19,11-covered bridges 4-estrene, the method of production thereof, pharmaceutical composition, the intermediate

 

(57) Abstract:

Describes the new 19, 11-covered bridges 4-estrene General formula I, where R6aand R6beach denotes a hydrogen atom or together a methylene group and R7denotes a hydrogen atom, or R6adenotes a hydrogen atom or a fluorine atom, chlorine, bromine or iodine, or represents a saturated, under -, or-position alkyl residue with a straight or branched chain with the number of C-atoms to 4, and R6band R7represents each a hydrogen atom or together an additional bond, or R14, R15, R16each denotes a hydrogen atom, R14denotes a hydrogen atom in the-position, and R15and R16represent together an additional bond or a methylene bridge in position; or R16together with R17denote a methylene bridge in-position and R17denotes the group-C-R22or R16denotes a hydrogen atom and R14and R15represent together an additional bond, R11, R11and R19denote each a hydrogen atom, or R11denotes a hydrogen atom in the-position, and R11and R19represent together an additional bond, or R19about the 17represent-OR21/-(CH2)n-A, -OR21/-(CH2)m-CC-B, -OR21/-(CH2)p-CH= CH-(CH2)k-D, -OR21/-HC=C=CEG,-OR21/-CF3, -C-R22/-OR23, -C-R22/-C1-C4-alkyl or C-R22/-False or R17/R17indicate together of formula II, where x = 1, U = 0; R21denotes a hydrogen atom, R23represents C1-C4is an alkyl group, R22stands WITH1-C3is an alkyl group, And denotes a hydrogen atom, cyano or-or SIG25and R25represents hydrogen, represents a hydrogen atom, a C1-C4is an alkyl group, a C2or C3is an alkyl group, D represents a hydrogen atom or a hydroxy-group, E and G denote each hydrogen atom or a C1-C3-alkyl, N denotes 0, 1, 2, 3 or 4, m is 0,1 or 2, p represents 0 or 1, k represents 0, 1, 2 or 3 and R16denotes a hydrogen atom or methyl group. New connections have a strong gestagenna activity and is used to obtain drugs. Also describes the method of production thereof, pharmaceutical composition and intermediate compounds. 4 c. and 9 C.p. f-crystals, 2 PL.

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The present invention is Otoscope or two hydrogen atom,

R1and R2each denotes a hydrogen atom or together an additional bond or in-position methylene bridge,

R6aand R6bdenote each hydrogen atom or together a methylene group or formed together with the carbon atom 6 three-membered ring, and R7in these cases represents a hydrogen atom or

R6adenotes a hydrogen atom or a fluorine atom, chlorine, bromine or iodine, or represents saturated in or standing position alkyl residue with a straight or branched chain with the number of carbon atoms up to 4, and R6band R7represent each a hydrogen atom or together an additional bond, or

R6band R7indicate together - or-position methylene bridge, and R6ais in this case a hydrogen atom,

R7denotes a saturated standing in or the position of the alkyl residue with a straight or branched chain with the number of carbon atoms up to 4 or denotes tighrope-SR20where R20represents a hydrogen atom or a group of alkanol with 1-4 carbon atoms,

R14, R15and R16denote each hydrogen atom or

R14means in the position nakadashi terenowy bridge, or R14and R15denote each a hydrogen atom and R16means or the position of the standing C1-C4is an alkyl group, or R16together with R17denote the in-position methylene bridge and R17refers to a group ,

R16denotes a hydrogen atom and R14and R15represent together an additional bond,

R11, R11and R19denote each hydrogen atom or R11denotes the position of the hydrogen atom and R11and R19represent together an additional bond, or R19denotes a hydrogen atom and R11and R11represent together an additional bond,

R17/R17denote

-OR21/-(CH2)n-A

-OR21/-(CH2)m-CC-B

-OR21/-(CH2)p-CH=CH-(CH2)k-D

-OR21/-HC=C=CEG

-OR21/-CF3< / BR>
< / BR>
< / BR>
< / BR>
or R17/R17indicate together

< / BR>
< / BR>
< / BR>
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< / BR>
c x = 1 or 2, with U=0 or

c R21and R23in the meaning of a hydrogen atom, a group WITH a1-C4-alkyl group or a C1-C4alkanoyl,

R22- value group C1-C1-C4-alkyl and R25denotes hydrogen, C1-C4-alkyl or C1-C4-alkanoyl,

B - in the meaning of a hydrogen atom, groups C1-C4-alkyl, groups C2or C3-quinil, fluorine atom, chlorine, bromine or iodine, group oxyalkyl, alkoxyalkyl or alkanoyloxy respectively with 1-4 carbon atoms in the alkyl-, alkoxy - or alkanoyloxy,

D - the value of a hydrogen atom, hydroxy, C1-C4-alkoxy or C1-C4-alkanoyloxy,

E and G - value for hydrogen or C1-C3-alkyl,

n - 0, 1, 2, 3, or 4

m - value of 0, 1 or 2,

p - value of 0 or 1,

k - value of 0, 1, 2 or 3 and

R18denotes a hydrogen atom or a methyl group.

According to the present invention preferred are those compounds of General formula I, in which

W represents an oxygen atom or two hydrogen atom,

R6aand R6beach denotes a hydrogen atom or designate formed together with the carbon atom 6 three-membered ring,

or

R6adenotes a chlorine atom or bromine atom or a saturated b - or-C1-C4is an alkyl residue with a straight chain, or

R6band R
R7indicates rich - or-position alkyl residue with a straight or branched chain with the number of carbon atoms up to 4,

R14, R15and R16denote each hydrogen atom or

R14denotes the position of the hydrogen atom and

R15and R16represent together more communication - or b-position methylene bridge,

R17/R17denotes-OH/-CH3,

-OC(O)CH3/-CH3;

-OH/-CCH,

-OC(O)CH3/-C=CH;

-OH/-CC-CH3,

-OC(O)CH3/-CC-CH3,

-C(O)CH3/-OC(O)CH3;

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other substituents can have all the above in formula I values.

Especially preferred are the following compounds:

17-(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11]- 19-norpregna-4-ene-3,20-dione;

17-(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11] - 19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-9,11-dihydro-6-methyl-6'H-benzo [10,9,11] -19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-9,11-dihydro-6-methyl-6'H-benzo[10,9,11]- 19-norpregna-4-ene-3,20-dione;

17-(atomic charges)-6-chloro-9,11-dihydro-6'H-benzo [10,9,11] -19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-6-chloro-1 ,2 ,9,11-tetrahydro - 3'H-cyclopropa[1,2] [6 H]benzo-[10,9,11]-19-nonproxy)-6-methyl-4', 5',9,11-tetrahydro-6'H-benzo- [10,9,11]-19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-6-chloro-1 , 2 ,4",5",9,11 - hexahydro-3'H-cyclopropa[1,2][6 H]benzo-[10,9,11]- 19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-5', 6'-dihydro-9H-benzo[10,9,11)-19-norpregna-4 - ene-3,20-dione;

17-(atomic charges)-5', 6'-dihydro-6-methyl-9H-benzo[10,9,11] - 19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11] - 18a-Homo-19-norpregna-4-ene-3,20-dione;

17-(atomic charges)-9,11-dihydro-6-methyl-6'H-benzo [10,9,11]]-18a-Homo-19-norpregna-4,6-diene-3,20-dione;

9,11-dihydro-17-methyl-6'H-benzo[10,9,11]-19 - norpregna-4-ene-3,20-dione;

3', 9,11 16-tetrahydrocyclopent[16,17][6H]benzo [10,9,11]-19-norpregna-4-ene-3,20-dione;

9,11-dihydro-17-methyl-6'H-benzo[10,9,11] -18a-Homo - 19-norpregna-4-ene-3,20-dione;

3', 9,11 ,16-tetrahydrocyclopent[16,17][6H]benzo [10,9,11]-18a-Homo-19-norpregna-4-ene-3,20-dione;

9,11-dihydro-17 hydroxy-17-methyl-6'H-benzo [10,9,11]variety-4-EN-3-one;

9,11-dihydro-17-ethinyl - 17-hydroxy-6'H-benzo [10,9,11]-variety-4-EN-3-one;

9,11 dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H-benzo- [10,9,11]variety-4-EN-3-one;

9,11-dihydro-17-hydroxy-17 -(1,3 - pentadienyl)-6'H-benzo[10,9,11]variety-4-EN-3-one;

(Z)-9,11-dihydro-17 hydroxy-17 -(3-hydroxy-1 - propenyl)-6'H-benzo[10,9,11]variety-4-EN-3-one;

9,11 dihydro-17 hydroxy-17 -(3-oksipropil)-6'H-benzo- [10,9,11] variety-4-EN-3-one;

17-hydroxy-17-methyl-4',5',9,11 -tetrahydro--(1-PROPYNYL)-4', 5', 9,11-tetrahydro-6'H-benzo[10,9,11]variety-4-EN-3-one;

5',6'-dihydro-17-ethinyl-17-hydroxy-9H-benzo [10,9,11]variety-4-EN-3-one;

5', 6'-dihydro-17-hydroxy-17 -(1-PROPYNYL)-9H-benzo [10,9,11]variety-4-EN-3-one;

9,11-dihydro-17-ethinyl-17-hydroxy-6'H-benzo [10,9,11]-18a-gamester-4-EN-3-one;

9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H-benzo [10,9,11]18a-gamester-4-EN-3-one;

17 -(1-butynyl)-9,11-dihydro-17 hydroxy-6'H-benzo [10,9,11]-18a-gamester-4-EN-3-one;

9,11-dihydro-17 -(1,2-PROPADIENE)-17-hydroxy-6'H-benzo[10,9,11]-18a-gamester-4-EN-3-one;

17-ethinyl-17-hydroxy-4',5',9,11 tetrahydro-6' H-benzo[10,9,11]-18a-gamester-4-EN-3-one;

17-hydroxy-17 -(1-PROPYNYL)-4', 5', 9,11-tetrahydro-6'H-benzo [10,9,11]-l8a-gamester-4-EN-3-one;

5', 6'-dihydro-17-ethinyl-17-hydroxy-9H-benzo[10,9,11]-18a - gamester-4-EN-3-one;

5, '6'-dihydro-17 hydroxy-17 -(1-PROPYNYL)-9H-benzo[10,9,11]-18a-gamester-4-EN-3-one;

9,11-dihydro-17 ethinyl-17-hydroxy-6'H-benzo[10,9,11] variety-4,15-Dien-3-one;

9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H-benzo [10,9,11]östra-4,15-Dien-3-one;

17-ethinyl-17-hydroxy-4',5',9,11 -terravita - 6'H-benzo-[10,9,11] östra-4,15-Dien-3-one;

5', 6'-dihydro-17-ethinyl-17-hydroxy-9H-benzo[10,9,11] östra-4,15-Dien-3-one;

5', 6'-dihydro-17-hydroxy-17 -(1-PROPYNYL)-9H-benzo[10,9,11]östra-4,15-Dien-3-one;

9,11-dihydro-17-ethinyl-17-hydroxy-6'H-benzo [10,9,11]-18a-gamestro-4,15-Dien-3-one;

9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H-benzo [10,9,11]-18a - 6'-dihydro-17 ethinyl-17-hydroxy-9H-benzo[10,9,11-18a - gamestro-4,15-Dien-3-one;

5', 6'-dihydro-17-hydroxy-17 -(1-PROPYNYL)-9H - benzo[10,9,11]-18a-gamestro-4,15-Dien-3-one;

4", 5", 9,11-tetrahydrofuro[6'H-benzo [10,9,11]variety-4-ene-17 , 2"(3"H)-furan)-3-one;

3", 4", 9,11-tetrahydrofuro[6'H-benzo[10,9,11] variety-4 - ene-17 , 2"(5"H)-furan]3,5-dione;

3"", 4"", 6 ,7 ,9,11 ,15 ,16 - octahydroxy[3'H,3"H-dicyclopropyl[6,7: 15,16] - [6H]benzo[10,9,11]variety-4-ene-17 , 2""(5""H)-furan] - for 3,5""- dione;

3"",4"",9',11' ,15',16' - hexahydrofuro[cyclopropane-1,6'-[3H] -cyclopropane-[15,16] [6H]benzo[10,9,11]variety-4-ene-17' , 2""(5"")-furan] -3',5" ' -dione;

3"", 4"", 9', 11 ,15' ,16' -hexahydrofuro [cyclopropane-1,6'-[3H] cyclopropa[15,16] -[6H] benzo[10, 9,11] östra-1,4-diene-17' , 2""(5""H)-furan-3',5" ' -dione;

3"",4"',4"",5"',6 ,7 ,9,11 ,15 ,16 -decahydrate-[3'H, 3"H-dicyclopropyl-[6,7:15,16][6H]benzo[10,9,11] variety-4-ene-17 , 2""(5""H)-furan-3,5""-dione;

3", 4", 9,11-tetrahydrofuro[6'H]-benzo[10,9,11]-18a - gamester-4-ene-17 ,2"(5")-furan] - for 3,5"-dione;

3"", 4"",6 ,7 ,9,11 ,15 ,16 octahydrate [3',H,3"H]-dicyclopropyl[6,7: 15,16] [6H] -benzo[10,9,11] - 18a-gamestro-4-ene-17 , 2""(5""H)-furan] - for 3,5""-dione;

9,11-dihydro-17-ethinyl-H'6-benzo [10,9,11]variety-4-EN-17-ol;

17-ethinyl-4',5',9,11 -tetrahydro-6'H-benzo [10,9,11]variety-

4-EN-17-ol;

5',6'-dihydro-17-ethinyl-9H-benzo[10,9,11]variety-4-EN - 17-ol;

9,11-dihydro-17-ethinyl-6'H-benzo[10,9,11]variety - 4,15-Dien-17-ol;

9,11-dihydro-17-ethinyl-6'H-benzo[10,9,11] -18a-homiest the mi steroids as the most similar in structure to the proposed compounds are described for the first time in the patent application Germany 3708942 (EP-A 10283428). However, the known compounds in contrast to the compounds discussed here do not have any ateno or econometica between C11 and C19; there both carbon atom is blocked by a bridge across two adjacent carbon atom substituted usually venereologia rings. Both known and described here they differ extremely high affinity to gestagenna receptor.

In the test binding gestagennah receptor using cytosol from homogenate of rabbit uterus and3H-progesterone as an initial matter, the new compounds show a very strong affinity for gestagenna receptor and high efficiency in the test save of pregnancy in rats after subcutaneous injection.

In table. 1 shows the factors of competition (KFin the test connection gestagennah receptor. The competition factor KFas a criterion for the coupling strength is defined as the ratio of the concentration of the test substance to the concentration of the substance ethanol (progesterone), in which both compounds show the same magnitude of displacement3H-progesterone complex of progesterone-receptor, since the low value of KFshows great strength of the connection (high affinity) (table. 1).

Noncurrent progesterone-antagonistic activity, and therefore, these compounds can be used primarily for abortion, against hormonal imbalance, menstruation and the beginning of labour, the compounds according to the invention unexpectedly have strong agonistic, i.e. gestagenna, activity.

Gestagenna action in the famous test of conservation of pregnancy in rats was determined after subcutaneous administration of the compounds. The results are summarized in table. 2.

Therefore, compounds of General formula I according to the invention have a very strong gestagenna efficiency only at a weak androgenic or even weakly antiandrogenna activity (dissociation).

On the basis of their gestagenna the effectiveness of the new compounds of General formula I can be used alone or in combination with estrogen in drugs for contraception.

The dosage of the compounds according to the invention in contraception drugs should be primarily from 0.01 to 2 mg per 1 day.

Gestagennoy estrogenic components of the active substance in contraception drugs prescribed along orally. Daily dose of mostly disposable.

As estrogen is used primarily synthetic estrogens as Atini is SS="ptx2">

Estrogen is administered in an amount which corresponds to the number of from 0.01 to 0.05 mg of ethinyl estradiol.

The new compounds of General formula I can also be used in preparations for the treatment of gynecological disorders and for substitution therapy. Due to their favorable spectrum of the compounds according to the invention is particularly well suited for the treatment of premenstrual pain, like headaches, depressive bad mood, water retention and mastodinia. The daily dose in the treatment of premenstrual pain is about 1-20 mg

Obtaining pharmaceutical drugs based on new compounds carried out in a known manner, with the active substance, if necessary in combination with estrogen to normal galenovye substances-carriers, solvents, if necessary with substances, corrective unpleasant taste of the medicine, and so on, processed and transferred in the desired form of application.

For the preferred oral administration is used, in particular, tablets, coated tablets, capsules, pills, suspensions or solutions.

For parenteral use, in particular, oil solutions, as, for example, solutions in sesame oil, the example, the benzyl benzoate or benzyl alcohol.

You can also include substances according to the invention in the subcutaneous system and thereby to enter them under the skin.

Finally, you can use the new connection as well as gestagenna components that have recently become known compositions for the control ability of women to produce offspring that differ by additional application of competitive progesterone.alternate (H. B. Croxatto and A. M. Salvatierra in Female Contraception and Male Fertility Regulation, ed. by Runnebaum, Rabe & Russ. name, volume 2, Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group, 1991, page 245).

Dosage lies in the already mentioned area, the preparation of the composition can be performed as in a typical OC-drugs. The use of a competitive progesterone antagonist can be carried out consistently.

The new compounds of General formula I get the method of the invention due to the fact that the compound of General formula II

< / BR>
where k denotes a protective keto - or oxygraph and a hydrogen atom,

X is in the SYN - or anti-position, a chlorine atom or bromine,

R18denotes a hydrogen atom or a methyl group,

Q denotes oxygraph in-position and S denotes the y of the above formula I, R17/R17- combinations of substituents, including spiraeoideae, and available in them actigraphy and/or catography, if necessary, protected,

a) radical cyclization transferred to the compound of General formula III

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where k, R18and Q and S are specified in the formula II is,

b) then, if Q denotes oxygraph, the latter optionally oxidized,

c) if R11, R11and R19in the end should represent a hydrogen atom, 19,11 - economistic hydronaut, or

d) if R19in the end must denote a hydrogen atom and R11and R11together shall designate additional double bond, the double bond in 19,11-economistic subjected to isomerization in the 11-position (Exo-position)

e) optionally injected into the D-ring 15,16-double bond and this link

f) optionally isomerizing in 14,15-position, or

g) medienraum in the corresponding 15 ,16 - methylene compound and

h) if Q and S together represent the oxygen atom of geograpy, turn the nucleophilic addition of substituent R17or its reactive precursor and optionally by esterification with the formation of simple or complex ester 17-oxigenio, and 17 - oxygraph, if necessary, subjected to the esterification of c the formation of simple or complex ester with the appropriate giving the remainder R23reagent,

i) if necessary, partial or complete hydrogenation of unsaturated C17-side chain and

j) optionally, oxidation of the corresponding 17-(3-oksipropil) or 17 - (4-oxobutyl) connection to education 17-spirolactone or

k) optionally, the reaction of cyclization of the corresponding (Z)-17-(3 - oxoprop-1-enyl)- or (Z)-17 -(4-hydroxy-but-1-enyl)-17-oxycoedone or the corresponding saturated in the side chain of the compounds for the formation of simple spirometer and

l) by treatment with an acid to mix with water, the solvent is transferred to ketoester, and other available protective group also otscheplaut, and this is transferred to the compound of General formula I, and this compound is General formula I, if necessary, turn

m) the introduction of the 1,2 - and/or 6,7-double bond, if necessary, by methylanilinium one or both double bonds,

n) the introduction of in - or-position alkyl residue with a straight or branched chain or tighrope SR20in the 7-position,

o) epoxydecane 6,7-double bond disclosure EPO is followed by removal of water for 6-methylene compounds

q) isomerization standing in the Exo-position double bond group 6-methylene or a direct introduction of group 6-alkyl (6 - alkyl-4,6-Dien-3-one),

r) group by hydrogenation of 6-methylene turn the compound of General formula I,

where R1, R2, R14, R15, R16, R17,, R17, R18, R11and R19have the desired value,

and R6arepresents a group is methyl and R6band R7represent each a hydrogen atom or together represent an additional bond,

or

s) if R6ashould provide rich in - or-position alkyl residue with a straight or branched chain with the number of carbon atoms up to 4, turn-while simultaneously catalyzing the isomerization of 4 (5)-double bond in the 5(6), epoxydecane 5 (6)-nucleophilic double bond and disclosure of 5,6-epoxide with a protected 3-geography put into deep alkalinisation or alkylpyridinium straight or branched chain with the number of carbon atoms up to 4 in the alkyl residue and splitting protective 3-ketogroup formed in the compound 5 - hydroxy-6-alkyl with a mild acidic conditions to the corresponding 3-keto-5-hydroxy-6-alkylamino I in-position 6-alkyl group or the removal of protective 3-ketogroup under severe conditions translate into the corresponding 3-keto-4-ene-the compound of General formula I in-position band 6-alkyl and

t) if necessary one of the above 3 - catasetinae turn with hydroxylaminopurine in the presence of tertiary amines at temperatures between -20 and +40oC 3-akcionirovanie (W=>N~OH; indicates SYN - or antipyrene OH) or

u), if necessary, make a 3-thioketal, mostly 3-(1', 3'-ethylenedithio)-ketal, and the last split restoration to compounds of General formula I, where W denotes two hydrogen atoms.

The mechanism of synthesis of compounds containing a new type of bridge, shown in figure 1 (see end of description).

According to the scheme 1 is described, for example, in European patent applications 0110434 and 0127864 epoxide I, in which R18denotes a hydrogen atom or a methyl group and K denotes a protective group Catala, opening with propargylglycine (receipt see "Synthesis of acetylenes, allenes and cumulenes", Z. Brandsma and H. D. Verkruijsse, page 16, Elsevier Scientific Publishing Company, Amsterdam, Oxford, new York (1981) transferred to the compound of formula 2. K denotes a leaving a protective group Catala, for example, Ethylenedioxy - or 2,2-dimethylpropylene-1,3-vaxigrip. Also use other common protective group Catala. K may denote also protected oxyr ethoxyethanol, tetracaprylate or salelologa ether. The removal of the protective group and oxidation of free actigraphy get ketogroup.

Then compound 2 by a known method bromilow at the end of the triple bond (H. Hofmeister, K. Annen, H. Laurent and R. Wiechert, Angew. Chem. 96, page 720 (1984)). Then the compound obtained 3 by hydrogenation or transfer of hydride transfer in vinylchlorid 4. Mostly the reaction is carried out restoration diimide.

Radical cyclization of compounds 4 perform similarly to the already described cyclization of the corresponding arilgalogenide (see B. E. Ottow, G. and R. Neef Wiechrt; Angew. Chem. 101, page 776 (1989)). Of the possible ways for the formation of intermediate radicals has been used here, in particular, two:

reaction with trialkylamine, mainly with tributyltinhydride, in suitable solvents, such as toluene, or transformation with lithium in liquid ammonia, mixed with an organic solvent, such as tetrahydrofuran at temperatures between -78 and -33oC.

Connection 5 in this case, in a known manner by oxidation of 17-oxytocin to translate in the connection 6. Compounds 5 and 6 represent the original products while obtaining compounds of General shape or 6 double bond can be gidrirovanii by known methods.

If R19must represent a hydrogen atom and R11and R11indicate together with additional double bond, the initial isomerization of the double bond (R11= H, R11and R19form instead of an additional connection) reach by heating compounds 5 or 6 in ethanol c catalyst is 5% palladium on coal, which has previously been treated with hydrogen, or by heating with a small amount of cyclohexene. But isomerization can be achieved by transformation with a catalyst of palladium/charcoal, for example, ethanol or mixtures of tetrahydrofuran/ethanol, in an atmosphere of hydrogen at room temperature, or boiling of this reaction mixture with cyclohexanol instead of hydrogen.

These stages include in this case, it might be desirable transformations in D-ring: introduction 15,16-double bond (R15and R16form General additional connection) is carried out, for example, modified by oxidation according to the method Saegusa (J. Minami, K. Takahashi, J. Shimizu, T. Kimura, J. Tsuji; Tetrahydron 42 (1986), pp. 2971; European patent A 0299913) corresponding enol compounds of the 17-ketone.

If necessary, you can isomerizate double bond at the 14-position. For this 15,16-EN-connections on the>5and R16present together in-position methylene group, the introduction of this group carry out, for example, by transformation of the corresponding 15,16-EN-17-one connection with Metricom dimethylsulfoxide (see, for example, the description of the invention it is lined accepted the application for patent in Germany 1183500, with the description of the invention to unaccepted application Germany 2922500, European patent A 0-019690, U.S. patent 4291029 A, E. J. Cozey, M. Chaykovsky, J. Am. Chem. Soc. 84, page 867 (1962)).

After the modification of the D-rings are other stages, especially the introduction of the residues R17and R17C-17-the atom. This introduction by analogy with the known literature methods (for example, J. Fried, J. A. Edwards, Organic reactions in the chemistry of steroids", van Nostrand Reinhold Company, 1972, vol. 1 and 2; "Terpenoids and steroids", Specialist Periodical Report, The Chemical Society, London, volume 1-2) is carried out in most cases, the nucleophilic addition of substituent R17or a reactive precursor to the C-17-atom.

In the case of easily analiziruemoi 17-ketone, such as, for example, 14,15-ene-compounds, nucleoli injected with the addition of salts of cerium (T. Jmamoto, N. Fakjana, K. Nakamura, Y. Sugiura, Tet.Lett., 25. 4233 (1984)).

The introduction of the Deputy CC-B as R17

Introduction 3-hydroxy-1-propyl in the 17-position is produced by the interaction of the 17-ketone with gianina propargilovyh alcohol (3 - oxypropyl), for example, formed "in situ" ditalini salt propargilovyh alcohol or with relevant protected on oxytocin derivatives, such as, for example, with a lithium compound 3- [(tetrahydro-2H-Piran-2-yl/oxy]-1-propene.

Connection oksipropil and oxypropane can be obtained from derivatives of oxypropylene. Chain oksipropil receive, for example, by hydrogenation at room temperature and under normal pressure in solvents, such as methanol, ethanol, tetrahydrofuran or ethyl acetate, with the addition of catalysts based on noble metal like platinum or palladium.

Obtaining compounds with a double bond with Z-configuration in the side chain Oswego metal, for example 10% palladium on barium sulphate, in the presence of an amine or of a 5% palladium on calcium carbonate, with the addition of lead (11)-acetate. Hydrogenation stop after absorption of one equivalent of hydrogen.

Compounds with double bonds with E-configuration in the side chain are formed by the restoration of the triple bond, for example with sodium in liquid ammonia (K. N. Cambell, L. T. Eby, J. Am.Chem.Soc., 63 (1941, page 216), with amidon sodium in liquid ammonia or with lithium in low molecular weight amines have had (R. A. Benkeser and others, J. Am.Chem.Soc., 77(1955), pp. 3378).

Introduction axialent and oxyalkyl can be made directly by the transformation of the 17-ketone with metal derivatives (E. J. Corey, R. H. Wollenberg, J. Org.Chem. 40, 2265 (1975); H. P. On.W.Lewis, G. Zweifel, Synthesis 1981, page 999; G. Gohiez, A. Alexakis, J. F. Normant, Tet.Lett. 1978, page 3013, P. E. Eaton and others, J. Org.Chem. 37, 1947). Introduction homologous oxyalkyl-, axelsen and onselchange may appropriately.

The products in which R17/R17denote

< / BR>
with x = 1 or 2, can be obtained from the 17-(3-oksipropil) or 17 - (4-oxobutyl)-compounds by oxidation in a known manner, for example with Jones reagent, manganese dioxide, pyridinium dichromate, chlorbromuron pyridinium, chromic acid - pyridine or with reacti the>BR>
with x = 1 or 2, can be obtained by the reaction of cyclization of the corresponding (Z)-17 -(3-oxoprop-1-enyl) or (Z)-17 - (4-hydroxy-1-butenyl)-17-oxyconti or saturated, respectively, in the side chain connection. Compounds with saturated simple spiropyran can be obtained by hydrogenation of unsaturated simple spiropyran on the catalysts of the platinum - palladium.

17-1,2-alkadiene-substituted steroids can be obtained, for example, by transformation, if necessary, protected in

plain tetrahydropyranyl ether, simple-alkoxyethanol ester, alkyl - or arylsulfonate 17 -(3 - hydroxy-1-alkyne)-substituted compounds with complex hydrides in aliphatic go alicyclic ethers (see , for example, A. Burger, J.-P. Roussel, C. Hetru, J. A. Hoffmann, and B. Luu, Tetrahedron 45, 155 (1989); A. Claesson, Z.-J. Olsson and C. Bogentoft, Acta Chem.Scand. 27, 2941 (1973); L.-J. Olsson and A. Claesson, Acta Chem. Scand. B31, 614 (1977)) and also other well-known from the literature methods (see , for example, the description of the invention it is lined accepted the application for patent in Germany 19585333; lined description of unaccepted application for patent in Germany 1668679).

Introduction triptoreline carry out the conversion of the 17-ketone with triftoratsetilatsetonom in the presence of tetrabutylammonium (see R. Krshnamurti, the accession of acetonitrile or splitting spiroepoxide using HCN by K. Ponsold, and others, Z. Chem. 18(1978)), 259-260.

Synthesis of 16,17-methylene-17-alkanoyl - substituted compound exercise is known from the literature methods. So, for example, on the basis of the 17-ketone, you can get16-17-perftoruglerodnaya that in the presence of catalysts based on transition metals can be combined with the compounds alkoxysilane or zinc (see, for example, M. Kosugi, T. Sumiya, Y. Obara, M. Suzuki, H. Sano, and T. Migita, Bull.Chem.Soc., Japan 60, 767 (1987); P. G. Ciattini, E. Morera and G. Ortar, Tetrahedron Lett. 31, 1889 (1990)). Acid hydrolysis products of combinations gives1617-acetylcodeine. These anony can be subjected to a transformation in the ways mentioned above to cyclopropylamine 1517-ketone with iodide trimethylsulfoxonium to 16,17-methylene - 17-acetylcodeine, or joining the paired relations alkylene connections translate into derivatives of 16-alkyltransferase.

Compounds in which R17represents the residue of alkyl and R17represents the residue of alkanoyl, can be obtained, for example, from16-17-alkanolamine or 17-hydroxy-17-alkanolamines, and recovery with lithium in liquid ammonia, mixed with tetrahydrofuran, get the 17-rolatini that you can alkilirovanii with alcolhol the(1964).

Obtaining derivatives, in which R17and R17together denote

< / BR>
< / BR>
carried out on the basis of the 17-ketone is known from the literature methods (for example, European patent A-04443951, 1991); and European patent A-0154429, 1989). To get this, for example, reducing allilirovanii above16-17-acetyl compound corresponding 17 -(2 - propenyl) connection (allilirovanie with allylbromide). End of the double bond in this case is transferred or gidroborudovaniya, for example 9.BBN (9-borabicyclo), the oxidation treatment and the further oxidation to the corresponding C3-aldehyde or cleavage by ozonolysis in C2-aldehyde. Spirometry with 6 - or 5 - rings can be obtained in this case through aldorino reaction. When first formed , -unsaturated ketones, which if necessary you can restore the well-known methods to saturated ketones.

Introduction sample substitution oksiprogesterona (17 = acetyl, 17 = hydroxy) or the synthesis of the corresponding homologous-hydroxy-17-alkanolamine exercise known from the literature methods. Thus it is necessary especially to highlight the way through the 17-cyano-17-oxycoedone (meth 57062296-300 (1982); J. C. Gase and L. Nedelec, Tet. Lett. 1971, p. 2005; J. N. Batist M., N. C. M. E. Barendze, A. F. Marx, Steroids, 1990, page 109).

This 17-ketone turn by reaction with, for example, acetonecyanohydrin (2-hydroxy-2-methylpropionitrile) in suitable solvent system such as ethanol or methanol and dichloromethane, if appropriate (mostly basic) pH value (regulate the addition of KCN or NaCN or KOH or NaOH). Under these reaction conditions can be achieved bicrystalline 17-cyanocobalamine. In this case, protect 17 oksyfenylo and then spend the reaction ceanography with C1-C4- alkyllithium, for example methyllithium or C1-C4-alkylpolyglucoside, such as methylacrylamide to get then after acid cleavage of the 17-hydroxy - 17 alkanolamine. On the basis of 17-hydroxy - 17 - alkanolamine you can get then in a known manner 17 alkanoyloxy-derivatives.

Then it is important to select translation 17-ethinyl-17 - nitroacetophenone (see H. Hofmeister, K. Annen,H. Laurent and R. Wiechert, Chem.Ber. III, 3086 (1978)) or formed from a 17-ethinyl-17-oxyconti reaction with phenylsulfonylacetate of allencalifornia (see V. Van Rheenen and K. P. Shephard, J. Org.Chem. 44, 1582(1979) 17-hydroxy-17 - acetylcodeine.

17-acetyl-17-persuadere Ministry) in suitable solvents, as, for example, trichlormethane.

The subsequent release of 3-metafunction with the elimination of water and formation of 4(5)-double bond is carried out by treatment with an acid or an acidic ion exchanger. The acid treatment takes place in a known manner, and the corresponding 5 - hydroxy-3-ketal dissolve in, mix with water solvent, such as water, methanol, ethanol or acetone, and affect a solution of catalytic amounts of a mineral acid or sulfonic acids, for example hydrochloric, sulfuric, phosphoric, perchloric, or p-toluenesulfonic acid, or organic acids as acetic acid, up until not remove existing protective group. The transformation that takes place at temperatures from 0 to 100oC, can be made with an acidic ion exchanger. The process of conversion can be monitored by analytical methods, for example selected thin-layer chromatography samples.

These stages include, for synthesis of the residues R6aand R6b, R7and R1, R2.

For the target compounds, which have 1,2 and 6,7-double bond, or for the corresponding intermediate products, which are desirable near both double bonds, it is possible on the basis of the 3-ketone (W= oxygen) relations (see, for example, the description of the invention it is lined accepted the application for patent in Germany 1119266). However, it is often necessary on the basis of other functions in the molecule to enter each other both double bonds. When this first occurs, as a rule, the introduction of a 6,7-double bond. This introduction is carried out via bromination simple dianalove ether and subsequent uncoupling of methyl hydrogen (see, for example, J. Fried, J. A. Edwards, Organic reactions in the chemistry of steroids, von Nostrand Reinhold Company 1972, page 265-374).

Bromination simple dianalove ester can be, for example, analogously to the directions in "Steroids" 1, 233. The elimination of hydrogen bromide carried out by heating 6-bromoaniline with bases, such as LiBr or LiCO3in aprotic solvents, such as dimethylformamide, at temperatures of 50-120oC or by heating 6-bromoaniline in collidine or lutidine.

The introduction of the 1,2-double bond is possible depending on the desired end connections take place immediately after the introduction of a 6,7-double bond or at a later intermediate stage. This dehydrogenation is carried out mainly by chemical or microbiological method known from the literature sposobem, for example, by heating with selenium dioxide, 2,3 - dichloro-5,6-dicyanobenzoquinone, chloranil, thallium triacetate or leads to compounds, which lead in suitable solvents, such as dioxane, tert.butanol, tetrahydrofuran, toluene, benzene, or mixtures of these solvents.

The introduction of the 1,2-double bond is possible, however, to also modified Saegusa oxidation (J. Minami, K. Takahashi, J. Shimizu, T. Kimura, J. Tsuji, Tetrahedron 42 (1986), pp. 2971; European patent A-0299913) corresponding enol compounds of the 3-ketone.

Compounds that are a function of 1,2-methylene derived from 1,2-unsaturated compounds by transformation with Metricom dimethylsulfoxide by analogy with getting 15,16-methylene compounds (see above). It is possible selective introduction of 1,2-functions of methylene in the presence of 4,6-Dien-3-one-unit (see, for example, with the description to the accepted application Germany 1183500).

For connections with the function of 6,7 - methylene introduction conduct of dienone transformation with Metricom dimethylsulfoxide, and there is, of course, mix-and - isomers (ratio depends on the applied substrates and is about 1:1), which can be separated by chromatography on a column.

Compounds with R

When this function introduction 7-alkyl carried out, as a rule, diallylmethylamine. Introduction SR20groups produce 1,6-attach teoksessa acid. This usually formed of a mixture of stereoisomers, and the effect on this reaction in the case of joining teoksessa acid in the additive of Lewis acids, such as, for example, nortriptilina in tetrahydrofuran as solvent, leads to a sharp increase 7-isomers.

Compounds in which R6arepresents a chlorine atom and R6band R7form together an additional bond, are also based on 4,6-Dien-3-one connections. To do this, first epoxidized 6,7-double bond in the application of organic nagkalat as meta-adharmasya acid in methylene chloride, if appropriate in the presence of sodium bicarbonate solution (see W. Adam and others J. Org.Chem. 38 (1973), pp. 2269). The opening of this epoxide and the destruction of the initially formed 7-oxypropyl produce, for example, by transformation of gaseous hydrogen chloride in glacial acetic acid (see, in particular, the patent Freefile reveal epoxide using, for example, halides of alkali metals (e.g., LiCl) in solvents, such as acetic acid, and then remove the formed 7 oxygraph after conversion into a leaving group (for example, mesilate or toilet).

Introduction group 6-methylene can be done, for example, derived from 3-amino-3,5-diene transformation with formaldehyde in an alcohol solution during the formation of oxymethyl groups and with subsequent removal of water by acid, for example hydrochloric acid in dioxane/water. But you can conduct the removal of water due to the fact that first introduced the allocated group and then removed. As exhaust groups are suitable, for example, mesilate, toilet or benzoate (see patent Germany A-3402329 A1; European patent A-0150157; U.S. patent 4584288(86); K. Nickisch and other J. Med.Chem., 34, 2464 (1991).

Another possibility for the introduction of a 6-methylenediphenyl is the direct conversion of 4(5)-unsaturated 3-ketones with acetals of formaldehyde in the presence of sodium acetate, for example with phosphorus oxychloride or pentachloride phosphorus in suitable solvents, such as chloroform (see, for example, K. Annen, H. Hofmeister, H. Laurent and R. Wiechert. Synthesis 1982, page 34).

Connection 6-methylene you can use to obtain the compounds of General formula I, in which is can be used for example, described D. Burn, etc. in Tetrahydron 21 (1965), page 1619, the way in which reach the isomerization of the double bond by heating compounds of 6-methylene in ethanol with a catalyst on the basis of a 5% palladium on coal, which was pretreated with hydrogen, or by heating with a small amount of cyclohexene. The isomerization can also be performed with untreated pre-catalyst if the reaction mixture is added a small amount of cyclohexene. The appearance of small amounts of hydrogenated products, you can prevent the addition of excess sodium acetate.

But you can also directly get derivatives of 6-methyl-4,6-Dien-3-one (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 1983, page 712).

Compounds in which R6ais-methyl-function, can be obtained from 6-methylenediphenyl by hydrogenation under suitable conditions. Best results (selective hydrogenation eksootilisemaid function) reaches the transfer hydrogenation (E. A. Brande, R. P. Linstead and P. W. D. Mitchell, J. Chem. Soc. , 3578 (1954). If derivatives of 6-methylene heated in a suitable solvent, such as ethanol, in the presence of a hydrogen donor, such as, for example, cyclohexene, you get a very good outputs proizvod, D. N. Kirk and J. Petrow, Tetrahedron, (1965), page 1619).

You can also purposefully to obtain compound 6-alkyl. For this purpose, 4-(5)-unsaturated 3-ketones can be converted, for example, ethylene glycol, triethylorthoformate in dichloromethane in the presence of catalytic amounts of acid (e.g. p-toluenesulfonic acid) into the corresponding 3-ketals. During this catalysis isomerizing double bond in position 5(6). Selective epoxidation of this 5(6)-double bond is carried out, for example, the use of organic nagkalat in suitable solvents, such as dichloromethane. Alternatively, this can be epoxidation with hydrogen peroxide in the presence of, for example, hexachloroacetone or 3-nitritification. Educated 5,6 - epoxides using, for example, alkylpolyglucosides or alkylimideazoline can then reveal axis.In this way receive 5-hydroxy-6-alkylamine. Splitting protective 3-ketogroup can be made when getting 5 - oxytocin as a result of processing under mild conditions acid (acetic acid or 4 N. hydrochloric acid at 0oC). The destruction of the bases 5-oxytocin using, for example, dilute aqueous Rastogi cleavage Catala under severe conditions (aqueous hydrochloric acid or another strong acid) gives the corresponding 6-alkylamine.

The compounds of General formula I, W is oxygen atom may, if desired, by conversion with hydroxylaminopurine in the presence of tertiary amines at temperatures between -20 and +40oC translate into oxime (in General formula I with X meaning and oxygraph can be SYN - or Antologiya).

Remove 3-oxypropyl to obtain the final product of General formula I, W is two hydrogen atoms can be, for example, specified in the Federal Republic of Germany patent A 2805490 instructions reductive splitting of tickets.

The object of the present invention are intermediate compounds of General formula III'

< / BR>
where k denotes a protected keto - or oxygraph and a hydrogen atom,

R11and R19represent together an additional bond and R11denotes a hydrogen atom in the-position or R19denotes a hydrogen atom and R11and R11represent together an additional bond, or R11, R11and R19denote each a hydrogen atom,

R14, R15and R16have indicated in formula I, the values

R18'denotes a hydrogen atom or a methyl group and

Q represents oxygraph in-Palma, Q and S denote one of these in the formula I R17/R17-combinations of substituents, including spiraeoideae, and available in them hydroxy - and/or catography, if necessary, protected.

These compounds have been cyclization reaction and can be in the 17-position is still the original oxygraph ketogroup or final sample R17/R17substituents.

The following examples serve for a more detailed explanation of the present invention.

Examples.

General remarks.

I) All experiments are performed in a protective gas atmosphere.

II) If not otherwise noted, the experiments is as follows.

The reaction solution is poured or in a saturated aqueous solution of sodium chloride (A), saturated aqueous sodium bicarbonate solution (B) or a saturated aqueous solution of ammonium chloride (C). Then extracted several times with ethyl acetate. The combined organic phases are washed or saturated aqueous ammonium chloride (D), or saturated aqueous sodium bicarbonate (E), or saturated aqueous sodium chloride (F) and dried over sodium sulfate. Then filtered and Katia on a column of silica gel with a mixture of hexane/ethyl acetate.

IV) General instructions.

1) the Splitting of the C-3-ketals, if necessary with the removal of 5-actigraphy and splitting possible protective group tetrahydropyranyl 17-side chain:

5 mmol of the original substance and 5 ml of 4 N. hydrochloric acid dissolved in 60 ml of acetone. Additionally stirred for 1 h at room temperature and 30 min at 40oC. Subsequent water treatment (A, E, F) and purification give the corresponding 3-ketone.

2) Attach ethinyl-PROPYNYL or 1-butylboronic chain to C-17:

100 ml of absolute tetrahydrofuran is saturated with 0oC for 30 min with gaseous ethyl or propylene; to attach 1-butylboronic chain introduced 5 g of 1-butyne in 100 ml of tetrahydrofuran. Then added 31 ml of a 1.6 molar solution

n-utility in hexane and additionally stirred for 30 min at 0oC. then added a solution of the corresponding original substance (5 mmol) in absolute tetrahydrofuran. Additionally stirred for 1 h at 0oC and treated then with water (C, F).

3) Oxidation with chromium trioxide/pyridine:

to 10 ml of pyridine in 80 ml of dichloromethane added at 0oC 30 mmol of chromium trioxide. Stirred for additional 30 min at the about is stirred 1 h at 0oC. thereafter, the reaction solution is decanted and washed three times to the residue dichloromethane. The combined organic phases are washed twice with 5% aqueous sodium hydroxide solution and once with saturated aqueous sodium chloride and dried over sodium sulfate. Then filtered and concentrated in vacuo.

4) Introduction 15(16)-double bond of a busy 17-ketone through education simple similaralcohol ether and subsequent oxidation by Saegusa.

a) receiving a simple similaralcohol ether:

15 mmol of Diisopropylamine in 100 ml of absolute tetrahydrofuran and 9 ml of 1.5 molar solution of n-utility in hexane get at -30oC diisopropylamide lithium. Then added a solution of 5 mmol of the corresponding 17-ketone in 50 ml of absolute tetrahydrofuran and additionally stirred for 1 h at -30oC. Then added 17 mmol of trimethylchlorosilane. Then bring the reaction mixture to room temperature and additionally stirred for 1 h In the processing water (B, D, F) will be given a simple selenology ether.

b) Introduction 15(16)-double bonds:

5 mmol described in paragraph (a) simple similaralcohol ester are dissolved in 60 ml acetate filtered reaction solution through celite and concentrated in vacuo.

Example 1

9,11-dihydro-17-hydroxy-17-methyl-6'H-benzo[10,9,11]variety-4-EN-3-one

a) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy] -19-ethinyl - 5-androst-9(11)-ene-5,17-diol

In the suspension to 48.6 g of magnesium shavings in 700 ml of absolute simple diethyl ether add 3 g of chloride of mercury(II). Stirred for 30 min and then cooled to 0oC. Then attach the first 7.5 ml 3-bromopropane. After the jump response (temperature) is cooled to -5oC. and Then added dropwise rest of 67.5 ml 3-bromopropane such a rate that the internal temperature did not exceed 0oC. After complete additive is stirred 30 min at 0oC and then slowly added dropwise a solution of 50 g of 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)] -5,10-epoxy-5-variety-9(11)-EN-17-ol in 300 ml of absolute tetrahydrofuran. Stirred for 1 h at 0oC and then remove excess magnesium. Then carefully added 500 ml of a saturated aqueous solution of ammonium chloride and stirred for 1 h at room temperature (strong evolution of gas). After this process the water (F). After recrystallization of the crude product from diisopropyl simple ether get 45,2 g 1a).

1H-NMR (CDCl3): = 5,42 ppm m (1H, H-11); however, 4.40 s (1H, OH); 3,75 dd, J = 14 and 7.5 Hz, 1H, H-17); 3,40-of 3.60 m (4H, ketal); 1,93 (J = 1.5 Hz, NCI)] -5-androst-9(11)-ene-5,17-diol

45 g described in paragraph 1a) of a substance is dissolved in 750 ml of acetone. Added 1.85 g of silver nitrate and 23.3 g of N-bromosuccinimide. Then stirred for 20 min at room temperature. Water treatment (B, F) gives 52,5 g 1b), which is used without purification in the next stage.

c) 19-(2-bromanil)-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)] -5-androst-9(11)-he-5,17-diol

52,5 g described in paragraph 1b) of a substance is dissolved in 1000 ml of a mixture of tetrahydrofuran and water (1:1). Attach 79 g of the hydrazide p-toluenesulfonic acid and 52 g of sodium acetate. Then boil for 4 h reflux. Water treatment (In, F) and purification gives 36,9 g 1c) as a white foam.

1H-NMR (CDCl3): = 6,18 ppm m (1H, vinyl); 5,85 m (1H, vinyl); 5,43 m (1H, H-11); however, 4.40 s (1H, OH); to 3.73 dd, J = 14 and 7.5 Hz, 1H, H-17); 3,48-to 3.58 m (4H, ketal); 1.00 s (3H, Me-ketal); and 0.98 s (3H, Me-ketal); 0,70 s (3H, C-18).

d) 9,11-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]- 6'H-benzo[10,9,11]-5-estran-5,17-diol

Getting when using hydride anti

20 g described in point 1c) of a substance is dissolved in 500 ml of absolute toluene. Add 12 ml of anti-hydride and 25 mg azobisisobutyronitrile and boiled for 1 h under reflux while irradiating an ultraviolet lamp. After complete conversion of d the th air. Get 9,1 g 1d) in the form of white crystals. Chromatography on a column of silica gel stock solution with a mixture of hexane/ethyl acetate receive the other of 3.84 g 1d) as a white foam.

1H-NMR (CDCl3): = 5,50 ppm dbr (J = 10 Hz, 1H, bridge); 5,47 m (1H, bow); 4,37 s (1H, OH); 3,50-3,62 m (5H, ketal and H-17); 2,47 m (1H, H-11); 0,99 s (3H, Me-ketal); and 0.98 s (3H, Me-ketal); 0,80 s (3H, C-18).

The receiving method Birha

To 400 ml of condensed ammonia is slowly added at -78oC 3.5 g of lithium. After complete dissolution was added dropwise a solution of 5 g described in point 1c) of the substance in 600 ml of tetrahydrofuran. After a full additive is stirred for 15 min at -40oC. and Then rapidly cooled down the reaction solution by addition of water. Per night is distilled ammonia and treated with water (F). After cleaning along with 1.9 g 1d) are obtained 1.6 g of 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]- 19-ethynyl-5-androst-9(11)-ene-5,17-diol.

1e) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)] -5-hydroxy-6'H-benzo-[10,9,11]-5-estran-17-he

1. Receiving from 1d)

Total recipe 3) of 12.9 g described in paragraph 1d) substances of 18.5 g of chromium trioxide and 62 ml of pyridine in 450 ml dichloromethane get 11,34 g 1e) as a white foam.

2. Alternative getting 1e)

1e1) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-19-this is 4,82 g 1e1) white foam.

1H-NMR (CDCl3): = 5,43 ppm dbr (J = 5.5 Hz, 1H, H-11); however, 4.40 s (1H, OH); 3,40-of 3.60 m (4H, ketal); 1,92 t (J = 1.5 Hz, 1H, etin); 1,02 s (3H, C-18); 0,95 s (3H, Me-ketal), 0,91 s (3H, Me-ketal).

1e2) 19-(2-bromanil)-3,3-[2,2-dimethyl-1,3-propanediylbis- (hydroxy)]-5-hydro-5-androst-9(11)-EN-17-one

Similarly 1b) 4,82 g described in paragraph (1e1) substances turn with 5.5 g of N-bromosuccinimide and 200 mg of silver nitrate in 100 ml of acetone. Obtain 5.7 g 1e2), which is used as the source in the next stage.

1e3) 19-(2-bromanil)-3,3-[2,2-dimethyl-1,3-propanediylbis- (hydroxy)]-5-hydroxy-5-androst-9(11)-EN-17-one

By analogy with example 1c) 5.7 g described in paragraph (1e2) substances turn with 9 g of hydrazide p-toluenesulfonic acid and 6 g of sodium acetate in 100 ml of a mixture of tetrahydrofuran and water (1:1). Get after cleaning 3 g 1e3) as a white foam.

1H-NMR (CDCl3): = is 6.19 m (1H, vinyl); of 5.83 m (1H, vinyl); 5,33 dbr (J = 5.5 Hz, 1H, H-11); however, 4.40 s (1H, OH); 3.45 points-of 3.60 m (4H, ketal); 1.00 s (3H, C-18); 0,95 s (3H, Me-ketal); 0,82 s (3H, Me-ketal).

1e) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-5-hydroxy-6'H-benzo[10,9,11]-5-estran-17 - he

By analogy with the 1d) 3 g described in paragraph 1e3) substances turn with 3 ml of anti-hydride and 25 mg azobisisobutyronitrile in 100 ml of absolute toluene. Get after cleaning 2,39 g 1e) as a white foam.

Me-ketal); of 0.98 s (3H, Me-ketal); 0,92 s (3H, C-18).

1f) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17-methyl-6'H-benzo-[10,9,11]-5-estran-5,17-diol

To 13 ml of a 1.6 molar solution metallice in simple diethyl ether at 0oC in an atmosphere of argon is added a solution of 882 mg obtained in point 1e) of the compound in 20 ml of absolute tetrahydrofuran. Stirred for 2 h at 0oC and treated with water (C, F). Receive 845 mg 1f) as a white foam, which was used without purification in the next stage.

1g) 9,11-dihydro-17-hydroxy-17-methyl-6'H-benzo[10,9,11]-variety-4-EN-3-one

General instructions 1) turn 839 mg 1f) 4 N. hydrochloric acid in acetone. Get after cleaning 594 mg 1g) as a white foam.

1H-NMR (CDCl3): = 5,81 MRP sbr (1H, H-4); 5,61 dbr (J = 10 Hz, 1H, bow); 5,50 m (1H, bridge); 2,69 m (1H, H-11); 1,23 s (3H, methyl); 0,95 s (3H, C-19).

Example 2

9,11-dihydro-17-ethinyl-17-hydroxy-6'H-benzo[10,9,11]variety-4-one-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]- 17-ethinyl-6'H-benzo-[10,9,11]-5-estran-5,17-diol

Total recipe 2) turn 1.24 g described in 1e) substances and 18.9 ml of a 1.6 molar solution of n-utility in hexane and gaseous Atina in absolute tetrahydrofuran. Get after cleaning 1.20 g 2a) as a white foam.

1H-NMR-ketal); 0,97 s (3H, Me-ketal); 0,90 s (3H, C-18).

b) 9,11-dihydro-17-ethinyl-17-hydroxy-6'H - benzo[10,9,11]-variety-4-EN-3-one

Total recipe 1) turn 1.2 g 2a) with 3 ml of 4 N. normal hydrochloric acid in acetone. After crystallization of the crude product from ethyl acetate receive 776 mg 2b) in the form of white crystals.

1H-NMR (CDCl3): = 5,81 MRP sbr (1H, H-4); 5,62 dbr (J = 10 Hz, 1H, bridge); 5,56 m (1H, bridge); 2,67 m (1H, H-11); 2,59 s (1H, etin); 0,91 s (3H, C-18).

Example 3

9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H - benzo[10,9,11]-variety-4-EN-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -(1-PROPYNYL)-6'H - benzo[10,9,11]-5-estran-5,17-diol

Total recipe 2) transform 1 g described in point 1e) of the connection and 15.1 ml of a 1.6 molar solution of n-utility in hexane and gaseous propene in absolute tetrahydrofuran. Get 1,05 g 3a) as a white foam, which is used without purification in the next stage.

3b) 9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H - benzo-[10,9,11] variety-4-EN-3-one

General instructions 1) turn 1 g described in paragraph 3 (a) substances with 2.5 ml of 4 N. aqueous solution of hydrochloric acid in acetone. After crystallization of the crude product from diisopropyl simple ester receive 600 mg 3b) in the form of white crystals.

Melting point = 161,6oCr (J = 10 Hz, 1H, bridge); 5,50 m (1H, bridge); 2,68 m (1H, H-11); 1,87 s (3H, propyne); 0,90 s (3H, C-18).

Example 4

(Z)-9,11-dihydro-17-hydroxy-17 -(3-hydroxy-1-propenyl)- -6'H-benzo[10,9,11]variety-4-EN-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-17 -[3-[(tetrahydro-2H-Piran-2-yl)oxy]-1-PROPYNYL]-6'H-benzo[10,9,11]- 5-estren-5,17-diol

From 17 ml of 3-[(tetrahydro-2H-Piran-2-yl)oxy]-1-propene in 600 ml of absolute tetrahydrofuran and 75.4 ml of a 1.6 molar solution of n-utility in hexane receive at 0oC in argon atmosphere organolithium compound. Then added a solution of 5 g described in point 1e) of the substance in 120 ml of absolute tetrahydrofuran. Stir once at 0oC and treated then with water (C, F). After cleaning they receive 5.75 g (4a) as a white foam.

1H-NMR (CDCl3); = 5,56 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 4,84 (1H, TNR); and 4.40 s (1H, OH); 4,32 m (2H, CH2OTHP); a 3.87 m (1H, TNR); 3,50-3,70 m (5H, ketal and TPR); 2,50 m (1H, H-11); 0,95 m (6H, Me-ketal); 0,89 s (3H, C-18).

b) (Z)-9,11-dihydro-3,3-[2,2-dimethyl-1,3-propanediyl - bis(oxy)]-17 -[3-tetrahydro-2H-Piran-2-yl)oxy]-1 - propenyl]-6'H-benzo[10,9,11]-5-estran-5,17-diol

To a solution of 5.4 g described in paragraph 4a) of the substance in 45 ml of tetrahydrofuran added 549 mg of palladium on barium sulphate (10%). Put the apparatus into the atmosphere water is clean get 4,56 g 4b) as a white foam.

1H-NMR (CDCl3): = 5,73 ppm dbr (J = 10 Hz, 1H, bridge); 5,55 m (2H); 5,47 m (1H, bridge); 4,71 m (1H, consumer goods); to 4.38 m (2H, CH2OTHP); 3,85 m (1H, TNR); 3,50-3,65 m (5H, ketal and TPR); 2,45 m (1H, H-11); 0,99 s (3H, Me-ketal); 0,38 s (3H, Me-ketal); 0,94 s (3H, C-18).

c) (Z)-9,11-dihydro-17-hydroxy - 17 -(3-hydroxy-1-propenyl)-6'H-benzo[10,9,11]-variety-4-EN-3-one

Total recipe 1 transform 1 g described in paragraph 4b) substances with 4 N. hydrochloric acid in acetone. After crystallization of the crude product from simple diisopropyl ether obtain 440 mg 4c) in the form of white crystals.

So pl. = 219-221oC. []2D0= 21,3o(CHCl3with=0,535)

1H-NMR (CDCl3: = 5,81 MRP sbr (1H, H-4); 5,70 m (1H); 5,62 dbr (J = 10 Hz, 1H, bow); 5,59 m (2H); 4.26 deaths m (2H, CH2OH); 2,63 m (1H, H-11); 1.00 s (3H, C-18).

Example 5

9,11-dihydro-17-hydroxy-17 -(3-oksipropil)-6'H-benzo -[10,9,11]variety-4-EN-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(hydroxy)]- 17 -[3-[(tetrahydro-2H-Piran-2-yl)oxy] propyl]6'H-benzo [10,9,11]-5-estran-5,17-diol

To a solution of 3.56 g described in paragraph 4b) substances in 175 ml of ethyl acetate was added 360 mg of palladium on charcoal (10%). Install the device in an atmosphere of hydrogen and stirred for 1 h at room temperature. Then the reaction mixture is filtered through celite and concentrated in vacuo. Obtained from the'H-benzo-[10,9,11] variety-4-EN-3-one

Total recipe 1) turn 3,23 g 5a) 4 N. hydrochloric acid in acetone. After clearing the receive 1.5 g 5b) as a white foam.

[]2D0= -23,7o(CHCl3; c = 0,510).

1H-NMR (CDCl3); = 5,81 MRP sbr (1H, H-4); 5,63 dbr (J = 10 Hz, 1H, bridge); 5,50 m (1H, bridge); 3,60-3,75 m (2H, CH2OH); 2,68 m (1H, H-11); 0,96 s (3H, C-18).

Example 6

5", 4", 9,11-tetrahydrofuro[6'H-benzo[10,9,11]variety - 4-ene-17 , 2"(5")-furan] - for 3,5"-dione

Total recipe 3) make 700 mg described in paragraph 5b) substances, 1.1 g of chromium trioxide and 3,62 ml of pyridine in dichloromethane. After cleaning they receive 485 mg 6) as a white foam.

[]2D0= -31,4o(CDCl3; c = 0,515).

1H-NMR (CDCl3); = of 5.82 ppm sbr (1H, H-4); 5,58 m (2H, bridge); 2,71 m (1H, H-11); 1,02 s (3H, C-19).

Example 7

5", 4", 9,11-tetrahydrofuro[6'H-benzo[10,9,11] variety-4-ene- 17 , 2"(5")-furan]-3-one.

600 mg described in paragraph (5b) compound is dissolved in 40 ml of dichloromethane. Mixed with 3.3 ml of triethylamine. Cooled to 0oC and added 770 mg of the acid chloride of p-toluenesulfonic acid. After stirred for 1 h at 0oC and 6 h at room temperature and treated then with water, (B, F). After cleaning get 380 mg 7) as a white foam.

1H-NMR (CDCl So pl. = RUB 127.3oC. []2D0= -52,3o(CHCl3; c = 0,485).

Example 8

9,11-dihydro-17-hydroxy-17 -(1,3-pentadienyl)-6'H-benzo [10,9,11] variety-4-EN-3-one

700 mg described in paragraph 2b) of a substance is dissolved in 60 ml of triethylamine. Saturate the solution at room temperature with gaseous propyne, added 250 mg of tetrakis (triphenylphosphine)palladium and 120 mg of copper iodide(I), heated to 60oC and while maintaining the flow propina stirred for 1 h at this temperature. Then filter the reaction solution through celite and concentrated in vacuo. After cleaning they receive 311 8 mg) as a white foam.

1H-NMR (CDCl3): = 5,80 MRP sbr (1H, H-4); 5,58 m (2H, bridge); 2,70 m (1H, H-11); 1,95 s (3H, butinyl); 0,82 s (3H, methyl).

Example 9

9,11-dihydro-17-ethinyl-17-hydroxy-6'H-benzo[10,9,11]- östra-4,15-Dien-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)] -17-[(trimethylsilyl)oxy-6'H-benzo[10,9,11]-5-variety-16-ene-5-ol

Total recipe 4a) transform 2.7 g described in point 1e) of the substance with 3.2 ml of Diisopropylamine, 14.4 ml of a 1.6 molar solution of n-utility in hexane and 4 ml of trimethylchlorosilane in absolute tetrahydrofuran. After recrystallization of the crude product from acetonitrile receive 2.5 g 9a).

b) 9,11-dihydro-3,3-[2,2-dianoga in paragraph 9a) connection with 1.3 g of palladium (II) acetate in acetonitrile. After cleaning get 1.8 g 9b).

1H-NMR (CDCl3): = 7,52 ppm dbr (J = 6 Hz, 1H, H-15); 5,98 dd (J = 6.3 Hz, 1H, H-16); the ceiling of 5.60 dbr (J = 10 Hz, 1H, bridge); 5,50 m (1H, bridge); 4,47 s (3H, OH); 3,50-3,60 m (4H, ketal); 2,60 m (1H, H-11); 1,18 s (3H, C-18); 1.00 s (3H, Me-ketal); and 0.98 s (3H, Me-ketal).

C) 9,11-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]- 17-ethinyl-6'H-benzo[10,9.11]-5-variety-15-ene-5,17-diol.

Total recipe 2) turn 1.8 g 9b), 15 ml of a 1.6 molar solution of n-utility in hexane and gaseous Atina in absolute tetrahydrofuran. Get 1,59 g 9c), which is used without purification in the next stage.

d) 9,11-dihydro-17-ethinyl-17-hydroxy-6'H - benzo[10,9,11]-östra-4,15-Dien-3-one

Total recipe 1) turn 1,59 g 9c) 4 N. hydrochloric acid in acetone. After cleaning they receive 970 mg 9d).

1H-NMR (CDCl3): = 6,00 dbr (J = 6 Hz, 1H, H-15); 5,72 sbr (1H, H-4); to 5.21 dd (J = 6.3 Hz, 1H, H-16); the ceiling of 5.60 (2H, bridge); 2,77 m (1H, H-11); 2,60 s (1H, etin); 1.00 s (3H, C-18).

So pl. = 98oC. []2D0= -202,9o(CHCl3; c = 0,515).

Example 10

9,11-dihydro-17-hydroxy-17 -(1 - PROPYNYL)-6'H-benzo-[10,9,11]östra-4,15-Dien-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl - 1,3-propanediylbis(oxy)]-17 -(1-PROPYNYL-6'H - benzo[10,9,11]-5-variety-15-ene-5,17-diol

Total recipe 2) transform 1 g 9b), 15 ml of a 1.6 molar solution of n-butelli enaut in the next stage.

b) 9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H-benzo- [10,9,11] östra-4,15-Dien-3-one

Total recipe 1) turn 1 g 10a) with 4 n hydrochloric acid in acetone. After cleaning they receive 610 mg 10b).

[]2D0= -204,2o(CHCl3; c = 0,520)

1H-NMR (CDCl3: = 5,94 dbr (J = 6 Hz, 1H, H-15); 5,72 sbr (1H, H-4); 5,20 dd (J = 6.3 Hz, 1H, H-16); the ceiling of 5.60 (2H, band); 2,73 m (1H, H-11); 1,90 s (3H, propyl); 0,99 (3H, C-18).

Example 11

9,11-dihydro-17-hydroxy-17-methyl-6'H - benzo[10,9,11]-östra-4,14-Dien-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-5-hydroxy-6'H-benzo[10,9,11]-5-variety-14-EN-17-one

2.3 g described in paragraph 9b) of a substance is dissolved in 300 ml of a mixture of ethyl acetate and hexane (9:1). Add 180 g of silica gel and 35 ml of triethylamine and stirred for 2 days at room temperature. Then filtered through celite and concentrated. Get 1,02 g (a) apart from 1.15 g of educt.

1H-NMR (CDCl3: = 5,65 ppm dbr (J = 10 Hz, 1H, bridge); 5,55 m (1H, bridge); 5,52 m (1H, H-15); and 4.40 s (1H, OH); 3,50-3,62 m (4H, ketal); 3,00 ddd (J = 20, 3.1 Hz, 1H, H-16); 2,80 dt (J = 20, 1.5 Hz, 1H, H-16); of 2.51 m (1H, H-11); 1,12 s (3H, C-18); 1.00 s (3H, Me-ketal); and 0.98 s (3H, Me-ketal).

b) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17-methyl-6'H - benzo[10,9,11]-5-variety-14-ene-5,17-diol.

2.5 g of anhydrous trichloride cerium is added to 20 ml absolutelty of magnicharters in absolute tetrahydrofuran. Stirred for another 1.5 h at 0oC and then added a solution of 413 mg described in paragraph 11a) of the substance in 5 ml of absolute tetrahydrofuran. Then stirred for 30 min at 0oC and then treated with water (C, F). After cleaning get 170 mg 11b).

1H-NMR (CDCl3): = ceiling of 5.60 ppm dbr (J = 10 Hz, 1H, bridge); 5,52 m (1H, bridge); 5,18 m (1H, H-15); and 4.40 s (1H, OH); 3,50-3,62 m (4H, ketal); 2,52 m (1H, H-11); 2,42 dtr (J = 10.1 Hz, 1H, H-16); 2,30 dtr (J = 20,1 Hz, 19, H-16); 1,22 s (3H, 17-methyl); 1,10 s (3H, C-18); and 0.98 s (6H, Me-ketal).

c) 9,11-dihydro-17-hydroxy-17-methyl-6'H - benzo-[10,9,11]östra-4,14-Dien-3-one

Total recipe 1) turn 170 mg) described in paragraph 11b) connection with 4 N. hydrochloric acid in acetone. After cleaning they receive 100 mg 11c).

[]2D0= -38,0o(CHCl3; c = worn: 0.505)

1H-NMR (CDCl3): = of 5.83 sbr (1H, H-4); 5,68 dbr (J = 10.0 Hz, 1H, bridge); 5,62 m (1H, bridge); 5,18 m (1H, H-15); 1,23 s (3H, 17-methyl); 1,13 s (3H, C-18).

Example 12

9,11-dihydro-17-hydroxy-17 -(1 - PROPYNYL)-6'H-benzo-[10,9,11]östra-4,14-Dien-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -(1-PROPYNYL)-6'H-benzo[10,9,11]-5-variety-14-ene-

5,17-diol

Total recipe 2) make a saturated solution of gaseous propene in 30 ml of absolute tetrahydrofuran with 6.25 ml of a 1.6 molar solution of n-utility in hexane. When the I was previously treated by analogy with example 11b. Then analogously to example 11b) turn with a solution of 413 mg described in paragraph 11a) of matter in absolute tetrahydrofuran. Obtain 420 mg of crude product which is used without purification in the next stage.

b) 9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H - benzo-[10,9,11] östra-4,14-Dien-3-one

General instructions 1) turn 420 mg 12a) with 4 N. hydrochloric acid in acetone. After clearing the receive 200 mg 12b) as a white foam.

1H-NMR (CDCl3): = of 5.82 ppm sbr (1H, H-4); 5,69 dbr (J = 10 Hz, 1H, bridge); 5,62 m (1H, bridge); 5,15 m (1H, H-15); 1,88 s (3H, propyne); 1,15 s (3H, C-18).

Example 13

17-(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11] -19-norpregna-4-ene-3,20-dione

a) 9,11-dihydro-5,17-dioxy-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-6'H-benzo[10,9,11]-5-estran-17-carbonitrile

10 g described in point 1e) of a substance is dissolved in 50 ml of 2-hydroxy-2-methylpropionitrile together from 0.74 ml of 20% aqueous solution of sodium hydroxide at 80oC. Precipitated after cooling the product is filtered and recrystallized from simple diisopropyl ether. Obtain 8.6 g 13a) in the form of white crystals.

1H-NMR (CDCl3): = 5,58 ppm dbr (J = 10.0 Hz, 1H, bridge); 5,50 m (1H, bridge); 4,60 (1H, HE); 3,50-3,62 m (4H, ketal); 2,59 m (1H, H-11); 1.00 s (3H, Me-ketal); 0,97 s (3H, Me-ketal); 0,96 s (3H, C-18).

in 100 ml of simple diethyl ether was added 350 mg of p-toluenesulfonic acid and 8.8 ml ethoxyethane. Stirred for 30 min at room temperature and then treated with water (B, F). The obtained crude product is dissolved again in 100 ml of simple diethyl ether, cooled to 0oC and added 16 ml of a 1.6 molar solution metallice in simple diethyl ether. Stirred for 3 h at 0oC and then treated with water (C, F). The resulting crude product turn on General recipe 1). After crystallization from diisopropyl simple ether/methanol to obtain 2.9 g 13b) as white crystals.

1H-NMR (CDCl3): = 5,81 MRP sbr (1H, H-4); 5,55 m (2H, bridge); 2,27 s (3H, acetyl); 0,71 s (3H, C-18).

13c) 17-(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11]- 19-norpregna-4-ene-3,20-dione

To a suspension of 2.9 g described in paragraph 13b) substances in 40 ml of glacial acetic acid are added at 0oC 15 ml of anhydride triperoxonane acid. Stirred for 4 h at room temperature and treated then with water, (B, F). After cleaning they receive 2.3 g 13c).

So pl. = 223oC. []2D0= -29,3o(CHCl3; c = 0,515)

1H-NMR (CDCl3: = of 5.82 ppm sbr (1H, H-4); 5,56 m (2H, bridge); 2,72 m (1H, H-11); 2,15 s (3H, acetyl); 2,10 s (3H, acetoxy); 0,70 s (3H, C-18).

Example 14

17-(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11]-19-norpregna - 4,6-diene-3,20-dione

a) 17-(acetylic is esta, 2 ml of triethylorthoformate, 2 ml of ethanol and 40 mg of p-toluenesulfonic acid in 20 ml of tetrahydrofuran is stirred for 1 h at 40oC. Then treated with water (B, F). The resulting crude product (850 mg) without purification enter into the next stage.

b) 17(atomic charges)-6-bromo-9,11-dihydro-6'H-benzo [10,9,11]-19-norpregna-4-ene-3,20-dione.

To a solution of 850 mg described in paragraph 14a) of the substance in 10 ml of dioxane was added 4 ml of 10% aqueous sodium acetate solution and then 285 mg of 1,3-dibromo-5,5-dimethylhydantoin. Stirred 5 min at 0oC and treated with water (B, F). After cleaning they receive 600 mg 14b).

1H-NMR (CDCl3): = 6,02 MRP sbr (1H, H-4); the ceiling of 5.60 m (1H, bridge); 5,52 dbr (J = 10 Hz, 1H, bridge); of 5.05 dbr (J = 4 Hz, 1H, H-6); 2,28 m (1H, H-11); 2,15 s (3H, acetyl); 2,10 s (3H, acetoxy); 0,79 s (3H, C-18).

c) 17(atomic charges)-9,11-dihydro-6'H - benzo[10,9,11]-19-norpregna-4,6-diene-3,20-dione

A mixture of 600 mg described in paragraph 14b) substances, 550 mg of lithium bromide and 375 mg of lithium carbonate in 10 ml of N,N-dimethyformamide stirred for 1 h at 100oC. Then treated with water (A, F). After cleaning they receive 435 mg 14c).

[]2D0= -35,5o(CHCl3; c = 0,520)

1H-NMR (CDCl3): = 6,13 MRP m (2H, H-6, H-7); 5,73 sbr (1H, H-4); the ceiling of 5.60 m (2H, bridge); 2,79 m (1H, H-11); 2,15 s (3H, acetyl); 2,10 s (3H, acetoxy); 0,73 s (3H, C-18).


To a solution of 2 g described in paragraph 14c) compound in 50 ml of dichloromethane was added 1.8 g m-adharmasya acid (70%). Stirred for 8 h at room temperature. Then pour the reaction mixture into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and the organic phase is washed with saturated solution of sodium thiosulfate and a saturated solution of sodium chloride. Cleaning gives 832 mg 15a)

1H-NMR (CDCl3): = 6,20 s (1H, H-4); 5,55 m (2H, bridge); 3,52 d, J = 4 Hz, 1H, H-6); 3,45 dbr (J = 4 Hz, 1H, H-7); 2,70 m (1H, H-11); 2,15 s (3H, acetyl); 2,10 s (3H, acetoxy); 0,73 s (3H, C-18).

b) 17(atomic charges)-6-chloro-9,11-dihydro-7 - hydroxy-6'H-benzo[10,9,11]-19-norpregna-4-ene-3,20-dione

To a solution of 832 mg described in paragraph 15a) of the compound in 20 ml of glacial acetic acid is added 4.8 g of lithium chloride. Stirred for 1.5 h and then treated with water (B, F). The resulting crude product (900 mg) without purification enter into the next stage.

c) 17(atomic charges)-6-chloro-9,11-dihydro-7 -[(methylsulphonyl)oxy] -6'H-benzo-[10,9,11]-19-norpregna-4-ene - 3,20-dione

To a solution of 900 mg described in paragraph 15b) of the substance in 10 ml of pyridine added at 0oC 1.2 ml of the acid chloride of methansulfonate. Stirred for 2 h at room temperature, then pour the reaction mixture into saturated aq is orida sodium. The resulting crude product without purification enter into the next stage.

(d) 17(atomic charges)-6-hdor-9,11-dihydro-6'H - benzo[10,9,11]-19-norpregna-4,6-diene-3,20-dione

To a solution of 930 mg described in paragraph 15c) substances in 25 ml of N,N-dimethylformamide add 3.5 g of anhydrous sodium acetate. Heated to 100oC and stirred for 1.5 h at this temperature. Then the reaction mixture was poured on ice water. Stirred for further 1 h and then filtered off the precipitate. After purification of the crude product is obtained 450 mg 15d).

So pl. = 225oC. []2D0= -39,2o(CHCl3; c = worn: 0.505)

1H-NMR (CDCl3): = 6,40 MRP sbr (1H, H-4); 6,35 d (J = 2 Hz, 1H, H-7); the ceiling of 5.60 m (2H, bridge); 2,80 m (1H, H-11); 2,13 s (3H, acetyl); 2,09 s (3H, acetoxy); 0,72 s (3H, C-18).

Example 16

17-(atomic charges)-9,11-dihydro-6-methylene-6'H - benzo[10,9,11]-19-norpregna-4-ene-3,20-dione

3 g described in example 13c) of a substance is dissolved in 75 ml of tetrahydrofuran. Added 7.5 ml of ethanol, 7.5 ml of triethylorthoformate and 170 mg of p-toluenesulfonic acid. Then stirred for 1 h at 40oC. then added to 2.3 ml of N-methylaniline and 2.6 ml of 37% aqueous formaldehyde solution. Stirred for further 30 min at 40oC. Then cooled to room temperature and add 7.5 ml of concentrated is given 2 g 16).

1H-NMR (CDCl3): = 6,02 MRP sbr (1H, H-4); 5,55 m (2H, bridge); 5,15 m (1H, hectometre); 5,02 m (1H, hectometre); was 2.76 m (1H, H-11); 2,13 s (3H, acetyl); 2,10 s (3H, acetoxy); 0,72 s (3H, C-18).

Example 17

17-(atomic charges)-9,11-dihydro-6-methyl-6'H-benzo- [10,9,11]-19-norpregna-4-ene-3,20-dione

2 g described in paragraph (16) of a substance is dissolved in 30 ml of ethanol. Add 3 ml of cyclohexane and 250 ml of palladium on charcoal (10%). Then boiled for 1 h with the phlegm. Then filter the reaction solution through celite. Concentrated in vacuo, absorb the residue in 30 ml of acetone, added to 1.4 ml of 4 N. hydrochloric acid and stirred for 2.5 h at 40oC. water Treatment (B, F) and purification gives 1.1 g 17).

So pl. = 248oC []2D0= -39,4o(CHCl3; c = 0,510).

1H-NMR (CDCl3): = 5,90 MRP sbr (1H, H-4); 5,57 m (2H, bridge); 2,73 m (1H, H-11); 2,13 s (3H, acetyl); 2,09 s (3H, acetoxy); 1,12 d (J = 6 Hz, 3H, 6-methyl); 0,72 s (3H, C-18).

Example 18

17-(atomic charges)-9,11-dihydro-6-methyl-6'H-benzo[10,9,11] - -19-norpregna-4,6-diene-3,20-dione

To 0.25 ml of cyclohexene in 15 ml of ethanol is added 125 mg of palladium on charcoal (10%). Boil for 1 h under reflux and then added a solution of 500 mg described in paragraph (16) of the substance in 5 ml of ethanol. Then boil another 2 hours Then f2D0= +28,1o(CHCl3; c = 0,515).

1H-NMR (CDCl3): = 6,0 MRP sbr (1H, H-7); of 5.92 sbr (1H, H-4); the ceiling of 5.60 m (2H, bridge); 2,77 m (1H, H-11); 2,14 s (3H, acetyl); 2,10 s (3H, acetoxy); 1,88 sbr (3H, 6-methyl); 0,73 s (3H, C-18).

Example 19

17-hydroxy-17-methyl-4',5',9,11 -tetrahydro - 6'H-benzo-[10,9,11]-variety-4-EN-3-one

a) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-5-hydroxy-4',5', 9,11-tetrahydro-6'H-benzo[10,9,11]-5-estran-17-he

Hydrogenation with the use of palladium on charcoal.

To a solution of 1.6 g described in point 1e) of the substance in 65 ml of ethanol are added 165 mg of palladium on charcoal (10%). Set the apparatus under hydrogen pressure of 15 bar and carry out reaction for 2 hours Then filtered through celite and concentrated in vacuo. Receive 1.5 g 19a), which is used without purification on.

Hydrogenation with the use of platinum oxide.

To a solution of 1 g described in point 1e) of a substance in a mixture of 24 ml of ethyl acetate and 6 ml of tetrahydrofuran was added 100 mg of platinum oxide(IV). Install the device in an atmosphere of hydrogen and stirred for 1 h at room temperature. Then filter the reaction solution through celite and concentrated. After cleaning they receive 600 mg 19a) and 150 mg of 3,3-[2,2-dimethyl-1,3 - propanediylbis(hydroxy)]-4',5',9,11 -tetrahydro is C, 1H, H-16); 1.00 s (3H, C-18); 0,96 s (3H, Me-ketal); 0,94 s (3H, Me-ketal).

(b) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)] -17-methyl-4',5',9,11 -tetrahydro-6'H-benzo[10,9,11]-5-estran - 5,17-diol

Analogously to example 1) turn of 1.65 g obtained in paragraph 19a) of a substance in 30 ml of absolute tetrahydrofuran from 18.8 ml of a 1.6 molar solution metallice in simple diethyl ether. Receive 1.5 g 19b), which is used without purification in the next stage.

c) 17-hydroxy-17-methyl-4',5',9,11 -tetrahydro-6'H-benzo-[10,9,11] variety-4-EN-3-one

General instructions 1) turn 1.5 g described in paragraph 19b) substances with 4 N. hydrochloric acid in acetone. After cleaning they receive 0.97 g 19c) as a white foam.

[]2D0= +107,8o(CHCl3c = 0,520)

1H-NMR (CDCl3): = 5,75 MRP sbr (1H, H-4); 1,22 s (3H, methyl); 1,03 s (3H, C-19).

Example 20

17-hydroxy-17 -(1-PROPYNYL)-4', 5', 9,11-tetrahydro-6'H - benzo[10,9,11]variety-4-EN-3-one

a) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-17 -(1 - PROPYNYL)-4',5', 9,11-tetrahydro-6'H-benzo[10,9,11]-5 - estren-5,17-diol

General instructions 2) transform 1 g described in paragraph 19a) connection and 15 ml of a 1.6 molar solution of n-utility in hexane and gaseous propene in absolute tetrahydrofuran. The resulting crude product (1.19 g) was injected without purification in th instructions 1) turn 1.19 g 20a) 4 N. hydrochloric acid in acetone. After cleaning they receive 720 mg 20b)

So pl. = 186,7oC. []2D0= +70,1o(CHCl3; c = 0,510)

1H-NMR (CDCl3): = 573 ppm s (1H, H-4); 1,84 s (3H, propyne); 1,01 s (3H, C-18).

Example 21

17-hydroxy-17 -(1-PROPYNYL)-4', 5', 9,11-tetrahydro - 6'H-benzo[10,9,11]-östra-4,15-Dien-3-one

a) 3,3-[2,2-dimethyl-1,3-propanediylbis(hydroxy)] - 4',5',9,11 - tetrahydro-17-[(trimethylsilyl)oxy]-6'H - benzo[10,9,11]-variety-16-ene-5-ol

When the common regulations 4a) transform 1 g described in paragraph 19a) connection with 1.2 ml of Diisopropylamine, 5.6 ml of a 1.6 molar solution of n-utility in hexane and 1.5 ml of trimethylchlorosilane in absolute tetrahydrofuran. By recrystallization of the crude product from acetonitrile receive 940 mg 21a).

(b) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-5-hydroxy-4',5',9, 11 -tetrahydro-6'H-benzo[10,9,11]-5-variety-15-EN-17-one

General instructions 4b) turn 940 mg 21a) with 475 mg of palladium (II) acetate in acetonitrile. After cleaning get 650 mg 21b).

1H-NMR (CDCl3): = 7,52 ppm dbr (J = 6 Hz, 1H, H-15); 5,96 dd (J = 6.3 Hz, 1H, H-16); 4,45 s (1H, OH); 3,50-3,60 m (4H, ketal); 1,21 s (3H, C-18); 1.00 s (3H, Me-ketal); 0,97 s (3H, Me-ketal).

c) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-17 -(1 - PROPYNYL)-4',5', 9,11-tetrahydro-6'H-benzo[10,9,11]-5 - variety-15-ene-5,17-diol

General instructions what hydrofuran receive 712 mg 21c). The crude product without purification enter into the next stage.

(d) 17-hydroxy-17 -(1-PROPYNYL)-4', 5',9,11 -tetrahydro-6'H-benzo[10,9,11]-östra-4,15-Dien-3-one

General instructions 1) turn 712 mg 21c) with 4 N. hydrochloric acid in acetone. After cleaning get 440 mg 2ld).

[]2D0= -79,6o(CHCl3; c = 0,510).

1H-NMR (CDCl3): = 5,98 ppm dbr (J = 6.0 Hz, 1H, H-15); 5,76 sbr (1H, H-4); 5,70 dd (J= 6.3 Hz, 1H, H-16); 1,90 s (3H, propyne); 1,09 s (3H, C-18).

Example 22

5',6'-dihydro-17-hydroxy-17 -(1 - PROPYNYL)-9H-benzo[10,9,11]-variety-4-EN-3-one

a) 5',6'-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-5-hydroxy-9H-benzo[10,9,11]-5-estran-17-he

4 g described in point 1e) of a substance is dissolved in 120 ml of a mixture of tetrahydrofuran and ethanol (1:1). Add 25 ml of cyclohexene and 1 g of palladium on charcoal (10%) and boiled for 24 h with the phlegm. Then filtered through celite and concentrated in vacuo. After clearing the receive and 1.9 g 22a).

1H-NMR (CDCl3): = of 5.29 ppm m (1H, bridge/11-Exo); and 4.40 s (1H, OH); 3,50-3,60 m (4H, ketal); 2,43 dd (J = 17,9 Hz, 1H, H-16); 1.00 s (3H, Me-ketal); and 0.98 s (3H, Me-ketal); 0,80 s (3H, C-18).

b) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]- 17 -(1-PROPYNYL)-9H-benzo[10,9,11]-5-estran - 5,17 - diol

General instructions 2) from 1 g described in paragraph 22a) substances and 15 ml of 1.61 g 22b) as the crude product, which is used without purification in the next stage.

c) 5', 6'-dihydro-17-hydroxy-17 -(1-PROPYNYL)-9H - benzo[10,9,11] extras-4-EN-3-one

General instructions 1 turn 1.1 g described in paragraph 22b) substances with 4 N. hydrochloric acid in acetone. After cleaning they receive 640 mg 22c).

So pl. = 197,3oC []2D0= +40,7o(CHCl3; c = 0,520)

1H-NMR (CDCl3): = 5,27 MRP sbr (1H, H-4); of 5.48 m (1H, bridge/11-Exo); 1,86 s (3H, propyne); 0,80 s (3H, C-18).

Example 23

5', 9'-dihydro-17-hydroxy-17 -(1-PROPYNYL)- 9H-benzo[10,9,11]östra-4,15-Dien-3-one

a) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)] - 17-trimethylsilyl)oxy]-9H-benzo[10,9,11]-5-variety-16-ene-5-ol

General instructions 4a) transform 1 g described in paragraph 22a) substances with 1.2 ml of Diisopropylamine, 5.6 ml of a 1.6 molar solution of n-utility in hexane and 15 ml of trimethylchlorosilane in absolute tetrahydrofuran. After recrystallization of the crude product from acetonitrile obtain 920 mg 23a).

b) 5',6'-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]- 5-hydroxy-9H-benzo[10,9,11]-5-variety-15-EN-17-one.

General instructions 4b) turn 920 mg described in paragraph 23a) connection with 470 mg of palladium(II) acetate in acetonitrile. After cleaning they receive 630 mg 23b).

1H-NMR (CDCl3

c) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]- 17 -(1-PROPYNYL)-9H-benzo-[10,9,11]-5-variety-15-ene-5,17-diol

General instructions 2) turn 630 mg 23b) with 10 ml of a 1.6 molar solution of n-utility and gaseous propene in absolute tetrahydrofuran. The crude product (685 mg), used without purification in the next stage.

d) 5', 6'-dihydro-17-hydroxy-17 -(1-PROPYNYL)-9H - benzo-[10,9,11]östra-4,15-Dien-3-one

General instructions 1) turn 685 mg 23b) with 4 N. hydrochloric acid in acetone. After cleaning get 430 mg 23d).

[]2D0= -128,7o(CHCl3); c = 0,515).

1H-NMR (CDCl3): = 5,97 ppm dbr (J = 6 Hz, 1H, H-15); 5,78 sbr (1H, H-4); 5,73 dd (J = 6.3 Hz, 1H, H-16); 5,40 m (1H, bridge/11-Exo); 1,90 s (3H, propyl); 0,90 s (3H, C-18).

Example 24

17-(acetyloxy)-5', 6'-dihydro-9H-benzo[10,9,11]-19-norpregna-4-ene-3,20-dione

a) 5', 6'-dihydro-5,17-dioxy-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-9H-benzo[10,9,11]-5-estran - 17-carbonitrile

By analogy with example 13a) of 1.6 g described in paragraph 22a) connection, 8 ml of 2-hydroxy-2-methylpropionitrile and 0.15 ml of 20% aqueous solution of sodium hydroxide obtain 1.3 g 24a).

1H-NMR (CDCl3): = 5,38 ppm m (1H, bridge/11-Exo); 4,50 s (1H, OH); 3,50-3,60 m (4H, ketal); 1.00 s (3H, Me-ketal); and 0.98 s (3H, Me-ketal); 0,90 s (nresult 1.3 g described in paragraph 24a) substances with 2.8 ml ethoxyethane and 120 mg of p-toluenesulfonic acid in a simple diethyl ether. The obtained crude product is dissolved again in a simple diethyl ether and turn with 5 ml of a 1.6 molar solution metallice in simple diethyl ether. The resulting crude product (General instructions 1) split by 4 N. hydrochloric acid in acetone. After recrystallization from diisopropyl simple ether/methanol receive 700 mg 24b).

1H-NMR (CDCl3): = 5,77 MRP sbr (1H, H-4); 5,32 m (1H, bridge/11-Exo); 2,28 s (3H, acetyl); 0,78 s (3H, C-18).

c) 17 atomic charges)-5', 6'-dihydro-9H-benzo[10,9,11] -19 - norpregna-4-ene-3,20-dione

700 mg described in paragraph 24b) connection turn on the analogy 13c) with 9 ml of glacial acetic acid and 3.5 ml of anhydride triperoxonane acid. After cleaning, get a 520 mg 24c).

1H-NMR (CDCl3): = 5,79 MRP sbr (1H, H-4); of 5.48 m (1H, bridge/11-Exo); 2,15 s (3H, acetyl); 2,10 s (3H, acetoxy); 0,62 s (3H, C-18).

Example 25

9,11-dihydro-17-ethinyl-17-hydroxy-6'H benzo[10,9,11]-18a-gamester-4-EN-3-one

a) 17-hydroxy-18a-gamester-5(10)-EN-3-one

Suspension 355 g of 17-hydroxy-3-methoxy-18a-gamestro - 2,5(10)-diene in 4 l of acetone pin for 15 min a solution of 252 g of dihydrate of oxalic acid in 2 l of water, then stirred for 3 h, then knead in 3.6 l of water and extracted twice, each time with 2 l of dichloromethane. United organizes and concentrated in vacuo. After recrystallization from acetic ester receive 293 g 25a).

So pl. 103-105oC []2D0= +155,0o(CHCl3c = worn: 0.505)

1H-NMR (CDCl3): = 3,78 MRP dd, J = 14 and 7.5 Hz, 1H, H-17); 1,00 t (J = 7.5 Hz, 3H, 18a-CH3).

b) 17-hydroxy-18a-gamestro-4,9-Dien-3-one

To a solution of 290 g described in paragraph 25a) connection in 4 l of pyridine is slowly added while cooling 443 g perbromide of pyridinesulfonamide so that the temperature did not exceed 25oC. and Then stirred for 2 h at 50oC then cooled in an ice bath, stir in 4 l of ice policecontributing hydrochloric acid and then extracted once with 4 l and twice in 2 l of dichloromethane. The combined organic phases are washed with 4 l of ice policecontributing hydrochloric acid, dried over sodium sulfate and concentrated in vacuo. After dispersion with warm acetic ether get is 147.5 g 25b). Chromatography of the mother liquor gives a further 415 g 25b).

So pl. 136-138oC []2D0= -293,9o(CHCl3c = 0,510).

1H-NMR (CDCl3): = 5,68 MRP sbr (1H, H-4); of 3.77 dd, J = 14 and 7.5 Hz, 1H, H-17); 1,08 t (J = 7.5 Hz, 3H, 18a-CH3).

c) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)] -18a-th is 180 g of 2,2-DIMETHYLPROPANE-1,3-diol, 84 g of triethylorthoformate and 1 g of the monohydrate of p-toluenesulfonic acid. After 3 h stirring diluted with 1 l of dichloromethane, washed with 2 l of saturated sodium bicarbonate solution, the aqueous phase is twice extracted with 400 ml of dichloromethane, and the combined organic phase after drying over sodium sulfate concentrated in vacuo. The residue is dissolved in 200 ml of dichloromethane, mixed with 900 ml of methanol and 180 g of potassium carbonate, and the mixture is heated for 1 h under reflux. The mixture is then strongly concentrated in vacuo, mixed with 2 l of water and then extracted with 2 liters and three more times in 400 ml dichloromethane. After drying, the United organic phases over sodium sulfate and removal of solvent in vacuo get 252 g 25c), which without treatment is administered to the next stage.

1H-NMR (CDCl3): = 5,55 ppm m (1H, 11-H); 3,86 dd, J = 14 and 7.5 Hz, 1H, H-17); 3,40-3,68 m (4H, ketal); 1,07 s (3H, Me-ketal); 0,94 t (J = 7.5 Hz, 3H, 18a-CH3); 0,90 s (3H, Me-ketal).

d) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-5,10 - epoxy-18a-Homo-5-variety-9(11)-EN-17-ol

252 g described in paragraph 25c) compounds are dissolved in 1.2 l of dichloromethane and mixed with 59 g of 2-(3-nitrophenyl)-1,1,1 - triptoreline and 190 ml of saturated sodium bicarbonate solution. While cooling in an ice bath, added 240 ml of 30% is l saturated solution of sodium thiosulfate, then diluted with 500 ml of water, separated phase and the aqueous phase is twice extracted by 500 ml of dichloromethane. The combined organic phases are washed with 500 ml saturated sodium chloride solution, twice with 500 ml of 5% sodium lye and again with 500 ml saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Receive 250 g raw 25d), which is used without purification in the next stage.

1H-NMR (CDCl3): = 6,03 ppm m (1H, 11-H); 3,82 m (1H, H-17); 3,36-3,63 m (4H, ketal); 1,07 s (3H, Me-ketal); and 0.98 t (J = 7.5 Hz, 3H, 18a-CH3); 0,87 s (3H, Me-ketal).

e) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-19-ethinyl-18a - Homo-5-androst-9(11)-ene-5,17-diol

50 g described in paragraph 25d) compounds by analogy with 1a) make educated with 3-bromo-propene Grignard reagent. After water treatment (F) and purification of the crude product get 33,6 g 25e).

So pl. 112-114oC []2D0= 16,2o(CHCl3c=0,510)

1H-NMR (CDCl3): = 5,42 ppm m (1H, H-11); 4,33 s (1H, OH); 3,82 m (1H, H-17); 3,42-of 3.60 m (4H, ketal); 1,88 t (J = 1.5 Hz, 1H, etin); 0,99 s (3H, Me-ketal); 0,92 s (3H, Me-ketal); 0,92 t (J = 7.5 Hz, 3H, 18a-CH3).

f) 19-(bromamines)-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-18a-Homo-5-androst-9(11)-ene-5,17-diol

75,5 g described in paragraph 25e) substance pravr is f), which is used without purification in the next stage.

g) 19-(2 - bromanil)-3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-18a - Homo-5-androst-9(11)-ene-5,17-diol.

96 g described in paragraph 25 (f) substances turn by analogy with 1c) in 1.8 l of a mixture of tetrahydrofuran and water (1:1) with 131 g of the hydrazide p-toluenesulfonic acid and 67 g of sodium acetate. Water treatment (B, F) and treatment results of 66.7 g 25 g) as a pale yellow foam.

[]2D0= -157,2o(CHCl3); c = 0,515

1H-NMR (CDCl3): = x 6.15 ppm m (1H, vinyl); 5,78 m (1H, vinyl); 5,34 m (1H, H-11)' and 4.40 s (1H, CH); 3,83 dd, J = 14 and 7.5 Hz, 1H, H-17); of 3.46-to 3.58 m (4H, ketal); and 0.98 s (3H, Me-ketal); 0,96 s (3H, Me-ketal); 0,94 t (J = 7.5 Hz, 3H, 18a-CH3).

h) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]- 6'H-benzo[10,9,11]-18a-Homo-5-estren-5,17-diol

to 66.3 g described in paragraph 25g) substances turn by analogy with 1d) in 1.3 l of toluene, 40 ml of anti-hydride and 75 mg azobisisobutyronitrile. After purification of the crude product to obtain 31 g 25h).

So pl. = 213-215oC. []2D0= -45,1o(CHCl3), c = worn: 0.505)

1H-NMR (CDCl3): = 5,70 MRP ddr (J = 10 Hz, 1H, bow); of 5.48 m (1H, bow); 4,37 s (1H, OH); 3,70 m (1H, 17-H); 3,48-3,63 m (4H, ketal); 1,07 t (J = 7.5 Hz, 3H, 18a - CH3); 0,99 s (3H, Me-ketal); 0,97 s (3H, Me-ketal).

i) 9,11-dihydro-3,3-[the Ute of 12.0 g described in paragraph 25h) substances, 16.7 g of chromium trioxide and 57 ml of pyridine in 500 ml of dichloromethane 11,0 g 25i) as white crystals.

So pl.=200-203oC. []2D0= -17,4o(CHCl3c = 0,510)

1H-NMR (CDCl3): = 5,61 ppm dbr (J = 10 Hz, 1H, bridge); 5,52 m (1H, bridge); and 4.40 s (1H, OH); 3,48-3,63 (4H, ketal); of 2.51 m (1H, H-11); 0,99 s (3H, Me-ketal); 0,97 s (3H, Me-ketal); 0,79 t (J = 7.5 Hz, 3H, 18a-CH3).

j) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17-ethinyl-6'H-benzo-[10,9,11]- 18a-Homo-5-estren - 5,17-diol.

General instructions 2) make 750 mg) described in paragraph (25i) substances and 11 ml of a 1.6 molar solution of n-utility in hexane and gaseous Atina in absolute tetrahydrofuran. After cleaning they receive 620 mg 25j) as white crystals.

So pl. = 124oC. []2D0= -49,6o(CHCl3), c = 0,520)

1H-NMR (CDCl3): = 5,72 ppm dbr (J = 10 Hz, 1H, bridge); 5,49 m (1H, bridge); and 4.40 s (1H, OH); 3,50-3,65 m (4H, ketal); 2,60 s (1H, etin); 2,50 m (1H, H-11); 1,06 t (J = 7.5 Hz, 3H, 18a-CH3); and 0.98 s (6H, Me-ketal).

k) 9,11-dihydro-17-ethinyl-17-hydroxy-6'H - benzo[10,9,11]-18a-gamester-4-EN-3-one

General instructions 1) turn 600 mg 25j) with 1.5 ml of 4 N. hydrochloric acid in acetone. After purification of the crude product to obtain 348 mg 25k) as white crystals.

So pl. = 242-245oC []2Dotic); 2,67 m (1H, H-11); 2,62 s (1H, etin); 1,08 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 26

9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H - benzo-[10,9,11]-18a-gamester-4-EN-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -(1-PROPYNYL)-6'H-benzo-[10,9,11]-18a-Homo-5-estren-5,17-diol

General instructions 2) make 750 mg) described in paragraph (25i) connection and 11 ml of a 1.6 molar solution of n-utility in hexane and gaseous propene in absolute tetrahydrofuran. Get 705 mg 26a) as amorphous solids.

[]2D0= -42,4o(CHCl3; c = 0,972)

1H-NMR (CDCl3): = 5,71 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 4,46 s (1H, OH); 3,50-3,63 m (4H, ketal); 2,50 m (1H, H-11); 1,88 s (3H, propyne); 1,06 t (J = 7.5 Hz, 3H, 18a-CH3); and 0.98 s (3H, Me-ketal); 0,96 s (3H, Me-ketal).

b) 9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H-benzo [10,9,11]-18a-gamester-4-EN-3-one

General instructions 1) turn 890 mg described in paragraph 26a) substances with 2 ml of 4 N. aqueous solution of hydrochloric acid in acetone. After purification of the crude product to obtain 380 mg 26b) as white crystals.

So pl. = 201-203oC. []2D0= -57,4o(CHCl3; c = 0,510)

1H-NMR (CDCl3): = 5,81 MRP sbr (1H, H-4); 5,76 dbr (J = 10 Hz, 1H, bridge); 5,56 m (1H, bridge); 2,68 m (1H, H-11); 1,87 s (3H, propyne); 1,07 t (J R> a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17-butenyl-6'H-benzo[10,9,11]- 18a-Homo-5-estren-5, 17-diol

General instructions 2) turn 800 mg described in paragraph (25i) connection and 15 ml of a 1.6 molar solution of n-utility in hexane and 5 g of 1-butyne in absolute tetrahydrofuran. Get 545 mg 27a) in the form of white crystals.

So pl. = 186-191oC. []2D0= -51,2o(CHCl3; c = 0,500)

1H-NMR (CDCl3): = 5,7 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 4,42 s (1H, OH); 3.46 in-3,62 m (4H, ketal); 2,48 m (1H, H-11); 2,23 q, J = 7.5 Hz, 2H, Butin-CH2); 1,12 t (J = 7.5 Hz, 3H, Butin-CH3); 1,06 t (J = 7.5 Hz, 3H, 18a-CH3); and 0.98 s (3H, Me-ketal); 0,96 s (3H, Me-ketal).

b) 9,11-dihydro-17 -(1-butynyl)-17-hydroxy-6'H - benzo[10,9,11]-18a-gamester-4-EN-3-one

General instructions 1) turn 485 mg described in paragraph 27a) substances with 1 ml of 4 N. aqueous solution of hydrochloric acid in acetone. After purification of the crude product receive 323 mg 27b) in the form of white crystals.

So pl. = 143-146oC; []2D0= -52,5o(CHCl3; c = 0,500)

1H-NMR (CDCl3): = 5,81 MRP sbr (1H, H-4); 5,77 dbr (J = 10 Hz, 1H, bridge); 5,56 m (1H, bridge); 2,68 m (1H, H-11); 2,23 q, J = 7.5 Hz, 2H, Butin-CH2); 1,12 t (J = 7.5 Hz, 3H, Butin-CH3); 1,07 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 28

9,11-dihydro-the Nile-6'H-benzo[10,9,11]-18a-Homo-5 - estran-5,17-diol

At 0oC in a solution of 1.32 g terminiology in 50 ml of simple diethyl ether buried at 14.5 ml of a 1.6 molar solution of n-utility in hexane and stirred for 1 h at room temperature. Then add a solution of 1 g described in paragraph (25i) compound in 25 ml of tetrahydrofuran. Stirred for 1 h at 0oC and then treated with water (C, F). After purification of the crude product to obtain 660 mg 28a) in the form of white crystals

So pl. = 117-121oC. []2D0= -37,8o(CHCl3; c = 0,520)

1H-NMR (CDCl3): = between 6.08 ppm dd (J = 17, 5,10 Hz, 1H, vinyl); 5,7 dbr (J = 10 Hz, 1H, bridge); 5,46 m (1H, bridge); 5,12 dd (J = 17,5, 2 Hz, 1H, vinyl); 5,07 dd (J = 10, 2 Hz, 1H, vinyl); to 4.38 s (1H, OH); 3,48-of 3.60 m (4H, ketal); 2,42 m (1H, H-11); 1,09 t (J = 7.5 Hz, 3H, 18a-CH3); and 0.98 s (6H, Me-ketal).

b) 9,11-dihydro-17-ethynyl-17-hydroxy-6'H - benzo[10,9,11]-18a-gamester-4-EN-3-one

General instructions 1) turn 600 mg described in paragraph 28a) substances with 1.3 ml of aqueous solution of 4 G. hydrochloric acid in acetone. After purification of the crude product is obtained 406 mg 28b) in the form of white crystals.

So pl. = 170-173oC; []2D0= -24,4 (CHCl3; c = 0,515)

1H-NMR (CDCl3): = 6,06 MRP dd (J = 17,5, 10 Hz, 1H, vinyl); 5,80 sbr (1H, H-4); 5,75 dbr (J = 10 Hz, 1H, bow); 5,56 m (1H, bow); 5,12 dd (J = 17,5, 2 Grivermail)-6'H - benzo-[10,9,11]-18a-gamester-4-EN-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -(trifluoromethyl)-5-(trimethylsilyloxy)-6'H - benzo[10,9,11]-18a-Homo-5-estren-17-ol

In a solution of 1 g described in paragraph (25i) compound in 15 ml of tetrahydrofuran was added dropwise at -10oC 1.7 ml of triftormetilfullerenov and then 2.8 ml odnopolyarnogo solution of Tetra-n-butylammonium in tetrahydrofuran. Stirred for 30 min, poured into a mixture of ethyl acetate and water, extracted the aqueous phase twice more with ethyl acetate, dried the combined organic phases over sodium sulfate and concentrated in vacuo. Obtain 1.39 g 29a) as a white foam, which is used without purification in the next stage.

1H-NMR (CDCl3) : J = 5,70 ppm dbr (J = 10 Hz, 1H, bridge); 5,50 m (1H, bridge); 3,63 m (2H, ketal); 3,30 m (2H, ketal); 2,50 m (1H, H-11); 1,16 s (3H, Me-ketal); 1,04 t (J = 7.5 Hz, 3H, 18a-CH3); 0,77 s (3H, Me-ketal); 0,14 s (9H, Me3Si).

b) 9,11-dihydro-17-hydroxy-17 -(trifluoromethyl)-6'H - benzo[10,9,11] -18a-gamester-4-EN-3-one

General instructions 1) turn 1,38 g described in paragraph 29a) substances with 2.8 ml of 4 N. water acid in acetone. After purification of the crude product to obtain 302 mg 29b) as a white foam.

[]2D0= -17,6o(CHCl3; c = worn: 0.505).

1H-NMR (CDCl3): = 5,80 MRP sbr (1H, H-4); 5,77 db)-17-hydroxy - 6'H-benzo[10,9,11]-18a-gamester-4-EN-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -(cyanomethyl)-6'H - benzo[10,9,11]-18a-Homo-5-estren-5,17-diol

Received General instructions 4a) of the 2.8 ml Diisopropylamine and 12.5 ml of a 1.6 molar solution of n-utility solution liedeseplein buried at -70oC 0,82 g of acetonitrile, stirred for 30 min at -70oC and then add a solution of 1.29 g described in paragraph (25i) substance in 10 ml of tetrahydrofuran and heated for 4 h to -40oC. After water treatment (C, F) and purification receive 1.06 g 30a).

1H-NMR (CDCl3): = 5,70 ppm dbr (J = 10 Hz, 1H, bridge); 5,49 m (1H, bridge); and 4.40 s (1H, OH); 3,47-3,65 m (4H, ketal); 2.65 and 2,52 AV-signal (JAB= 15 Hz, 2H, CH2CN); 2,50 m (1H, H-11); 1,06 t (J = 7.5 Hz, 3H, 18a-CH3); 0,93 s (6H, Me-ketal).

b) 9,11-dihydro-17 -(cyanomethyl)-17-hydroxy-6'H-benzo-[10,9,11]-18a-gamester-4-EN-3-one

General instructions 1) turn 1.04 g described in paragraph 30a) substances with 1.1 ml of 4 N. aqueous hydrochloric acid in acetone. After purification of the crude product receiving 640 mg 28b) as white crystals.

So pl. = 207-212oC

1H-NMR (CDCl3): = 5,80 ppm dbr (1H, H-4); 5,76 dbr (J = 10 Hz, 1H, bridge); 5,59 m (1H, bridge); 2,67 and 2.52 AB-signal (JAB= 15 Hz, 2H, CH2CN); 1,10 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 31

9,11-dihydro-17-hydroxy -[3-[(tetrahydro-2H-Piran-2 - yl)oxy] -1-PROPYNYL]-6'H-benzo-[10,9,11]-18a-Homo-5-estren - 5,17-diol

From 10,7 ml 3-tetrahydro-2H-Piran-2-yl)oxy]-1-propene in 380 ml of tetrahydrofuran and 48 ml of a 1.6 molar solution of n-utility in hexane receive at 0oC in argon atmosphere organolithium compound. 3 Quiroga added a solution of 3.3 g described in paragraph (25i) substances in 80 ml of absolute tetrahydrofuran. Stirred for 1 h at 0oC and then treated with water (C, F). After cleaning they receive 3.7 g 31a) as a white foam.

[]2D0= -39,4o(CHCl3; c = 0,545)

1H-NMR (CDCl3): = 5,70 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 4,82 m (1H, THP); 4,39 s (1H, OH); 4,32 m (2H, CH2OTHP); a 3.87 m (1H, THP); 3,47-3,63 m (5H, ketal and THP); 2,48 m (1H, H-11); 1,02 t (J = 7.5 Hz, 3H, 18a-CH3); 0,95 m (6H, Me-ketal).

b) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]- 17 -(1,2-PROPADIENE)-6'H-benzo[10,9,11]-18a-Homo - 5-estren-5,17-diol

In 30 ml odnopolyarnogo solution of lithium aluminum hydride in tetrahydrofuran was added dropwise a solution of 1.1 g described in paragraph 31a) of the compound in 25 ml simple diethyl ether and heated for 6 h under reflux. Then added dropwise with ice cooling 10 ml of acetone and then 50 ml of a saturated solution of sodium sulfate, is sucked off from the solids washed with dichloromethane, dried the combined organic phases over su is MESU from hexane/ethyl acetate. Get 230 mg 31b) as a white foam.

1H-NMR (CDCl3): = 5,71 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 5,42 dd (J = 7, 7 Hz, 1H, Allen); 4,88 m (2H, Allen); and 4.40 s (1H, OH); 3,48-3,63 m (4H, ketal); 2,46 m (1H, H-11); 1,08 t (J = 7.5 Hz, 3H, 18a-CH3); 0,38 s (6H, Me-ketal).

C) 9,11-dihydro-17-hydroxy-17 -(1,2-PROPADIENE)-6'H - benzo[10,9,11]-18a-gamester-4-EN-3-one

180 mg described in paragraph 31b) substances turn on General instructions 1) in acetone from 0.38 ml of 4 N. aqueous hydrochloric acid. After purification of the crude product get 135 mg C) as a white foam.

1H-NMR (CDCl3): = 5,80 MRP sbr (1H, H-4); 5,77 dbr (J = 10 Hz, 1H, bow); 5,57 m (1H, bow); 5,41 dd (J = 7, 7 Hz, 1H, Allen); 4,90 d (J = 7 Hz, 2H, Allen); 2,54 m (1H, H-11); 1,12 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 32

9,11-dihyro-17-hydroxy-17 -(3-methyl - 1,2-butadienyl)-6'H-benzo[10,9,17]-18a-gamester-4-EN-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -[3-methyl-3-[(tetrahydro-2H-Piran - 2-yl)oxy]-1-butenyl-6'H-benzo[10,9,11]-18a-Homo - 5-estren-5,17-diol

From 19,5 ml of 3-methyl-3-[(tetrahydro-2H-Piran-2-yl)oxy]-1 - butyne in 570 ml of absolute tetrahydrofuran and 72,5 ml of a 1.6 molar solution of n-utility in hexane receive at 0oC in argon atmosphere organolithium compound. Then added a solution of 5 g described in paragraph (25i) substances in 120 ml absolute 4,22 g 32a) as a white foam

[]2D0= -47,4o(CHCl3; c = 0,535)

1H-NMR (CDCl3): = 5,70 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 5,00 m (1H, THP); 4,30 s (1H, OH); 3,96 m (1H, THP); 3,42-3,65 m (5H, ketal and THP); 2,48 m (1H, H-11); 1,52 s (3H, Me); 1,49 s (3H, Me); 1,05 t (J = 7.5 Hz, 3H, 18a-CH3); 0,97 s (3H, Me-ketal); 0,95 s (3H, Me-ketal).

b) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -(3-methyl-1,2-butadienyl)-6'H-benzo[10,9,11] -18a - Homo-5-estren-5,17-diol

A suspension of 3.8 g of lithium aluminum hydride in 70 ml simple diethyl ether is heated for 1 h under reflux. Then added dropwise at room temperature over 30 min a solution of 4 g described in paragraph 32a) of the compound in 100 ml of simple diethyl ether and then heated for 2 hours under reflux. In the reaction mixture is stirred into 40 g of decahydrate sodium sulfate, stirred for 1 h, filtered through celite, washed with dichloromethane and remove the solvent in vacuo. After cleaning they receive 1.2 g 23b) in the form of white crystals.

So pl. = 155oC. []2D0= -54,0o(CHCl3; c = 0,525).

1H-NMR (CDCl3): = 5,72 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 5,42 m (1H, Allen); to 4.38 s (1H, OH); 3.46 in-3,64 m (4H, ketal); 2,45 m (1H, H-11); 1,75 d (J = 2 Hz, 3H, Me-Allen); 1,74 d (J = 2 Hz, 3H, Me-Allen); 1,08 t (J = 7.5 Hz, 3H, 18a-CH3); 0,99 s (3H-3-one

General instructions 1) turn 620 mg 32b) with 4 N. hydrochloric acid in acetone. After one-hour stirring at room temperature, treated with water (B, F) and after purification of the crude product to obtain 177 mg 36b) in the form of white crystals.

T square = 150-152oC. []2D0= -68,5o(CHCl3c = 0,460).

1H-NMR (CDCl3): = 5,78 MRP sbr (1H, H-4); 5,76 dbr (J = 10.0 Hz, 1H, bridge); 5,55 m (1H, bridge); 5,20 m (1H, Allen); 2,52 m (1H, H-11); 1,75 d (J = 2.5 Hz, 3H, Me-Allen); 1,72 d (J = 2.5 Hz, 3H, Me-Allen); 1,12 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 33

5",4",9,11 -tetrahydrofuro[6'H - benzo[10,9,11]-18a-gamester-4-ene-17 ,2"(5")-furan] - for 3,5"-dione

a) 5",4",9,11 -tetrahydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)] [Spiro[5-hydroxy-6'H-benzo[10,9,11] 18a-Homo - 5-estren-17 ,2"(5")-furan] -5-ol-5"-he.

In a mixture of 70 ml of tetrahydrofuran and 60 ml of a 1.6 molar solution of n-utility in n-hexane was added dropwise at -50oC for 20 min, a solution of 8.6 ml of allinternetsite.info in 40 ml of tetrahydrofuran and stirred for 1 h at -30oC. Then was added dropwise a solution of 2 g described in paragraph (25i) compound in 15 ml of tetrahydrofuran, heated for 1 h to room temperature and stirred for 4 hours After water treatment (C, F) and purification receive 995 mg 33a) in the form of white; ,03t (J = 7.5 Hz, 3H, 18a-CH3); and 0.98 s (6H, Me-ketal)

b) 5", 4",9,11 -tetrahydrofuro[6'H-benzo[10,9,11]-18a - gamester-4-ene-17 ,2"(5")-furan] - for 3,5"-dione

General instructions 1) turn 818 mg described in paragraph 33a) substances with 2.3 ml of 4 N. aqueous hydrochloric acid in acetone. After purification of the crude product is obtained 441 mg 33b) in the form of white crystals.

So pl. = 100-102oC. []2D0= +23,75o(CHCl3c =0,500)

1H-NMR (CDCl3): = of 5.82 ppm sbr (1H, H-4); 5,75 dbr (J = 10 Hz, 1H, bow); 5,58 m (1H, bridge); 2,68 m (1H, H-11); 1,05 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 34

9,11-dihydro-17-ethinyl-17-hydroxy-6'H - benzo[10,9,11]-18a-gamestro-4,15-Dien-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17-trimethylsilyl)oxy]-6'H-benzo[10,9,11]-18a - Homo-5 - variety-16-ene-5-ol

General instructions 4a) turn 2.15 g described in paragraph (25i) substances with 2.5 ml of Diisopropylamine, 11 ml of a 1.6 molar solution of n-utility in hexane and 3.1 ml of trimethylchlorosilane in absolute tetrahydrofuran. In the form of a crude product is obtained 2,52 g 34a), which without further purification enter into the next stage.

So pl.=172-174oC

1H-NMR (CDCl3): = 5,58 ppm dbr (J = 10 Hz, 1H, bridge); 5,44 m (1H, bridge); 4,46 m (1H, H-16); 4,37 s (1H, OH); 3,48 - 3,64 m (4H, ketal); 2,48 m (1H, H-11); and 0.98 s (3H, Me-ketal); 0,96 s (3H, M is XI-6'H-benzo[10,9,11]-18a-Homo-5 - variety-15-EN-17-one

General instructions 4b) turn 2,42 g described in paragraph 34a) connection with 1.19 g of palladium (II) acetate in acetonitrile. After cleaning gain of 1.34 g 34b) in the form of white crystals.

So pl. = 210-212oC. []2D0= -128,5o(CHCl3; c = worn: 0.505)

1H-NMR (CDCl3): = 7,54 ppm dbr (J = 6 Hz, 1H, H-15); 5,96 dd (J = 6, 3 Hz, 1H, H-16); 5,63 ddr (J = 10.0 Hz, 1H, bridge); 5,52 m (1H, bridge); 4,47 s (3H, OH); 3.46 in-3,63 m (4H, ketal); 2,56 m (1H, H-11); and 0.98 s (3H, Me-ketal); 0,96 s (3H, Me-ketal); 0,78 t (J = 7.5 Hz, 3H, 18a-CH3).

c) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17-ethinyl-6'H-benzo-[10,9,11]- 18a-Homo-5-variety-15-ene-5,17-diol

General instructions 2) make 1.0 g 34b), 15 ml of a 1.6 molar solution of n-utility in hexane and gaseous Atina in absolute tetrahydrofuran. After cleaning get 1,23 g 34c), which without treatment is administered to the next stage.

1H-NMR (CDCl3): = 5,97 ppm dbr (J = 6 Hz, 1H, H-15); 5,63 m (2H, H-16 and bridge); 5,48 s (1H, bridge); 4,42 s (1H, OH); 3,50-3,65 m (4H, ketal); 2,62 s (1H, etin); 2,58 m (1H, H-11); and 0.98 s (6H, Me-ketal); 0,82 t (J = 7.5 Hz, 3H, 18a-CH3).

d) 9,11-dihydro-17-ethinyl-17-hydroxy-6'H-benzo[10,9,11]-18a-gamestro-4,15-Dien-3-one

General instructions 1) turn 1.1 g 34c) with 4 N. hydrochloric acid in acetone. After cleaning they receive 620 mg 34d).

So pl. 1H, H-15); of 5.82 sbr (1H, H-4); 5,68 dd (J = 6.3 Hz, 1H, H-16); 5,66 m (1H, bridge); 5,58 m (1H, bridge); 2,75 m (1H, H-11); 2,66 s (1H, etin); 0,86 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 35

9,11-dihydro-17-hydroxy-17 -(1 - PROPYNYL)-6'H-benzo-[10,9,11]-18a-gamestro-4,15-Dien-3-one

a) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]- 17 -(1-PROPYNYL)-6'H-benzo[10,9,11]-18a-Homo-5 - variety-15-ene-5,17-diol

General instructions 2) make 600 mg 34b), and 8.7 ml of a 1.6 molar solution of n-utility in hexane and gaseous propene in absolute tetrahydrofuran. Receive 715 mg 35a), which without treatment is administered to the next stage.

1H-NMR (CDCl3): = 5,90 ppm dbr (J = 6 Hz, 1H, H-15); 5,62 m (2H, H-16 and bridge); of 5.48 m (1H, bow); 4,46 s (1H, OH); 3,48-3,63 m (4H, ketal); 2,56 m (1H, H-11); 1,90 s (3H, propyne); and 0.98 s (3H, Me-ketal); 0,97 s (3H, Me-ketal); 0,82 t (J = 7.5 Hz, 3H, 18a-CH3).

b) 9,11-dihydro-5,17-deoxy-17 - (1-PROPYNYL)-6'H-benzo-[10,9,11]-18a-Homo-5-variety-15-EN-3-one

542 mg described in paragraph 35a) compounds dissolved in 10 ml of acetone, mixed with 1.2 ml of 0.5 N. hydrochloric acid and stirred for 2.5 h at room temperature. Poured into a saturated sodium bicarbonate solution, extracted three times with dichloromethane and dried the combined organic phases over sodium sulfate. After removal of the solvent receive 438 mg 35b), which is used without purification in sleds (1H, bridge); 2,64 m (1H, H-11); 1,92 s (3H, propyne); 0,85 t (J = 7.5 Hz, 3H, 18a-CH3).

c) 9,11-dihydro-17-hydroxy-17 -(1-PROPYNYL)-6'H-benzo-[10,9,11]-18a-gamestro-4,15-Dien-3-one

400 mg described in paragraph 35b) compounds are dissolved in acetone, mixed with 0.5 ml of 4 N. hydrochloric acid and stirred for 5 h at room temperature. After water treatment (B, F) and purification receive 139 mg 35c) in the form of white crystals.

So pl. 68-73oC. []2D0= -53,2o(CHCl3; c= 0,500)

1H-NMR (CDCl3): = 5,90 dbr (J = 6 Hz, 1H, H-15); of 5.83 sbr (1H, H-4); 5,68 m (1H, bridge); 5,66 m (1H, H-16); 5,58 m (1H, bridge); 2,72 m (1H, H-11); 1,90 s (3H, propyne); 0,86 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 36

17 -(1-butynyl)-9,11-dihydro-17-hydroxy-6'H - benzo[10,9,11]-18a-gamestro-4,15-Dien-3-one

a) 17 -(1-butynyl)-9,11-dihydro-3,3-[2,2-dimethyl-1,3-

propanediylbis(oxy)]-6'H-benzo[10,9,11]-18a-Homo-5 - variety-15-ene-5,17-diol

General instructions 2) turn 800 mg 34b), 15 ml of a 1.6 molar solution of n-utility in hexane and 5 g of 1-butyne in absolute tetrahydrofuran. After cleaning they receive 637 mg 36a) as a white foam.

1H-NMR (CDCl3): = 5,90 ppm dbr (J = 6 Hz, 1H, H-15); 5,63 m (2H, H-16 and bridge); of 5.48 m (1H, bridge); 4,43 s (1H, OH); 3.46 in-3,63 m (4H, ketal); 2,25 q, J = 7.5 Hz, 2H, Butin-CH2); 1,16 t (J = 7.5 Hz, 3H, Butin-CH3); and 0.98 s (3H, Me-ketal); 0,96 s (3H, Me-ket is-3-one

General instructions 1) turn 364 mg 36a) with 4 N. hydrochloric acid in acetone. After three hours stirring at room temperature, treated with water (B, F) and after purification the crude product is obtained 145 mg 36b) as a white foam.

[]2D0= -195,2o(CHCl3; c = 0,500)

1H-NMR (CDCl3): = by 5.87 dbr (J = 6 Hz, 1H, H-15); of 5.82 sbr (1H, H-4); 5,68 m (2H, H-16 and bridge); 5,56 m (1H, bow); 2,72 m (1H, H-11); 2.26 and q (J = 7, 5 Hz, 2H, Butin-CH2); 1,14 t (J = 7.5 Hz, 3H, Butin-CH3); 0,85 t (J = 7.5 Hz, 3H, 18a-CH3)

Example 37

9,11-dihydro-17-hydroxy-17 -(1,3 - pentadienyl)-6'H-benzo-[10,9,11] -18a-gamestro-4,15-Dien-3-one

300 mg described in paragraph 34d) substances dissolved in 40 ml of triethylamine. Saturate the solution at room temperature with gaseous propyne, added 90 mg of tetrakis (triphenylphosphine)palladium and 45 mg of copper iodide(I), is heated to 600oC and stirred while maintaining the flow propina 1 h at this temperature. Then the reaction mixture was filtered through celite and concentrated in vacuo. After cleaning they receive 66 37 mg) as amorphous solids.

1H-NMR (CDCl3): = 5,95 dbr (J = 6 Hz, 1H, H-15); of 5.82 sbr (1H, H-4); 5,68 m (1H, bow); 5,63 dd (J = 6.3 Hz, 1H, H-16); 5,56 m (1H, bow); to 2.74 m (1H, H-11); 1,96 s (3H, pentadien-Me); 0,82 t (J = 7.5 Hz, 3H, 18a-CH3)

If a 1 , 15 ,16-tetrahydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)] -5-hydroxy-6'H-benzo[10,9,11] [3 H] cyclopropa- [15,16]-18a-Homo-5-estren-17-he

In the suspension 3,68 g of iodide trimethylsulfoxonium in 50 ml of dimethyl sulfoxide added 430 mg of sodium hydride, stirred for 90 min, then added 2 g described in paragraph 34b) substances and stirred for 6 hours the Mixture vmeshivat in ice water, the precipitated substance is sucked off, absorb in dichloromethane, dried over sodium sulfate and remove the solvent in vacuo. Get 1,67 g 38a) as white crystals.

So pl. = 226-230oC. []2D0= -70,0o(CHCl3; c = 0,500)

1H-NMR (CDCl3): = 5,56 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 4,45 s (1H, OH); 3.46 in-3,64 m (4H, ketal); 2,54 s (1H, H-11); 1.00 s (3H, Me-ketal); 0,97 s (3H, Me-ketal); 0,76 t (J = 7.5 Hz, 3H, 18a-CH3).

b) 9,11 , 15 ,16-tetrahydro-3,3-[2,2-dimethyl - 1,3-propanediylbis(oxy)] -17-ethinyl-6'H - benzo[10,9,11][3 H]cyclopropa[15,16]-18a-Homo-5-estren-5,17-diol.

General instructions 2) turn 1,0 described in paragraph 38a) substances and 14 ml of a 1.6 molar solution of n-utility in hexane and gaseous Atina in absolute tetrahydrofuran. After cleaning they receive 949 mg 38b) in the form of white crystals.

So pl. = 197-202oC []2D0= -86,8o(CHCl70s (1H, etin); 2,50 m (1H, H-11); 0,99 t (J = 7.5 Hz, 3H, 18a-CH3); 0,97 s (6H, Me-ketal); 0,81 m (1H, cyclopropyl-H).

c) 9,11 , 15, 16-tetrahydro-17-ethinyl-17 - hydroxy-6'H-benzo[10,9,11][3 H]cyclopropa[15,16]-18a-gamester-4-EN-3-one

General instructions 1) turn 650 mg 38b) with 4 N. hydrochloric acid in acetone. After cleaning they receive 348 mg 38c).

So pl. = 227-230oC. []2D0= -82,9o(CHCl3; c = worn: 0.505)

1H-NMR (CDCl3): = of 5.83 sbr (1H, H-4); 5,78 dbr (J = 10 Hz, 1H, bridge); 5,56 m (1H, bridge); 2,72 s (1H, etin); 1,02 t (J = 7.5 Hz, 3H, 18a-CH3); 0,48 (1H, cyclopropyl-H)

Example 39

17-(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11] -18a - Homo-19-norpregna-4-ene-3,20-dione

a) [17(21)S]-21-phenylsulfinyl)-9,11-dihydro-3,3- [2,2-dimethyl-1,3-propanediylbis(oxy)]-5-hydroxy-6'H - benzo[10,9,11]-18a-Homo-19-nor-5-pregn-17(20),20-Dien.

In a solution of 500 mg described in paragraph (25i) substances in 7 ml of dichloromethane and 1 ml of triethylamine was added dropwise at -70oC a solution of 285 mg of phenylalaninamide in 0.7 ml of dichloromethane, and then heated to -30oC and stirred for 3 h at -30oC. Mixing the reaction mixture with water, extracted twice with ethyl acetate, wash the combined organic phases 1 N. aqueous hydrochloric acid and water, dried over sodium sulfate and concentrated in vacuo. After cleaning they receive is hydrogen); 6,06 t (J = 3.5 Hz, 1H, Allen); the ceiling of 5.60 dbr (J = 10 Hz, 1H, bridge); 5,50 m (1H, bridge); 4,37 s (1H, OH); 3,48-3,63 m (4H, ketal); 0,97 s (3H, Me-ketal); 0,95 s (3H-Me-ketal); 0,93 t (J = 7.5 Hz, 3H, 18a-CH3).

b) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)] -5,17-dihydro-20-(metiloksi)-6'H-benzo[10,9,11]-18a-Homo-19-nor-5-pregn-20-EN

Into a solution of 3.3 g described in paragraph 39a) compound in 30 ml of tetrahydrofuran was added dropwise 24 ml of 1-molar solution methanolate sodium in methanol, stirred for 48 h at room temperature, then poured onto water, extracted three times with dichloromethane, dried the combined organic phases over sodium sulfate, filtered and the solvent is distilled off in vacuum. The residue is dissolved in 65 ml of methanol, add 10 ml of triethylphosphite, heated for 45 minutes under reflux and concentrated in vacuo. After cleaning get 2.1 g 39b).

1H-NMR (CDCl3): = 5,67 ppm dbr (J = 10 Hz, 1H, bridge); 5,43 m (1H, bridge); 4,30 d, J = 4 Hz, 1H, H-21); 4,30 s (1H, OH); 3,98 d, J = 4 Hz, 1H, H-21); 3,52 s (3H, MeO); 3,45-3,64 m (4H, ketal); 0,97 s (3H, Me-ketal); 0,95 s (3H, Me-ketal); 0,72 t (J = 7.5 Hz, 3H, 18a-CH3).

c) 9,11-dihydro-5-hydroxy-6'H-benzo-[10,9,11]-18a-Homo - 19-nor-5-pregnan-3,20-dione

To a solution of 2.0 g described in paragraph 39b) compound in 25 ml of acetone is added 2 ml of 4 N. aqueous hydrochloric acid, stirred for 1 h at room the Hai.

1H-NMR (D6-DMSO): = 5,76 ppm dbr (J = 10 Hz, 1H, bridge); 5,62 m (1H, bridge); 5.17 to s (1H, OH); and 4.40 s (1H, OH); 2,25 s (3H, acetyl); 0,70 t (J = 7.5 Hz, 3H, 18a-CH3).

(d) 17(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11] - 18a-Homo-19-norpregna-4-ene-3,20-dione

By analogy with example 13c) turn 1,3 g described in paragraph 39c) compound in 25 ml of glacial acetic acid with 6.6 ml of anhydride triperoxonane acid. After treatment with water (B, F) and purification receive 1.0 g 39d).

So pl. = 225-229oC.

1H-NMR (CDCl3): = of 5.82 ppm sbr (1H, H-4); 5,70 dbr (J = 10 Hz, 1H, bridge); 5,58 m (1H, bridge); 2,72 (1H, H-11); 2,12 s (3H, acetyl); 2,10 s (3H, acetoxy); 0,72 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 40

17-(atomic charges)-9,11-dihydro-6-methylene-6'H - benzo[10,9,11]-18a-Homo-19-norpregna-4-ene-3,20-dione

1,41 g described in paragraph 39d) substances turn on the analogy given in example 16) instruction. Get 1,03 g 40) in the form of white crystals.

So pl. = 215-219oC. []2D0= +126,4o(CHCl3; c = 0,500)

1H-NMR (CDCl3): = 6,01 MRP sbr (1H, H-4); 5,70 dbr (J = 10 Hz, 1H, bridge); 5,55 m (1H, bridge); 5,15 m (1H, hectometre); 5,00 m (1H, hectometre); 2,74 m (1H, H-11); 2,14 s (3H, acetyl); 2,12 s (3H, acetoxy); 0,72 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 41

17-(atomic charges)-9,11-dihydro-6-methyl-6'H - benzo[10,9,11]-18a-comprimere 18) instruction. Get 303 41) in the form of white crystals.

So pl. = 260-264oC. []2D0= +43,4o(CHCl3; c = 0,500)

1H-NMR (CDCl3): 6,00 MRP sbr (1H, H-7); of 5.92 sbr (1H, H-4); 5,72 dbr (J = 10 Hz, 1H, bridge); 5,62 m (1H, bridge); 2,75 m (1H, H-11); 2,15 s (3H, acetyl); 2,11 s (3H, acetoxy); 1,86 sbr (3H, 6-methyl); 0,73 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 42

5', 6'-dihydro-17-hydroxy-17 -(1-PROPYNYL)-9H - benzo[10,9,11]-18a-gamester-4-EN-3-one

a) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)] -9H-benzo[10,9,11]-18a-Homo-5-estren-5,17-diol

2 g described in paragraph 25h) compounds dissolved in the vessel for shaking in a mixture of 5 ml of tetrahydrofuran and 50 ml of ethyl acetate. Added 550 mg of palladium on charcoal (10%) installing the apparatus under hydrogen and shaken for 3 hours Then filtered through celite and concentrated in vacuo. After cleaning get 1,69 g 42a).

1H-NMR (CDCl3): = and 5.30 ppm m (1H, bridge); to 4.38 s (1H, OH); 3,85 dd, J = 14 and 7.5 Hz, 1H, 17-H); 3,50-3,65 m (4H, ketal); 1,04 t (J = 7.5 Hz, 3H, 18a-CH3); and 0.98 s (6H, Me-ketal).

b) 5',6'-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-5-hydroxy-9H-benzo[10,9,11]-18a-Homo-5-estren-17-he

General instructions 3) of 1.68 g described in paragraph 42a) substances of 2.35 g of chromium trioxide and 8 ml of pyridine in 70 ml of dichloromethane obtain 1.50 g 42b).

3
).

c) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -(1-PROPYNYL)-9H-benzo[10,9,11]-18a-Homo-5 - estren-5,17-diol

General instructions 2) of 1.35 g described in 42b) substances and 19.5 ml of a 1.6 molar solution of n-utility in hexane and gaseous propyne get 1,02 g 42c).

[]2D0= -78,8o(CHCl3; c = 0,510)

1H-NMR (CDCl3): = 5,31 ppm m (1H, bridge); of 4.44 s (1H, OH); 3,45-3,62 m (4H, ketal); 1,87 s (3H, propyne); 1,02 t (J = 7.5 Hz, 3H, 18a-CH3); and 0.98 s (3H, Me-ketal); 0,95 s (3H, Me-ketal).

d) 5', 6'-dihydro-17 hydroxy-17 -(1-PROPYNYL)-9H - benzo[10,9,11]-18a-gamester-4-one-3-one

General instructions 1) turn 0,99 g 42c) with 4 N. hydrochloric acid in acetone. After purification of the crude product is obtained 421 g 42d).

So pl. = 188-190oC. []2D0= +20,3o(CHCl3c = 0,515)

1H-NMR (CDCl3): = 5,78 MRP sbr (1H, H-4); of 5.48 m (1H, bridge); 1,88 s (3H, propyne); 1,05 t (J = 7.5 Hz, 3H, 18a-CH3)

Example 43

17-hydroxy-17 -(1-PROPYNYL)-4', 5', 9,11 - tetrahydro-6'H-benzo[10,9,11]-18a-gamester-4-EN-3-one

a) 3,3-[2,2-dimethyl-1,3-propanediylbis(hydroxy)] -4',5',9,11 tetrahydro-6'H-benzo[10,9,11]-18a-Homo-5-estren-5,17-diol

2 g described in paragraph 25h) compounds dissolved in the vessel for shaking in a mixture of 5 ml of tetrahydrofuran and 50 ml of ethyl acetate. the ez celite and concentrated in vacuo. After cleaning gain of 1.61 g 43a).

1H-NMR (CDCl3): = 4,28 ppm s (1H, OH); 3,68 ddbr (J = 14 and 7.5 Hz, 1H, 17-H); 3.46 in-3,62 m (4H, ketal); 1,02 t (J = 7.5 Hz, 3H, 18a-CH3); 0,95 s (3H, Me-ketal); of 0.95 (3H, Me-ketal).

(b) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-5-hydroxy- 4',5',9,11 - tetrahydro-6'H-benzo[10,9,11]-18a-Homo-5-estren-17-he

General instructions 3) of 1.4 g described in paragraph 43a) substances of 1.95 g of chromium trioxide and 6.7 ml of pyridine in 60 ml of dichloromethane obtain 1.26 g 43b).

1H-NMR (CDCl3): = 4,30 ppm s (1H, OH); 3,45-3,63 m (4H,

ketal); and 0.98 s (3H, Me-ketal); 0,96 s (3H, Me-ketal); 0,84 t (J = 7.5 Hz, 3H, 18a-CH3)

c) 3,3-[2,2-dimethyl-1,3-propanediylbis(oxy)]-17 -(1 - PROPYNYL)-4',5', 9,11-tetrahydro-6'H-benzo[10,9,11]-18a - Homo-5-extra-5,17-diol

General instructions 2) of 1.2 g described in paragraph 43b) substances and 29 ml of a 1.6 molar solution of n-utility in hexane and gaseous propyne get 761 mg 43c).

[]2D0= -5,1o(CHCl3; c = worn: 0.505)

1H-NMR (CDCl3): = 4,34 ppm s (1H, OH); 3,45-3,62 m (4H, ketal); 1,87 s (3H, propyne); 1,02 t (J = 7.5 Hz, 3H, 18a-CH3); and 0.98 s (3H, Me-ketal); 0,95 s (3H, Me-ketal);

(d) 17-hydroxy-17 -(1-PROPYNYL)-4',5',9,11 - tetrahydro-6'H-benzo[10,9,11]-18a-gamester-4-EN-3-one

General instructions 1) turn 700 mg 43c) with 4 N. hydrochloric acid in acetone. After clearing damp-NMR (CDCl3): = 5,73 MRP sbr (1H, H-4); 1,88 s (3H, propyne); 1,06 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 44

5', 6'-dihydro-17-ethinyl-17 hydroxy-9H - benzo[10,9,11]-18a-gamestro-4,15-dione-3-one

a) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)] -17-[(trimethylsilyl)oxy]-9H-benzo[10,9,11]- 18a-Homo-5 - variety-16-ene-5-ol

General instructions 4a) transform 4.1 g described in paragraph 42b) substances with 47 ml of Diisopropylamine, 20 ml of a 1.6 molar solution of n-utility in hexane and 5.7 ml of trimethylchlorosilane in absolute tetrahydrofuran. As a crude product is obtained 5.0 g 44a).

1H-NMR (CDCl3): = to 5.21 ppm m (1H, bow); to 4.52 m (1H, H-16); 4,35 s (1H, OH); 3,45-3,64 m (4H, ketal); 0,95 s (6H, Me-ketal); 0,83 t (J = 7.5 Hz, 3H, 18a-CH3); 0,18 s (9H, Me-Si).

b) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-5 - hydroxy-9H-benzo[10,9,11]-18a-Homo-5-variety-15-EN-17-one

General instructions 4b) turn 4,99 g described in paragraph 44a) connections with 2.5 g of palladium (II) acetate in acetonitrile. After cleaning get 3,15 g 44b).

1H-NMR (CDCl3): = at 7.55 ppm dbr (J = 6 Hz, 1H, H-15); 5,99 dd (J = 6.3 Hz, 1H, H-16); 5,35 m (1H, bridge); 4,42 s (1H, OH); 3,45-3,62 m (4H, ketal); 1.00 s (3H, Me-ketal); 1.00 s (3H, Me-ketal); 0,75 t (J = 7.5 Hz, 3H, 18a-CH3).

c) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(hydroxy)-17-ethinyl-9H-benzo[10,9,11]-18a - Homo-5-variety-15-ene-5,17-diol is in absolute tetrahydrofuran. Receive 1.2 g 44c).

1H-NMR (CDCl3): = 5,98 ppm dbr (J = 6 Hz, 1H, H-15); 5,65 dd (J = 6.3 Hz, 1H, H-16); 5,32 m (1H, bridge); 4,42 s (1H, OH); 3,45-3,65 m (4H, ketal); 2,62 s (1H, etin); and 0.98 s (3H, Me-ketal); 0,95 s (3H, Me-ketal); 0,82 t (J = 7.5 Hz, 3H, 18a-CH3).

d) 5', 6'-dihydro-17-ethinyl-17-hydroxy-9H - benzo[10,9,11]-18-Homo-östra-4,15-Dien-3-one

General instructions 1) turn 1.1 g 44c) with 4 N. hydrochloric acid in acetone. After purification of the crude product is obtained 432 mg 44d).

So pl. = 203-204oC. []2D0= -89,9o(CHCl3; c = 0,500)

1H-NMR (CDCl3): = 5,98 ppm dbr (J = 6 Hz, 1H, H-15); 5,78 sbr (1H, H-4); 5,73 dd (J = 6.3 Hz, 1H, H-16); 5,57 m (1H, bow); 2,65 s (1H, etin); 0,85 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 45

5', 6'-dihydro-17-hydroxy-17 -(1-PROPYNYL)-9H - benzo[10,9,11]-18a-gamestro-4,15-Dien-3-one

a) 5', 6'-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-17 -(1-PROPYNYL)-9H-benzo[10,9,11]- 18a-Homo-5 - variety-15-ene-5,17-diol

General instructions 2) turn 1.2 g 44b) with 29 ml of a 1.6 molar solution of n-utility and gas cutting in absolute tetrahydrofuran. Get 1.3 g 45a).

1H-NMR (CDCl3): = of 5.92 ppm dbr (J = 6 Hz, 1H, H-15); 5,62 dd (J = 6.3 Hz, 1H, H-16); 5,32 m (1H, bridge); 4,46 s (1H, OH); 3,48-3,64 m (4H, ketal); 1,88 s (3H, propyne); 0,97 s (3H, Me-ketal); 0,95 s (3H, Me-ketal); 0,82 t (J = 7.5 Hz, 3H, 18a-CH3)

b) 5',6'-dihydro-17-about the Noah acid in acetone. After purification of the crude product by chromatography on a column of silica gel and subsequent HPLC obtain 155 mg 45b).

So pl. = 210-217oC. []2D0= -117,6o(CHCl3; c = 0,500)

1H-NMR (CDCl3): = of 5.92 ppm dbr (J = 6 Hz, 1H, H-15); 5,78 sbr (1H, H-4); 5,70 dd (J = 6.3 Hz, 1H, H-16); 5,46 m (1H, bridge); 1,91 s (3H, propyne); 0,84 t (J = 7.5 Hz, 3H, 18a-CH3).

Example 46

3", 16 ,9,11-tetrahydro-6'H-benzo[10,9,11]cyclopropa[16,17]-18a-Homo-19-norpregna-4 - ene-3,20-dione

a) 9,11-dihydro-17-hydroxy-6'H-benzo[10,9,11]-18a-gamester-4-EN-3-one

General instructions 1) turn 7 g 25h) with 4 N. hydrochloric acid in acetone. After recrystallization from ethyl acetate to obtain 4 g 46a) as white crystals.

So pl. = 172-175oC

1H-NMR (CDCl3: = 5,80 MRP sbr (1H, H-4); 5,75 dbr (J = 10 Hz, 1H, bridge); 5,58 m (1H, bridge); 3,75 ddbr (J = 14 and 7.5 Hz, 1H, 17-H); 1,08 t (J = 7.5 Hz, 3H, 18a-CH3)

and 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-6'H-benzo[10,9,11]-18a - gamester-5-ene-17-ol

3,98 g 46a) turn on the analogy given in example 25c) instruction. After cleaning get 2,59 g 46b) as a white foam.

[]2D0= +7,40o(CHCl3; c = 0,500)

1H-NMR (CDCl3): = 5,70 ppm dbr (J = 10 Hz, 1H, bridge); 5,47 m (1H, bridge); 5,32 m (1H, H-6); 3,68 m (1H, 17-H); 3,42-of 3.60 m (4H, ketal); 1,06 t (J = 7.5 Hz,o[10,9,11]-18a-gamester-5-ene-17 - one

General instructions 3) to 2.57 g described in paragraph 46b) substances, 3,74 g of chromium trioxide and 13 ml of pyridine in 110 ml of dichloromethane get to 2.55 g 46c) in the form of white crystals.

So pl. = 190oC

1H-NMR (CDCl3): = 5,62 ppm dbr (J = 10 Hz, 1H, bridge); of 5.48 m (1H, bridge); 5,35 m (1H, H-6); 3,42-3,62 m (4H, ketal); 1,04 s (3H, Me-ketal); 0,92 s (3H, Me-ketal); 0,78 t (J = 7.5 Hz, 3H-18a-CH3).

d) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(hydroxy)] -17-[[(1,1,2,2,3,3,4,4,4- nonattributed)sulfonyl]oxy-6'H-benzo[10,9,11]-18a-gamestro-5,16-Dien

of 2.54 g described in paragraph 46c) substances dissolved in 30 ml of absolute tetrahydrofuran. Add a solution of 3.11 g Amida calibos(trimethylsilyl) in 15 ml of absolute 1,2-dimethoxyethane and a 1.45 ml fluoride performancelevel.

Then stirred for 5 h at room temperature and then treated with water (B, F). After cleaning they receive 1.73 g 46d).

1H-NMR (CDCl3): = ceiling of 5.60 ppm m (2H, H-16 and bridge); 5,50 m (1H, bridge); 5,35 m (1H, H-6); 3,42-of 3.60 m (4H, ketal); 1,02 s (3H, Me-ketal); 0,92 s (3H, Me-ketal); 0,89 t (J = 7.5 Hz, 3H, 18a-CH3).

e) 9,11-dihydro-3,3-[2,2-dimethyl-1,3 - propanediylbis(oxy)]-6'H-benzo[10,9,11]-18a-Homo-19-norpregna - 5,16-Dien-20-he

1.7 g described in paragraph 46d) compounds dissolved in 32 ml of absolute dimethylformamide and the MCA is of reperfusion. Heated 5 h to 60oC and then 20 min to 100oC. After water treatment (B, F) and after purification receive 682 mg 46e).

So pl. = 165-168oC

1H-NMR (CDCl3): = for 6.81 ppm, dd, J = 3.2 Hz, 1H, H-16); 5,68 m (1H, bridge); 5,46 m (1H, bridge); are 5.36 m (1H, H-6); 3,40-3,63 m (4H, ketal); 2,28 s (3H, acetyl); 1,02 s (3H, Me-ketal); 0,90 s (3H, Me-ketal); 0,73 t (J = 7.5 Hz, 3H, 18a-CH3)

f) 3", 16 , 9,11-tetrahydro-3,3-[2,2 - dimethyl-1,3-propanediylbis(oxy)] -6'H-benzo[10,9,11]cyclopropa[16,17]- 18a-Homo-19-norpregna-5-ene-20-he

To a suspension of 670 mg of iodide trimethylsulfoxonium 8.5 ml of dimethyl sulfoxide was added 78 mg of an 80% suspension of sodium hydride in mineral oil. Stirred for 90 min at room temperature and then added a suspension of 672 mg described in paragraph (46e) connection 2.8 ml of dimethylsulfoxide. After stirred for 10 h at room temperature and then treated with water (A, F). After cleaning get 168 mg range from 46f).

1H-NMR (CDCl3): = 5,64 ppm dbr (J = 10 Hz, 1H, bridge); the 5.45 m (1H, bridge); 5,33 m (1H, H-6); 3,40-3,61 m (4H, ketal); 2,03 s (3H, acetyl); 1.00 s (3H, Me-ketal)' 0,92 s (3H, Me-ketal); 0,73 t (J = 7.5 Hz, 3H, 18-CH3)

g) 3",16 ,9,11 -tetrahydro-6'H-benzo[10,9,11]cyclopropa- [16,17]-18a-Homo-19-norpregna-4-ene-3,20-dione

154 mg range from 46f) dissolved in 8 ml of acetone, mix of 0.18 ml of 2 N. hydrochloric acid and stirred the ke on silica gel and subsequent HPLC and receive 36 mg 46g).

1H-NMR (CDCl3): = of 5.82 ppm sbr (1H, H-4); 5,68 dbr (J = 10 Hz, 1H, bridge); 5,56 m (1H, bridge); 2,54 m (1H, H-11); 2,03 s (3H, acetyl); 0,78 t (J = 7.5 Hz, 3H, 18a-CH3).

Additional examples are given in the end of the description.

Example for the preparation of capsules.

2 g of the active ingredient, 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of silicon dioxide, and 1.2 g of magnesium stearate are mixed with each other. The mixture then fill 1000 suitable hard gelatin capsules, each containing 2 mg of the active ingredient.

Depending on the condition of the patient and how the introduction of a number of input connections can be 1-20 mg/day.

Example for the preparation of tablets.

A mixture of 1 g of the active ingredient, 570 g lactose and 200 g starch is thoroughly mixed and moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone approximately 200 ml of water. The wet mixture is sieved, dried, and sift again. Add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All are thoroughly mixed and pressed into tablets, getting 1000 tablets each containing 1 mg of active ingredient.

1. 19,11-Covered bridges 4-the new group, and R7denotes a hydrogen atom or R6adenotes a hydrogen atom or a fluorine atom, chlorine, bromine or iodine, or represents a saturated, under -, or-position alkyl residue with a straight or branched chain with the number of C-atoms to 4 and R6aand R7represents each a hydrogen atom or together an additional bond,

R14, R15, R16each denotes a hydrogen atom or R14denotes a hydrogen atom in the-position, and R15and R16represent together an additional bond or a methylene bridge in position; or R16together with R17denote a methylene bridge in-position and R17refers to a group, or R16denotes a hydrogen atom and R14and R15denote the incremental link;

R11, R11and R19denote each a hydrogen atom, or R11denotes a hydrogen atom in the-position, and R11and R19means together an additional bond, or R19denotes a hydrogen atom and R11and R11denote the incremental link;

R17/R17represent-OR21/-(CH2)n-A, -OR21/-(CH2)m-CC-B, -OR21/-(CHP>indicate together

< / BR>
< / BR>
< / BR>
,

where x = 1;

U = 0;

R21denotes a hydrogen atom;

R23represents C1- C4is an alkyl group;

R22represents C1- C3is an alkyl group;

And denotes a hydrogen atom, cyano or-OR25where R25denotes hydrogen;

In denotes a hydrogen atom, a C1- C4is an alkyl group, a C2or C3is an alkyl group;

D denotes a hydrogen atom or a hydroxy-group;

E and G represents each atom of hydrogen or C1- C3- alkyl;

n denotes 0, 1, 2, 3 or 4;

m denotes 0, 1 or 2;

p denotes 0 or 1;

k denotes 0, 1, 2 or 3;

R18denotes a hydrogen atom or methyl group.

2. 19,11-Covered bridges 4-estrene under item 1, in which R6aand R6beach denotes a hydrogen atom.

3. 9,11-Covered bridges 4-estrene under item 1, in which R6adenotes a chlorine atom or bromine or rich, in -, or-C1- C4is an alkyl residue with a straight or branched chain.

4. 19,11-Covered bridges 4-estrene under item 1, in which R6band R7denote together a double tie which denotes a hydrogen atom.

6. 19,11-Covered bridges 4-estrene under item 1, in which R14denotes a hydrogen atom in the-position, and R15and R16represent together an additional bond or a methylene bridge in position.

7. 19,11-Covered bridges 4-estrene under item 1, in which R17/R17mean-OH/-CH3, -OH/-CCH, -OH/-CC-CH3or

8. 9,11-Covered bridges 4-estrene under item 1, representing

17-(atomic charges)-9-11-dihydro-6'H-benzo[10,9,11] -19-norpregna-4-ene-3,20-dione;

17-(atomic charges)-9-11-dihydro-6-methyl-6 Benzo[10,9,11] -19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-9-11-dihydro-6-methyl-6 Benzo[10,9,11] -19-norpregna-4-ene-3,20-dione;

17-(atomic charges)-6-chloro-9,11-dihydro-6 Benzo[10,9,11] -19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-6-chloro-1, 2, 9,11-tetrahydro-3H-cyclopropa[1,2][6 H] -benzo[10,9,11]-19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-4', 5',9,11-tetrahydro-6 Benzo[10,9,11]-19-norpregna-4-ene-3,20-dione;

17-(atomic charges)-6-methyl-4', 5', 9,11-tetrahydro-6'H benzo[10,9,11]-19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-6-chloro-1, 2, 4", 5", 9,11-hexahydro-3'H-cyclopropa[1,2]]6"H]benzo[10,9,11]-19-norpregna-4,6-diene-3,20-dione;

17-(atomic charges)-5', 6', -dihydro-N-benzo[10,9,11] -19-norpregna-4-ene-3,20-dione;

17-(atomic charges)-5', 6',-dihydro-6-methyl-N-Benz is R>
17-(atomic charges)-9,11-dihydro-6-methyl-6'H-benzo [10,9,11]-18a-Homo-19-norpregna-4,6-diene-3,20-dione;

9,11-dihydro-17-methyl-6'H-benzo[10,9,11]-19-noclegi-4-ene-3,20-dione;

17-(atomic charges)-9,11-dihydro-6'H-benzo[10,9,11] -19-norpregna-4,6-diene-3,20-dione;

3', 9,11, 16-tetrahydrocyclopent[16,17][6H]benzo [10,9,11]-norpregna-4-ed-3,20-dione;

9,11-dihydro-17-methyl-6'H-benzo[10,9,11] -18a-Homo-19-norpregna-4-ene-3,20-dione;

3', 9,11, 16-tetrahydrocyclopent[16,17][6H]benzo [10,9,11]-18a-Homo-19-norpregna-4-ene-3,20-dione;

9,11-dihydro-17-hydroxy-17-methyl-6'H-benzo [10,9,11]-variety-4-EN-3-one;

9,11-dihydro-17-ethinyl-17-hydroxy-6'H-benzo [10,9,11]-variety-4-EN-3-one;

9,11-dihydro-17-hydroxy-17-(1-PROPYNYL)-6'H-benzo [10,9,11] -variety-4-EN-3-one;

9,11-dihydro-17-hydroxy-17-(1,3-pentadienyl)-6'H-benzo[10,9,11] -variety-4-EN-3-one;

(Z-9,11-dihydro-17-hydroxy-17-(3-hydroxy-1-propenyl)-6'H-benzo [10,9,11]-variety-4-EN-3-one;

9,11-dihydro-17-hydroxy-17-(3-hydroxypropyl)-6'H-benzo,9,11] -variety-4-EN-3-one;

17-hydroxy-17-methyl-4', 5',9,11-tetrahydro-6'H-benzo [10,9,11]variety-4-EN-3-one;

17-ethinyl-17-hydroxy-4', 5', 9', 11-tetrahydro-6'H-benzo[10,9,11] variety-4-EN-3-one;

17-hydroxy-17-(1-PROPYNYL)-4', 5',9,11-tetrahydro-6'H-benzo[10,9,11] ESTRO-4-EN-3-one;

5',6'-dihydro-17-ethinyl-17-hydroxy-N-benzo [10,9,11]variety-4-EN-3-one;

5', 6'-dihydro-17-hydroxy-17-(1-PROPYNYL)-N-benzo [10,9,11]variety-(1-PROPYNYL)-6'H-benzo [10,9,11]-18a-Homo-variety-4-EN-3-one;

17-(1-butynyl)-9,11-dihydro-17-hydroxy-6'H-benzo [10,9,11] -18a-Homo-variety-4-EN-3-one;

9,11-dihydro-17-(1,2-PROPADIENE)-17-hydroxy-6'H benzo [10,9,11]-18a-Homo-variety-4-EN-3-one;

17-ethinyl-17-hydroxy-4', 5',9,11-tetrahydro-6'H benzo[10,9,11]-18a-Homo-variety-4-EN-3-one;

17-hydroxy-17-(1-PROPYNYL)-4', 5', 9,11-tetrahydro-6 Benzo[10,9,11] -18a-Homo-variety-4-EN-3-one;

5', 6'-dihydro-17-ethinyl-17-hydroxy-9H-benzo [10,9,11] -18a-Homo-variety-4-EN-3-one;

5', 6'-dihydro-17-hydroxy-17-(1-PROPYNYL)-9H-benzo [10,9,11]-18a-Homo-variety-4-EN-3-one;

9,11-dihydro-17-ethinyl-17-hydroxy-6'H-benzo [10,9,11]-östra-4,15-Dien-3-one;

9,11-dihydro-17-hydroxy-17(1-PROPYNYL)6 Benzo [10,9,11] -östra 4-Dien-3-one;

17-ethinyl-17-hydroxy-4', 5', 9,11-tetrahydro-6 N benzo[10,9,11]-östra-4,15-Dien-3-one;

5', 6'-dihydro-17-ethinyl-17-hydroxy-N-benzo [10,9,11]-östra-4,15-Dien-3-one;

5', 6'-dihydro-17-hydroxy-17-(1-PROPYNYL)-N-benzo [10,9,11]-östra-4,15-Dien-3-one;

9,11-dihydro-17-ethinyl-17-hydroxy-6 Benzo [10,9,11] -18a-Homo-östra-4,15-Dien-3-one;

9,11-dihydro-17-hydroxy-17-(1-PROPYNYL)6 Benzo[10,9,11] -Homo-östra-4,15-Dien-3-one;

17-ethinyl-17-hydroxy-4', 5',9,11-tetrahydro-6'H benzo[10,9,11]-18a-Homo-östra-4,15-Dien-3-one;

5', 6'-dihydro-17-ethinyl-17-hydroxy-N-benzo [10,9,11]-18a-Homo-östra-4,15-Dien-3-one;

5', 6'-dihydro-17-hydroxy-17-(1-PROPYNYL)-N-benzo [10,9,11]-18a-Homo-östra a,16A-octahydroxy[3'H,3"H-dicyclopropyl[6,7: 15,16] -[6H] benzo[10,9,11] variety-4-ene-17, 2""(5"H)-furan] - for 3,5""-dione;

3"", 4"", 9', 11', 15',16'-hexahydrofuro [cyclopropane-1,6'-[3H] cyclopropane-[15,16] [6H] benzo[10,9,11]-variety-4-ene-17',2"""(5"")-furan] 3',5" ' -dione;

3"", 4"", 9', 11', 15',16'-hexahydrofuro [cyclopropane-1,6'-[3H] cyclopropane-[15,16] [6H] benzo[10,9,11]-östra-1,4-diene-17,2""(5"H)-furan]3',5" ' -dione;

3"",4"",5"',6,7,9,11,15,16-decahydrate[3'H,3"H-dicyclopropyl[6,7: 15,16][6H]benzo[10,9,11]extras-4-ene-17, 2""(5""H)-furan]-3"", 5" ' -dione;

3"", 4"", 9,11-tetrahydropyrido[6 Benzo[10,9,11] -18a - Homo-variety-4-ene-17,2""(5")-furan]3'.5" ' -dione;

3"", 4"", 6,7,9,11,15,16-octahydroxy[3'H,3"H-dicyclopropyl-[6,7, : 15,16][6H]benzo[10,9,11]-18a-Homo-variety-4-ene-17,2""(5"H)-furan] -3',5" ' -dione;

9,11-dihydro-17-ethinyl 6 Benzo[10,9,11]-variety-4-EN-17-ol;

17-ethinyl-4',5',9,11-tetrahydro-6'H-benzo[10,9,11]variety-4-EN-17-17-ethinyl-N-benzo[10,9,11]variety-4-EN-17-ol;

9,11-dihydro-17-ethinyl-6'H-benzo[10,9,11]östra-4,15-Dien-17-dihydro-17-ethinyl-6'H-benzo[10,9,11]-18a-Homo-variety-4-EN-17-dihydro-17-ethinyl-6'H-benzo[10,9,11] -18a-Homo-östra-4,15-Dien-17-ol;

9. The method of obtaining compounds of General formula I on p. 1, characterized in that the compound of General formula II

< / BR>
where To protected ketogroup;

X is a chlorine atom or bromine in the SYN - or Antologiya;

R18a hydrogen atom or methyl;

Q - oxygraph in-position

S - atom fodorites available to them actigraphy optionally protected,

conduct a) radical cyclization to obtain compounds of General formula III

< / BR>
where, R18, Q and S have the above meanings;

C) then if Q - oxygraph, if need be, oxidize, C) if R11and R19should represent hydrogen atoms, hydronaut 19,11-atanomy bridge, d) if R19represents a hydrogen atom and R11and together denote an additional bond, the double bond in 19,11-atenolol the bridge is subjected to isomerization in the 11-position, e) if desired, is introduced into the D ring 15,16 - double bond and the last f) if desired, is subjected to isomerization in 14, 15 - position, or (g) conduct metroidvania obtaining 15, 16 - methylene derivative and (h) if necessary oxidised to the corresponding 17-(3-oksipropil) or 16 -(4 - oxobutyl) connection to obtain 17-spirolactone, or i) if necessary, subjected to the reaction of cyclization of the corresponding (Z) -17-(3 - oxoprop-1-enyl)- or (Z)-17-(4-occiput-1-enyl)17-oxycoedone or the corresponding saturated in the side chain connections for easy spirometer and (j) processing the acid mixed with water, the solvent is transferred to4- 3 - ketoester, and other available protective group also otscheplaut with Poluchenie medienraum one double bond or two double bonds, l) have 6-oxymetholone with subsequent removal of water until the 6-methylene compounds, m) hydrogenation of the 6-methylene group receiving compound I where R6a- -methyl, and R6band R7each a hydrogen atom or together form an additional bond.

10. Pharmaceuticals with gestagennami activity containing the active substance and a pharmaceutically acceptable carrier, wherein the active substances they contain at least one compound of General formula I on p. 1 in an effective amount.

11. Pharmaceuticals under item 9, it is acceptable for the treatment of gynecological diseases, predmenstrualnogo syndrome and to maintain pregnancy.

12. 19,11-Covered bridges 4-estrene under item 1, used for getting medicines.

13. Intermediate compounds of General formula III'< / BR>
< / BR>
where K denotes a protected keto or hydroxy - group and a hydrogen atom;

R11and R19mean together an additional bond and R11denotes a hydrogen atom in the - position, or R19denotes a hydrogen atom and R11and R11represent together an additional bond, have designations specified in formula I;

R18denotes a hydrogen atom or methyl group;

Q denotes a hydroxy-group in the - position; and S denotes a hydrogen atom in the - position, or Q and S together represent the atoms ketoconazole or, in addition, Q and S denotes one of the above in the formula I R17/R17- combinations of substituents, including spiraeoideae indicated in formula I, and their hydroxy - and/or catography, if necessary, protected.

 

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The invention relates to organic synthesis

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The invention relates to extraction of valuable chemicals from waste timber, namely the allocation method betulin formula I from birch bark

The invention relates to a new method of obtaining 11-ketosteroid derivatives of General formula I, where R is H, acyl, C1- C8, R1- CH3CH2OR11, R11- H, acyl, C1- C8, 3-oxoprop protected in the form of atlanticocean consists in the fact that the compound of formula II is converted into gelegenheden formula III in the presence of alcohol, and the resulting product is treated with acid

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< / BR>
where

if OR3is set tothen

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if OR3is in "beta", then

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The invention relates to extraction of valuable chemicals from waste wood, namely the method of obtaining betulin formula 1 from birch bark used in medicine and perfumery industry [1]

< / BR>
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-l-rhamnopyranoside methyl ester of glycyrrhetic acid, manifesting hepatoprotective activity" target="_blank">

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< / BR>
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< / BR>
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FIELD: medicine, immunology.

SUBSTANCE: invention proposes an agent enhancing the immunogenic properties of tetanus anatoxin (adjuvant). Invention proposes the vegetable triterpenic compound miliacin as an agent enhancing immunogenic properties of tetanus anatoxin. Agent enhances the immune response value in its applying as a vaccine preparation of tetanus anatoxin. The agent miliacin elicits its stimulating effect for both the first and repeated administration of vaccine that allows suggesting its possible applying for prophylactic vaccinations with tetanus anatoxin. Taking into account the high tolerance of miliacin in the broad range of its doses it is suggested its practical applying as an agent promoting to the enhanced formation of vaccinal immunity in prophylactic vaccinations with tetanus anatoxin.

EFFECT: valuable medicinal properties of agent.

6 tbl

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