CS207571B2 - Method of preparation of new dibenzo/b,d/pyranes - Google Patents

Abstract

9-Hydroxydibenzob,d!pyrans useful as analgesics, hypotansives, immunosuppressants, tranquilizers; as anti-secretory and anti-anxiety drugs; having the formulae: I and II wherein R is hydrogen or alkanoyl having from one to five carbon atoms; R1 is hydrogen, alkanoyl having from one to five carbon atoms or -CO-(CH2)p-NR2R3 wherein p is 0 or an integer from 1 to 4; each of R2 and R3 when taken individually is hydrogen or alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; each of R4 and R5 is hydrogen, methyl or ethyl; R0 is oxo or alkylenedioxy having from two to four carbon atoms; Z is (a) alkylene having from one to nine carbon atoms; (b) -(alk1)m-X-(alk2)n- wherein each of (alk1) and (alk2) has from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than 9; each of m and n is 0 or 1; X is O, S, SO or SO2; and W is methyl, phenyl, p-chlorophenyl, p-fluoro-phenyl, pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cycloalkyl wherein the substituent is phenyl, p-chlorophenyl or p-fluoro-phenyl; with the proviso that when W is methyl, Z is -(alk1)m-X-(alk2)n-.

Description

The present invention relates to novel dibenzopyranes, more particularly to 1,9-dihydroxyhexahydroidibenzopyranes containing in the 3-position, 1) an aryl or cycloalkyl (W) bonded in this position via an alkylene group or 2) a methyl, aryl or cycloalkyl bonded to this position via a) (B) an alkylene group interrupted by an O, S, SO or ¹ SO group; or

c) an alkylene group attached to the 3-position or to said methyl, aryl or cycloalkyl via O, S, SO, or SO2 groups; and the use of these dibenzopyranes and derivatives thereof as analgesic, hypotensive, anti-secretory and anti-anxiety agents, as immunoreactive suppressants and as tranquillizers in mammals including humans.

Although a number of analgesic agents are currently available, the search for new better agents continues because there is a lack of agents useful for controlling broad levels of pain that would not be associated with side effects. The most commonly used substance, aspirin, is of no practical value for controlling severe pain and is known to exhibit various undesirable side effects. Other more potent analgesic agents, such as d-propoxyphene, codeine, and morphine, are susceptible to addiction. The need for better active substances is therefore evident.

The analgesic properties of 9-noir-9? -Hydroxyhexahydrocannabinol and other cannabinoid structures such as A8-tetrahydrocannabinol (88-THC) and its primary metabolites, 11-hydroxy-88-THC have been reported by Wilson and May Absts, Papers, Am. Chem ·. Soc., 168 Meet., MEDIA 11 (1974), and J. Mec. Chem., 17, 475-476 (1974).

U.S. Pat. Nos. 3,507,885 and 3,636,058 of Apr. 21. 1970 · I and 18, 1972, describes various 1 · hydroxx-3-alkyl-6H-dibe.nzo ^[b: d] pyrans having at the 9-position substituents such as: oxo, hydrocarbyl and hydroxy not Cl, hydrokareyliden and intermediates thereof.

U.S. Patent No. 3,649,650, issued March 14, 2004. 1972 discloses tetrahydro-6,6,9-trialkyl-6H-dibenzo [b, d] pyran derivatives having a ω-dialkylaminoalkoxy group at the 1-position, which are effective as psycho-therapeutic agents.

DE Patent No. 2,451,934, issued November 7, 1975, discloses dihydroxyhexahydrodieenzo [b.d] pyranes and certain 1-acyl derivatives having an alkyl or alkenyl group at the 3-position, which are hypotensive, psychotropic, sedative and analgesic agents. H-dibenzol b, d] pyran-9-one hexahydrate precursors used in this preparation having the same uses as the corresponding 9-hydroxy compounds are described in DE Patent No. 2,451,932, issued November 7, 1975.

DE Patent No. 2,415,697, issued Oct. 17, 1974, discloses 1,1-hydroxy-6,6,9-trimethylheahdrodibenzo [b, d] pyrans and intermediates thereof with the arylalkyl at the 3-position (substituted arylalkyl) or pyridylalkyl. They are useful as analgesic and mildly soothing agents.

U.S. Pat. No. 3,856,821 of 24. XII. 1974 discloses a series of 3-alkoxy-substituted dibenzo [b, d] pyranes with anti-arthritis, anti-inflammatory and central nervous system activity. .

The stereospecific synthesis of (-j-trans-6a, 7,8,10a-tetrahydro-3-pentyl-66,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol, more commonly known as (- JAMetrahydrocannabinol) was. reported by Razdan et al. (J. Am. Chem. Soc. 96, 5860-5, 1974) .The one-step synthesis involves the cis / trans- (+] -? - methane-2,8-dien-1-ol reaction. with olivetoleim in the presence of 1 ° / o bortrifluoridletherátu and anhydrous magnesium sulfate in of methylene chloride at 0 ° C. the resulting tetrahydro compound is converted into a ^deduction! sponding 9-ketohexahydroslo'učeniniu procedure. by Wildes et al., J. Org. Chem. 36, 721-3 (1971) The process involves methylation of a 1-hydroxytetrahydro compound to methyl ether and then to an adduct with hydrogen chloride by reaction with zinc chloride and HCl at 0 ° C in chloroform, and the adduct is then dehydrohalogenated by reaction with potassium tricyclopentylcarbinolate to give the corresponding 6a, , 8,9,10,10a-hexahydro-3-pentyl-6,6-dimethyl-9-methylene-6H-dibenzo [b, d] pyran-1 Oxidation of the 9-methylene group with periodate a. potassium permanganate gives the 9-ketone. Deimethylation of methyl ether with pyridinium chloride and other acidic substances provides the alcohol.

Bergel et al., J. Chem. Soc. 286-7 (1943) studied the substitution of the pentyl group at the 3-position 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol for alkoxyl (butoxy, pentoxyl, heeoxyl and octoxyl) and it was found that this substitution leads to a loss of biological activity. The hexoxide derivative is reported to have a weak hashish effect at 10 to 20 mg / kg. kg.

In recent work by Loiev et al., J. Med. Chem ·. 16, 1200-6 (1973) discloses a comparison of 7,8,9,10-tetrahydro-3-substituted 6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-ol, wherein the substituent in position 3 is -OCH ^ hi ^ Hn; -CH2CH (СНз] С Нц ₅ or CH (CH3] C5Hu.

A compound containing an ether side chain has 50% less central nervous system activity than the corresponding compound where the alkyl side chain is directly attached to the aromatic ring and not through the oxygen atom and is five times more active than the compound where the oxygen atom is replaced by the methylene group .

We have now found a group of compounds effective as analgesic, hypotensive agents. as anti-secretory agents and as anti-anxiety agents, as immunosuppressive agents, and as tranquillizers, namely, 1,9-dihydroxydibenzoiib, d] pyrans (Formula I). which are not narcotic and are not prone to addiction.

It is an object of the present invention to provide novel dibenzo [b, d] pyranes of formula (I)

where

R is an atom. Hydrogen or alkanoyl having from 1 to 10 carbon atoms; 5 carbon atoms,

R 1 is hydrogen, C 1 -C 5 alkanoyl or a group of the formula

-CO (CH 2) p -NR 2 R 3, wherein p is 0 or an integer from 1 to 4,

R 2 and R 3 are either individual hydrogen atoms or. C 1 -C 4 alkyl or R 2 and C 1 -C 4 alkyl; R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-C 1-4 alkylpiperazino,

R4 and R5 are hydrogen, methyl or ethyl,

Z is alkylene. C 1 -C 9; - (alkjm - X - (alk2) n -, wherein each substituent (aliki] and (alk-2) has 1 to 9 carbon atoms, the sum of the carbon atoms in (alkj and (alk2) being at most 9, m and n is 0 or 1,

X is O, S, SO or SO 2; and

W is methyl, phenyl, p-chlorophenyl, p-fluorophenyl, pyridyl, piperidyl, cycloalkyl of 3 to 7 carbon atoms or monosubstituted cycloalkyl of 3 to 7 carbon atoms in the cycloalkyl group wherein the substituent is phenyl, p-chlorophenyl or p-fluorophenyl, wherein when W is methyl, Z is - (alk) X - (alk2) n -, characterized in that the compound of formula II is reduced

where

R1, R4 _,. R 5, Z and W are as defined above, and when R in the compound of formula I is alkanoyl, the compound obtained, wherein R is a Vol atom, is reacted with the corresponding acid, its chloride or anhydride.

The compounds of the above formulas contain asymmetric centers at the 6a and / or 10a positions. Other asymmetric centers may be in the 3-position (-Z-W), 6-and 9-position in the subistituent.

Likewise, the trans- (6a, 10a) diastereoisomers are more preferred than the cis- (6,10a) diastereoisomers.

In the above formulas, wavy lines indicate diastereoisomers at positions 9 and 6a, 10a.

In general, optically active enantiomers containing the same absolute configuration at both positions 6a and 10a as natural kanhabinols are preferred because they have a quantitatively greater biological activity. Racemic modifications of these compounds can be used as such because they contain 50 why more active. enantiomer. The applicability of racemic mixtures, di-atheromeric mixtures, as well as pure enantiomers and diastereomers was determined by the bioassays described below.

Preferred compounds of formula I are those wherein the OR group at the 9-position has a β-configuration. These. the compounds are more potent than the corresponding " compounds.

Particularly effective are compounds of formula I wherein the substituents have the meaning given in Table A below:

Table A

STEED ORi OF m n w ¢ -01-1 OH alkenyl of 1 to 6 carbon atoms - - phenyl, pyridyl .Beta.-3-OH OH - (alkdm — X—) - - phenyl, - (alk2) n— 1 1 pyridyl £ -OH OH - (alkiU - X - 1 - phenyl, pyridyl / 3-OH OH ......... —X— (alk ₂ ) n— - 1 phenyl,

pyridyl

Particularly preferred in terms of activity are those compounds of formula I, of Table A, wherein Z-W, the substituent at the 3-position, has the meaning given in Table B below:

Table B (a)

-CH ₂ ) _q - ^ C ₆ H ₅ (b)

-CH (CH 3) - (CH ₂ ) 1 -C ₆ H ₅ (c)

- [(CH ₂ ) _q ] _m -O- [(CH ₂ ) _t ] _n - C ₆ H ₅ (d) - [CH (CH-) - (CH ₂ ) q] _m -O- [CH (CH-J) - - (CHHJJn-CiH, (θ))

- [(CH3qU-O-ICCH3) -c ^ (f)

- (CH (CH ₃ - (CH ₂ ) _q ) _m -O- (CH (CH -) - (CH ₂ ) t) n -CH 3

In the above table, each symbol qat is an integer of ¹ 1 to 4 and each of the symbols m and n is 0 or 1 · wherein only one of m · n is the 0th

The starting compound of formula II is prepared by Birch reduction of 6α, 7-dihydro-1 H -R 6,6-R 4 _{R 5} -3- (ZW) -6 H -dibenzo [b, d] pyran-9 (8 H) -one . The reduction is preferably carried out using lithium as the metal. Sodium or potassium may also be used. The reaction is carried out at a temperature of about -35 to 80 ° C. The Birch reduction is advantageous because it is stereoselective and results in the formation of the desired trans-ketone of formula II.

The reduction of the 9-oxo group in the compound of formula (II) is carried out with a metal hydride to give a compound of formula (I) wherein R is hydrogen.

Examples of metal hydrides useful in the conversion are lithium aluminum hydride, lithium borohydride and sodium borohydride. The most preferred reducing agent is sodium borohydride not only because it provides sufficient yields of the desired product, but reacts sufficiently slowly with hydroxylic solvents (methanol, ethanol, water) and thus allows their use as solvents. In general, temperatures of from 0 to 30 ° C are used. Lower temperatures up to about -70 degrees Celsius are used to increase the selectivity of the reduction. Higher temperatures cause sodium borohydride to react with hydroxyl solvents. If higher temperatures are required for the abovementioned reduction, isopropyl alcohol or dimethyl ether or diethylene glycol are used as solvents.

Compounds such as lithium borohydride or lithium (III) (III) (III) (III) (III) may require, without water conditions and the use of non-hydroxyl solvents (1,2- (1,2-dimethoxyphenol)). ethanol, tetrahydrofuran, ether, dimethyl ether or diethylene glycol).

The isomeric 9? And 9? -Hydroxy compounds are prepared by this sequence. The above reaction sequence is shown schematically:

if

Compounds of formula (I). wherein R is C 1 -C 5 alkanoyl is prepared by acylation with an appropriate acid, in the presence of a 'condensation' reagent, such as dicyclohexylcarbodiimide, or by reaction with an appropriate chloride or anhydride in the presence of a base such as pyridine.

The analgesic properties of the compounds of the present invention were determined by pain stimulation tests.

Tests using thermal stimuli of pain

a) Analgesic test using the behavior of mice on a bitter plate

The method used was a modification of the method of Woolfe and Mac Donald, J. Ph. Therap. 80, 300-307 (1944). A controlled thermal stimulus was applied to the paws of mice with an aluminum plate of 4 µm thickness. A 250 W infrared lamp was placed under the bottom of the plate and the temperature on the surface of the plate was controlled by thermistors to maintain a constant temperature of 57 ° C. Each mouse is placed in a 18 cm diameter glass cylinder laid. on the hot plate and time measurement is started from touching the hot plate animal. Mice are tested 0.5-2 hours after treatment with test compound a. the time until. the first 'swing' movement of one or both hindpaws, or whether 10 seconds without that movement. Morphine has an MPE50 = 4-5.6 mg / kg (subcutaneously).

b) Tail flick analgesic test

The tail flick test was modified according to the D'Amour and Smith test, J. ParmacolC Exp. Therap. 72, 74-79 (1941) by applying controlled heat intensity to the tail. Each mouse is placed in a comfortably mounted metal cylinder with a tail extending at one end. The cylinder is arranged such that the tail lies above the hidden lamina for heating. At the start of the test, the aluminum lamp cover is removed and the light beam is passed through the slit and focused on the tail of the tail. At the same time, the timer switches on. The time of unexpected tail flick is monitored. Untreated mice Usually respond within 3 to 4 seconds after the lamp is turned on. The end for protection is 10 s. Each mouse is tested 0.5 to 2 hours after treatment with morphine and test compound. Motfin 'has an MPE50 of 3.2 - 5.6 mg / kg (subcutaneously).

c) Tail immersion test

The method is a modification of the process developed by Benbasset et al., Arch. int. Pharmacodyn. 122, 434 (1959). Male white mice (19-21 g) of the Charles River CD-1 strain are weighed and labeled for. identification. Five animals are used for each test group, each animal serving as its own control. For general testing of new substances, these are first administered at a dose of 56 mg / kg intraperitoneally or subcutaneously and are supplied in an amount of 10 ml / kg. Prior to drug administration and 0.5 and 2 hours after administration, each animal was placed in a cylinder. Each cylinder is provided with holes to allow adequate ventilation and is closed with a circular nylon plug through which the tail of the animal is drawn. The cylinder is kept upright and the tail is fully immersed in a constant temperature water bath (56 ° C). The end for each test is a nergic jerk or tail twitch associated with a motor reaction. In some cases, the end may be less severe after drug administration. To prevent tissue damage, the test is terminated and the tail is removed from the water bath for 10 seconds.

The reaction is recorded in seconds with the shortest time period of 0.5 s. At the same time, the carrier and the standard with known effect are tested as controls. If the activity of the test substance does not return to baseline within two hours, the reaction is measured after 4 to 6 hours. A final measurement is made after 24 hours, if an effect is still observed, then at the end of the test day.

Test using chetical pain stimuli

Suppression of Winding Induced by Phenylbenzoquinone

Groups of five Carworth Farmus CF-1 mice are treated subcutaneously or orally with sodium chloride solution, morphine, codeine or the test compound. After twenty minutes (under subcutaneous treatment) or: · after fifty minutes (under oral treatment), each group is treated by intraperitoneal injection of phenylbenzoquinone, an irritant known to induce abdominal contractions. Mice are monitored for five minutes to determine whether or not writhing is induced after the irritant injection. The MPE50 of drugs that protect against writhing is detected.

Test Time - Check Time% MPE = Stop Time - Check Time

The compounds of the present invention are active analgesics for oral and parenteral administration and are preferably administered as a mixture. These compositions include a pharmaceutical carrier selected according to the mode of administration and conventional pharmaceutical practice. For example, they may be administered in the form of tablets, pills, powders or granules containing starch, lactose,

Tests using pressure stimuli of pain

Haffner's tail squeeze effect

A modification of the Haffner procedure, Experimentelle Prufung Schmerzstillender Mittel Deutch, is used. Copper. Wschr., 55, 731-2 (1929), which monitors the activity of the test compounds · aggressive responses induced by _pressing: the tail. Male White (50-60) Charles River (Spraque-Dawley) CD strain was used. Before drug administration and again 0.5, 1.2 and 3 hours after administration, they are attached to Johns Hopkins. “Bulldog” clamp 5.6 cm tail of rat's tail. The end of each test is a clear attack and bite directed against the pressure stimulus and the reaction is monitored in seconds. The clamp is removed within 30 s if no attack has occurred yet. Morphine is active in amounts

17.8 mg / kg intraperitoneally.

Tests using electrical stimuli for pain

Finch — jump test (dodging, jumping)

An illustration of this procedure described by Tenena in Psychopharmacologia, 12, 278-285 (1968) is used to determine the pain threshold. Male white rats (175-200 g) of the Charles River (Sprague-Dawley) CD strain were used for the assay. Before application, the feet of each rat are soaked in ^20% glycerol and sodium chloride solution. The animals are then placed in a chamber to receive a series of 1 foot shocks, increasing in intensity at 30-second intervals. These intensities are 0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04. mA. Animal behavior is evaluated for the presence of a) dodging, b) whistling, c) jumping or fast forward at the start of the shock. One series of shocks of increasing intensity is performed for each rat prior to drug administration and at 0.5, 2, 4, and 24 hours after drug administration.

The results of the above tests are evaluated as · percent of the maximum possible effect (% MPE). The MPE percentages for each group are statistically compared to the% MPE of the standard and control values obtained prior to drug administration. MPE percentages are calculated as follows:

x 100 types of clays and the like. They may be administered as capsules in admixture with the same or equivalent ingredients. They can also be administered in the form of oral suspensions, solutions, emulsions, syrups and infusions, which may contain flavoring and coloring agents. For oral administration of the therapeutic compositions of the present invention, tablets or capsules containing from about 0.01 to about 100 mg are most preferred for most applications.

The physician will determine the dose that is most appropriate for an individual patient and may vary according to the age, weight and response of the particular patient and the route of administration. In general, however, the initial analgesic dose in adults may range from 0.01 to 500 mg per day in single or divided doses. In many cases it may not exceed 100 mg per day. A preferred oral dose is about 0.01 to about 300 rng / d, preferably about 0.10 to 50 mg / d. A preferred parenteral dose is about 0.01 to about 100 mg / d, preferably about 0.01 to about 20 mg / d.

The analgesic effect of some of the compounds of the present invention and some of the known compounds is determined by the methods described above. Results are reported for maximum possible effect.

The following abbreviations are used in the table:

PBQ - Winding test induced by phenylbenzoquinone

TF - tail flick test

HP - Hot plate behavior test

RTC - Rat Tail Squeeze Test

FJ - test "flinch jump" (dodging, jumping

TI - Tail Immersion Test

N.T. - not tried.

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The antihypertensive effect is determined by the ability to statistically significantly lower the blood pressure of hypertensive rats and dogs when the above dosages are administered orally.

The triacillization effect is determined by oral administration to rats at a dose of from about 0.01 to 50 mg / kg, thereby reducing spontaneous motor activity. The daily dosage in mammals is from about 0.01 to * 100 mg.

In addition to the analgesic, hypotensive and soothing effect, the compounds of the present invention are also useful as immune suppressants and anti-secretory agents.

The effect against gastric secretion in dogs (Heidenhein) provided with a gastric bag is determined as follows.

The effect against gastric secretion was studied in overnight fasted Heidenhain dogs with a gastric bag using pentagastrin, histamine or food to stimulate acid production. Pentagastrin or histamine is administered by continuous infusion into the superficial vein of the foot at a predetermined dose that stimulates almost maximum acid production from the stomach bag. The feed stimulus consists of half the canned Ken-L-Ration (about 220 g) per dog, using dogs weighing 9 to 12.5 kg. Gastric juice is collected at intervals of 30 minutes after the order of histamine or pentagastrin infusion or after ingestion of standard food. During the experiment, a total of 10 samples were taken for each dog. The drug is administered orally in an amount of 0.01 to 50 mg / / kg after the third intake of gastric juice.

All sample volumes are recorded and the acid concentration is determined by titrating the all-quota portion (1.0 mL) to pH 7.4 using 0.1 N NaOH and a pH meter (Radiometer) and automatic burettes. The drug is administered orally after being placed in gelatin capsules.

The immune suppressive effect is determined by a mixed lymphocyte culture assay. This assay measures the effect of test compounds on antigen-stimulated lymphocyte growth. Lung lymphoid cells from BALB / C and 57 BL / 6 mice, 8 x 10 ⁶ cells from each strain, are suspended in 2.0 ml serum-free medium containing the test compound and incubated at 37 ° C in a 10% atmosphere. carbon dioxide.

The culture conditions and method are described in J. Exp. Copper. 122, 759 (1965) and the nutrient medium is described by W. T. Weber in J. Retic. Soc. 8, 37 (1970). Half of the medium, 1 ml, is replaced with fresh medium every 24 hours. Incorporation of 3H-TdR (24 hours each) into desoxyribunucleic acid is then determined by precipitation of desoxyribonucleic acid with trichloroacetic acid and determination of radioactivity in a scintillation process. Percent inhibition is determined by comparing the mixed culture with the test compound to the mixed control culture.

Example 1 dl-6a '/ ^, ^ 7,100L1a.a -Tetitr ^ I ^ H ^ ^C ^ ¹¹ o - ^ L-hydio ^ x ^ y ^ -6,6-dimethyl-3- (l-methyl- 4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one

A solution of dl-6a, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one (0.976 g) ) in tetrahydrofuran (7 ml) was added to a rapidly stirred solution of lithium (0.1 g) in liquid ammonia (35 ml) (distilled through potassium hydroxide pellets). The reaction mixture was stirred for 15 minutes and then solid ammonium chloride was added to remove the blue color. The excess ammonia was allowed to evaporate and the residue was diluted with water (35 mL) and acidified with concentrated hydrochloric acid. The aqueous solution was extracted with dichloromethane (3 x 25 mL) and the dichloromethane extracts were dried over sodium sulfate. Evaporation gave 0.98 g of a mixture of trans-cis-6a, 10a-diastereomers as a crude oil, which was purified by column chromatography to give the trans-diastereoisomer followed in later fractions by the cis-diastereoisomer. This gives you:

dl-6a / 37, 11αa-tettahydrogen-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dib (i.e. [b, Liipyran-9 (8H) - on, 0.393 g, mp 200-205 ° C.

NMR · O

INIVIIX. ϋCDC1

1-2.35 (M, 11, α-methyl, ethylene, residual protons),

1.55 (s, 6, g-dimethyl);

2,35-3,0 (M, 7, α-methylenes, benzyl methylene, methinyl),

6.2—6.45 · (M, 2, ArH),

7-7.35 (M, 5, ArH),

7.8 (broad S, 1, hydroxyl-D ₂ O overlap).

IR: (CHCl 3) C = 0 1600 cm 4 and dl-6α α δ 7.00.00 α-t-tetramido-1-hydroxy-6,6-dimethyl-3- [1-methyl-4-phenylbutyl) - ^6H-l DIBE nzO' b, d] pyran-9 (8H) -one as a solid foam.

IC: (CHCl 3) C = 0, 1690 cm ** OH 3275 cm 4.

^{NMR δ} X

0.95-2.12 (Μ, 11, N-methyl, ethylene, residual protons),

1.35, 1.4 (2S, 6, gem.dimethyl),

2.25-2.95 (M, 7, .alpha.-methylenes, benzylmethylene, methethinyl),

6.1-6.35 (M, 2, ArH),

7.1 (b. D. S, 1, hydroxyl),

7.25 (s, 5, ArH).

Repeating the procedure, but using the appropriate starting compounds, the preparation of dl-6'aA7, L1-l1aat teteahydro-Hydroxy-6,6-dimethyl-3- (l-Methyl-5-fehylpentyl) ^-6-dlbe: NZO [ b, d] pyran-9 (8H) -cn, mp 159-163 ° C

NMR: δ

1.1, 1.5 · 22 ^, 6, ger ^ u ^ iii ^ etl ^ h ^ 1),

0.9-3.1 (M, 19, .alpha.-methyl, O ^ 2- (O ^) 3-N (S)), benzyl, remaining protons), 3.9--4.4 (bd) D, 1, α-carbonyl),

6.2 (M, 2, ArH)

7.0-7.4 (M, 5, ArH),

7.8 (S, 1, phenolic hydroxyl),

IR: (KBr) C = O 1695 cm- ⁴ .

Analysis for C27H34O3:

calculated:

% C, 79.76;% H, 8.43; found:

, 79.49% C, 8.43% H, and the corresponding cis-rihsterromrg:

dl-6a37,10,10,10a _[( 3-tetrahydro-1-hydroxy-6,6-dimethyl-1H-1-methyl-5-phenylpentyl) -6H-dibenzo [b, d] pyran-B (8H) -one mp 91-130 ° C.

IR: (KBr) C = 0 1709 cm ^-1 .

MS: (molecular ion) 406.

r-6αЗ ^: 7,11,0όα-Tetrahydro-1-hydroxy-6,6-dimerhyllЗ-2-phenylethyl-6H-dibenzo [b (d) py-hhn-9 (8H) -oπ t, t, 206 · Up to 209 ° C.

IR: (KBr) OH 3260 cm ^-1 , C = O 1710 cm ⁴ .

NMR: δ

1.05-1.45 (2S, 6, gem-dimethyl),

2.75 (bS, 4, ethylene),

3.1-3.1 (M, 7, remaining protons),

3.75, 4.0 (2H, 1, 10aa proton),

6.2 (d, 2, ArH),

7.15 (s, 5, ArH),

8.8 (S, 1, hydroxyl-D 4 O overlay).

MS: molecular ion 350.

dl-6a (β (7 (10 (10ahjeerrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenyl) propyl) -6H-dibenzo [b, d] pyra) Mp -9 (8H) -one, mp 165 ° C.

IR: (KB ') OH 3175 cm -1, C = O 1695 cm ⁴ .

RL-.6a /], 7, (0.101, 0-Tetrahhdrг ---- ldrгoxy-6 (6-dimlethdl-3- (1-1Пг№11-3-Впу11Л 'propylpyrid) ^-6-DIBE; NZO · [ b, d] pyran-9 (8H) -one as a solid foam.

IR (CHCl 3) C = 1685 cm -1,, 3250 cm ⁴ .

^{NMR: δ} ™ ^s3

1.35, 1.45 (2S, 6, gem.dimethyl),

2.8 (bd, s, 4, ethylene),

1.75-3.6 (M, 8, protons remaining),

6.3 (M, 2, ArH), 1.25 (M, 6, ArH, hydroxy).

r-6α < 3 (7,10,10a-h-eerogghydro-1-hddroxy-6, N -dimethyl-3- (1,1-tetrahydro-4-methoxybutyl) -6H-dibenzo [b, d] pyran); -G (8H) -one.

mp, 160-175 ° C.

MS: (molecular ion) 408

Rf = 0.53 (silica gel, silica gel 1: 2)

NMR: .delta

7.41 - 6.67 (multiplet, 6, phenolic OH, C ^),

6.3 (S, 2, arolmatic H ₂ + HJ,

4.33-1.50 (Ms, 15, remaining · methylene, metric protons),

1.47, (S, 3, CH 3),

1.27 and 1.17 (D, 3, Mel,

1.12 (s, 3, CH 3).

Analysis for · Ο26Η32Ο4:

calculated:

H, 7.89; H, 7.89;

found:

% C, 76.61;% H, 7.90.

rl · 6h ((, 7,11aa-Tetrahydrotrophenyl-6,6-dimethyl-3- [1-methyl-1- (4-pyridyl) butyl) -6H-dibenzo [Ь] [.Alpha.] Pyran-9 (8H) -one, mp 60-70 ° C.

Rf = 0.4 (еШ ^ д ^, rthylhrtrtate)

MS: (molecular ion) 393

NMR: δ

0.83-1.73 (M, 15, methyl, methylene),

1.73-3.0 (M, 8,1-methine, remaining protons),

3.97-4.2 (width D, 1, aliphatic),

6.27 (s, 2, ArH),

7.03, 7.13 (D, 2, pyridine ArH),

7.55 (s, 1, hydroxyl),

8.42 (M, 2, pyridine ArH).

dl-6h (7 (10,10aα'-Tetrahydro-1-hydroxy-6h-methyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [Ь, Ь] pyran-9 (8H) -one) mp 163-167 ° C (melting at 140 ° C).

IR: (KBr) C = 0 1709 cm ⁴ .

Analysis for С ₂ 5Нзо0 ₃ :

calculated:

79.33% C, 7.99% H; found:

% C, 79.43;% H, 8.03.

MS: (molecular ion) 378.

dl-0oai, 7,10,110a-Tetraliydi-1-hydroxylmethyl-2- (2-phenylethoxy) ethyl] -6H-dibenzo {b, d] pyran-9 (8H) -one (solid glass):

NMR: [delta].

1.13 (s, one methyl of gem-dimethyls),

1.24 (d, J = 7Hz, methyl)

1.50 (s, one methyl of g. Dimethyl),

1.6-3.2 (Mj,

32-3.8 (M),

4.05 (M, one proton),

4.30 (M, one proton),

6.33 (s, two ArHs),

7.30 (s, Ph);

7.70 (s, phenol).

MS: · (molecular ion) 408 (M®, 100%),

392, 375, 304, 287, 286, 274, and 273.

Rf = 0.57 (silica gel, ether) and the corresponding cis-isomer:

dl-6a7,7,11,10a; 1-tetrraydro-1-hydroxy [-6,6-dimethyl-3- [1-methyl [-2- (2-phenylethoxy) ethyl] -1H-dibenzo] b, d] pyran-9- (8H) -one, mp 127-130 ° C.

NMR: δ

1.20 (d, J = 7 Hz, methyl),

1.32 and 1.39 (s, g-dimethyl),

1.1-3.8 (M)

6.25 (s, two ArH),

7.07 (s, phenyl);

7.28 (s, Ph).

MS: (molecular ion) 408 (M + 100%)

393, 391, 325, 316, 304, 287, 286, 274, 273, and 245.

Rf = 0.50 (silica gel, ether).

EXAMPLE 2 dl 6I ^ _l '3,7,8,9,10 <^ - ^ - hydroxy-6,6-di'met.hyl [3- (l-meth.yl-4- [phenylbutyl) - 6H-idibenzo (b, d) pyran-93-ol

To a solution of dl, α, 7, 10, 10, 3, 4, 4, 3, 3, 4, 1 - [1-hydroxy [6,6 [dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibiyl] b] [b, d] pyran-9 (8H) -one (0.25 g), prepared according to the procedure for the preparation of the starting compounds of formula II in Example 1, in ethanol (200 ml) stirred at room temperature under nitrogen atmosphere, sodium borohydride (0) is added. , 5 g). The reaction mixture was stirred for 30 minutes and acidified with 6 N hydrochloric acid, then diluted with water (50 mL) and extracted with ether (3 x 50 mL). The combined ether extracts were dried over sodium sulfate and concentrated in vacuo to give 0.25 g of a mixture of 9-OH- and β-isomers: Column chromatography (silica gel) gave 0.087 g of ^ -687.7,8.9,10,103 N -hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl [4-phenylbutyl) -6H-dibenzo [b, d] pyran-9,3-ol, mp 156-158 ° C, after crystallization from ether: hexane (1: 2).

MS: (molecular ion) 394

Analysis for C 26 H 34 O 3: calculated:

% C, 79.15;% H, 8.69; found:

% C, 78.94;% H, 8.79.

The following compounds were prepared as described above. by the corresponding starting compounds prepared according to Example 1.

dl-6α, 7,8,9,10,10aα-Hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-5-phenylpentyl) -6H-dibenzo [b, d] pyran-93- ol:

_NMR: Anal. l> _CDCl3

1.0, 1.4 (2S, 6, gem.dimethyl),

1.2 (D, 3, α-methyl, J = 7 cps),

0.8-4.0 (M, 18, protons remaining),

4.1-4.7 (M, 2, phenolic OH and alcoholic OH),

6.1, 6.2 (2D, ArH, J = 3 cps), 7? (? - 7, 3 (M, 5, ArH)).

Analysis for C27H36O3:

calculated:

79.37% C, 8.88% H; found:

% C, 79.58;% H, 8.92.

dl [6a, 7 (8 (- (11,10a) [Hexahydror [hydrOxyl] [6,6-dimethyl [3- (2-phenylethyl) -OH] -dibenzo [b, d] pyran-ol) mp 213-215 ° C.

IR: (KBr) OH 3367 cm ^-1 , 3125 cm ⁴ .

_{NMR: á} ™ ^s'

ΙΝίνίΛ. О _опс , _ь

1.0, 1.35 (2S, 6, gem.dimethyl),

2.85 (S, 4, ethylene),

3.85 (bs, 1, hydroxyl-D2O · overlap),

3.6 (Μ, 1, 10aa proton),

0.8-3.6 (M, 8, remaining protons),

6.2 (2d, 2, ArH)

7.2 (s, 5, ArH),

8.75 (s, 1, hydroxyl 40 overlap).

MS: (molecular ion) 352.

dl-6a (3-7,8,9,1,10,10 α-Hex ahydrol-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylpropyl) -6H-dibenzole [b, d m.p. 070-172 ° C, m.p.

NMR: 5 ™ _b

0.05, 1.25 (d, 3, methyl),

1.35 (s, 6, g. Dimethyl),

0.6-0.95 (M, 2, methylene),

2.05-2.7 (M, 3, benzylmethynyl and methylene),

0.0-1.8 (M, 00, protons and hydroxyl remaining), 6.0, 6.25 (2d, 2, ArH),

7.2 (s, 5, ArH).

Analysis for · C25H32O3:

calculated:

% C, 78.90;% H, 8.47; found:

% C, 78.57;% H, 8.50.

dl-6aa, 4 ', 1', 9,000Lo-b 'exahydro-6'-hydroxy-6a-methyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzio [b, d] pyran-93-ol.

This product is obtained as a mixture of diastereomeric alcohols. The foam mixture was separated into two components by preparative silica gel chromatography using 5% methanol in chloroform as the elution solvent.

The diastereoisomeric mixture showed peaks in the infrared (chloroform) at 3827 and 3333 cm @ -1 (OH).

00 mg of component A Rf = 0.65 was isolated from 60 mg of foam. The NMR spectrum is given below.

NMR: δ ™, ₃

7.0-7.5 (M, 5, ArH),

6.2 6.3 (2D, 2, ArH),

0.2 (D, 3, α-methyl, J · 7 Hz),

0.8-4.5 (M, 22, protons remaining).

Component B, 42 mg, R f = 0.75, was similarly isolated. The NMR spectrum is shown below.

NMR. <5

7.0 - 7.5 (M, 5, ArH),

6.0, 6.3 (2D, 2, ArH),

0.2 (D, 3, .alpha.-methyl, J = 7 Hz),

0.1 (.delta. = 4.5) (m, 22, protons remaining).

dl · 6a (, 1,8,9,00,00α'-Hexxhydro-1-hydroxy-6,6-trimethyl-3- (1-methyl-4-phenoxybutyl) -6H) -benzo [b, d] pyran-93-ol, mp 044-046 ° C.

Rf = 0.30 (silica gel, ether-hexane 9: 0)

Analysis for ^Ο 26 ^Η 34 ^Ο 4 ^: calculated:

% C, 76.06;% H, 8.35;

found:

% C, 75.85;% H, 8.22.

_NMR: δ ^TMS .

nran. υ _{( Dcb} .

6.75 (M, 6, phenolic OH + + C ₆ H ₅ ),

7.95 and 7.80 (BS, 2, AR H2 + H4)

4.07-0.00 [M, 26, non-aromatic 0.42 (S, Me), 0.28 and 0.07 (D, Me), 0.00 (S, CH3), methylene, methine and hydroxyl 0 .

r-6aβ, 7,8,9,00,00Oh-hexahydro-1-oxyl-6,6-dimethyl-3- (1-methoxy-4-phenoxybutyl) -6H-dibenzo {b, d ] pyran19a-o-, oil.

Rf = 0.37 (silica gel, ether-hexane 9: 0)

MS: (molecular ion) 400.

ГУХ-З, 7,8,9,00,00aa-Hxxa -drro-O-hydroxy-6,6-dimethyl-3- [1-methyl-4- (4-pyridyl) butdl] -XH-dibreo M.p. = 107-190 ° C;

Rf = 0.09 (Si-iqgx-, benzene-methanol -: 0) _{NM R:} δ ™ ^{with 11 U} CCC15

8.50-8.45 (D, 2, Pyridine)

ArH),

7.32 (S, O, phenolic hydroxyl),

7.02-7.07 (D, 2, pyridine ArH),

6.26 (BS, 0, benzene ArH),

6.00 (BS, 0, benzene ArH);

4.60-3.30 [M, 3, methine + OH (singlet 3.83)],

2.80-0.80 [M, 26, alkyl, including singlet at 0.44 (Me), doublet 0.24-0.07 (CH3), singlet 0.02 (CH3) and remaining methylene and methine absorption] , d-6a, 3,7,70,00aa-Tetrahydro-1-hydroxy-6,6- (2-phenyl-2- (2-phenylethoxy) ethyl) The 6H-dibenzo [b, d] pyran-9 (8H) -one was converted to the (1H-a-N, N-carboxy-1-hydroxy-6,6-dimethyl-3- [1-methyl] -). -2-

- (2-phenylethoxy) ethyl] -bH-dibenzo [b, d] pyran-93-ol (solid).

IR (CHCl3) OH 3597 and 3333 cm &lt; ^{NMR: δ} ™

0.02 (s, one methyl of g. Dimethyl),

0.20 (d, J = 7Hz, methyl)

0.37 (s, one methyl of gemimethyls),

4.6-4.2 (M),

6.09 (bs, ArH),

6.30 (bs, ArH), a

7.27 (s, Ph).

dl-6a $, 7,00,00aЗ-TeXtahydro-4-hydroxy-6,6-oxo-3- [i-methyl-2- (2-phenyleithoxy) ethyl] -6H-dibenzo [ b, d] pyran-9 (8H) -one was converted to N - ₁ ¢ 6a, _{and 7,8,9-00,} 00aЗ hexaУydro-4-6,6-hyУroxy di.mxthyl-3- [1-methyl-2-

- (2-Phenyloxy-ethyl) -6H-dibenzo [b, d] pyran-9/3-ol, m.p. 90-105 ° C.

IR: (CHCl3) OH 3534 and 3279 cmA

NMR: .delta

1.12 (M, three methyls),

1.73 (M),

2.32 (M),

2.82 (t, J = 7Hz, CH2-h),

3.0-4.1 (M),

6.13 (d, J = 2Hz, ArH)

6.30 (d, J = 2Hz, ArH)

6.90 (bs, phenol) and

7.25 (s, Ph).

MS: (molecular ion) 410 (MH +) and 105.

Example 3 dl-6aVJ1,10a '' Tctiahydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo [b, d] pyaan-9 (8H) -one

A solution of dl-6α, β-7-dihydro-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo [b, d] pyran-9 (8H) -one (1.2 g, 3.3 mmol] in tetrahydrofuran (9 mL) was added dropwise to a rapidly stirred solution of lithium (25 mg) in liquid ammonia (45 mL) at -78 degrees Celsius and an additional 75 mg of lithium was added dropwise to give a blue color. After stirring for 15 minutes, solid ammonium chloride was added to remove the blue color, excess ammonia was allowed to evaporate, the residue was diluted with water (45 ml) and acidified with 10% hydrochloric acid. The dichloromethane extracts were dried over sodium sulfate and evaporated to give 1.30 g of a crude semi-solid which was purified by silica gel chromatography to give 0.614 g (50.9%) of the product, mp 155-158 ° C after crystallization from chloroform and m.p. hexane.

NMR (CDCl 3) δ - 8.2 (single proton singlet, phenolic OH], 5.8-6.3, (two proton multiplet, aromatic hydrogens), 3.9-4.6 (two proton multiplet, methine ether and equatorial C - 10), 0.3 - 3.2 (26 protonU, multiplet, remaining protons).

IR: (KBr) C = O 1737 cm @ ^-1 MS (m / e) 360 (M @ +), 261 (M @ + 99).

Analysis for C22H32O4:

calculated

73.30% C, 8.95% o H; found:

73.05% C, 8.82% H.

and the corresponding cis-isomer:

dl-Bj ·, δ, 10, 10 and 4-ω-tetrahydro-1-hydroxy-6,6-dimethyl-2- (2-hieptyloxy) -6H-dibenzo [b, d] pyran-9 (8H) mp 141-146 ° C (from ether-hexane).

IC: (KBr) C = 0 1718 cmA

MS: ^(m) / e) 360 (M +), 261 (M-99).

Similarly, the following compounds were prepared from analogous starting compounds:

dl-6a) 3i, 7,10,10a-tetrahydro-1-hydroxyda-6,6-dimethiol- (1-thioethyl-4-phenylbutoxy) -6H-dlbenzylb, d] pyran 9 (8H) -one, mp 122-125 ° C.

NMR: ^.delta

1.3 (D + 3, .alpha.-methyl, J = 7 Hz),

1.1 - 3.0 (M, 16, remaining protons),

2.3-3.0 (bd, T, 2, benzyl methylene),

4.1 (bd. D, 1, C — 10 equivalents, J = 14 Hz),

4.1-4.7 (M, 1, methine),.

5.95 (D, 1, Ar H, J = 2 Hz),

6.1 (D, 1, Ar H, J = 2 Hz),

7.4, 7.4 (M, 5, ArH),

7.9 (S, 1, phenolic proton).

IR: (KBr) C = 0 1709 cmA

Analysis for .26 ^ 204:

calculated:

% C, 76.44;% H, 7.90;

found:

% C, 76.22;% H, 7.79.

and the corresponding cis-isomer:

dl-6a | 3-7,10,10-thieno-3-trans-1-hydroxy-6,6-dimethyl-2- (1-methyl-4-phenylbutoxy) - H -dibenzolb, d] pyran-9 (8H) mp 141-142 ° C.

IR (KBr) C = 0 1707 cm ^-1

MS: (molecular ion) 408

Analysis for C26H32O4:

calculated:

76.44% J, J, 99 J / o H; found:

% C, 76.58;% H, 7.92.

dl-6a3:, 7,10,10a-Tetetahydro-1-hydroxy-6,6-dimethyl-2- (1-methyl-3-thenylalkylpoxy) - H-dibenzolb, d] pyran-9 (8H) -on, tt 160 degrees Celsius.

1.2, 1.3 (d, J, methyl),

1.4 (S, 6, gem, diioethyl),

1.65—2.9 (M, 11, protons remaining) ·,

39-4.5 (M, 2,10aa-proton, methinyl),

5, - 6.1 (2d, 2, ArH),

7.2 (s, 5, ArH),

7.9 (S, 1, hydroxyl-D 2 O overlap).

MS: (molecular ion) 394.

dl-6a, 7,11,10aa-Tetrahydo-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6H-dibenzo [b, d] pyran-9 (8H) -one, mp 215-218 ° C.

IR: (KBr) C = O 1695 ^cm-1, OH 3225 cm ^-1 MS (molecular ion) 344

NMR: δ

1,0-3,2. (M, 18, Hio C. _{5-cyclohexyl,} 6a / J 7,8,10,00aa protons)

1.5 (S, 6, gem.dimethyl),

3,9-4,3 (Μ, 1, cyclohexylmethynyl),

5.9, 6.05 (2d, 2, ArH),

8.9 (bs, 1, hydroxyl 40 O overlap).

dl-6α-β, 7,1,0,10α-Tetrahyddo-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenoxypropyl) -1H-dibenzoyl, d] ryran-9 (8H) mp 167-170 ° C.

MS: (molecular ion) 394

Analysis for C ^ · ₅ H ₃₀ Or calculated:

C, 76.11; H, 7.66; found:

% C, 75.93;% H, 7.63.

^NMR : ^δ

7.87 (S, 1, phenolic proton),

7.42- 6.67 (M, 5, C6H5),

6.33 (s, 2 ,. aromatic H ₂ + H 5)

4.42-1.00 (M, 22, non-aromatic protons including triplet centered at 3.90 for —CH2 —O—, singlet at 1.48 for CH3, doublet centered at 1.27 for CH3, singlet at 1.13 for CH3 and 11 other methylene, methine protons).

Example 4 dl-6a, β 7,7,8,9,10,10aa-Hexabydro-1-hydroxy-6,6-dimethyl-1H- (2-heptyloxy) -6H-dibenzyl [b, d] pyran-93-ol

To a solution of dl-7αa, 7,10,10α-tetrahydro-1'-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo [b, d] pyran-9 (8H) -one (0.60 g, 1.66 mmol) in ethanol (18 mL), stirred at room temperature under a nitrogen atmosphere, was added sodium borohydride (275 mg). The reaction mixture was stirred for 30 minutes and poured into a mixture of ice (35 mL), 10% hydrochloric acid (35 mL) and ether (200 mL). The ether phase was separated and the aqueous phase was extracted with an additional amount of ether (2 x 100 mL). The combined ether extracts were dried over sodium sulfate and evaporated to an oily residue. Crystallization from hexane gave 305 mg (50.3%) of m.p. 102-104 ° C.

NMR: δ TMS13

7.9-6.7 (single proton broad singlet, hydroxyl)

6.1-5.8 (two proton broad singlet, aromatic protons),

4.5 - 0.5 (31 protons multiplet, remaining protons).

IR: (KBr) OH 3390

Analysis for C22H34O4:

calculated:

% C, 72.89;% H, 9.45;

found:

% C, 72.52;% H, 9.18.

Similarly, the following compounds are prepared from the corresponding tetrahydrofuran compounds:

dl-7a8,7,8,9,10,10-hexxhydro-1-hydroxy-7,6-dimethyl-3- (1-methyl-4-phenynylbutoxy) -7H-dibenzoethyl, d] ryran-93-ol , as an amorphous solid.

IR (KBr): OH 3390 cm ¹

MS: (molecular ion) 410 ^NMR : δ with _δ

1.3 (β, 3, α-methyl),

1.0-4.5 (M, 24, protons remaining),

5.8 - 6.0 (M, 2, ArH),

6.8-7.3 (M, 5, ArH).

6aj3,7,8,9 dl-l (^, 5L ΰ0α-hexahydro-hydroxy-7,6-di · m (tthyl-3- (l-3-mtthyl ftnylrroρo. ⁱ xy) ^ H- dibenzo · [b, d] pyran-93-ol, amorphous solid.

MS: (molecular ion) 396 dl-Ba 1, 8,9,10,10 aa-1-Hydroxy-4-dimethyl-O-cyclohexyloxy-4 H -dibenzoyb, d] pyran-9e ₍ 3-ol, mp.) Mp 214-216 ° C.

IR: (KBr) OH 3365 cm ^-1 , 3125 cm ^-1

MS: (molecular ion) 346 ^NMR : ^δ

1.0-3.0 (M, 23, C ₅ H 10 -cycloohexyl, gem.dimethyl, 7D 9ral (0 pgotones),

3.5-4.15 (M, 2, 6a, 11 Caa-protons), 4.35-4.7 (M, 1, cyclohexylene), 4.85-5.05 (bd, 1, hydroxyl-D ₂ O) overlap),

7.1-7.45 (M, 2, ArH),

9.7 (S, 1, hydroxyl 40 O overlap).

dl-6a / 3,7,8,9,10,10aa-Hexahydro-1-hydroxy-7,6-dimethyl-3- (1-methyl-3-phenoxypropyl) YH-dibenzo [b, d] pyran- 93-ol, mp 151-152 ° C.

R _f = 0.25 (s-ilikagel, hexane-ether 9: 1)

MS: (molecular ion): 396

Analysis for; C25H32O4:

calculated:

% C, 75.72;% H, 8.14;

found:

75.79% С, 8.39% Η.

dl-6aI / 3-7,8,9,10,10aa-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenoxypropyl) -6H-dibenzo [b, d] pyran- 9a-ol, oil. R _f = 0.35 (silicagel ,. ether-hexane 9: 1) MS (molecular ion) 396th

Example 5 (-) -trans-3- (1-Methyl-4-phenylbutyl) -6a, 7,8,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzoyb, d] pyran-ln / S -ol

To a stirred solution of (+) p-mentha-2,8-dien-1-ol (4.9 g, 0.0322 mol) and 5- (1-methyl-4-phenylbutyl) resorcinol (8.2 g, Anhydrous magnesium sulfate (4 g, 0.332 mol) was added in anhydrous methylene chloride (200 mL). The mixture was stirred under nitrogen and cooled to 0 ° C. Fresh distilled boron trifluoride etherate (2 mL, 0.016 mol) was then added dropwise over 5 minutes. The reaction mixture was stirred at 0 ° C for 1.5 h and anhydrous sodium bicarbonate (10 g, 0.119 mmol) was added. Stirring is continued until the dark color fades. The reaction mixture was filtered and evaporated to give 11.7 g (93.6%) of the resin product. The product is purified by activated magnesium silicate column chromatography (supplied by M.S. Manufacturing Chemists, Cincinnati, Ohio, USA, under the designation "Florisil") to give 3.4 g (27%) of the desired product as an optically active mixture. diastereomers [α] _D ²⁵ - 100.8 ° (c - 1.0, CHCl ₃ ).

NMR: δ

1.1 (S, 3, C-methyl),

1.3, 1.45 (2S, 6, gem.dimethyl),

1.75 (S, 3, C8-methyl),

0.7-3.0 (M, 12, protons remaining),

3.0-3.6 (M, 1, C _10α -protone), 5.05 (S, 1, hydroxyl, D ₂ O overlap),

6.1 (S, 1, C / - proiton, ArH),

6.4 (M, 2, C ₂ -proton, ArH, C ₁₀ -proton),

7.1-7.5 (M, 5, ArH).

MS: (molecular ion) 390

To the optically active diastereoisomers 6a, 7,7,10,10aa-tetrahydro-1-hydroxy-3- (1-methyl-4-phenylbutyl) -6,6-dimethyl-6H-dibenzo | [b, d] pyran- 9 (8H) -one was converted by the method of Wldes et al., J. Org. Chem., 36, 721-3 (1971).

Example 6 dl-6a & 7,10,10aa-Tetrahydro-1- (4-morpholinoibutyryloxy) -6,6-dimethyl-3- (1-methyl-4-phenylhutyl) -6H-dibenzole [b, d] pyran-9 (8H) -one hydrochloride

To a stirred solution of dl-6a, 3,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran- 9 (8H) -one (0.52 g, 1.28 mmol) in anhydrous methylene chloride (25 mL) was added 4-morpholinobutyric acid hydrochloride (0.268 g, 1.28 mmol). The mixture was stirred under nitrogen at room temperature. A 0.1 molar solution of dicyclohexylcarbodiimide in methylene chloride (12.8 mL, 1.28 mmol) was then added dropwise and the mixture was stirred for 24 hours. Filtration and evaporation gave the title compound, which was then purified by silica gel column chromatography.

Example 7 dl-6aI / 3,7,10,10aa-Tetrahydro-1-acetoxy-6,6-diimethyl-3- (1-methyl-4-phenylbutoxy) -6H-dibenzo [b, d] pyran-9 (8H) )-he

Pyridine (15 ml), acetic anhydride (15 ml) and dl-6aI (3,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-4-phenylbutoxy) -6H The (dibenzoyl) pyran-9 (8H) -one (4.06 g) was mixed at 0 ° C and stirred at 0 ° C for half an hour. The reaction mixture was poured into ice-water and acidified with dilute hydrochloric acid. The acidified mixture was extracted with ethyl acetate (2 x 100 mL), the extracts were combined and washed with brine. The extracts were then dried (MgSO4) and evaporated to give a colorless oil which crystallized from ether / pentane. Yield 1.69 g, m.p. 95-96 ° C.

Analysis for C ₂₈ H ₃₄ O ₅ :

calculated:

% C, 74.64;% H, 7.61; found:

74.55% C, 7.59% H.

Evaporation of the mother liquors gave a second crystalline fraction, which was rinsed with hexane. Yield 1.74 g, mp 94-96 ° C.

By this procedure using the appropriate alkanoic anhydride and the corresponding dl-6aI, 7,10,10aa-tetrahydro-6,6-R4R5-3- (Z-W, -6H-dibenzo [b, d] pyran-9 ( The corresponding proipionyloxy, butyryloxy and valeryloxy esters are prepared by the 8H) -ones.

Reduction of the 9-keto group and the monioesters thus formed according to Example 2 gives the corresponding 9-hydroxy derivatives. This results in the 9α and 9β isomers.

Example 8 dl-6aii3,7,8,9,10,10aa-Hexahydro-1,9-diacetoxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran

Solution dl-6a / S-7,8,9,10,10aa-hexahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenyl207S71 butyl) -6H-dibenzo [b, d] of pyran-93-ol (2.0 g) in pyridine (20 mL) was treated with acetic anhydride (20 mL) at 10 ° C and stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was worked up as in Example 7.

In the same manner, the 1,9-dihydroxy compounds of the preceding examples are converted to the diacetoxy esters of dipropionyloxy esters, dibutyryloxy esters and divaleryloxy esters.

Example 9 dl-6a), 7,11,11a-Tetrahydro-1- (4-N-piperidyl-butyloxy) -? - dimethyl-5- [2- (5-phenyl) pentyloxy] -6H-dibenzo [b] d] pyran-9 (8H) -one hydrochloride

A mixture of dl-6a, 1 ', 7,10,10aa-t-tetrahydrohydro-1-hydroxy-6,6-dimethyl-3- [2- (5-phenyl) pentyloxy] -6'-tetrahydro-6,6-dimethyl-6- [beta] pyran-9 (8H) -one, (1.26 g,

3.08 mmol), 4-N-piperidylbutyric acid hydrochloride (0.639 g, 3.08 mmol) and dicyclohexylcarbodiimide, (0.698 g, 3.39 mmol) in anhydrous dichloromethane (3.5 mL) were stirred at 20 ° for 18 h. C. The reaction mixture was cooled to 0 ° C, stirred for half an hour and then filtered. The filtrate was evaporated to an oily residue, which was washed three times with ether to give 1.78 g (97%) of L-6a / -7,10,10a-tetrahydro-1- (4-N-piperidylbutyroxy) -6,6-7,4-7,8-7,7-7,4-tetrahydro-2-ol. methyl O- [2- (5-phenyl) pentyloxy] -6H-dibenzofb, d] pyran-9 (8H) -one hydrochloride as a white solid foam.

IR (KBr): NH + 2667, 2564, C = O 1779 and 1730 cm ^1st

MS (molecular ion) (M + -HCl), 407, 262, 247, 154, 98, and 91.

Claims (4)

I will invent the subject A process for the preparation of novel dibeazo [b, d] pyranes of the general formula I (I) wherein R is hydrogen or C 1 -C 5 alkanoyl. R 1 is hydrogen, C 1 -C 5 alkanoyl or a group of formula - CO (CH ₂ ) _p -NR _{2 R} 3, wherein p is 0 or an integer from 1 to 4, R ₂ and R ₃ are either individually hydrogen or C 1 -C 4 alkyl; R ₂ and R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidio, pyrrolo, pyrrolidino, morpholino and C 1 -C 4 -alkylpiperazino, R4 and _R5 are atoimy hydrogen, methyl or ethyl, Z is (C 1 -C 9) alkylene; or - (alpha 1-X - (alk ₂ ) n -) wherein each substituent (-alk ₁ ) and (alk ₂ ) has 1 to 9 carbon atoms, wherein the sum of the carbon atoms in and (alk <2) is at most 9, m and n are 0 or 1, X is · O, S, SO or · SO ₂ and W is methyl, phenyl, p-chlorophenyl, p-fluorophenyl, pyridyl, piperidyl, C 3 -C 7 cycloalkyl or C 3 -C 7 monosubstituted cycloalkyl wherein the substituent is phenyl, p-chlorophenyl or p-fluorophenyl, wherein when W is methyl, Z is - (alpha-X - - (afc) - characterized by reducing the compound of formula II wherein R1, R4, R5, Z and W are as defined above, and when R in the compound of formula I is alkanoyl, the compound obtained, wherein R is hydrogen, is reacted with the corresponding acid, its chloride or anhydride. 2. The process according to item 1, for the preparation of dibenzo [bi, d] pyraa of the general formula: wherein R4, R5, Z and W have the meaning given in item 1, characterized in that the compound of formula II is reduced wherein: R4, R5, Z and W are as defined above. 3. The method of item 1 or. 2, characterized in that the reduction of the compound of the formula II is carried out with a metal hydride. 4. A process according to claim 3, wherein the metal hydride is sodium borohydride.