CS207574B2 - Method of preparation of dibenzo/b,d/pyranes - Google Patents

Description

The present invention relates to novel dibenzopyrans, more particularly tetrahydrodibenzo [b, d] pyran-9 (8H) -ones containing in the 3-position 1) aryl or cycloalkyl (Wj bonded in this position via an alkylene group or 2) methyl, aryl or cycloalkyl bonded to this position through an O, S, SO, or SO ₂ group or bj by an alkylene group interrupted by an O, S, SO or SO ₂ group; or c) an alkylene group attached to position 3 or to said methyl, aryl or cycloalkyl via O, S, SO, or SO ₂ groups; and the use of these dibenzopyrans and derivatives thereof as analgesic agents for hypotensive, anti-secretory and anti-anxiety agents, as immunosuppressants and as tranquillizers in mammals, including humans, and as intermediates for the preparation of these agents.

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 suppressing severe pain and is known to have undesirable side effects. Other more potent analgesics, 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-fluoro-9 / S-hydroxyhexahydrocannabinol and other cannabinoid structures such as ^{8 8} -tetrahydrocannabinol- ( ^{8 8} -THC) and its primary metabolites, 11-hydroxy- ^{8 8} -THC have been reported by Wilsotn and May Absts Papers, Am. Chem. Soc. 168 Meet MEDI 11 (1974) and J. Med. Chem., 17, 475-476 (1974).

U.S. Patent Nos. 3,507,885 and 3,636,058 of 21, IV. 1970 and January 18, 1972 disclose various 1-hydroxy-3-alkyl-6H-dihenzo [b, d] pyrans containing substituents at the 9-position such as oxo, hydrocarbyl and hydroxyl or chlorine, hydrocarbylidene 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 psychotherapeutic agents.

DE Patent No. 2,451,934, issued September 7, 1975, discloses 1,9-dihydroxyhexahydrodibenzo [b, d] pyranes and certain 1-acyl derivatives having an alkyl or alkenyl group at the 3-position, which are hypotensive, psychoitropic, sedative and analgesic agents. Hexahydro-9H-dibenzO [b, d] 207574 pyran-9-olines precursors used in this preparation and having the same uses as the corresponding 9-hydroxy compounds are described in DE No. 2,451,932, issued September 7, 1975.

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

U.S. Patent 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.

Stereospecific synthesis of (-) -trans-6a, 7,8,10a-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dihenzo [b, d] pyran-1-ol, more commonly known as - (- j) Amotrahydrocannabinol, was reported by Razdan et al. (J. Am. Chetm. Soc. 96, 5860-5, 1974) The process, a one-step synthesis, involves the reaction of cis / trans- (+) -? - mentha-2,8- dien-1-ol with olivetoleim in the presence of 1% boron trifluoride etherate and anhydrous magnesium sulfate in methylene chloride at 0 [deg.] C. The resulting tetrahydrofuran compound is converted to the corresponding 9-ketohexahydro compound by the procedure of Wildes et al., J. Org.

36, 721-3 (1971). The process involves methylation of the 1-hydroxytetrahydro compound to methyl ether and then to the hydrochloride adduct by reaction with zinc chloride and HCl at 0 ° C in chloroform. The addition product is then dehydrohalogenated by treatment with potassium tricyclopentylcarbinolate to give the corresponding 6α, 7,8,9,10,10α-hexahydro-3-pentyl-6,6-dimethyl-9-methylene-6H-dibenzo [b, d Pyran-1-ol methyl ether. Oxidation of the 9-methylene group with periodate and potassium permanganate gives the 9-ketone. Demethylation of methyl ether with pyridinium chloride and other acidic substances affords 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 by alkoxy ( butoxyl, pentoxyl, hexoxyl and o-octoxyl J, and this substitution has been found to result in a loss of biological activity The hexoxiderivative has been reported to have a weak hashish effect at 10 to 20 mg / kg. kg.

In a recent paper by Loev et al., J. Med. Chem. 16, 1200-6 (1973) provides a comparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo [b, d] pyran-1-oles, wherein substitutable nt of the 3 - OCHfCHaJCsHjj, -CH ₂ CH (CH ₃₎ C ₅ H _u or CH (CH ₃₎ C ₅ H _U.

A compound containing an ether side chain m (O 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 methylene group.

We have now found a class of compounds effective as analgesic, hypotensive, anti-secretory and anti-anxiety, anti-immunological, and tranquilizers, namely, 1,9-dihydroxydihenzo [b, d] pyranes (Formula I), which are not narcotic and are not prone to addiction. The preparation of these compounds from the compounds of the present invention is described in Patent No. 207,571. In addition, valuable intermediates of the present invention have been found (Formula IIJ for the preparation of these compounds and derivatives thereof useful in dosage forms (Formula I, R = H). These compounds have the general formulas I and II

where

R is a substituent selected from the group consisting of hydrogen and C 1 -C 5 alkanoyl, or OR together with the hydrogen atom bonded to the ring carbon is = O,

R 1 is a substituent selected from the group consisting of hydrogen, C 1 -C 5 alkanoyl, and a group of formula

R ₂ /

-CO- (CH _{2) p} -N

R ₃ wherein p is 0 or an integer from 1 to 4 a

R @ ₂ and R @ 1 may each be hydrogen or C1 -C4 alkyl or, taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered h -etherocyclic ring selected from the group consisting of piperidino or 207574 ^; u, pyrrolo, pyrrolidino, morpholino and N-C 1-4 alkylpiperazino,

R ₄ and R ₅ are hydrogen, methyl or ethyl,

R _a is oxo or alkylenedioxy having from 2 to 4 carbon atoímy,

Z is a substituent selected from the group consisting of

(a) C 1 -C 9 alkylene;

b) - (alk,) _m —X— (alka) ,, wherein each of (alkj and (alk ₂ ) contains 1 to 9 carbon atoms, wherein the sum of the carbon atoms in (alk,) and (alk ₂ ) is at most 9, man is 0 or 1,

X is a substituent selected from the group consisting of O, S, SO and SO ₂ and

W is a substituent selected from the group consisting of methyl, pyridyl, piperidyl, -

where

W 1 is a hydrogen, fluorine or chlorine atom, or a group of formula c4 wherein

W ₂ is a hydrogen atom or a group of the formula

a is an integer from 1 to 5 and b is 0 or an integer from 1 to 5, wherein the sum of a plus b is not greater than 5, and when W is methyl, Z is - (alkali-X - (alk ₂ ) _n - ·

The compounds of the above formulas contain asymmetric centers at the 6a and / or 10a positions. Other asymmetric centers may be in the 3 - (- Z-W) -substituted position, in the 6 and 9-positions. Diastereoisomers with the 9ββ configuration are generally more preferred than the 9w-isomers as they exhibit a quantitatively greater biological activity. Similarly, trans- (6a, 10a) diastereoisomers are more preferred than cis- (6a, 10a) diastereoisomers.

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

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

Although the compounds of formula II are described below as intermediates for the preparation of the compounds of formula I, many, especially those having an oxo substituent (= O) at the 9-position, are analgesically active and have a further calming effect.

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

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

Table A

STEED STEED, OF m n w t / S-OH OH alkylene having 1 to 6 carbon atoms - - phenyl, pyridyl β-OH OH - (alk) _{m -} X - (alk ₂ ) _n - - phenyl, 1 1 pyridyl (3-OH OH - (alkik-X- 1 - phenyl, pyridyl .Beta.-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 [bj - CH (CH ₃ ) - (CH ₂ ) _{t -} C ₆ H ₅ (c)

- [(CH ₂ ) _q ] _{m -} O - [(CH ₂ ) _t ] _n -C ₆ H ₅ (d) - [CH (CH ₃ ) - (CH ₂ ) _q ] _{m -} O - [CH (CH _3] - (CH _{2) t} J _n -C ₆ H ₅ (e)

- [(CH ₂ ) _q ] _m -O- [(CH ₂ ) _t ] _n -CH ₃ (fj - [CH (CH ₃ ) - (CH ₂ ) _q ] _m -O- (CH (CH ₃ ) - (CH _{2) t] n} -CH _third

In the above table, each of the symbols q and t is an integer from 1 to · 4 and each of the symibals mi and n is 0 or * 1, with only one of the symbols m and n being 0.

Furthermore, intermediates of the above-mentioned preferred compounds (Tables A and B), in particular 6α, 7-dihydro-6H-dibenzo [b, d] pyran-9 (8H) -ones and 6α, 7,10,10α-tetrahydro-6H-dibenzo [ b, d] pyran-9 (8H) -ones of formulas II and III are preferred groups of intermediates because they are precursors of the compounds listed in Tables A and B above.

The compounds of the present invention are prepared from 6α, 7-dihydro-1-OR ₁ -6,6-R 4 R 5 -3- (Z-W j -6 H -dibenzo [b, d] pyran-9 (8 H i -one by Birch reduction). to give the corresponding 6a / 3,7,10,10aa-tetrahydrosloučenlny (formula II, R _o = oxo). the reduction is preferably carried out using lithium as the metal. also, they may be used sodium or potassium. the reaction is carried out at a temperature from about -35 to -80 degrees Celsius Birch reduction is preferred because it is stereoselective and results in the formation of the desired trans-ketone of formula II.

The reaction of compounds II and equivalent starting materials, wherein R _a is oxo with the appropriate alkylene glycol having 2 to 4 carbon atoms in the presence of a dehydrating agent such as, p-toluenesulfonic acid or other acid used in ketalisaci (oxalic acid, adipic acid] gives the corresponding ketaly.

Compounds of formula (I) are prepared from compounds of formula (II) as described in U.S. Patent 207,571. 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 adequately slowly with hydroxylic solvents (methanol, ethanol, water) to allow their use as solvent, generally from 0 to 30 ° C. temperatures lower than about -70 [deg.] C. are used, higher temperatures cause the reaction of sodium borohydride with hydroxyl solvents, and when higher temperatures are required for the reduction, isopropyl alcohol or dimethyl ether or diethylene glycol are used as solvents.

Compounds such as lithium borohydride or lithium aluminum hydride require anhydrous conditions and the use of non-hydroxy solvents (1,2-dimethoxyethane, tetrahydrofuran, ether, dimethyl ether or diethylene glycol).

The isomeric 9 '- and 9'-hydroxy compounds were prepared by this sequence. The above reaction sequence is shown schematically:

z-w (+ cis isomer)

The preparation of compounds of formula IV is described in U.S. Pat. No. 207,573 and the conversion of compounds of formula IV to compounds of formula III is disclosed in U.S. Pat. No. 207,572.

Compounds of formula II wherein —Z — W is _ (alk _t ) _m —X— (alk ₂ ) _{n —} W and X is -SO- or —SO ₂ - are obtained by oxidation of the corresponding compounds wherein X is -S- . A preferred agent for the oxidation of thioether to sulfoxides is hydrogen peroxide. The oxidation of the thioethers to the corresponding sulfones is preferably carried out with peracids such as perbenzoic acid, perphthalic acid or m-chloroperbenzoic acid. This latter peracid is particularly useful because the by-product m-chlorobenzoic acid is readily removed.

Esters of compounds of formulas II and III wherein R ₍ is alkanoyl or a group of formula —CO-- (CH2 _{) p —} NR ₂ R ₃ are readily prepared by reacting compounds of formulas 207574 c II or III with the corresponding alkanoic acid or acid of formula

HOOC - (CH ₂ ) _{P -} NR ₂ R ₃ in the presence of a condensing agent such as dicyclobexylcarbodiimide. Alternatively, they can be prepared by reacting compounds of formula II or III with an appropriate alkanoic acid chloride or anhydride, for example acetyl chloride or acetic 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 mouse behavior on a hot plate

The method used was a modification of the Woolfe method and Mac Donald, J. Pharmacol. Exp. 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 placed on a hot plate, and timing is started from the touch of an animal on the plate. Mice are tested 0.5 to 2 hours after treatment with the test compound and the time to the first "whipping" movement of one or both of any paws is read, or; whether 10 seconds have passed without this ¹ movement. Morphine has an MPE of ₅₀ = 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. Pharmacol. Exp. Therap. 72, 74-79 (1941) by applying controlled heat intensity to the tail. Each mouse was placed into po'hodlně mounted metal cylinder ¹ with elongated tail one end. The cylinder is arranged so that the tail lies above a hidden lamp for heating. At the beginning of the test, the aluminum lamp cover is removed and the light beam is passed through the slit and the tail end is focused. 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 protection end is 10 s. Each mouse is tested 0.5-2 hours after treatment with morphine and test compound. Morphine has an MPE _{50 of} 3.2-5.6 mg / kg (subcutaneously j.

c) Tail immersion test

The method is a modification of the procedure developed by Benhasset, J. Arch. int. Pharmacodyn. 122, 434 (1959). Male white mice (19-21 grams) of the Charles River CD-1 strain are weighed and labeled for identification. Five animals are used for each test group, each 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. Each animal is placed in a cylinder before drug administration and at 0.5 and 2 hours after administration. Each cylinder is provided with holes that 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 completely immersed in a constant temperature water bath (56 ° C). The end for each test is an energetic jerk or; tail twitch associated with motor reaction. In some cases, the end of the drug may be less potent. To avoid tissue damage, the test ends and the tail is removed from the water bath after 10 seconds. The reaction is recorded in seconds with the shortest time period of 0.5 seconds. Simultaneously, the vehicle is tested as a control and standard with known effect if substances do not return to baseline during! 2 hours, the reaction is measured after 4-6 hours. The final measurement is performed at ppi 24 hours, if an effect is still observed, then at the end of the test day.

Test using chemical pain stimuli

Suppression of Winding Induced by Phenylbenzoquinone

Groups of five Carworth Farmls CF-1 mice are treated subcutaneously or orally with sodium chloride solution, morphine, codeinepine test compound. After twenty minutes (subcutaneous treatment) or; after fifty minutes (oral treatment), each group is treated with an 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. An MPE of ₅₀ drugs that protect against writhing is detected.

Tests using pressure stimuli of pain

Haffner's tail squeeze effect

A modification of the procedure of Haffner, Experimentalle Prufung Schmerzstillender Mitel Deutch, is used. Copper. Wschr., 55, 731-2 (1929), which monitors the effect of test compounds on aggressive tail-induced reactions. A white rat (50-60 g) Charles River (Spraque-Dawley) CD strain was used. Prior to drug administration and again 0.5, 1, 2, and 3 hours after administration, a 6.5 cm root of the rat's tail was attached to the Johns Hopkins " bulldog " The end of each test is clearly attacking and biting 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 at 17.8 mg / kg intraperitoneally.

Tests using electrical stimuli for pain

Flinch Jump Test

A modification of this procedure, described by Temen in Psychopharmacologia, 12, 278-285 (1968), is used to determine the pain threshold. Male white rats (175-200 g) of the Carlee River (Spraque-Dawley) CD strain were used for the assay. Prior to administration, the feet of each rat were soaked in 20% glycerol solution and sodium chloride solution. The animals are then placed in a chamber where they receive a series of 1 foot shocks, increasing 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 in each rat prior to drug administration and 0.5, 2, 4, and 24 hours after drug administration.

The results of the above tests are evaluated as a percentage of the maximum possible; The MPE percentages for each group are statistically compared to the% MPE of the standard and the pre-drug control values calculated as follows:

% MPE = Test Time - Check Time Stop Time - Check Time x 100

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

The physician will determine the dose that is most suitable for an individual patient and which may vary according to the age, weight and response of the particular patient and the mode 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.

Oirální preferred dose ranges from about 0.01 to about 300 mg / d, a preferred range is from about 0.10 to ⁱ 50 mg / d. A preferred parenteral dose is from about 0.01 to about 100 mg / d, a preferred range is from 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 - phenylbenzoquinone-induced writhing test

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 attempted

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Example 1 dl-6aJ / 3 ^; 7,10,10aa-Tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-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-imethyl-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- and cis-6a, 10a-diastereomers as a crude oil, which was purified by silica gel column chromatography to give the trans-diastereoisomer followed in later fractions by the cis-diastereoisomer. This gives you:

dl-6α3 ', 7,10,10a-artetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one,

0.393 g, mp 200-205 ° C.

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

1.55 (S, 6, gemi-dimethyl),

2.35-3.0 (M, 7'-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 j.

IC: (CHCl ₃ ) C = 0 1600 cm ⁴ , and dl-6α, 7,10,10α, tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dihenzo [b, d] pyran-9 (8H) -one as a solid foam.

IR: (CHCl ₃ ) C = O 1690 cm ⁴ , OH 3275 cm ⁴ .

NMR: 0 '

IMS cnch

0.95-2.12 (M, 11'-methyl, ethylene, residual protons),

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

2.25-2.95 (M, 7''methylenes, benzyl methylene, methylene),

6.1-6.35 (M, 2, ArH),

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

7.25 (s, 5, ArH).

By repeating the procedure, but using the appropriate starting compounds, the following are obtained:

dl-6α / β, 7,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-5-phenylpentyl) -6H-diibenzo [b, d] pyran -9 (8H) -one, mp 159-163 ° C,

1.1, 1.5 (2S, 6, gem.dimethyl),

0,9-3,1 (M, 19'-methyl, OCH ₂ - (CH ₂ ) ₃ -CH (CH ₃ J-Ar, benzyl, the remaining protozoa),

3.9-4.4 (b. D. D, 1, .alpha.-carbonyl),

6.2 (M, 2, ArH),

7.0-7.4 (M, 5, ArH),

7.8 (S, 1, phenoil hydroxyl).

IR: (KBr) C = 0 1695 cm @ -1.

Analysis for C ₂₇ H ₃₄ O ₃ :

calculated:

79.76 ° / o C, 8.43% H; found:

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

dl-6a | 3,7,10,10α / 3-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-5-phenylpentyl) -6H-dibenzo [b, d] pyran- 9 (8H) -oin, mp 91-130 ° C.

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

MS: (molecular ion) 406, dl-6α / β ^; 7,10,10aia-tetrahydro-1-hydroxy-6,6-dimethyl-3- (2-phenylethyl-6H-dlbenzo [b, d] pyran-9 (8H) -one, mp 206-209 ° C). IR (KBr): OH 3260 ^'4 cm, C = O 1710 cm ^1st

1.05-1.45 (2S, 6, dimethyldimethyl),

2.75 (bs, 4, ethylene),

1.1-3.1 (M, 7, remaining protons),

3.75, 4.0 (2d, 1, 10? Proton),

6.2 (d, 2, Ar H),

7.15 (s, 5, ArH),

8.8 (S, 1, hydroxyl-D ₂ O overlap).

MS: (molecular ion) 350, d1-6a1S, 7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylpropyl) -6H-dibenzo [b, d] pyran-9 (8H) -one, mp 165 ° C.

IR: (KBr) OH 3175 cm ⁴ , C = 0 1695 cm ⁴ , and dl-α1,110,10α-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylpropyl) 207574

-6H-dibenzoyb, d] pyran-9 (8H) -one as a solid foam.

IR: (C'HCl ₃ ) C = O 1685 cm ^-1 , OH 3250 cm ^-1 .

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);

7.25 (δ, 6, ArH, hydroxyl), dl-6a, 7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenoxybutyl) -6H -dibenzo [b, d) pyran-9 (8H) -one. mp 160-175 ° C.

MS: (molecular ion) 408.

R _f = 0.53 (silica gel, benzene-ethyl acetate 8: 2).

7.41-6.67 (multiplet, 6, phenolic OH, C ₆ H ₅ ),

6.3 (S, 2, aromatic H ₂ + H ₄ ),

4.33-1.50 (Ms, 15, remaining methylene, methine protons),

1.47 (s, 3, _CH3);

1.27 and 1.17 (D, 3, Me),

1.12 (s, 3, _CH3).

Analysis for C ₂₆ H ₃₂ O ₄ :

calculated:

H, 7.89; H, 7.89;

found:

76.61% C, 7.90% H, dl-6a3,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-4- (4-pyridyl) butyl] -6H-dibenzo [b, d] pyran-9 (8H) -one, mp 60-70 ° C.

Rf = 0.4 (silica gel, ethyl acetate).

MS: (molecular ion) 393.

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

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

3.97-4.2 (broad O, 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-6a, 7,10,10aa-tetrahydro-1-hydroxy-6c-methyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b d] pyran-9 (8H) -one, mp 163-167 ° C (melting at 140 ° C).

IR: (KBr) C = 0 1708 cm ^-1 .

Analysis; for C ₂ 5H ₃₀ O ₃ :

calculated:

79.33% C, 7.99% H; found:

% C, 79.43;% H, 8.03.

MS: (molecular ion) 378, dl-6a and 3,7,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylethoxy) ethyl] -6H -dibeUzo [b, d] pyran-9 (8H) -one (solid glass):

NMR: δ ™ * _l5

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

1.24 (d, J = 7Hz, methyl)

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

1.6-3.2 (M),

3.2-3.8 (M),

4.05 (M, one proton),

4.30 (M, one proton),

6.33 (s, two ArH),

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-6aI, 7,10,10a (3-tetrahydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylethoxyethyl) -6H-dibenzo [b, d] Pyran-9 (8H) -one, mp 127-130 ° C.

1.20 (d, J = 7Hz, methyl)

1.32 and 1.39 (s, g. Dimethyl),

1.8-3.8 (M),

6.25 (s, two ArH),

7.07 (s, phenol) and

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-6a3,7,10,10a-Tetrahydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenizo [b, d] -9 (8H) -one

Dl-6α / 3 ', 7-dihydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo [b, d] pyran-9 (8H) -one solution (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. An additional 75 mg of lithium is added during the dropwise addition to provide a blue color. After stirring for 15 minutes, solid ammonium chloride was added to remove the blue color. The excess ammonia was allowed to evaporate, the residue was diluted with water (45 mL) and acidified with 10% hydrochloric acid. The aqueous solution was extracted with dichloromethane (3 x 50 mL) and the dichloromethane extracts were dried over sodium sulfate and evaporated. 1.30 g of crude semi-solid was obtained, which was purified by silica gel chromatography to give 0.614 g (50.9,%) of the product, m.p. 155-158 ° C, after crystallization from chloroform and hexane.

NMR (CDCl ₃ ) δ - 8.2 (single proton singlet, phenolic OH),

5.8- 6.3 (two-protein multiplet, aromatic hydrogen),

3.9-4.6 (two diproton multiplet, methine ether and equatorial C-10),

0.3-3.2 (26 protons, multiplet, remaining protons).

IR: (KBr) C = O 1737 cm ^-1 .

MS: (m / e) 360 (M &lt; + &gt;), 261 (M-99).

Analysis for C 22 H 32 O 4: __________ calculated:

73.30% C, 8.95% H; found:

73.05% C, 8.82% H, and the corresponding cis-isomer:

17a, 13a, 7, 10, 10a, l] 3-Tetrahydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6H-dibenzo [b, d] pyran-9 (8H) -one mp 141-146 ° C (from ether-hexane).

IR: (KBr) C = O 1718 cm ^-1 .

MS: (m / e) 360 (M &lt; + &gt;), 261 (M-99).

Similarly, the following compounds were prepared from the products of Example 1:

dl-6ai (3,7,10,10a-Tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H-dibenzo [b, d] pyranr 9 (8H) - mp, mp 122-125 ° C.

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 (broad D, 1, C — 10 equatorial, J = 14 Hz),

4.1-4.7 (M, 1, methine),

5.95 (D, 1, ArH, J = 2 Hz),

6.1 (D, 1, ArH, J = 2 Hz),

7.2-7.4 (M, 5, ArH),

7.9 (S, 1, phenolic proton).

IR (KBr): C = 1709 cm ^1st

Analysis for C26H32O4:

calculated:

% C, 76.44;% H, 7.90;

found:

76.22% C, 7.79% H, and the corresponding cis-isomer:

dl-6a, 7,10,10a / 3-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H-dibenzo [b, d] pyran-9 ( M.p. 141-142 ° C.

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

MS: (molecular ion) 408.

Analysis for C ₂₆ H ₃₂ O4:

calculated:

% C, 76.44;% H, 7.90; found:

76.58% C, 7.92% H, dl-6a, 3,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylpropoxy) -6H -dibenzo [b, d] pyran-9 (8H) -one, mp 160 ° C.

1.2, 1.3 (d, 2, -methyl),

1.4 (S, 6, g. Dimethyl),

1.65-2.9 (M, 11, protons remaining),

3.9-4.5 (M, 2,10aa-proton, methinyl),

5.9- 6.1 (2d, 2, ArH),

7.2 (s, 5, ArH),

7.9 (S, 1, hydroxyl-D ₂ C overlap).

MS: (molecular ion) 394, dl-6a / 3,7, 10,10aa-tetrahydro-1-hydroxy-6,6-dlmethyl-3-cyclohexyloxy-6H-dibenzo [b, d] pyran-9 (8H) mp 215-218 ° C.

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

· NMR δ ™ ^s

INIVIIX. y _{CDCl 3}

1.0-3.2 (M, 18, C ₅ H ₁₀ -cyclohfexyl, 6a 3,7 3,7,8,10,10aa -protons),

1.5 (S, 6, dimethyl dimethyl),

3.9-4.3 (M, 1, cyclohexylmethynyl),

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

8.9 (bs, 1, hydroxyl-D ₂ O overlay), dl-6a, 7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenoxypropyl) - 6H-dibtenzo [b, d] pyran-9 (8H) -one, mp 167-170 ° C.

MS: (molecular ion) 394

Analysis for C25H30O4:

calculated:

C, 76.11; H, 7.66;

207S74 found:

75.93 0 / oC, 7.63% H.

7.87 (S, 1, phenolic proton),

7.42-6.67 (M, 5, C ₆ H ₅ ),

6.33 (S, 2, aromatic H ₂ + H ₅ ),

4.42- 1.00 (m, "22, non-aromatic protons including a triplet centered at 3.90 -CI-I ₂ - -0-, singlet at 1.48 for CH _3, doublet centered at 1.27 for CH _3, singlet at 1.13 for CH ₃ and 11 other methylene, methine protons).

Example 3 dl-6a, 1, 7,10,10aa-Tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylsulfinylpropyl) -6H-dibenzo [b, d] pyran-9 (8H) -one

Equimolar amounts of m-chloroperbenzoic acid and dl-6a _; 3,7,10,10aa-Tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylthiopropyl) -6H-dibenzo [b, d] pyran-9 (8H) -one to be reacted together for 1 hour at room temperature in a 2: 1 mixture of chloroform and acetic acid. The organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness to give the product. In the same manner, thioethers are oxidized to the corresponding sulfoxides of the formula

EXAMPLE 4 d1-α1,11,10,10 -ate-Tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylsulfonylpropyl) -6H-dibenzo [b, d] pyran-9 (8H) ) -on

The procedure of Example 3 was repeated, but using 2 equivalents of m-chloroperbenzoic acid as the oxidizing agent per mole of thioether reaction component.

Similarly, thioethers are converted to the corresponding sulfonyl derivatives to give compounds of the formula:

Example 5 dl-6a, 7,10,10aa-Tetrahydro-1- (4-morpholinobutyryloxy) -6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran -9 (8H) -one hydrochloride

To a stirred solution of dl-6a, 7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, dj 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 6

Dl-6a, e, 7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyloxy) -6H-dibenzo [b, d] pyran-9 ( 8H) -one

Solution dl-6a / β, 7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyloxy) -6H-dibenzo [b, d] pyran-9 ( 8H) -one (60 mg, 0.145 mmol), ethylene glycol (0.5 mL), benzene (10 mL) and the p-toluenesulfonic acid crystal were heated to reflux for 3 hours. The reaction mixture was then cooled and concentrated. The concentrate was shaken with chloroform and the chloroform phase was washed first with sodium bicarbonate and then with water. Dry over magnesium sulfate and concentrate to give the ketal as a light brown oil (63 mg).

Repeating this procedure using propylene glycol, trimethylene glycol and tetramethylene glycol instead of ethylene glycol yields the corresponding ketals.

In this way, the ketones of Examples 2, 3, 4 and 5 are converted to the corresponding ethylene, trimethylene and tetramethylene ketals.

Example 7 dl-6ai (3,7,10,10aa-Tetrahydro-1-acetoxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6 H -dibenzo [b, d] pyran-9 [ 8H) -one

Pyridine (15 mL), acetic anhydride (15 mL) and dl-6αS, 7,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H- dibenzo [b, d] 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.

Using this procedure using the appropriate alkanoic anhydride and the corresponding dl-6a, 7,10,10a-tetrahydro-6,6-R4R5-3- (Z-WJ-6H-dibenzo [b, dj pyran-9 (8H)) The corresponding propionyloxy, butyryloxy and valeryloxy esters are prepared according to Examples 1 and 2.

By reduction of the 9-keto group and the thus-formed moniesters, the corresponding 9-hydroxy derivatives are prepared. This results in the 9α and 9β isomers.

Example 8 dl-6a, 7,10,10aa-Tetrahydro-1- (4-N-piperidyl-butyroxy) -6,6-dimethyl-3- [2- (5-phenyl) pentyloxy] -6H-dibenzo [B, d] pyran-9 (8H) -one hydrochloride

Dl-6aI / 3,7,10,10aa-tetrahydro-1-hydroxy-6,6-dimethyl-3- [2- (5-phenyl) pentyloxy] -6H-dibenzo [b, d] 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) was stirred at 20 ° C for 18 hours. 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 dl-6a / 3,7,10,10aa-tetrahydrol- (4-N-piperidylbutyroxy) -6,6- dimethyl 3- [2- (5-phenyl) pentyloxy] -6 H -dibenzo [b, d] pyran-9 (8 H) -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 (3)

Subject A process for the preparation of dibenzo (b, d) pyranes of formula A wherein O Q is group C, / \ R 1 is hydrogen, C 1 -C 5 alkanoyl or R ₂ / -CO- (CH _{2) p} R ₃ --N invention wherein p is 0 or an integer of 1 to 4 and R ₂ and R ₃ may each be hydrogen or C 1 -C 4 alkyl, or taken together with the nitrogen 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 -C 4) alkylpiperazino; R ₄ and R ₅ are hydrogen, methyl or ethyl, Z is a substituent selected from the group consisting of (a) C 1 -C 9 alkylene; b) - (alkjm-X- (alk ₂ ) _n -, wherein each of (alkj and (alk ₂ ) contains 1 to 9 carbon atoms, the sum of the carbon atoms in (alkt) and (alk ₂ ) being at most 9, man is 0 or 1, X is a substituent selected from the group consisting of O, S, SO or SO ₂ and W is methyl, phenyl, p-chlorophenyl, p-fluorophenyl, pyridyl, piperidyl, cycloalkyl of 3 to 7 carbon atoms which is optionally monioisubstituted and wherein the substituents are phenyl, p-chlorophenyl or p-fluorophenyl, wherein when W is methyl, Z is - (alk-X - (alk ₂₎ n- »wherein reducing a compound of formula B 2. The process according to claim 1, wherein the reduction of the compound of formula B is carried out by Birch reduction. 3. A process according to claim 3, wherein lithium is used as the reducing metal in the Birch reduction.