Estratriene containing bridge

 

(57) Abstract:

Use: as intermediate products in the synthesis of pharmaceuticals. The inventive product is estratriene containing 14, 17 - bridge General formula I:

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where: if OR3is in-position, R1, R2and R3independently from each other H, acyl, C1-C2or R1- benzyl, or C1-C8alkyl, and if OR3located in the b - position, R1, R2and R3independently of one another, H, C1-C12acyl or C1-C8alkyl, and in both cases a-B ateno or ethano-bridge. 2 C. and 10 C.p. f-crystals, 1 tab., 1 Il.

The invention relates to covered bridge in position 14, 17 estratriene General formula I

< / BR>
where

if OR3is in position , it

R1, R2and R3independently from each other represent a hydrogen atom, acyl group in which R4represents an organic residue with a number of carbon atoms up to 11, or a residue -/CH2/nCOOH carboxylic acid, with n=1-4, and, in addition, R1denotes benzyl, C1-C8-alkilany or C3-C5-cycloalkenyl balance, and

if OR3on what kind acyl group with 1-12 C-atoms, and R1additionally represents C1-C8is an alkyl residue, and in both cases A-B denote ateno or ethano-bridge,

the method of production thereof, pharmaceutical preparations that contain these compounds and to the use for the preparation of drugs.

As acyl groups, R1, R2and R3take into account the residues of organic carboxylic acids with 1 to 12 C-atoms. They are produced from aliphatic, cycloaliphatic, alifaticheskii-cycloaliphatic, cycloaliphatic-aliphatic and aromatic monocarboxylic acids with 1 to 12 C-atoms. The number of carbon atoms in the ring varies from 3 to 7. As residue R1, R2and R3preferred acyl groups are acetic, propionic, butyric, isoalkanes, pavlinovoi, nylon, acrylic, crotonic, p, Caprylic, pelargonate, decanoas, undecanol, dodecanol, 3-cyclopentylpropionate and benzoic acids.

In particular acyl residues R1, R2and R3must come from such carboxylic acids which contain 2 to 8 C-atoms.

Acyl group, R1, R2and R3also the strong acid.

If R1denotes alkyl residue, then first of all it is a methyl residue; also attach special importance ethyl, sawn and isopropyl residues. As cycloalkyl residue R1preferred cyclopentadienyl the rest.

In the framework of the invention it should be noted the following connections:

3-benzyloxy-14, 17-ethano-1,3,5/10/-estratrien 16, 17-diol;

14, 17 ethano-1,3,5/10-estratrien-3, 16, 17-triol;

14, 17 ethano-3-methoxy-1,3,5/10-estratrien - 16, 17-diol;

16, 17 diacetoxy-14, 17-ethano-3-methoxy-1,3,5/10/-estratrien;

3,16, 17 triacetoxy-14, 17-ethano-1,3,5/10/-estratrien;

14, 17 ethano-1,3,5/10/-estratriene-3,16, 17-triol;

14, 17-etheno-3-methoxy-1,3,5/10/-estratrien - 16, 17-diol;

14, 17-etheno-3-methoxy-1,3,5/10/-estratrien - 16, 17-diol;

14, 17 ethano-1,3,5/10/-estratrien-3, 16, 17-triol;

3-acetoxy-14, 17-etheno-1,3,5/10/-estratrien - 16, 17-diol;

3,16-diacetoxy-14, 17-etheno-1,3,5/10/-estratrien - 17-ol;

14, 17-etheno-1,3,5/10/-estratrien-1,16, 17-triol-triacetate;

16, 17 diacetoxy-14, 17-etheno-1,3,5/10/-estratrien-3-ol;

14, 17-etheno-1,3,5/10/-estratrien-3, 3,16, 17-triol;

3,16-diacetoxy-14, 17-ethano-1,3,5/10/-estratrien - 17-ol;

14, 17 ethano-1,3,5/10/-estratriene-3,16, 17-triol-triacetate;

3-acetoxy-14, 17-ethano-1,3,5/10/-estratrien - 16, 17-diol;

Proposed in the invention compounds of General formula I differ from the known blocked 14, 17-bridges of estratriene, the additional presence of a free or esterified ester to located in the a - or b-position hydroxyl group of 16 carbon atoms.

On the other hand, as orally estrogeno effective steroid with 3 hydroxyl functions of known natural 16-estriol [1,3,5/10/-3,16, 17-triol] /E. Schroder, C. Rufer, R. Schmiecken, Pharmazeutische Chemie, Georg Thieme Werlag Stuttgart, New York, 1982, S. 571 and subsequent/.

As known related prior art compounds proposed in the invention compounds differ extremely strong estrogenic activity.

Compounds of General formula I in Allen-Disy-test after subcutaneous injection is more effective than estriol /see table, column 4/.

In the Allen-Doisy test carry out the assessment of smears from vagina if ovariectomised rats in the estrus /leukocytes and nucleated epithelial cells/

2 proestrus /nucleated cell epithelia/

3 estrus /Horny tubercles/

4 metestrus /nuclear-free Horny tubercles, leukocytes, epithelial cells/.

Estrogeno effective substances after oral or subcutaneous administration lead to proliferation matinales epithelium and keratinization of the surface layers of cells. As the threshold is assumed that amount of estrogen at which 50% of the animals reached stage 3.

Otherwise, as estriol proposed in the invention compounds but also strongly estrogeno effective after oral administration, since the destruction of 17-OH-group is blocked tertiary 17-carbon atom.

The drawing shows an extremely clear superiority 14, 17 ethano-östra 1,3,5/10/-triene-3, 16, 17-triol, compared with 14, 17 ethano-östra 1,3,5/10/-triene-3,17-diola /and also compared with estradiol and ethinyl estradiol/ also after oral administration.

This effect is unexpected. The transfer of estradiol to the corresponding overlapped 14, 17-bridge derived - 14, 17-ethano-östra 1,3,5/10/-triene-3,17-diol relative to astrogenetix barely affected when subcutaneous injection; accordingly proposed in Isabelle.

Thus, the invention relates also to compounds of General formula I for the treatment of phenomena caused by the lack of estrogen and to control the ability to produce offspring women.

Proposed in the invention compounds can be formulated and used in the same way as with levonorgestrel, which is the most commonly used estrogen. These compounds together with conventional pharmaceutical additives, carriers and/or improving the taste substances in a usual way can be processed in conventional dosage forms. For oral administration are taking into account in particular tablets, coated tablets, capsules, pills, suspensions or solutions. For parenteral administration are taking into account in particular oil solutions, for example, solutions in sesame or castor oil, which, if necessary, may additionally contain a diluent, such as benzyl benzoate or benzyl alcohol.

The concentration of biologically active substances in the pharmaceutical compositions depends on the form of application and scope. So, for example, capsules or tablets for the treatment of symptoms of lack of oestrogens may contain 0.001 to 0.05 mg of biologically asset is logically active substances and vaginal ointment about 0.1-10 mg per 100 ml of ointment. For contraception for women offered in the invention astrogeny used in combination with gestagens. Tablets or pills for daily intake of one tablet or one bean should contain preferably 0.003 to 0.05 mg offered in the invention of estrogen and 0.05-0.5 mg progestogen.

Proposed in the invention compounds can be used in case of insufficiency of estrogen in women, such as amenorrhea, limenaria, infertility, endometritis, colpitis and menopausal ailments and for the prevention of osteoporosis. Connections may be used as the estrogen component in hormonal contraceptives /single-phase, multiphase and multistage drugs/. In addition, in combination with other biologically active substances are suitable for use in carrying hormones intrauterine pessaries, implantable carriers for biologically active substances, and also used in transdermal systems.

The new compounds of General formula I

< / BR>
where

if OR3is in-position,

R1, R2and R3independently from each other represent a hydrogen atom, acyl group in which R4represents the organic residue with SUP> denotes benzyl, C1-C8-alkyl or C3-C5-cycloalkenyl the rest,

if OR3is in-position,

R1, R2and R3independently from each other represent a hydrogen atom, acyl group with 1-12 C-atoms, and R1additionally represents C1-C8is an alkyl residue, and in both cases A-B denote ateno or economistic,

get that

And the compound of General formula II

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where

R1denotes acetyl or methyl residue,

R2denotes acetyl residue, and

X is acetoxy-residue or a chlorine atom,

a) when R1denotes acetyl residue, or enter into an interaction with a three-second-butylbromide potassium or with a basis for obtaining the compounds of formula III:

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and then the compound of formula III or restore using sociallyengaged to a mixture of 16-hydroxy - 16-hydroxy-compounds of formula IV and IV:

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either the compound of formula III is then catalytically hydronaut to compound IIIA:

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and the connection IIIA restore using alanate to a mixture of lithium compounds VII and VII:

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and the connection VII and VII in clorhidrato sodium obtaining the compounds of formula IV:

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or

b/ when R1denotes a methyl residue, compound II omelet to the compounds of formula V:

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and then use alanate lithium restore a mixture of 16-hydroxy - 16-hydroxy-compounds of formula VI and VI:

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and then in a desirable scenario 3 simple methyl ester cleaved with formation of compounds IV and IV, and desirable in the case of

or

in/ after stage and/ or b/ first compound of the formula IV or mixture of compounds of formulas IV and IV or catalytically hydronaut to the compounds of formula VII or to a mixture of compounds of formulas VII and VII and then, if necessary, the compound of formula VII or mixture of compounds of formulas VII and VII partially or fully amyraut and, if necessary, a free hydroxyl group in position 3 is transformed into ether and/or other free hydroxyl group atrificial to ester or, however, desirable in the case of

g/ after stage and/ or stage b/ first compound of the formula IV or mixture of compounds of formulas IV and IV selectively at the 3-position atrificial to esters with the formation of the compounds of formula VIII or mixture of compounds of formulas VIII and VIII:

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where R1denotes an acyl residue with 1 to 12 C-Utomlennye formula HB or mixture of compounds A and HB:

< / BR>
where R1denotes an acyl residue with 1 to 12 C-atoms, catalytically hydronaut and, if necessary, the connection HB or Ha/HB partially or fully atrificial to esters or if necessary atrificial to simple essential free 3-hydroxy group and/or etherification to ester other free hydroxyl group or VIII or VIII/VIII, if necessary, sequentially next atrificial to obtain esters and, if necessary, the 3-acyl group selectively omelet and/or 3-hydroxyl group in case of need atrificial to simple broadcasting, or

B/ to obtain compounds where OR3is in-position, the compound of General formula Ha

< / BR>
where

R' represents acetyl or methyl group, or a compound of General formula HB

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where

R denotes a hydrogen atom or a methyl group, A-B denotes C-C single or C=C-double bond, and R"' represents a hydrogen atom or acyl group with 1-12 C-atoms, restore by means of an alkali metal in liquid ammonia to obtain an aromatic system in the A-ring and, if necessary, the double bond in the A-B and 14 -, 17-ateno-Mosteiro, as already indicated above, or

At/ To produce compounds where OR3is only in a-position, and A-B denote only one ethano-bridge, the compound of General formula XXII

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where

R1Ndenotes benzyl or methyl residue, cyclist to compounds of General formula I':

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and then, if necessary, a simple 3-benzyl or 3-methyl ether is cleaved and the free hydroxyl group is then, if necessary, partially or fully omelet, or, if necessary, a free 3-hydroxyl group atrificial simple to broadcasting and/or other free hydroxyl group atrificial to ester, or if necessary after cyclization first etherification to ester available 16-, 17-hydroxyl group and then, if necessary, split 3-benzyl or 3-methyl simple ether and, if necessary, a free 3-hydroxyl group again atrificial to simple ether or ester to.

To the alternative method AND

Getting the original products of General formula II is carried out by introducing into the interaction of 3-acetoxy - 3-methoxy-1,3,5/10/-14,16-astreinte-17-ol-acetate /G. H. Rasmusson and other Steroids is irout as ketone equivalents for cycloaddition /4+2/ diene system in the D-ring of the steroid starting compounds. Until now it was known only by their interaction with cyclopentadiene /"Ketene Equivalents" Synthesis, 1977, S. 289-296/. These initial products of General formula II therefore also apply to the subject matter.

Obtaining compounds of General formula IV and the General formula IV of the parent compounds of General formula II, R1acetyl/ flows through the 16-ketone of formula III. When the saponification of compound (II) with suitable for reaction of saponification of the Foundation or restoration of compound II with a complex hydride, as selected(R)/three-Deut.-butylbromide potassium / reaction stops at the stage of the 16-ketone III.

16-Keto-group in compound III can then be restored later when applying a different, less spatially constrained complex hydride to the hydroxyl function. Examples are sodium borohydride or sociallyengaged, which is a spatial less difficult complex hydride. Restore the original connections II /R1acetyl/ using both of these last reductants also causes the 16-hydroxy function. Depending on the size /space/ complex hydride 16-keto-group is translated only in 16-hydroxy-funanage complex hydride, as if this should occur, the impact on it from the side of the double bond from the direction 14, 17-atenololo bridge/.

Under these conditions, at the same time restorative Malaysia acetoxy group at the 3 - and 17-position. Depending on the desired target product, based on the compounds IV/IV, if necessary after pre-separation of both isomers can join in further reactions.

The double bond 14, 17-atenololo bridge can easily catalytically to gidrirovaniya /IV/IV _ _ _ VII/VII/ and a hydroxyl group acanoaaeyeoa /connections/ VII/VII then aeriferous to ester. Also, you can first partially atrificial to esters IV/IV and then catalytically to gidrirovanii double bond 14, 17-atenololo bridge, so in the end come to the same partially or fully esterified ester to 14, 17 etano connections.

For the esterification of free hydroxyl groups using known methods /interaction of free OH-compounds with an appropriate anhydride or acid chloride of the carboxylic acid. Given the different reactivity of free 3-, 16 - and 17-hydroxyl and using various reagents esterification can be obtained esterified to ester compounds, which contain various acyl group, R1and/or R2and/or R3. Thanks to selective saponification of compounds of General formula I, which, in addition to position 3, also tarifitsirovana 16 and/or 17-position, come to 3-hydroxy-compounds, which tarifitsirovana 16 and/or 17-position.

Thus, of the three-oxy compounds IV/IV and VII/VII you can get not only described in the examples acetoxy-connection, but also a higher esters, as propionate, butyrate, valerate, etc. which may be of interest, for example, for tapicerki applied formulations.

The following proposed variant of the invention consists in the fact that the 16-keto-compound III receive as described and its catalytically hydronaut to the corresponding 14, 17 etano connection, and then restore formed 14, 17 ethano-16-keto-compound, and applying sociallyengaged as reductant again get both 16-hydroxy-isomer VII/VII, which can be divided and, as mentioned, to process next.

To get proposed in the invention compounds can also proceeding from compounds of General formula II, where R1denotes a methyl group by saponification using an OS which you can restore later; using sociallyengaged you can also get a mixture of 16-hydroxy - 16-hydroxy-compounds VI/VI; desirable in the case of this mixture can be separated. Otherwise, the application of 3-acetoxy-compounds as the starting material 3-methoxy-connection when the saponification and the recovery remains intact, so that if R1in the end there must be another group than methyl residue, then you need to split 3-methyl simple ether. For this purpose are conventional methods for cleavage of ethers, such as interacting with diisobutylaluminium. The resulting products of formula IV/IV, as described above, may be introduced into the interaction further.

The scope of the present invention also cover intermediate compounds of General formulas III, IIIA and V

To the variant of method B.

Connection of the Diels-alder reaction of IIA with alkali metals in liquid ammonia stereoselective give 3, 16, 17-trioli I', which then can also be gidrirovanii to etano connections I". Clearly this transformation proceeds via the radicals and formation of thermodynamically stable products.

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Above described method is also 16-ketones HB' and HB" sodium in ammonia radical and starosele noatime group, for example, in tertiary 17-position, the reaction conditions Malaysia.

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Preferably the recovery of B is carried out according to the invention using sodium as the alkali metal.

The reaction temperature in this case is preferably maintained below -60oC, for example, by cooling in a dry ice /-78oC/.

Under these reaction conditions remains an aromatic a-ring.

To the variant of the method/

Cyclization of compounds of General formula II proceeds via a radical-anion as the reactive species; it is formed from the aldehyde function according to the invention due to restoration using a mixture of TiCl4/Zn powder. For restorative compounds, however, also possible to use systems Mg/Hg-TiCl4, Mg-TiCl3or Al/Hg.

The splitting of the simple benzyl ester according to the invention hydrolytically. 3-Methoxy-group is cleaved due to the interaction with Lewis acids; for example, for this purpose you can apply a mixture of sodium iodide with trimethylchlorosilane. This splitting can take place directly after cyclization, which leads to the compound of General formula I, where R1that is the General formula I' can be initially atrificial ester to 16 - and 17-hydroxy group and then split simple essential function in the 3-position and the resulting 3-oxy group, then in the desirable case again atrificial to ester /R1C6H5CH2or CH3/ or to simple essential.

For the esterification ester to the free hydroxyl groups using known methods /interaction of free OH-compounds with the appropriate acid chloride of carboxylic acid or carboxylic acid anhydride/. Thanks to various reaktsionnosposobnykh free 3-, 16 - and 17-hydroxy groups can be obtained partially esterified compounds, as well as by successive esterification using various reagents esterification to obtain esters esterified compounds that have different acyl groups, R1and/or R2and/or R3.

By selective saponification of compounds of General formula I, which, in addition to position 3, also tarifitsirovana /obtaining esters/ in position 16 and/or 17, come to 3-hydroxy-compounds, which tarifitsirovana to ester at position 16 and/or 17.

In the scope of the present invention also includes compounds of General formula XXII:

< / BR>
where

denotes methyl or benzyl residue;

they serve as initial products assalat hydrolytically, in the desirable case, after cyclization.

Example 1. 3, 16, 17 Triacetoxy-14, 17-etheno-1,3,5/10/-estratrien 16-carbonitrile.

A solution of 1.0 g of 1,3,5/10/-14,16-astreinte-3,17-diol-diacetate in 5 ml of anhydrous benzene is mixed with 5 ml of 1-cyanophenylacetic, and 10 mg of hydroquinone and heated at 140oC in a sealed tube for 3 days. Partially pitched the reaction mixture is treated with boiling dichloromethane. After separation by decantation and evaporation of the solvent remains of 1.61 g of crystalline residue, which chromatographic on 400 g of silica gel. Elute the gradient hexane-ethyl acetate /0-50% ethyl acetate/ and get 1.30 grams, which is recrystallized from a mixture of dichloromethane with diisopropyl ether and receive 882 mg 3, 16, 17 triacetoxy-14, 17-etheno-1,3,5/10/-estratrien-16-carbonitrile. So pl. 164oC.

Primer.16, 17 Diacetoxy-14, 17-etheno-3-methoxy-1,3,5/10/-estratrien-16, 17-diacetoxy-14, 17-etheno-3-methoxy-1,3,5/10/-estratrien-16, 17-Etheno-1,3,5/10/-estratrien-3, 16, 17-triol.

A solution of 240 mg of 3, 16, 17 triacetoxy-14, 17-etheno-1,3,5/10/-estratrien-16-carbonitrile in 6 ml of anhydrous ethanol is mixed with 600 mg of sodium borohydride in 13 ml of ethanol and stirred at room temperature for 15 hours, the Reaction mixture was diluted with these is referat on 150 g of silica gel with a mixture of dichloromethane with methanol /95:5/. Elute 140 mg of oil. After crystallization from a mixture of dichloromethane hexane obtain 83 mg, 14, 17-etheno-1,3,5/10/-estratrien-3 16, 17-triol. So pl. 199oC.

Example 4. 3-Methoxy-14, 17-ateno-17-hydroxy-1,3,5/10/-estratrien-16-he.

Restorm, 17 diacetoxy-14, 17-ethano-3-methoxy-1,3,5/10/-estratrien-16, 17-ateno-17-hydroxy-1,3,5/10/-estratrien-16-she's so square 159oC.

Example 5. 14, 17-Etheno-3-methoxy-1,3,5/10/-estratrien-16-diol and 14, 17-etheno-3-methoxy-1,3,5/10/-estratrien-16-diol.

A solution of 170 mg of 3-methoxy-14, 17-ateno-17-hydroxy-1,3,5/10/-estratrien-16-she's in 10 ml of tetrahydrofuran under nitrogen atmosphere and at 0oC is mixed with 60 mg of sociallyengaged. After 1.5 h the reaction due to the additive aqueous solution of ammonium hydrochloride ends. Then extracted with ethyl acetate, the extract washed with water, dried over magnesium sulfate and evaporated in vacuum. Remain 160 mg of crystalline product, which chromatographic on 16 g of silica gel using mixtures of ethyl acetate with hexane /3:2 as eluent. Get 123 mg, 14, 17-etheno-3-methoxy-1,3,5/10/-estratrien-16-diol, so pl. 162oC /from a mixture of chloroform with methanol/ and 32 mg, 14, 17-etheno-3-methoxy-1,3,5/10/-estratrien-16-diol, so pl. 195oC /from a mixture of methanol with toluene/.

Example 6. 14,from 6 ml of ethanol and 1.5 ml of tetrahydrofuran is mixed with 20 mg of palladium-on-coal /10% Ro/ and hydronaut at normal pressure. After absorption of 10.5 ml of hydrogen /is designed to 8.7 ml/ 30 minutes, the catalyst is filtered off. The filtrate is evaporated in vacuo and the residue will recrystallized from a mixture of methanol with diisopropyl ether. Yield: 105 mg, 14, 17, ethano-1,3,5/10/-estratriene-3,16, 17-triol. So pl. 230oC.

Example 7. 3-Acetoxy-14, 17-etheno-1,3,5/10/-estratrien-16, 17-diol and 3,16-diacetoxy-14, 17-etheno-1,3,5/10/-estratrien-17-ol.

A solution of 130 mg 14, 17-etheno-1,3,5/10/-estratriene-3,16, 17-triol in a mixture of 1,4 ml of pyridine and 0.6 ml of acetanhydride incubated 3 h at room temperature. The reaction product is precipitated by adding water and dissolved in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue, recrystallized from a mixture of dichloromethane with diisopropyl ether, to give 43 mg of 3-acetoxy 14, 17-etheno-1,3,5/10/-estratrien-16, 17-diol. So pl. 185oC. the mother liquor chromatographic two silikagelevye plates, layer thickness of 1 mm, the surface of 20 x 40 cm, eluting agent: hexane-ethyl acetate /7:3/. After elution and recrystallization from a mixture of dichloromethane with diethyl ether and pentane receive 75 mg of 3, 16-diacetoxy - 14, 17-etheno-1,3,5/10/-estratrien-17-ol. So pl. 202oC.

Example 8. 14, 17-Etheno-1,3,5/10/-estratrien-3, 16, 17-Tr of acetanhydride mixed with 40 mg of 4-dimethylaminopyridine and incubated at room temperature for 18 hours The reaction product is precipitated by adding water and dissolved in dichloromethane. The organic phase is washed with water, dried and evaporated. The remainder chromatographic 5 silikagelevye plates, layer thickness of 1 mm, the surface of 20 x 40 cm, eluting tool hexane-ethyl acetate /7:3/. After elution and recrystallization from a mixture of diethyl ether and pentane obtain 230 mg, 14, 17-etheno-1,3,5/10/-estratrien-3, 16, 17-triol-triacetate. So pl. 76oC.

Example 9. 16, 17 Diacetoxy - 14, 17-etheno-1,3,5/10/-estratrien-3-ol.

A solution of 50 mg of 14, 17-etheno-1,3,5/10/-estratrien-3, 16, 17-trilliaceae in 2.5 ml of methanol together with 0.4 ml of water and 100 mg of calcium carbonate is boiled for 24 hours the Reaction solution is then applied directly on 2 silikagelevye plate, a layer thickness of 1 mm and the surface of 20 x 40 cm, and chromatographic with a mixture of hexane with ethyl acetate /7:3/. After elution and recrystallization from a mixture of dichloromethane hexane get 33 mg, 16, 17 diacetoxy-14, 17-etheno-1,3,5/10/-estratrien-3-ol. So pl. 214oC.

Example 10. 14, 17-Ateno-3, 17-deoxy-1,3,5/10/-estratrien-16-he.

A solution of 150 mg of 3, 16, 17 triacetoxy-14, 17-etheno-1,3,5/10/-estratrien-16-carbonitride in 15 ml of tetrahydrofuran is mixed in an argon atmosphere with 3 ml of K-SelectrideRand mix R the IDT is extracted with a mixture of dichloromethane in methanol /9:1/. The extracts are dried and evaporated in vacuum. The remainder chromatographic on 100 g of silica gel. By elution with gradient hexane-ethyl acetate /0-40% ethyl acetate/ will receive 50 mg of the obtained crystalline from diethyl ether. Yield: 28 mg, 14, 17-ateno-3, 17-deoxy-1,3,5/10/-estratrien-16-she. So pl. above 300oC.

Example 11. 14, 17-Ateno-3, 17-deoxy-1,3,5/10/-estratrien-16-he.

A solution of 384 mg 3, 16, 17 triacetoxy-14, 17-etheno-1,3,5/10/-estratrien-16-carbonitrile in a mixture of 8 ml of dimethanesulfonate and 8 ml of tetrahydrofuran at 0oC is mixed with 1,12 ml of 2n potassium hydroxide solution and incubated for 15 h at 5oC. the Reaction product is extracted with ethyl acetate, the extract washed with water, dried and evaporated in vacuum. The remainder, approximately 370 mg, chromatographic on silica gel with a mixture of hexane with ethyl acetate /1:1/. Yield: 130 mg, 14, 17-ateno-3,3,17-deoxy-1,3,5/10/-estratrien-16-she. So pl. above 300oC.

Example 12. 14, 17-Etheno-1,3,5/10/-estratrien-3, 16, 17-triol and 14, 17-etheno-1,3,5/10/-estratrien-3, 16, 17-triol.

A solution of 120 mg, 14, 17-ateno-3, 17-deoxy-1,3,5/10/-estratrien-16-she's in 15 ml of tetrahydrofuran is mixed with 100 mg of alanate lithium and stirred for 90 min at 10oC. the Reaction mixture after addition of 20 ml of aqueous saturated solution FPO the Aqueous phase is evaporated in vacuum to dryness, the residue is mixed with 100 ml of methanol and briefly boil. After filtration and evaporation of the solvent remains 130 mg solids. Solid and oil after the unification chromatographic on a column of silica gel /d=4 cm, l=20 cm/ s by using a mixture of 1 liter of hexane with ethyl acetate /7: 3/. Allocate 20 mg of the mixture, as well as 60 mg, 14, 17-etheno-1,3,5/10/-estratrien-3, 16, 17-triol. The mixture is chromatographically separated on cityreach silikagelevye plates /20x20 cm, layer thickness 0.25 mm/ with a mixture of hexane with ethyl acetate /7:3/ as the eluting means and receiving 7 mg, 14, 17-etheno-1,3,5/10/-estratrien-3, 16, 17-triol.

Example 13. 3,16-Diacetoxy-14, 17-ethano-1,3,5/10/-estratrien-17-ol.

A solution of 90 mg 14, 17 ethano-1,3,5/10/-estratrien-3, 16, 17-triol in a mixture of 1.3 ml of pyridine and 0.7 ml of acetanhydride incubated 6 h at room temperature. The reaction product is precipitated by adding water and dissolved in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue, recrystallized from a mixture of pentane with diethyl ether, to give 43 mg of 3, 16-diacetoxy-14, 17-ethano-1,3,5/10/-estratrien-17-ol. So pl. 129,5oC.

Example 14. 14, 17 Ethano-1,3,5/10/-estratrien-3, 16, 17-triol-triacetate.

A solution of 250 mg 14, 17 ethano-1,3,5/10/-östra ribaut 15 h at room temperature. The reaction product is precipitated by adding water and dissolved in dichloromethane. The organic phase is washed with water, dried and evaporated. The remainder chromatographic on a column of silica gel /d=4 cm, l=20 cm/ s (1 l) a mixture of diethyl ether and pentane /6:4/ s /1:1/. After recrystallization from a mixture of diethyl ether and pentane obtain 108 mg, 14, 17, ethano-1,3,5/10/-estratriene-3,16, 17-triol-triacetate. So pl. 122oC.

Example 15. 3-Acetoxy-14, 17-ethano-1,3,5/10/-estratrien-16, 17-diol.

180 mg of 3-Acetoxy-14, 17-etheno-1,3,5/10/-estratrien-16, 17-diode will dissolve in a mixture of 10 ml ethanol and 4 ml of tetrahydrofuran. After addition of 40 mg of palladium-on-coal as a catalyst /10% Pd/ hydronaut at the 22oC and a pressure of 1024 hPa. After absorption of 15.0 ml /designed: to 12.52 ml/ hydrogen for 10 min sucked off from the catalyst and the filtrate is evaporated to dryness and the residue will recrystallized from a mixture of diethyl ether and hexane. Obtain 91 mg of 3-acetoxy-14, 17-ethano-1,3,5/10/-estratrien-16, 17-diol. So pl. 191oC.

Example 16. 14, 17 Ethano-3,17-deoxy-1,3,5/10/-estratrien-16-he.

260 mg, 14, 17-Ateno-3,17-deoxy-1,3,5/10/-estratrien-16-she dissolved in a mixture of 20 ml ethanol and 10 ml of tetrahydrofuran. After addition of 30 mg of palladium-nascituro: vs. 20.62 ml) of hydrogen for 15 min sucked off from the catalyst, the filtrate is evaporated to dryness and the residue will recrystallized from a mixture of dichloromethane with methanol. Obtain 124 mg, 14, 17, ethano-3,17-deoxy-1,3,5/10/-estratrien-16-she. So pl. 259oC.

Example 17. 14, 17 Ethano-1,3,5/10/-estratrien-3, 16, 17-triol and 14, 17 ethano-1,3,5/10/-estratrien-3, 16, 17-triol.

A solution of 110 mg 14, 17 ethano-3, 17-deoxy-1,3,5/10/-estratrien-16-she's in 10 ml of tetrahydrofuran is mixed with 75 mg alanate lithium and incubated for 90 min at 20oC. After adding 10 ml of aqueous saturated solution of sodium fluoride mixture is evaporated in vacuum to dryness, the residue is mixed with 75 ml of methanol and heated to boiling, after filtration the solvent is evaporated. The remaining residue is subjected to chromatographicaliy on a column of silica gel using a mixture of 1 liter of hexane with ethyl acetate (7:3) as eluent, to give 53 mg, 14, 17, ethano-1,3,5/10/-estratrien-3, 16, 17-triol, so pl. 228oC (from diisopropyl ether) and 12 mg, 14, 17, ethano-1,3,5/10/-estratrien-3, 16, 17-triol, so pl. 308oC (from a mixture of dichloromethane with methanol).

Getting the initial connection for option B.

Example 18. 3,16, 17 Triacetoxy-14, 17-ethano-östra 1,3,5/10/-triene-16-carbonitrile.

A solution of 3.0 g östra-1,3,5/10/,14,16-pentaen-3,17-diol-diacetate in 10 ml of dichloromethane is mixed with molchat in a mortar and treated with boiling acetone. After decantation and evaporation of the solvent remains of 4.9 g of residue, which chromatographic on silica gel. Elute with a mixture of hexane and acetic ether (7:3) and receive of 3.78 g, which after recrystallization from a mixture of dichloromethane hexane to give 3.28 g 16, 17 triacetoxy-14, 17-ateno-östra 1,3,5/10/-triene-16-carbonitrile. So pl. 162oC.

Example 19. 17-Acetoxy-14, 17-etheno-3-hydroxy-östra 1,3,5/10/-triene-16-he and 14, 17-ateno-3,17-deoxy-östra 1,3,5/10/-triene-16-he.

A solution of 385 mg, 16, 17 diacetoxy-14, 17-etheno-3-methoxy-östra 1,3,5/10/-triene-16-acetoxy-14, 17-etheno-3-hydroxy-östra 1,3,5/10/-triene-16-she's so square 245oC, and 130 mg 14, 17-ateno-3,3,17-deoxy-östra 1,3,5/10/-triene-16-she's so square 313oC.

Example 20. 14, 17 Ethano-3,17-deoxy-östra 1,3,5/10/-triene-16-he.

A solution of 130 mg 14, 17-ateno-3,17-deoxy-östra 1,3,5/10/-triene-16-she's in a mixture of 10 ml of tetrahydrofuran and 20 ml of ethanol is mixed with 30 mg of palladium-on-coal as a catalyst (10% Pd) and hydronaut at the 22oC using hydrogen at atmospheric pressure. The catalyst is filtered off, the solvent is evaporated in vacuum and the residue is crystallized from a mixture of dichloromethane with methanol. Get 91 mg, 14, 17, ethano-3,17-deoxy-östra 1,3,5/10/-triene-16-she's so square 259oC.

Example 21. 14, 17 Ethano-17-hydroxy-3 the si of 25 ml of tetrahydrofuran and 25 ml of ethanol is mixed with 125 mg of palladium-on-coal as a catalyst (10% Pd) and hydronaut at 25oC hydrogen at atmospheric pressure. The catalyst is filtered off, the solvent is evaporated in vacuum and the residue is crystallized from a mixture of hexane and acetic ether. Obtain 355 mg, 14, 17, ethano-17-hydroxy-3-methoxy-östra 1,3,5/10/-triene-16-she.

Example 22.

a) Condense 20 ml of ammonia and slowly over 20 min add 200 mg of finely cut sodium. Forms a dark blue solution. Now in the solution of metallic sodium in liquid ammonia was added dropwise 450 mg 3, 16, 17 triacetoxy-14, 17-ateno-östra 1,3,5/10/-triene-16-carbonitrile dissolved in 20 ml of tetrahydrofuran. The reaction mixture is stirred for 30 minutes under cooling with dry ice. Then carefully add a saturated solution of ammonium chloride and the mixture is brought to room temperature. After evaporation of the ammonia is mixed with water and extracted 6 times with 50 ml of a mixture of dichloromethane with methanol (4:1). The combined extracts are dried over magnesium sulfate and evaporated in vacuum. The oily residue (319 g) chromatographic on a column of silica gel. Using a mixture of dichloromethane with methanol (9: 1) elute 260 mg, which is recrystallized from a mixture of dichloromethane with methanol, and receive 125 mg, 14, 17-ateno-östra 1,3,5/10/-triene-3, 16, 17-triol with so pl. 271oC.

Example 23. Condense 15 ml of ammonia and slowly over 20 min add 125 mg of finely cut sodium. Forms a dark blue solution. Then in a solution of metallic sodium in liquid ammonia was added dropwise 250 mg 16, 17 diacetoxy-14, 17-etheno-3-methoxy-östra 1,3,5/10/-triene-16, 17-etheno-3-methoxy-östra 1,3,5/10/-triene-16-diol with so pl. 193oC.

Example 24. Condense 10 ml of ammonia and added dropwise a solution of 100 mg 14, 17-ateno-3,17-deoxy-östra 1,3,5/10/-triene-16-she's in 10 ml of tetrahydrofuran. This solution is mixed with 40 mg of finely cut sodium and stirred while cooling with dry ice within 30 minutes After this time, the originally dark blue solution becomes colourless. Then carefully add a saturated solution of ammonium chloride and the mixture is brought to room temperature. After sparcstorage dried over sodium sulfate and evaporated in vacuum. The crystalline residue will recrystallized from a mixture of dichloromethane with methanol. Get 62 mg, 14, 17-ateno-östra 1,3,5/10/-triene-3,16, 17-triol with so pl. 267oC.

Example 25. Condense 20 ml of ammonia and added dropwise a solution of 200 mg, 14, 17, ethano-3,17-deoxy-östra 1,3,5/10/-triene-16-she's in 10 ml of tetrahydrofuran. The solution is mixed with 75 mg of finely cut sodium and stirred while cooling with dry ice within 30 minutes After this time, the originally dark blue solution becomes colourless. Then carefully add a saturated solution of ammonium chloride and the mixture is brought to room temperature. After evaporation of the ammonia is mixed with water and repeatedly extracted with a mixture of dichloromethane with methanol /4:1/. The combined extracts dried over sodium sulfate and evaporated in vacuum. The remainder will recrystallized from a mixture of dichloromethane with methanol. Get 120 mg, 14, 17-ethanoate-1,3,5/10/-triene-3, 16, 17-triol with so pl. 314oC.

Example 26. Condense 10 ml of ammonia and added dropwise a solution of 50 mg of 14, 17 ethano-17-hydroxy-3-methoxy-östra 1,3,5/10/-triene-16-she's in 10 ml of tetrahydrofuran. This solution is mixed with 20 mg of finely cut sodium and stirred for 30 minutes under cooling with dry ice. After this time, originally todat to room temperature. After evaporation of the ammonia is mixed with ode and repeatedly extracted with a mixture of dichloromethane with methanol /4:1/. The combined extracts dried over sodium sulfate and evaporated in vacuum. The oily residue chromatographic on silica gel. Get 47 mg, which after recrystallization from a mixture of dichloromethane with methanol to give 22 mg, 14, 17, ethano-3-methoxy-östra 1,3,5/10/-triene-16-diol with so pl. 251oC.

Example 27. Condense 10 ml of ammonia and added dropwise a solution of 150 mg 14, 17-ateno-17-hydroxy-3-methoxy-östra 1,3,5/10/-triene-16-she's in 10 ml of tetrahydrofuran. This solution is mixed with 60 mg of finely cut sodium and cooled with dry ice, stirred for 30 minutes After this time, the originally dark blue solution becomes colourless. Then carefully add a saturated solution of ammonium chloride and the mixture is brought to room temperature. After evaporation of the ammonia is mixed with water and repeatedly extracted with a mixture of dichloromethane with methanol /4:1/. The combined extracts dried over sodium sulfate and evaporated in vacuum. The oily residue chromatographic on silica gel. Obtain 116 mg, which after recrystallization from a mixture of hexane and acetic ether, to give 65 mg, 14, 17-etheno-3-methoxy-östra 1,3,5/10/-triene-16-diol with so pl. 195ooC.

Example 29. Condense 20 ml of ammonia and added dropwise a solution of 250 mg of 14-acetoxy-14, 17-ethano-3-methoxy-östra 1,3,5/10/-triene-16-she's in 20 ml of tetrahydrofuran. This solution is mixed with 100 mg of finely cut sodium and cooled with dry ice, stirred for 30 minutes After this time, the originally dark blue solution becomes colourless. Then carefully add a saturated solution of ammonium chloride and the mixture is brought to room temperature. After evaporation of the ammonia is mixed with water and repeatedly extracted with dichloromethane. The combined extracts are dried neem give 165 mg 14, 17 ethano-3-methoxy-östra 1,3,5/10/-triene-16-diol with so pl. 248oC.

Example 30. 17-Acetoxy-3-benzyloxy-14, 17-etheno-1,3,5/10/-estratrien-16-carbaldehyde (30).

19,44 g of 3-Benzyloxy-1,3,5/10/-14,16-astreinte-17-yl-acetate (I. pl. 114-115oC; obtained from 3-benzyloxy-estrone similar sequence of reactions according to F. Pataki and others J. Org.Chem. 37, 2127,1972) and 13.2 ml of acrolein in 205 ml of toluene under cooling with ice mixed dropwise with 0.6 ml of epirate boron TRIFLUORIDE in 20 ml of toluene in a nitrogen atmosphere. The reaction mixture was stirred 16 h at room temperature and then poured onto a mixture of ice water. Then extracted with acetic ether, the organic phase is washed with water until neutral and dried over sodium sulfate. Filtration and evaporation of the solvent give 24.2 g of the solid residue. By recrystallization from acetic ester will obtain 16.7 g of the compound(30) with so pl. 150-151oC.

Example 31. The aldehyde 3-benzyloxy-17-oxo-1,3,5/10/ 15-estracecream-14-propionic acid (31).

16.7 g joint (30) 556 ml of tetrahydrofuran and 149 ml of methanol is mixed with 382 ml of 0.1 n solution of lithium hydroxide and stirred for 18 h at room temperature. The reaction mixture is acidified with 45 ml of 1N hydrochloric acid and then tetrahydro reaction and dried over sodium sulfate. Filtration and evaporation of the solvent give 17 g of an oil as residue. By chromatography on silica gel using a mixture of acetic ether with hexane /1: 2/ get the 5.65 g of compound (31) as a foam solid.

Example 32. 14-/E/Z/-3-Acetoxy-2-propenyl/-3-benzyloxy-1,3,5/10/-15-estracecream-17-it /32/.

5.6 g of the compound (31), 101,6 ml isopropenylacetate and 1.09 g of p-toluenesulfonic acid is refluxed for 6 h under nitrogen atmosphere. The reaction mixture is diluted with acetic ether, the organic phase is washed with sodium hydrogen carbonate solution and water and dried over sodium sulfate. Filtration and evaporation of the solvent give 6.7 g of the compound (32) in the form of oil residue, without further purification subjected to oxidation by Lemieux-Johnson.

Example 33. 3-Benzyloxy-17-oxo-1,3,5/10/-15-estracecream-14-acetaldehyde /33/.

6.6 g of the compound (32) in 117 ml of tetrahydrofuran at room temperature is mixed with 295 mg of osmium tetroxide in 59 ml of tetrahydrofuran and after 5 min with 59 ml of water. After these 5 minutes under ice cooling type of 17.7 g of periodate sodium and stirred for 4 h at room temperature. The reaction mixture is admixed in a solution of sodium chloride and extrage the air traffic management of the solvent and filtration foam residue through silica gel using a mixture of acetic ether with hexane /1:2/ obtained after concentration of 2.53 g of compound (33) as a colorless oil.

Primer 34. 3-Benzyloxy-17-oxo-1,3,5/10/-estratrien--acetaldehyde (34).

of 2.23 g of Compound (33) in 67 ml of tetrahydrofuran hydronaut at normal pressure using 0.45 g of Pd-BaSO4/10%/. After removal of the catalyst and concentration of the filtrate get 2,48 g of oil. Chromatography on silica gel with a mixture of acetic ester/hexane /1:2/ gives 1.8 g of compound (34) as a colourless oil.

Example 35. 3-Benzyloxy-14, 17-ethano-1,3,5/10/-estratrien-16, 17-diol (35).

of 1.75 g of compound (34) in 29 ml of tetrahydrofuran at -10oC and in an atmosphere of nitrogen is mixed drop by drop from 8.7 ml of a 1M solution of titanium chloride /IV/ methylene chloride. After 10 min portions over 40 min added 850 mg of zinc. Then stirred for further 1 h with ice cooling and then the reaction mixture was poured into ice a solution of potassium carbonate. After dilution with methylene chloride is separated from the sludge, the organic phase is washed with water until neutral and dried over sodium sulfate. After filtration and evaporation of solvent to obtain 1.35 g of oil. Chromatography on silica gel with a mixture of acetic ether with hexane /1:1/ give 270 mg joint (35) so pl. 186oC.

Example 36. 14, 17 Ethano-1,3,5/10/-estratrien-3, 16, 17-triol (36).

260 mg of Soy and concentration of the filtrate receive 60 mg of solid substances. Chromatography on silica gel with a mixture of acetic ether with hexane /3:1/ give 23 mg of the compound (36) with so pl. 310-312oC.

Example 37. 17-Acetoxy-14, 17-etheno-3-methoxy-1,3,5/10/-estratrien-161/ get 8,55 g of the compound (37) with so pl. 183-185oC. ()2D0= +102,5=0,120, CHCl3/.

Example 38. 17-Acetoxy-14, 17-ethano-3-methoxy-1,3,5/10/-estratrien-16-Acetoxy-16-acetoxymethyl-14, 17-ethano-3-methoxy-1,3,5/10/-estratrien (39).

A solution of 29.1 g of 17-acetoxy-14, 17-ethano-3-methoxy-1,3,5/10/-estratrien-16-Acetoxy-14, 17-ethano-16-oxymethyl-3-methoxy-östra 1,3,5/10/-triene.

While cooling with ice water 63,0 g chloride heptahydrate cerium/III/ contribute in 1096 ml of methanol and the resulting solution was added the solution to 87.1 g of 17-acetoxy-14, 17-ethano-3-methoxy-östra 1,3,5/10/-triene - 16-carbaldehyde in 1218 ml of tetrahydrofuran and 957 ml of methanol. After adding portions to 8.45 g of sodium borohydride was stirred 16 h at room temperature. For handling poured into 5 l of water and extracted with dichloromethane. After drying /sodium sulfate/ and concentration get 86,5 g of the title compound as a colourless oil.IH-NMR /CDCI3/: d1,02ppm /singlet, 3H, H-18/; 2,07 /singlet, 3H, Acetyl/; 3,52-of 3.65 and a 3.83-3,94 /multiplet, 2H, CH2OH/; 3,78 /singlton-3-methoxy-1,3,5/10/-estratrien-16-he (40).

A solution of 30.0 g of enolacetate (39) in 900 ml of dichloromethane and 450 ml of methanol is cooled to -70oC. Through a solution under vigorous stirring miss the current ozone-oxygen. A mixture of O2/O3obtained by passing O2with a speed of 30 l/h ozonator /ozone generator OZ II, Fischer-Labortechnik, Bad Godesberg/. The concentration of O3in the primary stream after exiting the ozone generator also corrected by mixing oxygen again by a factor of 2-3. After about 2 hours transmittance of the thus obtained mixture of O2/O3the reaction solution is "washed" with nitrogen and then portions over 15 min add 20.7 g of triphenylphosphine. After adding stirred for a further 30 minutes at -70oC, leave the temperature to rise to room temperature and the reaction solution was poured in about 3 l of a solution of sodium bicarbonate. Methylenchloride phase is separated, dried over sodium sulfate and concentrated. After chromatography on silica gel using mixtures of hexane with ethyl acetate and recrystallization of the main product from a mixture of ethyl acetate with diisopropyl ether get to 17.2 g of compound (40) with so pl. 216-218oC.

Example 40A. 17-Acetoxy-14, 17-ethano-3-methoxy - 16-/4-toluensulfonyl-oxy/-methyl-acridine while cooling with ice water portions mixed with 171,4 g of 4-toluensulfonate. After adding stirred for 2.5 h at room temperature, the reaction solution was poured then into 5 l of water and added in several portions 75 g NaHCO3. Stirred for 30 min at room temperature and then extracted with ethyl acetate. An ethyl acetate extracts washed with water and 2n HCI solution, dried over sodium sulfate and concentrated. The thus obtained crude product of the title compounds /245,8 g/ without further purification used in the next reaction.

Example 41. 14, 17 Ethano-3-methoxy-1,3,5/10/-estratrien-16-diol (41).

To a solution of 2.3 g of the ketone (40) in 160 ml of ethanol under cooling with ice water was added dropwise a solution of 500 mg of sodium borohydride in 100 ml of 80% aqueous ethanol. Then stirred for 14 h at room temperature, pour about 1 liter of water and extracted with ethyl acetate. After recrystallization of the crude product from a mixture of ethyl acetate with diisopropyl ether get 2,05 g soedineniya (12) with so pl. 170-172oC. ()2D0= +48,8/CHCI3c=0,510/.

Example 41A. 3-Methoxy-14-/2-propanol/-östra 1,3,5/10/-triene-17-one.

The solution 245,8 g obtained in example 40A crude product in 2400 ml of methanol and 964 ml of 2n NaOH is stirred for 2.5 h at 60oC. After cooling, poured prio4/active carbon/ and concentrate. The oily residue is dissolved by heating in 150 ml of methanol and 15 ml of ethyl acetate and then brought to crystallization at room temperature. After filtering off getting 164, 8mm g of the title compound with so pl. 75-77oC. Chromatography of the mother liquor on silica gel with a mixture of hexane with ethyl acetate gives the following 19,0 g of the product.

IH-NMR/ CDCI3/; d1,11 ppm /singlet, 3H, H-18/; 3,78 /singlet, 3H, OCH3/; 5,00-5,14 /multiplet, 2H, /; 5,70-5,85 /multiplet, IH, CH2/.

Example 42. 3-Methoxy-17-oxo-1,3,5/10/-estratrien - 14-acetaldehyde (42).

A solution of 1.9 g of diol (41) in 23 ml of dichloromethane and 23 ml of isopropanol under cooling with ice water portions mixed with a 2.01 g H5O6. Stirred for 15 min at 25oC, poured into water and extracted with dichloromethane. Methylenechloride extracts washed with 5% aqueous solution of NaHCO3, dried over Na2SO4and concentrate. After crystallization of the crude product from ethyl acetate/diisopropyl ether get 1,74 g of compound (42) with so pl. 126-128oC.

Example 42A. 3-Methoxy-17-oxo-östra 1,3,5/10/-trien-14-acetaldehyde.

A solution of 25 g of 3-methoxy-14-/2-propanol/-östra 1,3,5/10/-triene-17-she's in 750 ml of dichloromethane is oxygen /O2- the flow of 80 l/h, O3generation of 10 g/h/. After passing over a 50 min the reaction solution "rinse" nitrogen, portions add 17,33 g of triphenylphosphine, stirred for a further 30 min at 70oC and allowed to warm to room temperature. Processing is then poured into a solution of NaHSO3and extracted with dichloromethane. After chromatography on silica gel using mixtures of hexane/ethyl acetate and crystallization from a mixture of ethyl acetate with diisopropyl ether get to 21.6 g of the title compound with so pl. 216-218oC.

Example 43. 14, 17 Ethano-3-methoxy-1,3,5/10/-estratrien-16-diol (43).

To a solution of 500 mg of the aldehyde (42) in 9 ml of dichloromethane at -10oC was added dropwise 2.5 ml of 1M solution of titanium tetrachloride in dichloromethane. Then for 40 min add 242 mg of zinc powder is added and stirred for 60 min at 0oC. For handling poured the reaction mixture is cooled in ice, a solution of potassium carbonate, filtered the resulting suspension through celite and washing the residue on the filter with dichloromethane. The dichloromethane phase is washed with water, dried over sodium sulfate and concentrated. Chromatography on silica gel with a mixture of hexane with ethyl acetate to give 320 mg of crystalline compound (43):

I

To a suspension of 310 mg of diol (43) and 1.42 g of sodium iodide in 20 ml of acetonitrile under cooling with ice water was added dropwise to 0.68 ml acetylchloride and stirred for 30 min at 5-10oC. Then poured into a solution of NaHSO3and extracted with ethyl acetate. After crystallization of the crude product from a mixture of ethyl acetate with diisopropyl ether obtain 270 mg of the compound (44) with so pl. 170-172oC.

Example 45. 3, 16, 17 Triacetoxy-14, 17-ethano-1,3,5/10/-estratrien (45).

A suspension of 49 mg of the diacetate (44) and 178 mg of sodium iodide in 3 ml of acetonitrile and after adding 0.15 ml of trimethylchlorosilane refluxed for 3 hours, After cooling, poured into a solution of NaHSO3and extracted with ethyl acetate. Obtained after concentration the crude product is stirred for 30 min at 60oC in 1 ml of acetic anhydride and 0.5 ml of pyridine. The reaction solution was added dropwise to a saturated solution of NaHCO3and extracted with ethyl acetate. After chromatography on silica gel obtain 29 mg of the compound (45) with so pl. 159-161oC.

1. Estratriene containing the bridge, the General formula I

< / BR>
where if OR3is in-position, R1, R2, R3
is in-position, R1, R2, R3independently from each other - H or C1WITH12-acyl or1-C8-alkyl and in both cases, And In - ateno or ethano-bridge.

2. Estratriene General formula I on p. 1, characterized in that the OR3is in-position, And means ateno-bridge.

3. Estratriene General formula I on p. 1, characterized in that the OR3is in-position, And means ethano-bridge.

4. Estratriene General formula I on p. 1, characterized in that the OR3is in-position, And means ateno-bridge.

5. Estratriene General formula I on p. 1, characterized in that the OR3is in-position, And means ethano-bridge.

6. Estratriene General formula I on PP.1 4 or 5, wherein R1, R2and/or R3mean2WITH8acyl.

7. Estratriene General formula I according to one of paragraphs.1 to 5, characterized in that R1, R2, R3identical and mean WITH2-C8-acyl.

8. Estratriene General formula I according to one of paragraphs.1 to 5, characterized in that R1, R3identical and mean WITH2-C8-acyl and R2N or other than R1and R, R3identical and mean WITH2-C8-acyl, and R1N or other than R2and R3WITH2-C8-acyl.

10. Estratriene General formula I on PP.1 to 5, characterized in that R2and R3N and R1WITH2WITH8acyl.

11. Estratriene General formula 1 on PP.1 to 5, where R1CH3and R2and R3N or R2and R3WITH2-C8-acyl, and then R2and R3identical.

12. 3-Benzyloxy-14, 17 - ethano-1,3,5(10)-estratrien -16, 17-diol,

14, 17 ethano-1,3, 5(10)-estratrien -3,16, 17-triol,

14, 17 ethano-3-methoxy-1,3, 5(10)-estratrien -16, 17-diol,

16, 17 diacetoxy -14, 17 ethano-3-methoxy-1, 3, 5(10)-estratrien,

3,16, 17 triacetoxy -14, 17 ethano-1,3, 5(10)-estratrien,

14, 17 - etheno-1,3,5(10)-estratrien -3,16, 17-triol,

14, 17 - etheno-3-methoxy-1,3,5(10)-estratrien -16, 17-diol,

14, 17 - etheno-3-methoxy-1,3,5(10)-estratrien -16, 17-diol,

14, 17 ethano-1,3, 5(10)-estratrien -3,16, 17-triol,

3-acetoxy -14, 17 - etheno-1,3, 5(10)-estratrien -16, 17-diol,

3,16 - diacetoxy -14, 17 - etheno-1,3, 5(10)-estratrien-17-ol,

14, 17 - etheno-1,3,5(10)-estratrien -1,16, 17 - triol-triacetate,

16,,17 diacetoxy -14, 17 - etheno-1,3, 5(10)-estratrien-3-ol,

14, 17 - etheno-1,3,5(10)-estratrien -3,16 --17-triol,

3,16 - diacetoxy -14, 17 the but-1, 3, 5(10)-estratrien -16, 17-diol,

14, 17 ethano-1, 3, 5(10)-estratrien -3,16, 17-triol,

14, 17 ethano-3-methoxy-1, 3, 5(10)-estratrien -16, 17-diol.

Priorities signs:

29.11.89 when R1- C1-C8-alkyl, or R1R2R3WITH1-C12-acyl.

22.10.90 when R1R2R3H, or R1- CH3.

 

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II R - OH manifesting anti-AIDS activity

-glycyrrhizic acid methyl ester, l - histidine, exhibiting anti-aids activity" target="_blank">

The invention relates to new biologically active compound, particularly, to Amida-glycyrrhizic acid with methyl ester of L-histidine: 3-0-[2-0-(-D-glucopyranosyloxy)--D-glucopyranosyloxy]-(3, 20)-11,30-dioxo-30-(N-L-histidine methyl ester)-30-norolean- -12-ene of the formula I

exhibiting anti-AIDS activity
The invention relates to the field of biotechnology and can be used in pharmaceutical, microbiological and chemical industry for preparation of intermediates for the synthesis of steroid drugs

The invention relates to the field of steroid compounds, such as esters of organic acids with alcohols of General formula I

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(I) where R1methyl or ethyl;

G is phenyl, substituted in position 4 by the radical, selected from dialkyl(C1-C4)amino, alkyl(C1-C4)thio, acyl(C1-C4);

X means WITH-A-Z group, where a linear aliphatic divalent radical WITH1-C6Z denotes-COOH or SO3H-group, which may be in the form of a salt of an alkali metal;

Y means WithCH; CH=CH2; -CH=CH-CH3;WITH1;C-CH3wavy line in position 13 means that R1can beor-position

The invention relates to the chemistry of steroid compounds astranova number and relates to an improved method for semi - treatment extra-1,3,5(10)-triene-3-ol-17-she (estrone) of formula I:

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(I)

Estrone is a key compound in the synthesis of a large number of drugs astranova number, for example, estradiol dipropionate, methylestradiol, ethinyl estradiol, penalolen, retabolil, cerabolini [1]

Drugs astranova series are also used as the estrogen component (levonorgestrel, methyl ether of estradiol), oral contraceptives (ipankonin, limovan)

The invention relates to the chemistry of astronav and relates to an improved method for obtaining variety-4-ene-3,17-dione (astrantia) of the formula (I)

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(I)

Variety-4-ene-3,17-dione is used as an intermediate in the industrial synthesis of norethisterone and its acetate [1] used in medicine as gestagenna funds or gestagenna component in oral contraceptives

The invention relates to new steroid compounds exhibiting valuable pharmacological properties
The invention relates to biotechnology and can be used in pharmaceutical, microbiological and chemical industry for preparation of intermediates for the synthesis of steroid drugs

The invention relates to new esters estramustine and the way they are received, namely esters of the General formula I:

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(I) where R1hydrogen atom, a lower alkyl WITH1-C4;

R2a hydrogen atom, a lower alkyl WITH1-C4;

R3a hydrogen atom, a lower alkyl WITH1-C4; or R2and R3together-CH2-CH2-CH2-CH2-,

n is 0,1 or 2

or their pharmaceutically acceptable salts have anti-tumor properties

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.

EFFECT: valuable properties of compounds and composition.

4 cl, 3 sch, 1 tbl, 8 ex

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