NO742546L - - Google Patents

Description

Process for the production of 1,3-oxygenated 8a-bstratrienes

The present invention relates to a process for the production of 1,3-oxygenated 8a-ostratrienes with the general formula: where X is oxygen or the group

R 1 and R 3 are hydrogen, acyl, alkyl, cycloalkyl or oxygen-containing saturated heterocyclic groups,

2

R is lower alkyl, and

R 4 is hydrogen or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group.

Acyl groups are those of physiologically acceptable acids. Preferred acids are organic carboxylic acids or sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic or heterocyclic series. These acids can also be saturated and/or polybasic and/or substituted in the usual way. As examples of these substituents, alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms can be mentioned.

For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, smoric acid, isosmuric acid, valerian acid, iso-valeric acid, caproic acid, onantic acid, caprylic acid, pelargonic acid, capric acid, undecyl acid, lauric acid, tridecyl acid, myristic acid, pentadecyl acid, trimethylacetic acid, diethylacetic acid, t-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidineacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, nicotinic acid, isonicotinic acid, and furan-2-carboxylic acid.

Sulphonic acids include, for example, methanesulfonic acid, ethanesulfonic acid, fS-chloroethanesulfonic acid, butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid, N,N-diethylaminosulfonic acid, N,N-bis-([5-chloro ethyl)-aminosulfonic acid, N,N-diisobuty 1-aminosulfonic acid, N,N-dibutylaminosulfonic acid, pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino- and morpholinosulfonic acid on speech.

1 3

As the alkyl groups R or R, preferably lower alkyl groups with 1-5 carbon atoms come into consideration, which may be substituted or branched in the usual way. As examples of the substituents, mention may be made of halogen or lower alkoxy groups. Particularly preferred is the methyl or ethyl group.

As cycloalkyl groups, for example, those with 3-8 carbon atoms come into consideration, and of these, the cyclopentyl group is preferred.

Saturated oxygen-containing heterocyclic groups are those derived from heterocyclic compounds with at least one oxygen atom in the ring and which are perhydrated in the oxygen-containing ring.

can

The tetrahydrofuryl and tetrahydropyranyl groups are mentioned, of which tetra-

the hydropyranyl group is preferred.

As the substituent R, lower alkyl groups come into consideration, examples of which include methyl, ethyl, propyl and butyl. Preferred groups are the methyl or ethyl group.

As the hydrocarbon group R<4>, the alkyl, alkenyl or alkynyl group with up to 6 carbon atoms comes into consideration, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl, ethynyl, propenyl, butadienyl, butadiynyl can be mentioned. The group can also be substituted in the usual way, as substituents such as other halogens are mentioned. Preferred hydrocarbon groups R<4> are ethynyl, respectively the chloro-ethynyl group.

The compounds produced according to the invention exhibit a favorable dissociated pharmacological activity. Due to the strong vaginotropic and weak uterotropic effect, they are preferred for the treatment of postmenopausal women. Thus, they can be used in the treatment of dstrogen-deficient conditions, in which a centrally directed effect on the uterus is to be avoided, while an effect on the vagina is, however, desirable. The compounds produced according to the invention are also usable as starting materials for the production of pharmacologically valuable steroids.

The favorable estrogenic dissociation allows e.g. demonstrate

in the sialic acid sample of mice. Thus, the compounds produced according to the invention, as shown in Table 1 for the known estrogens 17a-ethynyl-1,3,5(10)-dstratriene-3,17B-diol (I) and 1,3,5(10) -6stratriene-3,17p-diol (II) and the new steroids 1,3,17(3-triacetoxy-8a-6stra-1,3,5(IO)-triene (III), 1,3-diacetoxy-8a -dstra-1 ,3 ,5( 10) -trien-17[3-ol (IV) , 1,3-diacetoxy-8a-ostra-1 ,3 ,5( 10 ) , tr i en-17-one ( V), 1,3-dimethoxy-8a-ostra-1,3,5(10)-trien-17-one (VI), 1,3-dicyclopentyloxy-8a-5Stra-1,3,5(10)- trien-17-one (VII) , 1,3-dihydroxy-8a-6stra-l,3,5(IO)-trien-17-one (VIII), 1,3-dimethoxy-17a-ethyny1~8a-dstra -1,3,5(10)-trien-17p-ol (IX), 1,3-diacetoxy-17a-ethynyl-8a-dst~a-1,3 ,5( 10)-trien-17(3- ol (X) and 1,3-dimethoxy-8a-6stra-1,3,5(10)-trien-17(3-ol (XI), a dissociation quotient that far exceeds the standard compounds.

The sialic acid test is carried out as follows:

The mice over ectome es. From den'lo. day after castration, the mice receive the prdve compound once a day for three days. On the 4th day the animals are killed. The vagina and uterus are immediately removed and weighed for hydrolysis in a test tube. The sialic acid is determined according to Svennerhold [Biochem. Biophys. Acta 24 (1957), 604]. The dose-dependent increase in organ weight ay vagina and uterus as well as the decrease in the sialic acid content is determined, from which the relative potency of the first compound compared to the standard compound estradiol (II) is determined. The relative activities are put into relation and give the degree of dissociation Q. For the standard compound ostradiol, Q = 1. Compounds with Q 1 are relatively vaginotropic, and with Q-< 1 they are relatively uterotropic.

The threshold values given in Table I were determined by it

normal Allen-Doisy test in rats.

The production of pharmaceutical preparations with the compounds according to the invention takes place in the usual way, as the active substance is transferred to the desired administration forms such as tablets, dragées, capsules, solutions, etc., with the carriers, diluents, flavoring agents, etc. used in galenic pharmacy. The concentration of the active substance in the drugs thus prepared depends of the administration form, Thus a tablet preferably contains 0.01 - 10 mg; solutions for parenteral administration contain 0.1 - 20 mg/ml solution.

The dosage of medicinal products containing the method compounds may vary with the method of administration and the compound chosen in each case. Moreover, it can also vary with the patient. In general, the compounds prepared according to the invention are administered in a concentration which can produce the effective results without causing any adverse or harmful side effect; thus they are administered, e.g. in a dose-sized els e that lies in the area from approx. 0.Q2 mg to approx. 20 mg, although changes may occur depending on the circumstances, so that a dose of more than 20 mg, e.g. up to 50 mg can be used. However, a dose size in the range from approx. 0.05 mg to approx. 5 mg.

Formula

The compound with the general gel can be prepared by hydrogenating a 6stra-oligo-ene with the general gel in a manner known per se

- formula:

12

where R , R and X are as indicated above, and A... B is denoted a single or double bond, and optionally then, depending on the ultimately desired meaning of X and R, reduces the 17-keto group and/or splits off the ether or the acrylic group, and/or esterifies and/or etherifies free hydroxy groups. '

The compounds of formula I can also be prepared by oxidizing a 3-hydroxy-13-R 2-8a-ostra-1,3,5(10)-trien-17-one with lead. tetraacylate, rearranges the reaction product in the presence of a strong acid and optionally then, depending on the desired meaning of X and r, reduces the 17-keto group, and/or splits off ether or acyl groups, and/or esterifies and/or etherifies free hydroxy groups.

The production of the new compounds takes place at i and for

known procedures.

The hydrogenation of the dstra oligoenes with formula II can e.g. happen by catalytic hydrogenation. Catalysts include heavy metal catalysts such as palladium, optionally distributed on carriers such as calcium carbonate, activated carbon or barium sulphate, or Raney-Nickel. During the hydrogenation, an unsaturated hydrocarbon group R 4 that may be present in the molecule can be partially hydrogenated at the same time. If the compounds with R 4 in the sense of an unsaturated hydrocarbon group in finally desired compounds, it is advantageous to carry out the hydrogenation of the compounds of formula II where X is oxygen, and then carry out reduction with a meta.1 organic compound where the organic group R 4 is an unsaturated hydrocarbon group.

The oxidation with lead tetraacetate and the subsequent rearrangement in the presence of acid is known in the literature for 3-hydroxy-8S-dstra-1,3,5-(10)-trienes, but cannot, however, be transferred to the corresponding 3-hydroxy-8a- dstratriene [Ruf er et al., Liebig's Ann. Chem. 752 (1971), p}. In contrast to Rufer et al. successful completion of the reaction

when the oxidation with lead tetraacylate is carried out in the usual way, the reaction being however interrupted already after a short time, e.g. after 3 minutes. This is followed by processing and resettlement.

A 17-keto group can then be reduced, to which several processes known per se stand for 1, advisedly. The reduction can take place by reaction with hydrogen in the presence of a common catalyst, e.g. Raney-Nickel in benzene. Moreover, the hydrogen can be transferred from metal hydrides to the 17-keto group. As hydrogen donors, particularly complex hydrides, such as sodium hydride borate, lithium hydrido-aluraihat, sodium hydride trimethoxoborate, lithium hydride tri-t-butoxy-aluminate, etc. proved beneficial.

The reduction can also be carried out by known methods with an organometallic compound where the organic group is R 4, and which may be an alkylmagnesium halide, such as e.g. methylmagnesium bromide or iodide, an alkenyl magnesium and/or alkenyl zinc halide, such as e.g. vinylmagnesium bromide or allyl-magnesium bromide, an alkynylmagnesium halide, such as ethynylmagnesium-. bromide, propynylmagnesium bromide or propynylzinc bromide, or an alkali metal acetylide, such as potassium acetylide. The organometallic compound used as reducing agent can also be formed in situ and reacted with the 7-ketone of formula II. Thus, e.g. for reaction with organometallic alkynyl compounds an alkyne, chloroalkyne or alkadiyne and an alkali metal act on the ketone, preferably in the presence of a tertiary alcohol or ammonia, optionally under elevated pressure.

Free hydroxy groups can then be esterified or etherified.

Esterified or etherified hydroxy groups can be transferred into hydroxy groups.

The acylation in the 1- and 3-position preferably takes place with pyridine/acid anhydride, respectively pyridine/acid chloride, at room temperature. Alkylating compounds such as preferably diazomethane, dialkyl sulphate, cycloalkyl halides and dihydropyran are used for etherification in the 1- and 3-position.

For esterification of the 17B-hydroxy group in 1,3-diesters and 1,3-diethers, e.g. acid anhydrides in the presence of strong acids such as p-toluenesulfonic acid, HCIO^, or pyridine/acid anhydride act on the steroid during heating. The latter methods can also be used to transfer the free trihydroxy compound immediately to the triacylate. From the triacylates, the 1- and 3-hydroxy groups can be released by gentle partial saponification.

1,3-diester and 1,3-diether can be converted to the corresponding 17-tetrahydropyranyl ether with dihydropyran in the presence of a strong

acid such as p-toluenesulfonic acid. The etherification of the 17-hydroxy group of the 1,3-diethers with an alkyl group is preferably carried out with alkylhalo-,

nides in liquid ammonia. The two latter methods also make it possible to prefer all hydroxy groups in the hydroxy compounds in one work step.

From 1,3-diacyl-17-tetrahydropyrany1-derivatives, 1- and

The 3-hydroxy group is released by alkaline saponification.

The ether cleavage is carried out by methods known in the art.

Examples include the cleavage with pyridine hydrochloride or pyridine/concentrated hydrochloric acid at elevated temperatures (180 - 220°C) or with hydrogen halides in the presence of lower carboxylic acids at temperatures below 150°C, and the cleavage and tetrahydropyranyl ethers take place under mild conditions with acid addition .

In order to increase the yield, it may be appropriate to proceed from such compounds where the hydroxy groups in the 1- and 3-positions are esterified or etherified. When e.g. the ether groups are only to be introduced as provisional protecting groups, it is advantageous to ether with dihydropyran, as this group is particularly easily cleavable after continued reaction.

The reduction can also be carried out so that ester groups present in the starting material are retained. On the other hand, hydroxy groups in the 1- and/or 3-position which are released during the reduction can be selectively reacylated.

3-Hydroxy-8α-ostra-1,3,5(10)-trien-17-ones are known from the literature" The other starting compounds can be prepared as described in the example of 1,3-dimethoxy-1,3 ,5 10),8,14-dstrapentaen-17-one (A), 1,3-dimethoxy-17B-acetoxy-1,3,5( 10),8,14-ostrapentaene (B) and 1,3- dimethoxy-17S-acetoxy-1,3,5(10),8-osteratetraene (C)„

A: 1, 3- dimethoxv-l, 3 , 5 ( IO ), 8, 14- ostrapentaen- 17- one

For a suspension of 17 g magnesium shavings in 15 ml abs. A trace of iodine and 2 ml of ethyl bromide are added to THF, and after heating to 50°C, vinyl chloride is introduced slowly until the temperature drops to room temperature. During the introduction, 250 ml of abs. THE A solution of 52.4 g of 6,8-dimethoxy-tetralone in 84 ml of abs is slowly dripped into this vinyl-grignard solution at 20°C. THF and 82 ml abs. benzene, and the reaction mixture is left overnight in a dressing room under nitrogen. After heating to room temperature, the reaction mixture is poured into a mixture of 84 ml of glacial acetic acid and 350 ml of ice water, stirred for 30 minutes, the water phase is separated and extracted with benzene. The combined organic extracts are washed sterile with sodium bicarbonate solution and water, and dried. In this solution of the vinyl compound, 38 g of 2-methyl-cyclopentane-dione are added

(1,3) and 160 mg of powdered potassium hydroxide, which is evaporated to half, 170 ml of methanol are carefully added dropwise and heated for 3 hours to boiling under nitrogen. The reaction mixture is allowed to cool, diluted with ether and the excess of 2-methylcyclopentanedione-(1,3) is removed by extraction with 10% caustic soda. After neutral washing with water, drying and evaporation, recrystallize from ethanol. 66 g of 1,3-dimetboxy-8,14-seco-1,3,5(10),9(11)-distratetetraene-14,17-dione with melting point 87/88-89°C are obtained.

A solution of 69 g of 1,3-dimethoxy-8,14-s eco-1,3,5(10)-,-9(11)-distratetetraene-14,17-dione in 940 ml of distilled benzene is added to 3 g of -toluenesulfonic acid and heated to boiling for 20 minutes.

After cooling, extract with cold sodium bicarbonate solution, wash neutrally with water and dry. After circumscribing tallis as ion from

acetone/hexane over charcoal gives 60 g of ras. -1,3-dim ethoxy-1,3,5(10),8,14-dstrapentaen-17-one with melting point 120 - 121°C.

B: 1T 3- dimethoxy- 178- acetoxy- 1, 3, 5( 10), 8, 14- ostrapentaene

A solution of 60 g of ras.-1,3-dimethoxy-1,3,5(10),8,14-ostrapentaen-17-one in 2.4 1 methanol and 1.0 1 THF is added at

room temperature slowly 6.0 g NaBH^ 0<3 there is stirred for 30 minutes under nitrogen at room temperature. The reaction mixture is neutralized with glacial acetic acid, evaporated, taken up in ether, washed neutral with saturated sodium chloride solution, dried and evaporated. The residue is dissolved in 140 ml of pyridine, the solution is added to 80 ml

acetic anhydride and stirred for one hour at 80°C under nitrogen. After cooling, ice water is added, the precipitate is filtered off and taken up in ether. The ethereal solution is washed neutrally with saturated sodium chloride solution, dried and evaporated. Recrystallization from methanol over charcoal yields 61.0 g of ras.-1,3-dimethoxy-17B-acetoxy-1,3,5(10),8,14-ostrapentaene with melting point 122 - 124°C.

C: 1, 3- dimethoxy- 17B- acetoxy- 1, 3, 5( 10) , 8- ds tratetraene

700 mg ras. 1,3-dimethoxy-76-acetoxy-1,3,5(10),8,14-dstrapentaene in 10 ml of distilled THF is hydrated over 200 mg of Pd/CaCO3 (5%-ig) at room temperature under normal pressure until absorption _ se of 46.6 ml of H2• After filtering off the catalyst, drying and evaporation, 447 mg of ras .-1, 3-dimethoxy-7B-acetoxy-1,3,5(10),8-distratetetraene with melting point were obtained from methanol 111/112-113°C.

When using 2-ethyl-cyclopentane-dione-(1,3) , respectively 2-propylcyclopentane-dione-(1,3) and further processing according to

A; B and C are obtained 1,3-dimethoxy-18-methy1-1,3,5(10),8,14-dstrapentaen-17-one respectively. 1,3-dimethoxy-18-ethy 1-1,3 , 5( 10 ), 8 ,14-os trapentaen-17-one and 1,3-dimethoxy-17B-acetoxy-18-methyl-1,3, 5( 10),8,14-dstra_

the pentane or 1,3-dimethoxy-17B-acetoxy-18-ethyl-1,3,5(10),8,14-'

dstrapentaene and 1,3-dimethoxy-17B-acetoxy-18-methyl-1,3,5(10)-8-dstratetetraene respectively. 1,3-dimethoxy-17B-acetoxy-18-ethyl-1,3,5(10)8-distratetetraene.

The following examples serve to illustrate the invention. From the starting method, the compound can be obtained as well as the racemate, which ...enantiomers are. It is obvious to the person skilled in the art that the racemates can be separated into the enantiomers by the known methods for separating optical antipodes.

Example 1

rag.- 1, 3- dimethoxy- 8a- dstra- 1, 3, 5( 10)- trien- 17- one

0.3 g ras:.-1,3-di methoxy-1,3 , 5( 10 ), 8 , 14-ds trapentaen-17-one

in 50 ml of THF is hydrated in the presence of 0.15 g of palladium/CaCO3 (5% strength) over a period of 17 hours at room temperature under 50 atm hydrogen pressure. The catalyst is then filtered off, the filtrate is evaporated and the residue is recrystallized from isopropyl ether. You get 40 mg of product with a melting point of 158 - 160°C.

Example 2

rac.- 1, 3- dimethoxy- 176- acetoxy- 8g- dstra- l, 3, 5( 10)- tri en

a) 61 g of ras.-1,3-dimethoxy-17S-acetoxy-1,3,5(IO),8,14-ostrapentaene in 400 ml of benzene are hydrated in the presence of 14 g of Raney-Nickel over the course of 17 hours at room temperature below 50 ato hydrogen pressure kk. The catalyst is then filtered off, the filtrate is evaporated and the residue is recrystallized from methanol over charcoal. You get 50 g of material with a melting point of 136 - 138°C.

b) 100 mg of ras.-1,3-dimethoxy-17B-acetoxy-1,3,5(10),8-distratetetraene is hydrated in 1.4 ml of distillate. THF over 30 mg Pd/CaC03 (5%-ig) below

normal pressure at room temperature until no more hydrogen is released. After filtration and evaporation, 44 mg of material with a melting point of 126/130-131°C is obtained from methanol.

Analogously: ras.-1,3-dimethoxy-17B-acetoxy-18-methyl-8a-ds tra-1,3,5(10)-tri en r as . -1, 3 -d i me t hoxy -17J3 - ac e t oxy -18 - e t h v 1 - 8.a ds t r a -1. 3. 5 ( 10) -1 r in one.

Ex empel<_>3

ras .- 1, 3, 17B- triacetoxy- 8a- dstra- l. 3, 5( 10)- triene

A mixture of 1 g of ras.-1,3-dimethoxy-17B-acetoxy-8a-dstra-1,3,5(10)-triene and 10 g of pyridine hydrochloride is heated under nitrogen and stirring for 3 hours at 200°C . After cooling, the melt is dissolved in 50 ml of pyridine and stirred with 5 ml of acetic anhydride for one hour at room temperature. After precipitation in ice water, the product is filtered off and processed. The crude product is purified by gradient chromatography (methylene chloride/acetone 9 + 1). 930 ing of material with melting point 146/147-148°C is obtained.

In an analogous way: ras.-1,3,17B-triacetoxy-18-methyl-8a-dstra-1,3,5(10)-triene ras.-1,3,17B-triacetoxy-18-ethyl-8g -dstra-1,3,5(10)-triene.

When using caproic acid or caprylic anhydride instead of acetic anhydride is obtained: raso-1,3,17S-tris-hexanoyloxy-8a-ostra-1,3,5(10)-triene raso-1,3,17B-tris-octanoyloxy-8a-dstra- 1,3,5(10)-tri one.

Example 4

ras.- 1, 3- dimethoxy- 8g- dstra- l, 3. 5( 10)- trien- 17B^ ol

4.5 g of ras.-1,3-dimethoxy-17B-acetoxy-8a-dstra-1,3,5(10)-triene are saponified in 100 ml of methanol with 13 ml of aqueous 10% potassium hydroxide solution at 1, 5 hours heating under reflux under nitrogen. After cooling, carefully neutralize with glacial acetic acid, evaporate to half the volume, pour into ice water/sodium chloride and work up. You get 4.1 g of raw product. Recrystallization of 500 mg from methanol yields 330 mg with melting point 153/153.5-154°C.

In an analogous way: ras.-1,3-dimethoxy-18-methyl-8α-dstra-1,3,5(10)-tri en-17S-ol ras.-1,3-dimethoxy-18-ethyl- 8α-dstra-1,3,5(10)-trien-17B-ol.

Example 5

ras.- 1, 3- dimethoxy- 17B- acetoxy- 8a- dstra- l. 3, 5( 10)- tri en

A solution of 60 mg of ras.-1,3-dimethoxy-8g<->dstra-1,3,5-(1O)-trien-17-one in 3 ml of methanol and 1.0 ml of THF is slowly added at room temperature 60 mg of NaBH4 and stirred for 30 minutes under nitrogen at room temperature. The reaction mixture is neutralized with glacial acetic acid, evaporated, taken up in ether, washed neutral with saturated sodium chloride solution, dried and evaporated. The residue is dissolved in 1 ml of pyridine, 0.5 ml of acetic anhydride is added to the solution and kept for one hour at 80°C under nitrogen. After cooling, pour into ice water, filter off the precipitate and take up in ether. The ethereal solution is washed neutrally with saturated sodium chloride solution, dried and evaporated. After recrystallization from methanol over charcoal, 42 mg of product with a melting point of 131 - 134°C are obtained.

Example 6

breed. - 1, 3-dimethoxy-17a-ethynyl-8g-dstra-l, 3,5(10)-trioen-176-ol

1.2 g of potassium t-butylate (10 mmol), 2.5 ml of t-butanol and 20 ml of abs. THF in an autoclave, purge with nitrogen and fill with acetylene to 4.5 ato. After 30 minutes, 740 mg of ras.-1,3-dimethoxy-8a-dstra-1,3,5(10)-trien-17-one are added in 5 ml of abs. THF and allow it to react for 45 minutes under acetylene pressure. Pour into 40 ml of diluted sulfuric acid (20% strength) and ice, extract with methylene chloride and work up. The crude product is purified by liquid chromatography. One obtains from hexane/acetone 430 rng of product with melting point 177/178-179°C..... i,

Analogously, but without t-butanol as a solvent during the ethynylation, the following is obtained: ras.-1,3-dimethoxy-18-methyl-17a-ethynyl-8a-dstra-1,3,5(10)-trien-17B-ol ras .-1,3-dimethoxy~18-ethyl-17α-ethynyl-8α-dstra-1,3,5(10)-trien-17B-ol.

Example 7

ras.- 1, 3- diacetoxy- 8g- dstra- l, 3. 5( 10)- trien- 17- one

A mixture of 25 g of pyridine hydrochloride and 2.5 g of 1,3-dimethoxy-8g<->dstra-1,3,5(10)-trien-17-one is heated under nitrogen and stirring for 3 hours at 200° C. After cooling, adding 120 ml of pyridine and 12 ml of acetic anhydride and stirring for one hour at room temperature, the solution is poured into ice water/sodium chloride, stirred for half an hour, the product is filtered off and worked up. The crude product (2.5 g) is purified by gradient chromatography (60 g SiO 2>methylene chloride/10% acetone). After recrystallization from methanol, 710 mg of product with a melting point of 179 - 180.5°C are obtained.

Example 8

race. - 1. 3- diacetoxy- 17g-ethyny l- 8a- dstra- l , 3 , 5( IO) - tri en- 17B-Q.1

A mixture of 8.3 g potassium t-butylate, 2.5 ml t-butanol in 20 ml abs. After flushing with nitrogen, the THF is rotated in the roller bomb for one hour at room temperature under acetylene. Then 740 mg of ras.-1,3-diacetoxy-8g<->dstra-1,3,5(10)-trien-17-one are added in 5 ml abs. THF and there is rolled under acetylene at our els et erap is that ur for two hours. The reaction mixture is poured into 40 ml of diluted sulfuric acid (20%), the solid is filtered off and worked up. The crude product is post-acetylated in 5 ml of pyridine in 2 ml of acetic anhydride. After water sweeping and work-up, the crude product (850 mg) is purified by gradient chromatography (20 g SiO2, hexane/25% acetone). 152 mg of product with a melting point of 154-155°C is obtained.

Analogously, but without t-butanol as a solvent in the ethynylation, the following is obtained: ras.-1,3-diacetoxy-18-methyl-17a-ethynyl-8a-dstra-1,3,5(10)-tri en-' 17S- 01 ras.-1,3-diacetoxy-18-ethyl-17a-ethynyl-8a-ostra-1,3,5(10)-trien-17B-ol.

Example 9

1. 3- diacetoxy- 8g- ostra- l, 3, 5( 10)- trien- 17- one

To a suspension of 42 g of 3-hydroxy-8a-dstra-1,3,5(10)-trien-17-one in 500 ml of glacial acetic acid, 120 g of lead tetraacetate is added, then stirred for 3 minutes at room temperature while excluding moisture and then the reaction mixture is poured into 600 ml of ice water. The precipitate was suctioned off, washed with water and the filter residue taken up in methylene chloride. This material solution was washed neutral with sodium bicarbonate solution, dried and evaporated. The concentrate was filtered with methylene chloride over 400 g of silica gel (+ 10% water). The material-containing fractions were combined and freed from solvent. 7 g of 10S-acetoxy-8a-dstra-1,4-dien-3,17-dione were obtained as an oil.

A suspension of 13.0 g of 10B-acetoxy-8a-dstra-1,4-diene-3,17-dione in 125 ml of acetic anhydride was added dropwise with 0.7 ml of concentrated sulfuric acid and stirred at room temperature for 3 hours, whereby the material the whole thing slowly became enlightened. The reaction mixture was then poured into the tenfold amount of ice water, 7 g of sodium carbonate was added, the mixture was stirred for one hour and then filtered. The washed and dried residue was recrystallized from methanol. 7 g of material with a melting point of 208-211°C were obtained. [α]<20>= +89° (CHC1: , c = 0.5).

D

Analogously, one got:

1,3-Diacetoxy-18-methyl-8α-ostra-1,3,5(10)-trien-17-one.

Example 10

1. 3. 3 7B- triacetoxy- 8a- ostra- l, 3 , 5( 10)- triene

A solution of 6 g of 1,3-diacetoxy-8a-dstra-1,3,5(1O)-triene- in 240 ml of methanol and 100 ml of THF was slowly added at room temperature to 600 mg of NaBH4 and stirred for 30 min under nitrogen at room temperature. The reaction mixture was neutralized in glacial acetic acid and acetylated according to Example 5 and worked up. Yield 4.8 g. Melting point: 149/50-151°C. [ci]<2>° = +4.2° (CHC1 , c=0.5).

D 3

Analogously, one got:

1,3,17B-triacetoxy-18-methyl-8a-dstra-1,3,5(10)-triene.

Example 11

1, 3- diacetoxy- 17a- ethynvl- 8a- dstra-l, 3, 5( 10)- trien- 17B-ol"

750 mg of 1,3-diacetoxy-8a-dstra-1,3,5(10)-trien-17-one was ethynylated according to Example 8 and worked up. Yield 230 mg of a non-crystalline foam. [α]<2>° = -33.8° (CHCl , c =0.5).

D

Analogously, one obtained: 1,3-diacetoxy-18-methyl-17a-ethynyl-8a-ostra-1,3,5(10)-trien-17B-ol.

Example 12

1, 3- bis- cvclopentyloxv- 8a- dstra- l, 3 , 5 ( 10 )- trien- 17B-ol

A solution of 850 mg of 8a-dstra-1,3,5(10)-trien-1,3,517B-triol in 30 ml of ethanol was heated under nitrogen with 2.5 ml of cyclopentyl bromide and 2.5 g of potassium carbonate in five hours during cooking. The mixture was then poured into ice water, taken up in ether, the organic phase was washed, dried and evaporated. After chromatographic purification on silica gel, 365 mg was obtained.

Example 13

1. 3- bis-butyloxv- 8g- dstra- l, 3 , 5( IO)- trien- 17B-ol

Analogous to Example 12, 500 mg of 8a-dstra-1,3,5{10)-trien-1,3,17S-triol was reacted with 1.5 ml of n-butyl bromide and worked up. One received 230 mg.

Example 14

1, 3, 17B- tris- tetrahydropyranyloxy- 8a- dstra- 1. 3, 5( 10)- tri en

To a solution of 800 mg of 8α-dstra-1,3,5(10)-trien-1,3,17B-triol in 40 ml of abs. benzene was added to 1.4 ml of dist. dihydropyran and 10 mg of p-toluenesulfonic acid. The solution was stirred for 1.5 hours at room temperature, then washed neutrally with sodium bicarbonate solution and water, dried and evaporated. 700 mg of crude product was obtained.

Eczema gel _15

1, 3. 17-tris-hexanoyloxy-8g-dstr, a-l, 3. 5( 10) - the trien

A solution of 450 mg of 8g<->dstra-1,3,5(10)-trieneTl,3,17B-triol in 3 ml of pyridine was added to 1.5 ml of caproic anhydride and heated under nitrogen for five hours at 90°C. The mixture was then poured into ice water, some methanol added and stirred for one hour to decompose excess anhydride. It was taken up in ether, the ethereal solution was washed neutral with dilute sulfuric acid, sodium bicarbonate solution and water, dried and evaporated. After chromatographic purification over silica gel, 320 mg was obtained.

Example 16

1 ^- dimethoxy- l^ g- chlorethynyl- Sg- dstra- l , 3 , 5( 10)- trien- 17P-ol

Of 1.39 g lithium and 6.9 ml methyl iodide in 50 ml abs. ether, a methyl-lithium solution was produced by heating under reflux (45 minutes under nitrogen). After cooling to 0°C, 3.75 ml of dichloroethylene in 15 ml of abs. ether instilled. After stirring for 1.5 hours at room temperature, a solution of 1.3 g of 1,3-dimethoxy-8g-dstra-1,3,5(10)-trien-17-one in 50 ml of THF was added over the course of 30 minutes , and the mixture was heated to boiling for one hour. Saturated sodium chloride solution was then added under ice cooling, diluted with ether, washed neutral, dried and evaporated. After purification over silica gel, 475 mg were obtained.

Example 17

1, 3- diacetoxy- 8a-- dstra- l, 3, 5(1O)- trien- 17B-ol

A solution of 1 g of 1,3-diacetoxy-8g<->dstra-1,3,5(10)-trien-17-one in 30 ml of abs. The THF was stirred under ice cooling with 2 g of lithium-tri-t-butoxy-aluminium hydride for 45 minutes under ice cooling. The reaction mixture was then poured into acetic acid ice water/sodium chloride and extracted with ether. The organic phase was washed neutral, dried and evaporated. The residue (1 g) was purified by layer chromatography and, after recrystallization from hexane/acetone, 380 mg of 1,3-diacetoxy-8α-dstra-1,3,5(10)-trien-17B~ol was obtained with a melting point of 210-211° C.

Example _18

1. 3- dihydroxy- 8g- dstra- 1, 3 , 5( 10)- trien- 17- one

A solution of 3 g of 1,3-diacetoxy-8g<->dstra-1,3,5(10)-trien-17-one in 9 ml of methylene chloride and 18 ml of methanol was added at 0°C under nitrogen to 0, 23 ml of perchloric acid (70%) in 1 ml of methanol, and stirred for three days at room temperature.

It was then diluted with acetic acid ester and washed neutrally with sodium chloride solution. After drying and evaporation, 2.9 g of 1,3-dibydroxy-8a-dstra-1,3,5,(10)-trien-17-one were obtained as an oily material.

Example 19

1. 3- bis- mesyloxy- 8a- dstra- 1, 3, 5 ( 10 )- trien- 17- one

A solution of 1 g of 1,3-dihydroxy-8a-dstra-1,3,5(10)-trien-17-one in 14 ml of pyridine was added at 0°C with 1.9 ml of methanesulfonic acid chloride and stirred for three days at 0-10°C. The mixture was then poured into ice water (acidified with hydrochloric acid), filtered and the residue was dissolved in methylene chloride. After chromatography on silicic acid, 800 g of 1,3-bis-mesyloxy-8a-dstra-1,3,5(10)-trien-17-one were obtained.

Example 20

1. 3- bis- mesyloxv- 8a- dstra- l, 3 , 5( 10)- trien- 17B-ol

To a solution of 400 mg of 1,3-bis-mesyloxy-8a-dstra-1,3, 5(10)-trien-17-one in 10 ml of absolute tetrahydrofuran was added 800 mg of lithium-tri-t-butoxy-aluminum hydride and stirred for 60 minutes at 0°C. It was then neutralized with glacial acetic acid and extracted with acetic acid ester. The organic phase was washed with water, dried and evaporated. The crude product obtained (400 mg) was purified by layer chromatography. 320 mg of 1,3-bis-mesyloxy-8a-dstra-1,3,5(10)-triene-17p-ol were obtained.

Example_21

1, 3- bis- mesvloxy- 17B- acetoxy- 8a- dstra- l, 3 , 5 ( 10 )- triene

A solution of 200 mg of 1,3-bis-mesyloxy-8a-dstra-1,3,5(10)-trien-17B-ol in 3 ml of pyridine was added to 2 ml of acetic anhydride and left for three days at room temperature. The reaction mixture was then poured into ice water, extracted with methylene chloride, washed with water, dried and evaporated. The residue (180 mg) was purified by layer chromatography. 150 mg of 1,3-bis-mesyloxy-17B-acetoxy-8a-dstra-1,3,5(10)-triene was obtained.

Example 22

1, 3, 17p- tris- mesyloxy- 17a- ethynyl- 8a- dstra- l, 3, 5( 10)- tri en

Acetylene was introduced into a suspension of 1.2 g of potassium t-butylate in 20 ml of absolute tetrahydrofuran at -10°C for 60 minutes. Into the thus obtained suspension of potassium acetylide is poured the solution of 400 mg of 1,3-diacetoxy-8a-dstra-1,3,5(10)-trien-17-one in 8 ml of absolute tetrahydrofuran. Additional acetylene is introduced at -10°C with stirring for 1.5 hours, the reaction mixture is then neutralized by adding glacial acetic acid, the reaction mixture is poured into ice water and extracted with ether. The ether solution is washed with water, dried and evaporated. The crude product obtained (250 mg) is dissolved in 5 ml of pyridine, 1 ml of methanesulphonic acid chloride is added at 0°C and stirred at 0-10°C for three days. The mixture is then poured into ice water (acidified with hydrochloric acid), filtered off and the residue dissolved in methylene chloride. After chromatography on silicic acid, 250 mg of 1,3,17B-tris-mesyloxy-17a-ethynyl-Ba-ds tra-1,3,5(10)-triene is obtained.

Example 23

1, 3- bis-(p- tosyloxy)- 8g- dstra- l, 3. 5( 10)- trien- 17- one

A solution of 1 g of 1,3-dihydroxy-8a-dstra-1,3,5(10)-trien-17-one in 14 ml of pyridine is added at 0°C to 2.5 g of p-toluenesulfonic acid chloride and stirred for three days at 0-10°C. The reaction mixture is then poured into ice water (acidified with hydrochloric acid), the precipitate is filtered off and dissolved in methylene chloride. After chromatography on silica gel, 820 mg of 1,3-bis-(p-tosyloxy)-8α<->dstra-1,3,5(10)-trien-17-one is obtained.

Example 24

1, 3- bis-(diethylamino- sulfonyloxy)- 8a- astra- 1, 3, 5( 10)- trien- 17- one

250 mg of sodium hydride (50% suspension in oil) and rotated for 30 minutes at room temperature. A solution of 1.05 g of diethylaminosulfonyl chloride in 2 ml of dimethylsulfoxide is then added and stirred for 25 hours at room temperature. The reaction mixture is poured into acetic acid ice water (sodium chloride), the organic material is extracted with ether and the extract is washed, dried and evaporated. After chromatographic purification, 150 mg of 1,3-bis-(diethylamino-sulfonyloxy)-8a-dstra-1,3,5(10)-trien-17-one is obtained.

Example 2 5

1. 3 - bis-(piperidino-sulfonyloxy)-8a- dstra-l, 3, 5(10)-trien-17-one

The aforementioned compound is prepared from 1,3-dihydroxy-8α-dstra-1,3,5(10)-trien-17-one by reaction with piperidino-sulfonyl chloride analogously to Example 24.

Claims (2)

1. Analogous method for the preparation of therapeutically active 1,3-oxygenated 8a-ostratrienes of the general formula where X is oxygen or the group R 1 , R 3 are hydrogen, acyl, alkyl, cycloalkyl or an oxygen-containing saturated heterocyclic group, 2 R is lower alkyl, and R 4 is hydrogen or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group, characterized in that: (a) a dstra-oligo-ene with the general formula: 12 where R , R and X are as indicated above, and A... B denotes a single or double bond, is hydrogenated, or , (b) a 3-hydroxy-13-R 2-8a-dstra-1,3,5(10)-trien-17-one is oxidized with lead tetraacylate, and the reaction product is rearranged in the presence of a strong acid, and that, depending on the ultimately desired meaning of X and R <1> , the 17-keto group is reduced and/or the ether or acyl groups are split off and/or free hydroxy groups are esterified and/or etherified.