.

Found: C, 72.66; H, 5.23.

Example 9 (5aa,6aa, 12aa,13aa)-6,6a,12, 12a, 13a, 14-Hexahydro-4,8-dihydroxy-6,6-dimethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one A solution of 1.0 gram of the product of Example 8 was dissolved in ethyl acetate and was hydrogenated over 1 gram of freshly prepared Raney nickel.

Hydrogenation was carried out for one hour at room temperature and at 60 psig.

The mixture was filtered, and the filtrate was evaporated to accomplish removal of the solvent. The resulting was crystallized from a mixture of benzene and ethyl acetate. The product was collected and recrystallized again from benzene-ethyl acetate to obtain 0.15 gram (about 15% yield) of the title compound, m.p. 194-198 C. ir (mull) 3520 (OH), 1720 cm-l (C=O); #max (MeOH) 277 (E 3,400), 283 nm 3,300); nmr (DMSO-d6) a 1.48 (s, 3H, 6a-CH3), 1.66 (s, 3H, 6ss-CH3), 2.86 (broadened qt, J's=7 and 13 Hz, 12p-H and 14ss-H), 3.36 (s, OH), 3.52 (broad m, 4H, 12a-H, 13a-H, and 14a-H, 4.26 (d, 2H, 5a-H and 6a-H), 6.59 (m, 6H, Ar-H).

Analysis, Calculated for C22H22O5: C, 72.12; H, 6.05.

Found: C, 71.91; H, 5.86.

Example 10 (5a&alpha;6a&alpha;)-6,6a-Dihydro-4,8-diethoxy-6,6-dimethyl-5aH,13H-(1) benzopyrano(3,2-b)xanthen-13-one A solution of 1.0 g (2.76 mmoles) of (5aa,6aa) - 6,6a - dihydro - 4,8 dihydroxy - 6,6 - dimethyl - 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one in 25 ml. of dry hexamethylphosphoric triamide (HMPT) was treated with 1 g (7.25 mmoles) of potassium carbonate and 2 ml. (2,9 g; 27 mmoles) of ethyl bromide. The mixture was heated under nitrogen at 70 C. overnight. After cooling, the mixture was poured into 200 ml. of cold water. The resulting product was collected and recrystallized twice from ethanol-water. There was obtained 0.54 g (47% yield) of the title compound, m.p. 211-213 C. ir(CHCl3) 1680 (C=O), 1635 cm-1 (C=C); #max (MeOH) 224 (# 41.200), 356 (# 19,800), 434 (E 9,100), 456 sh nm (E 7,200); nmr (CDCI3) 1.26 (s, 3H, 6a-CH3), 1.42 (t, J=7 Hz, 6H, OEt), 1.59 (s, 3H, 6ss-CH3), 4.06 (qt, J=7 Hz, 4H, OEt), 4,90 (d, J=2.3 Hz, 2H, 5a-H and 6a-H), 6.87 (m, 6H, Ar-H), 7.58 (d, J=2.3 Hz, 2H, 12-H and 14-H).

Analysis, Calculated for C26H26O: C, 74.62; H, 6.26.

Found: C, 74.92; H, 6.51.

Example 11 (5aa,6aa, 1 2aa, 1 3aa)-6,6a, 12,1 2a, 1 3a, 1 4-Mexahydro-4,8-diethoxy-6,6-dimethyl- 5aH,13H-( l )benzopyrano(3,2-b)xanthen- 13-one A solution of 0.45 g of the product of Example 10 in ethyl acetate was hydrogenated over Raney nickel for 24 hours. The resulting mixture then was filtered, and the filtrate was evaporated to a pale yellow, solid residue. The resulting crude product was dissolved in 10 ml of methylene chloride. To the resulting solution then was added 0.3 grams of pyridinium chlorochromate, and the resulting mixture was stirred under nitrogen overnight. The resulting mixture then was 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 magnesium silicate column. Thin-layer chromatography (TLC) showed primarily one spot material with a very faint trace of two other components. The product was recrystallized from a mixture of benzene and hexane. The resulting product was collected and dried to afford 0.23 g (51%) of the title compound, m.p. 219-221 C. ir (mull) 1735 cm-1 (C=O); #max (MeOH) 277 (# 3,300), 282 nm (# 3,330); nmr (CDCl3) # 1.28 (t, J=7 Hz, 6Hz, OEt), 1.45 (s, 3H, 6&alpha;-CH3), 1.67 (s, 3H, 6ss-CH3).

2.73 (qt, J's=8 and 17 Hz, 2H, 12ss-H and 14ss-H), 3.32 (qt, J's=2.8 and 8 Hz, 2H, 12a-H and 13a-H), 3.40 (d, J=17 Hz, 2H, 12&alpha;-H and 14&alpha;-H), 4.03 (m, 4H), OEt), 4.16 (d, J=2.8 Hz, 2H, 5a-H and 6a-H), 6.68 (m, 6H, Ar-H).

Analysis, Calculated for C26H30O5: C, 73.91; H, 7.16.

Found: C, 73.98; H, 7.10.

Example 12 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,12a,13a,14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one A mixture of 200 g of (5a,6acr) - 6,6a - dihydro - 4,8 - dimethoxy - 6,6 dimethyl - 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one in 3.7 liters of tetrahydrofuran (THF) was hydrogenated at an initial hydrogen pressure of 50-60 psi and at 50-60 C. for 24 hours in the presence of 100 g of PtO2. The reaction mixture then was cooled, and the catalyst was removed by filtration and washed well with methylene chloride. The methylene chloride wash was added to the filtrate, and the filtrate was concentrated in vacuo. The resulting residue was triturated with hexane to provide the hexahydro compound in which the carbonyl group in the 13-position had been reduced to a hydroxyl. The product was recovered as a crude colorless solid. Upon recrystallization from toluene-hexane, pure compound was obtained, m.p. 180-181 C. ir (CHCl3) 3550 cm-1 (OH); nmr (CDCl3) # 1.12 (s, 3H), 6&alpha;-CH3),1.66 (s, 3H, 6ss-CH3), 2.35 (broadened qt, J's=2 and 8 Hz, 2H, 12a-H and 13a-H), 2.89 (d, J=17 Hz, 2H, 12&alpha;-H and 14&alpha;-H), 3.19 (broadened qt, J's=8 and 17 Hz, 2H, 12ss-H and 14ss-H), 3.80 (broad s, 9H, OCH3, 5a-H, 6a-H, and 13-H), 6.70 (mult, 6H, SAr-H).

Analysis, Calculated for C241128O3: C, 72.89; H, 6.88.

Found: C, 73.01; H, 6.71.

To a 12 liter flask containing 3 liters of methylene chloride were added 250 g (0.16 mole) of pyridinium chlorochromate. The resulting suspension was stirred vigorously, and 250 g (0.63 moles) of the above product in 4 liters of methylene chloride were added rapidly at room temperature and under a nitrogen atmosphere. The mixture was stirred for 24 hours. Toluene (3 liters) then was added followed by 300 grams of decolorizing carbon. The resulting mixture then was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure, and the concentrate was passed through a column (30 cm.x55 cm.) containing one kg. of silica gel packed with methylene chloride and eluted with methylene chloride. The eluant was concentrated under reduced pressure to yield crude title compound. The crude product was recrystallized from a mixture of methylene chloride and hexane to afford colorless needles (62% yield), m.p. 208-2090C. ir (mull) 1718 cm-1 (C=O); #max (EtOH) 275 (# 3.660), 280 nm (# 3,630); nmr (CDCl2) # 1.34 (s, 3H, 6&alpha;-CH3), 1.65 (s, 3H, 6ss-CH3), 2.68 (broadened qt, J's=7 and 17 Hz, 2H, 12ss-H and 14ss-H), 3.26 (broadened qt, 2H, 12a-H and 13a-H), 3.37 (broadened d, J=17 Hz, 2H, 2&alpha;-H and 14&alpha;-H), 3.77 (s, 6H, OCH3), 4.15 (d, J=2.8 Hz, 2H, 4a-H and 6a-H), 6.68 (s, 6H, Ar-H).

Analysis, Calculated for C24H26O5: C, 73.08; H, 6.64.

Found: C, 72.83; H, 6.81.

Example 13 5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,61,12,12a,13a,14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one A solution of 10 g (25.6 mmoles) of the product of Examples 5 in 1 liter of ethyl acetate was hydrogenated over 10 g of Raney nickel at 600C. and at 60 p.s.i. for two hours. After filtering, the solvent was removed. The residue was dissolved in 200 ml of methylene chloride, and the solution was stirred overnight under nitrogen with 6.0 g of pyridinium chlorochromate. The mixture was diluted with 200 ml. of benzene. After stirring for 30 min., the mixture was suction filtered through diatomaceous earth. The solvents were removed. The residue was passed through a short column of magnesium silicate and was eluted with benzene.

Crystallization of the product from benzene-hexane gave 7.1 g of a mixture determined by high pressure liquid chromatography (HPLC) to contain 70% of (Saa,6aa,12aa,l3aa) -6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethoxy - 6,6 dimethyl - 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one (1), 19% of (Saa,6a,12ap,13a) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethoxy - 6,6 dimethyl - 5aH,13H - (1)benzopyrano - (3,2 - b)xanthen - 13 - one (2) and 11% of (5a&alpha;m6q&alpha;,12a&alpha;,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dimethoxy 6,6 - dimethyl - 5aH,13H - (I)benzopyrano(3,2 - b)xanthen - 13 - one (3).

Further recrystallizations produced a mixture containing 90% of (1) and 10% of (2). m.p. of mixture: 206-2100C.

Example 14 (5a&alpha;,6a&alpha;,12ss,13ass)-6,6a,12,12a,13a,14-hexahydro-4,8-dimethoxy-6,6-dimethyl SaH ,1 3H-( I )benzopyrano(3,2-b)xanthen- 1 3-one The mother liquor obtained from the product purification in Example 13 and enriched in compounds (2) and (3) of Example 13 was purified by high pressure liquid chromatography (HPLC). A six foot long, 5/8 inch diameter HPLC column was packed dry with about 150 grams of 10-20 jt silica gel. The product mixture (100 mg.) was chromatographed in 6 separate portions using, as eluant, a 30:70 mixture of tetrahydrofuran and isooctane. By this method, the residual amounts of the title compound of Example 13 and other trace materials were removed. The fraction containing compounds (2) and (3) was rechromatographed, using as eluant, a 10:90 mixture of tetrahydrofuran and isooctane. The fraction containing the title compound was collected and evaporated. The residue was washed with hexane and dried overnight in vacuo to obtain 30 mg. of the title compound, m.p.

272-273 C. ir (KBr) 1720 cm-' (C=O); Amax (MeOH) 275 (E 3,500), 280 sh nm (E 3,300); nmr (CDCl3) â 1.40 (s, 3H, 6a-CH3), 1.57 (s, 3H, 6A-CH3), 2.97 (m, 6H, H's at 12, 12a, 13a, and 14), 3.54 (m, 2H, 5a-H and 6a-H), 3.85 (s, 6H, OCH3), 6.76 (m, 6H, Ar-H).

Analysis, Calculated for C24H26O5; C, 73.08; H, 6.64, Found: C, 73.34; H, 6.33.

Example 15 (5a&alpha;,6a&alpha;)-6,6a-Dihydro-6ss-methyl-6&alpha;-ethyl-5aH,13H-(1)benzopyrano(3,2 b)xanthen-l 3-one To 220 ml. of benzene were added with ice bath cooling 18.2 grams (149 mmoles) of salicylaldehyde, 13.3 grams of pyrolidine, and 8.9 grams of acetic acid.

To the resulting solution there were added 10.0 grams (73.5 mmoles) of 4 - ethyl 4 - methyl - 2,5 - cyclohexadienone. The resulting mixture was allowed to stir at 55 C. under nitrogen for a total period of five days. The mixture then was cooled and was poured into a large volume of ice water. The resulting organic layer was separated, washed twice with 1% aqueous acetic acid, three times with 1N sodium hydroxide, and once with saturated aqueous sodium chloride. The organic layer then was dried over sodium sulfate, and the benzene solvent was removed using a rotary evaporator. The residue was recrystallized from a mixture of benzene and hexane to obtain 4.6 grams (18.2%) of the title compound, m.p. 189-190 C. ir (mull) 1665 (C=O), 1622 cm-1 (C=C); # max (MeOH) 217 (# 35,800), 2.57 (# 11,700), 324 (E 13,800), 430 nm (E 11,800); nmr (CDCl3) â 1.03 (t, J=Hz, 3H, Et), 1.20 (s, 3H, CH3), 2.01 (qt, J=7Hz, 2H, Et), 5.07 (d, J=2Hz, 2H, 5a-H and 6a-H), 7.08 (m, 8H, Ar-H), 7.60 (d, J=2Hz, 2H, 12-H and 14-H).

Analysis Calculated for C23H,803: C, 80.21; H, 5.85.

Found: C, 80.48; H, 6.13.

Example 16 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6.6a,12,12a,13a,14-Hexahydro-6ss-methyl-6&alpha;-ethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one A solution of 1.0 gram (0.29 mmole) of the product from Example 15 in 49 ml. of tetrahydrofuran was hydrogenated over 0.5 grams of platinum dioxide at 50 p.s.i. and at room temperature for a total of 32 hours. The mixture was filtered, and the filtrate was evaporated in vacuo. The residue was chromatographed over silica gel using benzene as eluant. Crystallization from ether afforded 0.28 grams (27%) of the hexahydro compound having the carbonyl group in the 13-position reduced to a hydroxyl. The product was a colorless solid, m.p. 161-1620C.

Analysis, Calculated which the carbonyl group in the 13-position had been reduced to a hydroxyl, m.p.

222-223 C. ir (CHCI3) 3550 cm-' (OH); Amax (MeOH) 274 nm (E 2760).

Analysis, Calculated forC23H30O3: C, 73.15; H, 7.37.

Found: C, 72.91; H, 7.53.

To 6 ml. of acetic acid were added 400 mg. (0.98 mmole) of the above alcohol.

The mixture was cooled in an ice bath and then was treated with a previously chilled solution of 258 mg. of sodium dichromate dihydrate in 13 ml. of acetic acid. The mixture was maintained for 4 hours and then was poured into 150 ml. of cold water. The resulting precipitate was too fine to be collected; therefore, it was extracted with several portions of methylene chloride. The methylene chloride extract was dried over sodium sulfate, and the solvent was removed by evaporation. The residue was dissolved in a small portion of ethyl acetate and was placed on a small column of magnesium silicate. The product was collected; however, it would not crystallize. The product was chromatographed over silica gel using benzene as eluant. The recovered material was collected and recrystallized from a mixture of benzene and hexane to obtain the title compound as colourless crystals, m.p. 191-192 C. ir (CHCl3) 1733 cm-1 (C=O); #max (MeOH) 276 (# 3070), 281 sh nm (# 3030); nmr (CDCl3) # 1.11 (t, J=7Hz, 3H, Et), 1.64 (s, 3H, CH3), 1.90 (qt, J=7Hz, 2H, Et), 2.75 (broadened qt, J's=8+17Hz, 2H, 12p-H and 14p-H), 3.31 (broadened qt, J's=8+2.5 Hz, 2H, 12a-H and 13a-H), 3.39 (broadened d, J=17Hz, 2H, 12a-H and 14&alpha;-H), 3.78 (s, 6H, OCH3), 4.29 (d, J=2.5Hz, 2H, 5a-H and 6a-H), 6.68 (m, 6H, Ar-H).

Analysis, Calculated forC25R28O3: C, 73.51; H, 6.91.

Found: C, 73.28; H, 7.00.

Example 19 (5a&alpha;,6a&alpha;)-6,6a-Dihydrospiro[5aH,13H-(1)benzopyrano(3,2-b)xanthene-6,1'- cyclohexan]-1 3-one To 85 ml. of benzene were added 7.52 grams (61.6 mmoles) of salicylaldehyde, 5.5 grams of pyrrolidine, and 3.7 grams of acetic acid. The mixture was cooled, and 5.00 grams (30.8 mmoles) of 4 - cyclohexanespiro - 2,5 cyclohexadienone were added. The mixture then was allowed to stir for two days at 55 C nitrogen. The mixture then was cooled and was poured into a large volume of ice water. The resulting organic layer was separated and was washed twice with 1% aqueous acetic acid, three times with IN sodium hydroxide, and then with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, and the benzene was removed using a rotary evaporator. The residue was recrystallized from methanol; however, a considerable amount of product was retained in the mother liquor. The mother liquor therefore was concentrated, and the residue was chromatographed over silica gel using benzene as eluant. The combined product (recrystallized and chromatographed materials) then was recrystallized from a mixture of chloroform and methanol to afford 3.62 grams (32%) of the title compound, m.p. 162-163 C. ir (CHCl3) 1671 (C=C), 1622 cm-' (C=C); Amax (MeOH) 218 (E 35,800), 256 (E 9900), 322 (e 13,100), 388 nm (E 12,900); nmr (CDCl3) â 1.8 (broad m, 10H, CM2), 5.03 (d, J=2Hz, 2H, 5a-H and 6a-H), 7.1 (m, 8H, Ar-H), 7.53 (d, J=2Hz, 2H, 12-H and 14-H).

Analysis, Calculated for C25H22O3: C, 81.06; H, 5.99.

Found: C, 81.13; H, 6.12.

Example 20 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,12a,13a,14-Hexahydrospiro[5aH,13H- (I )Benzopyrano(3,2-b)xanthene-6. 1 '-cyclohexan]- 13-one A solution of 2.0 grams (0.55 mmoles) of the product from Example 19 in 97 ml. of tetrahydrofuran was hydrogenated over 1.0 gram of platinum dioxide at 50 p.s.i. and at room temperature for 16 hours. The catalyst was removed from the mixture by filtration, and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of benzene and hexane to obtain 1.10 grams (54 Ó) of the hexahydro compound in which the carbonyl group in the 13-position had been reduced to a hydroxyl, m.p. 236-238 C. ir (CHCl3) 3580 cm-' (OH); #max (MeOH) 277 nm (E 4150).

Analysis, Calculated for C25M28O3: C, 79.76; H, 7.50.

Found: C, 79.49; H, 7.68.

To 20 ml. of acetic acid was added 1.00 gram (2.66 mmole) of the above alcohol. The mixture was chilled in an ice bath, and a chilled solution of 0.70 gram (1.75 mmole) of sodium dichromate dihydrate in 35 ml. of acetic acid was added.

The mixture was maintained at room temperature for 4 hours and then was slowly poured into 500 ml. of cold water. The resulting precipitate was collected by filtration. The material then was dissolved in a small amount of ethyl acetate and was chromatographed over magnesium silicate using ethyl acetate as eluant. The ethyl acetate fractions were evaporated, and the residue was recrystallized from a mixture of benzene and hexane to afford 385 mg. (38%) of the title compound, m.p. 2260C. ir (mull) 1720 cm-' (C=O); Amax (MeOH) 274 (E 3450), 282 nm (E 3450).

Analysis, Calculated forC23R24O3: C, 80.18; H, 7.00.

Found: C, 80.43; H, 6.77.

Example 21 (Sacu,6ap)-6,6a-Dihydro-6,6-dimethyl-5aH ,1 3H-( I )benzopyrano(3,2-b)xanthen- 13 one A solution of 8.72 g (71.4 mmoles) of salicylaldehyde in 60 ml of benzene was cooled as 8.2 g (115 mmoles) of pyrrolidine were added followed by 4.7 g (77 mmoles) of acetic acid. After stirring for 15 minutes, 4.36 g (35.7 mmoles) of 4,4 dimethyl - 2,5 - cyclohexadienone were added, and the solution was stirred at 50 overnight under nitrogen. After cooling, the mixture was poured into cold water and extracted with benzene. The extracts were washed with dilute sodium hydroxide solution and then with sodium chloride solution. After drying the extract over sodium sulfate, the solvent was removed under vacuum. Two crops totalling 4.43 g of the Sacr,6aa-isomer were crystallized from the crude product mixture using benzene-hexane. The mother liquor was evaporated to dryness, and chromatographed on a column of 100 g of activity I silica gel eluting with benzene.

*Three main fractions were collected from the column. The first fraction contained another 0.18 g of pure Saa,6aa - isomer. The second fraction contained 0.97 g of a 1:2 mixture of Saa,6aa - isomer and title compound. The third fraction contained 0.66 g of pure title compound. This product was crystallized from hexane, m.p.

121-123 C. ir (CHCI3) 1670 (C=O), 1622 cm-' (C=C); nmr (CDCl3) a 1.32 (s, 6H, CH3), 4.79 (d, J=2Hz, 2H, 5a-H and 6a-H), 7.11 (m, 6H, Ar-H), 7.50 (d, J=2Hz, 2H, 12-H and 14-H).

Analysis, Calculated forC22H,803: C, 79.98; H, 5.49.

Found: C, 80.24; H, 5.61.

Example 22 (Sacr,6aa)-6,6a-Dihydro-6,6-dimethyl-SaH, I 3H-( I )benzopyrano(3,2-b)xanthen- 13 one A solution of 50 mg. of (5aa,6a/3) - 6,6a - dihydro - 6,6 - dimethyl 5aH,13H - (I)benzopyrano(3,2 - b)xanthen - 13 - one in 5 ml. of toluene was refluxed under nitrogen overnight. Analysis of a sample by thin-layer chromatography indicated that conversion to the title compound was complete.

The solvent was removed, and the residue was chromatographed over a short silica gel column, benzene being employed as eluant. The product (48 mg.) was recovered from the benzene eluant and was recrystallized from the mixture of benzene and hexane to afford 45 mg. of the title compound, m.p. 183--184"C. The product was again recrystallized from a mixture of benzene and hexane to afford pure title compound, m.p. 211-212 C.

Example 23 (5a&alpha;,6ass)-6,6a-Dihydro-4,8-dimethoxy-6,6-dimethyl-5aH,13H-(1) benzopyrano(3,2-b)xanthen-13-one A solution of 100 g (0.66 mole) of 3-methoxysalicylaldehyde in 800 ml of toluene was cooled as 60 g (0.85 mole) of pyrrolidine were added followed by 39.4 g (0.66 mole) of acetic acid. The mixture was cooled to < 0 and 40 g (0.33 mole) of 4,4 - dimethyl - 2,5 - cyclohexadienone were added. The mixture was stirred under nitrogen overnight and permitted 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 IM sodium hydroxide solution, several portions of 1M hydrochloric acid (until little color was extracted), three more portions of 1M sodium hydroxide, and one portion of saturated sodium chloride solution. During the course of these extractions, methylene chloride was added as cosolvent. After drying the organic solution over sodium sulfate, the solvents were removed in vacuo, leaving a crystalline residue which, after washing with hexane and air drying, weighed 14 g (11%), m.p.

175180 C. (tends to resolidify almost immediately). Spectral examination of the product revealed that it was nearly pure title compound contaminated with less than 5% Saa,6aa - isomer. Efforts to remove this contaminant by cautious recrystallization from benzene-hexane were unsuccessful. ir (CHCl3) 1665 (C=O), 1620 cm-1 (C=C); #max (EtOH) 223 (# 45,400), 350 nm (# 24,400); nmr (CDCl3) # 1.39 (s, 6H, CH3), 3.86 (s, 6H, OCH3), 4.82 (d, J=2Hz, 2H, 5a-H and 6a-H), 6.90 (s, 6H, Ar-H), 7.51 (d, J=2Hz, 2H, 12-H and 14 H).

Analysis, Calculated for C24H220: C, 73.83; H, 5.68.

Found: C, 73.97; H, 5.76.

Example 24 (5a&alpha;,6a&alpha;)-6,6a-Dihydro-4,8-dimethoxy-6,6-dimethyl-5aH,13H-(1) benzopyrano(3,2-b)xanthen-13-one A solution of 100 mg. of (Saa!,6ajB) - 6,6a - dihydro - 4,8 - dimethoxy - 6,6 dimethyl - 5aH,13H - (I)benzopyrano - (3,2 - b)xanthen - 13 - one in 5 ml. of benzene was refluxed under nitrogen overnight. Analysis of a sample by thin-layer chromatography indicated that the reaction was complete. The solvent was removed, and the residue was chromatographed over a short silica gel column using a mixture of 10% ethyl acetate in benzene as eluant. The product (89 mg.) was recovered from the eluant and was recrystallized twice from a mixture of benzene and hexane to afford the title compound, m.p. 237-239 C.

Example 25 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,12a,13a,14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one To 75 ml. of acetonitrile containing 5 percent water were added 15.0 grams of tributylamine p-toluenesulfonate and 4.0 grams of benzoic acid. To the resulting mixture were added 1.0 grams of (Saa,6aa) - 6,6a - dihydro - 4,8 - dimethoxy 6,6 - dimethyl - 5aH,13H - (I)benzopyrano(3,2 - b)xanthen - 13 - one. The solubility of the substrate at 250C. is about 45 mg./ml.; therefore, the substrate remained in the mixture as a suspension. The mixture was placed in the cathode compartment of an electrolytic cell comprising a mercury-pool cathode and a platinum anode. A -1.6 volt potential vs. a saturated calomel reference electrode was applied to the cell, and electrolysis was continued until analysis by thin-layer chromatography indicated that the reaction was complete. The reaction mixture was removed from the electrolysis cell, and the solvent was removed. The residue was dissolved in ethyl acetate, and the resulting solution was washed sequentially three times with 1N hydrochloric acid, 3 times with saturated aqueous sodium bicarbonate, 3 times with 1N hydrochloric acid, twice with saturated aqueous sodium bicarbonate, and once with water. Analysis of the product by highpressure liquid chromatography (HPLC), indicated that approximately 65% of (5a&alpha;,6a&alpha;12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethoxy - 6,6 dimethyl - 5aH,13H - (1)benzopyrano - (3,2 - b)xanthen - 13 - one was formed.

The ethyl acetate was removed, and the product was dried. The product was crystallized from a mixture of methanol and chloroform to obtain approximately a 50% yield of the above compound in approximately 90% purity.

Example 26 (5a&alpha;,6a&alpha;,12ass,13ass)-6,6a,12,12a,13a,14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH-13H-(1)benzopyrano(3,2-b)xanthen-13-one Employing the procedure of Example 25, a mixture of 0.8 gram of lithium perchlorate and 4.0 ml. of glacial acetic acid in 75 ml. of acetonitrile containing 5% water was prepared. To the resulting mixture was added 1 gram of)5a&alpha;,6a&alpha;) 6,6a - dihydro - 4,8 - dimethoxy - 6,6 - dimethyl - 5aH, 13H (1)benzopyrano(3,2 - b)xanthen - 13 - one. The resulting mixture was subjected to electrolytic reduction at a mercury-pool cathode and platinum anode at 250C. and at constant -1.5 volt potential vs. a saturated calomel reference electrode.

Upon workup and crystallization from chloroform-methanol, (5a&alpha;,6a&alpha;,12ass,13ass) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethoxy - 6,6 dimethyl - 5aH,13H - (1)benzopyrano - (3,2 -b)xanthen - 13 - one was obtained as white to cream-colored platelets in approximately 65% yield. The product had a purity of approximately 92%. Melting point 235-245 C. (est).

Example 27 (5aa,6aa, 1 2aa, 1 3aa)-6,6a, 12,1 2a, I 3a, 14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one Employing the procedure of Example 25, to a mixture of 50 ml. ot N,Ndimethylformamide containing 5% water were added 2 g. of benzoic acid and an amount of tetrabutylammonium perchlorate sufficient to achieve a 0.2 M concentration. To the resulting mixture then were added 100 mg. of (5a&alpha;,6a&alpha;) 6,6a - dihydro - 4,8 - dimethoxy - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one. The resulting mixture was subjected to electrolytic reduction at a mercury-pool cathode at 250C. and at constant-1.6 volt potential vs. a saturated calomel reference electrode. Upon work up and crystallization, (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dimethoxy - 6,6 - dimethyl - 5aH,13H - (I) - benzopyrano(3,2 - b)xanthen 13 - one was obtained in approximately 70% yield.

Example 28 (5acu,6aa,l2acr,l 3aa)-6,6a,12,12a, 13a, 14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aG,13H-(1)benzopyrano(3,2-b)xanthen-13-one Employing the procedure of Example 25, to a mixture of 60 ml. of methanol and 4.9 ml. of glacial acetic acid was added an amount of tetrabutylammonium chloride sufficient to achieve a 0.1 M concentration. To the resulting mixture then were added 100 mg. of (5a&alpha;,6a&alpha;) - 6,6a - dihydro - 4,8 - dimethoxy - 6,6 dimethyl - 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 - one. The resulting mixture was subjected to electrolytic reduction at a mercury-pool cathode at 25 C. and at constant -1.4 volt potential vs. a saturated calomel reference electrode. Upon workup and crystallization, (5a&alpha;,6a&alpha;12a&alpha;,13a&alpha;) 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethoxy - 6,6 - dimethyl - 5aH,13H (1)benzopyrano - (3,2 - b)xanthen - 13 - one was obtained in approximately 85% yield.

Example 29 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12a,13a,14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one Employing the procedure of Example 25, a mixture of 2.57 grams of tetrabutylammonium perchlorate and 2.5 grams of benzoic acid in 50 ml. of toluene and 25 ml. of methanol was prepared. To the resulting mixture then were added 300 mg. of (Saa,6aa) - 6,6a - dihydro - 4,8 - dimethoxy - 6,6 - dimethyl 5aH,13H - (l)benzopyrano(3,2 - b) - xanthen - 13 - one. The resulting mixture was subjected to electrolytic reduction at a mercury-pool cathode at 250C. and at constant -1.6 volt potential vs. a saturated calomel reference electrode. Upon workup and crystallization, (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 hexahydro - 4,8 - dimethoxy - 6,6 - dimethyl - 5aH,13H - (l)benzopyrano(3,2 b)xanthen - 13 - one was obtained in approximately 65% yield.

Example 30 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,12a,13a,14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one Employing the procedure of Example 25, to a mixture of 75 ml. ofacetonitrile containing 5% acetic acid and 5% water was added an amount of tetra - n hexylammonium chloride sufficient to achieve a 0.1 M concentration. To the resulting mixture then were added 200 mg. of (Saa,6aa) - 6,6a - dihydro - 4,8 dimethoxy - 6,6 - dimethyl - 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 one. The resulting mixture was subjected to electrolytic reduction at a mercurypool cathode at 250C. and at constant -1.7 volt potential vs. a saturated calomel reference electrode. High pressure liquid chromatography (HPLC) indicated the presence of (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 4,8 dimethoxy - 6,6 - dimethyl - 5aH,13H - (1)benzopyrano - (3,2 - b)xanthen 13 - one in approximately 6570% yield.

Example 31 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,12a,13a,14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH,13H-( l )benzopyrano(3,2-b)xanthen- 13-one Employing the procedure of Example 25, to a mixture of 75 ml. of acetonitrile containing 5% acetic acid was added an amount of methyltrioctylammonium chloride (aliquot 336) sufficient to achieve a 0.1 M concentration. To the resulting mixture then were added 200 mg. of (5aa,6aa) - 6,6a - dihydro - 4,8 dimethoxy - 6,6 - dimethyl - 5aH,13H - (l)benzopyrano(3,2 - b)xanthen - 13 one. The resulting mixture was subjected to electrolytic reduction at a mercurypoolcathode at 25 C. and at constant - 1,6 volt potential vs. a saturated calomel reference electrode. HPLC indicated the presence of (5a&alpha;,6a&alpha;,12a&alpha;,1&alpha;a) 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethoxy - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one in approximately 6570% yield.

Example 32 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,13a,14-Hexahydro-4,8-dimethoxy-6,6-dimethyl- 5aH,13H-(1)benzopyrano(3,2-b)xanthen-13-one Employing the procedure of Example 25, to a mixture of 67 ml. of acetonitrile containing 5% water and 1.5% acetic acid was added an amount of N,N diisopropylethylamine tosylate sufficient to achieve a 0.1 M concentration. To the resulting mixture then were added 100 mg. of (Saa,6aa) - 6,6a - dihydro - 4,8 Dimethoxy - 6,6 - dimethyl - 5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 one. The resulting mixture was subjected to electrolytic reduction at a mercurypool cathode at 250C. and at constant -1.5 volt potential vs. a saturated calomel reference electrode. HPLC indicated the presence of (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethoxy - 6,6 - dimethyl - 5aH,13H (1)benzopyrano(3,2 - b)xanthen - 13 - one in approximately 60-65% yield.

Example 33 (5a&alpha;,6a-Dihydro-3,9-dicyano-6,6-methyl-5aH,13H-(1)benzopyrano(3,2- b)xanthene-13-one The reaction scheme of Example I is followed in general to react 4cyanosalicylaldehyde with 4,4 - dimethyl - 2,5 - cyclohexadienone in the presence of pyrrolidine and acetic acid. The product is purified according to the scheme of Example 1 to obtain a substantial yield of the desired product.

Example 34 (5a&alpha;,6a-Dihydro-3,9-diethyl-6,6-dimethyl-5aH,13H-(1)benzopyrano(3,2- b)xanthen-13-one The process of Example 1 is followed generally in the reaction of 4ethylsalicylaldehyde and 4,4 - dimethyl - 2,5 - cyclohexadienone in the presence of pyrrolidine and acetic acid under nitrogen. The product is isolated and the crude product is recrystallized as described generally in Example I to obtain a worthwhile yield of the desired product.

Example 35 (5a&alpha;,6,6a-Dihydro-2,10-dichloro-6,6-dimethyl-5aH,13H- (1)benzopyrano(3,2-b)xanthen-13-one A solution of -5chlorsalicylaldehyde is treated with pyrrolidine and acetic acid and reacted with 4,4 - dimethyl - 2,5 - cyclohexadienone according to the general scheme of Example 1. Isolation and purification according to Example 1 produces an economical yield of the desired product.

Example 36 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,12a,13a,14-Hexahydro-3,9-dicyano-6,6-dimethyl- 5aH,13H-(1)benzopyrano-(3,2-b)xanthen-13-one The product of Example 33 is reduced according to procedures shown in the examplea above to prepare an economical yield of (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) 6,6a,12,12a,13a,14 - hexahydro - 3,9 - dicyano - 6,6 - dimethyl - 5aH,13H (1)benzopyrano(3,2-b)xanthen - 13 - one.

Example 37 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,12a,13a,14-Hexahydro-3,9-diethyl-6,6-dimethyl- 5aH,13H-(1)benzpüyrano(3,2-b)xanthen-13-one The reduction methods taught in the examples above are followed again to reduce the product of Example 34 and thereby prepare a substantial yield of (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 - hexahydro - 3,9 - diethyl - 6,6 dimethyl - 5aH,13H - (1)benzopyrano(3.2 - b)xanthen - 13 - one.

Example 38 (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;)-6,6a,12,12a,13a,14-Hexahydro-2,10-dichloro-6,6-dimethyl- 5aH,13H-(1)benzopyrano-(3,2-b)xanthen-13-one As taught in the examplea above, the product of Example 35 is reduced to prepare a substatial yield of (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) - 6,6a,12,12a,13a,14 hexahydro - 2,10 - dichloro - 6,6 - dimethyl - 5aH,13H - (1)benzopyrano (3,2 - b)xanthen - 13 - one.

Claims (37)

WHAT WE CLAIM IS:

1. A compound of the formula

wherein each R is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, cyano, or halo, and both R groups are identical and are symmetrically located;R1 is C1-C3 alkyl and R2 is methyl, or R1 and R2 taken together are-(-CH2-)-in which n is an integer from 4 to 6; and (1) Xc and Xd are hydrogen, and the combination of Xa and Ya and of Yb each represents a double bond, subject to the limitation that when R1 is C1-C3 alkyl and is other than methyl, Xc, Xd, and R1 are all in an &alpha;configuration; or (2) Xa, Xb, Xc, Xd, Ya, and Yb are hydrogen, subject to the limitation that both Xc and Xs are in an a-configuration, both Xa and Xb are in an a-configuration or in a p-configuration, and, R1, when it is C1-C3 alkyl, is in an a- configuration.

2. A compound of Formula I of claim I wherein the combination of Xa and Ya and of Xb and Yb each represents a double bond.

3. A compound of Formula I of either of claims I or 2 wherein Xc and Xd are trans to each other.

4. A compound of Formula I of either of claims I or 2 wherein Xc and Xd are cis to each other.

5. A compound of Formula I of claim 1 wherein Xa,Xb,Xc,Xd, Ya and Yb are hydrogen.

6. A compound of Formula I of either of claims 1 or S wherein Xa and Xb are in an a-configuration.

7. A compound of Formula I of either of claims 1 or S wherein X a and Xb are in a ss-configuration.

8. A compound of Formula I of any of claims 1-7 wherein R1 and R2 taken together are -(-CH2-)n-.

9. A compound of Formula I of any of claims 1-7 wherein R, is C1-C3 alkyl.

10. A compound of Formula I of claim 9 wherein R, is methyl.

11. A compound of Formula I of any of claims 8-10 wherein R is methoxy.

12. A compound of Formula I of any of claims 8-10 wherein R is hydroxy.

13. A compound of Formula I of any of claims 8-10 wherein R is ethoxy.

14. A compound of Formula I of any of claims 8-10 wherein R is cyano.

IS. A compound of Formula I of any of claims 8-10 wherein R is hydrogen.

16. The compound of Formula I of any of claims 11--15 wherein the R groups are located in the 3- and 9- positions.

17. The compound of Formula I of any of claims 11--15 wherein the R groups are located in the 4- and 8- positions.

18. The compound of Formula I of any of claims 11-15 wherein the R groups are located in the 2- and 10- positions.

19. The compound of Formula I of claim 1 which is (Saa,6aa) - 6,6a dihydro - 6,6 - dimethyl - 5aH,13H - (1)benzopyrano(3,2 - b)xanthen - 13 one.

20. The compound of Formula I of claim 1 which is (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;), 6,6a,12,12a,13a,14 - hexahydro - 6,6 - dimethyl - SaH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one.

21. The compound of Formula I of claim 1 which is (Saa,6aa) - 6,6a dihydro - 4,8 - dimethoxy - 6,6 - dimethyl - SaH,13H - (l)benzopyrano(3,2 b)xanthen - 13 - one.

22. The compound of Formula I of claim I which is (Saa,6a/3) - 6,6a - dihydro - 4,8 - dimethoxy - 6,6 - dimethyl - 5aH,13H - (1)benzopyrano(3,2 b)xanthen - 13 - one.

23. The compound of Formula I of claim 1 which is (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) 6,6a,12,12a,13a,14 - hexahydro - 2,10 - dimethoxy - 6,6 - dimethyl - SaH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one.

24. The compound of Formula I of claim I which is (5a&alpha;,6a&alpha;) - 6,6a dihydro - 4,8 - dihydroxy - 6,6 - dimethyl - 5aH,13H - (l)benzopyrano(3,2 b)xanthen - 13 - one.

25. The compound of Formula I of claim 1 which is (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) 6,6a,i2,12a,13a,14 - hexahydro - 4,8 - dihydroxy - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one.

26. The compound of Formula I of claim I which is (5a&alpha;,6a&alpha;,12a&alpha;,13a&alpha;) 6,6a,12,12a,13a,14 - hexahydro - 4,8 - dimethoxy - 6,6 - dimethyl - 5aH,13H (I)benzopyrano(3,2 - b)xanthen - 13 - one.

27. A process for preparing a compound of Formula I which comprises reacting a 2-hydroxybenzaldehyde of the formula

wherein Ra is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, cyano or halo, with a 2,5cyclohexadiene of the formula

in the presence of pyrrolidine or a pyrrolidine mono- or disubstituted with chloro, bromo or C1-C3 alkyl groups, and a Cl-C, carboxylic acid, in an inert solvent, at a temperature from 0 C. to 65 C.. to form a dihydrobenzopyranoxanthenone of Formula I of the formula

wherein Ra, Rl and R2 are as defined above, and Xc and Xd are in either the a,a or a,/3-configuration; and, if a biologically active dihydrobenzopyranoxanthenone of Formula I is desired, and the reaction of the compounds of Formulae II and III was at a temperature below the ambient temperature, heating the compound of Formula IV to a temperature between the ambient temperature and 100"C. to prepare the corresponding compound of Formulae I and IV of the formula

wherein Ra, Rl and R2 are as defined above, and Xc and Xd are in the a,a- configuration; and, if a compound of Formula I wherein R is hydroxy is desired, reacting a compound of Formula V wherein Ra is Cl-C4 alkoxy with boron tribromide in an inert solvent to prepare the corresponding compound of Formula V wherein Ra is and, if a hexahydrobenzopyranoxanthenone of Formula I, wherein Xa Xb Y and Yb are hydrogen, of the formula

is desired wherein R, Rl and R2 are as defined above, reducing a compound of Formula V wherein Ra is R; provided that, if the reduction is in the presence of platinum dioxide, the reduction product is further reacted with pyridinium chlorochromate, sodium dichromate or potassium dichromate.

28. A process of claim 27 wherein the reduction of a compound of Formula V to prepare a compound of Formula VI is an electrolytic reduction carried out at a temperature of from 5"C. to 800 C. in an organic or aqueous-organic medium at a mercury cathode in the presence of a proton source and in the presence of an electrolyte selected from the group consisting of alkali metal salts, quaternary ammonium salts having a total of 10 to 28 carbon atoms in the cation moiety, and tertiary amine salts having a total of 7 to 21 carbon atoms in the cation moiety.

29. A pharmaceutical composition comprising a physiologically-acceptable carrier or diluent and a compound of Formula I of any of claims 1--26.

30. A composition of claim 29 which is in unit dosage form.

31. A composition of claim 30 which comprises from 1 mg. to 500 mg. of the compound of Formula I.

32. A composition of claim 31 which comprises from 50 mg. to 250 mg. of the compound of Formula I.

33. The use of a compound of Formula I of any of claims 1--26 as an antiandrogen.

34. A compound of Formula I as claimed in claim 1, substantially as described hereinabove with particular reference to any one of the examples.

35. A process as claimed in claim 27, substantially as described hereinabove with particular reference to any one of the examples.

36. A composition as claimed in claim 29, substantially as described hereinabove with particular reference to any one of the examples.

37. A use as claimed in claim 33, substantially as described hereinabove with particular reference to any one of the examples.