14,17-c2-bridge steroids or pharmaceutical drug

 

(57) Abstract:

The invention relates to 14,17-C2-bridged steroids of formula I, where R3- O, R6- H, or -(C1-C4)-alkyl, where R6and R7together form an additional bond; R7- or -(C1-C4)-alkyl, where R6and R6both H, or R9and R10each H or together form a bond, R11and R12each H or together form a bond, R13- CH3or2H5; R15- H or C1-C3-alkyl; R16and R16independently H, (C1-C3)-alkyl or C1-C4alkenyl or together form a (C1-C3-alkyliden; R15and R16together form a cycle where n = 1, and h - O and R16- H, - H, (C1-C3)-alkyl, - H, (C1-C3)-alkyl, and each H or together form a bond, R21- H or (C1-C3)-alkyl, R21- H, (C1-C3)-alkyl or HE; except 14,17-ethano-19-norpregna-4-ene-3,20-dione. The compounds exhibit very high gestagenna activity, and impact on other steroid receptors, which is used in pharmaceutical preparations. 2 S. and 9 C.p. f-crystals.

R>
where

R3means an oxygen atom, hydroxyimino or two hydrogen atoms;

R6means a hydrogen atom, fluorine, chlorine or bromine, or located in or position (C1-C4)-alkyl residue, and then R6and R7represent hydrogen atoms or, however,

R6means a hydrogen atom, fluorine, chlorine or bromine, or (C1-C4)-alkyl residue, and then R6and R7together form an additional bond;

R7means located in or permanent position (C1-C4)-alkyl residue, and then R6and R6represent hydrogen atoms or, however,

R6and R7together means located in or permanent position methylene group and R6means a hydrogen atom or

R6and R6together mean ethylene or methylene group and

R7means a hydrogen atom;

R9and R10each mean a hydrogen atom or together form a bond;

R11and R12each mean a hydrogen atom or together form a bond;

R13means a methyl or ethyl group;

R15means atuga mean a hydrogen atom, (C1-C3)-alkyl residue, or (C2-C4)-alkanniny residue or together denote (C1-C3)-alkylidene group;

R15and R16together form a bond, and

R16means a hydrogen atom or (C1-C3)-alkyl residue

or

R15and R16together form a cycle of partial formula:

< / BR>
where n = 1 and 2, and X is a methylene group or an oxygen atom, and

R16means a hydrogen atom;

means a hydrogen atom or (C1-C3)-alkyl residue;

means a hydrogen atom, (C1-C3)-alkyl residue, or (C2-C4)-alkanniny the rest;

and , each represent a hydrogen atom or together form a bond;

R16means a hydrogen atom or (C1-C3)-alkyl residue;

R21means a hydrogen atom, (C1-C3)-alkyl residue or a hydroxyl group;

except for the connection 14,17-ethano-19-norpregna-4-ene-3,20-dione.

Winding line in the General formula of the present invention means that the corresponding Deputy can be in - or - position to the corresponding carbon atom.

If (C2-C4)-alkenylphenol balance values of R16, R16and/or we are talking about vinyl, allyl or but-3-anilino residue, preferred is a vinyl residue.

According to the present invention preferred are such compounds of General formula (I), in which

R3means an oxygen atom or two hydrogen atoms, and/or

R6means a hydrogen atom or located in or position (C1-C4)-alkyl residue, when R6and R7represent hydrogen atoms or, however,

R6means a hydrogen atom, chlorine or bromine, or (C1-C4)-alkyl residue, when R6and R7together represent an additional bond, and/or

R16and R16each mean a hydrogen atom, methyl group, or one of these two substituents means (C1-C4)-alkyl or vinyl group, and the other of these both the foam; and/or

and , independently of one another, mean a hydrogen atom or methyl group, and/or

and , each represent a hydrogen atom or together form a bond; and/or

R21means a hydrogen atom or (C1-C3)-alkyl residue,

and

R21means a hydrogen atom or a hydroxyl group;

moreover, other substituents can have all the above in formula (I) values.

According to the invention particularly preferred are the following compounds:

14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

14,17-ethano-19-norpregna-4,15-diene-3,20-dione;

14,17-ethano-19-norpregna-4,6,15-triene-3,20-dione;

14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4,15-diene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione;

14,17-ateno-19-norpregna-4-ene-3,20-dione;

14,17-ateno-19-norpregna-4,6-diene-3,20-dione;

14,17-ateno-19-norpregna-4,9-diene-3,20-dione;

21-methyl-14,17-ateno-19-norpregna-4-ene-3,20-dione;

21-methyl-14,17-ateno-19-norpregna-4,6-diene-3,20-dio is R>21-hydroxy-14,17-ateno-19-norpregna-4-ene-3,20-dione;

21-hydroxy-14,17-ateno-19-norpregna-4,9-diene-3,20-dione;

171-methyl-14,17-ateno-19 - norpregna-4-ene-3,20-dione;

171-methyl-14,17-ateno-19-norpregna-4,6-diene-3,20-dione;

172-methyl-14,17-ateno-19-norpregna-4-ene-3,20-dione;

172-methyl-14,17-ateno-19-norpregna-4,9-diene-3,20-dione;

15,16-dimethyl-14,17-ateno-19-norpregna-4-ene-3,20-dione;

6-methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

6-chloro-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

-methyl-14,17-ethano-19-norpregna-4-ene-3, 20-dione;

6,21-dimethyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

15,16-dimethyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

6-chloro-21-methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

16-methyl-14,17-ethano-19-norpregna-4-ene-3, 20-dione;

16-methyl-14,17-ethano-19-norpregna-4, 6-diene-3,20-dione;

16-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

16 ,21-dimethyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

21-hydroxy-16-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-ethyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-ethynyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-methyl-14,17-ethano-19-norpregna-4,15-diene-3,20-dione;

(171R)-171-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

(171S)-171-methyl-14,17-ethano-19-norpregna-4-ene-3,,17, ethano-19-norpregna-4,9-diene-3,20-dione;

(172R)-172-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

(172R)-172-methyl-14,17-ethano-19-norpregna-4,6-diene - 3,20-dione;

(172R)-172-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

(172)-172,21-dimethyl-14,17-ethano-19-norpregna-4,6-diene - 3,20-dione;

(172R)-172,21-dimethyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

(172R)-172,21-dimethyl-14,17-ethano-19-norpregna-4,9,11 - triene-3,20-dione;

16-methylene-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-methylene-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

16-methylene-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

21-hydroxy-14,17-ethano-19-norpregna-4-ene-3,20-dione;

21-hydroxy-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

21-hydroxy-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

21-hydroxy-14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione;

(21R)-21-hydroxy-21 - methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

(21S)-21-hydroxy-21-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

(21R)-21-hydroxy-21-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

(21S)-21-hydroxy-21-methyl-14,17-ethano-19-norpregna-4,9-diene - 3,20-dione;

(21R)-21-hydroxy-21-methyl-14,17-ethano-19-norpregna - 4,6-diene-3,20-dione;

(21S)-21-hydroxy-21-methyl-14,17-ethano-19 - norpregna-4,6-diene-3,20-dione;

(21R) -21-hydroxy-21-methyl-14,17-a,17 ethano-18a-Homo - 19-norpregna-4-ene-3,20-dione;

14,17-ethano-18a-Homo-19-norpregna-4,6 - diene-3,20-dione;

14,17-ethano-18a-Homo-19-norpregna-4,9-diene-3, 20-dione;

14,17-ethano-18a-Homo-19-norpregna-4,15-diene-3, 20-dione;

21-methyl-14,17-ethano-18a-Homo-19-norpregna-4-ene-3,20-dione;

21-methyl-14,17-ethano-18a-Homo-19-norpregna-4,6-diene-3,20-dione;

21-methyl-14,17-ethano-18a-Homo-19-norpregna-4,9-diene-3,20-dione;

(21R)-21-hydroxy-21-methyl-14,17-ethano-18a-Homo-19-norpregna-4-ene - 3,20-dione;

(21S)-21-hydroxy-21-methyl-14,17-ethano-18a-Homo-19 - norpregna-4-ene-3,20-dione;

(21R)-21-hydroxy-21-methyl-14,17-ethano - 18a-Homo-19-norpregna-4,9-ene-3,20-dione;

(21S)-21-hydroxy-21 - methyl-14,17-ethano-18a-Homo-19-norpregna-4,9-ene-3,20-dione;

(21R)-21-hydroxy-21-methyl-14,17-ethano-18a-Homo-19-norpregna-4,6-ene - 3,20-dione;

(21S)-21-hydroxy-21-methyl-14,17-ethano-18a-Homo-19 - norpregna-4,6-ene-3,20-dione;

In the test for binding of the receptor gestagen on gestagenna action, when using cytosol of homogenate from the uterus of the rabbit and3H-progesterone as a reference substance, the new compounds exhibit a very strong affinity for the gestagen receptor. In the test for conservation of pregnancy in rats proposed according to the invention compounds of General formula (I) show a very high gestagenna activity.

Compounds of General formula (I) also represent a connection, excluded from the scope of the compounds of General formula (I), already described A. J. Solo, and J. N. Kapoor in J. Med.Chem., 16, 270 (1973). This connection test on the transformation of the endometrium (the test Clauberg) exhibits good gestagenna action after subcutaneous injection, however, only a slight effect after the introduction of oral. According to the literary source factor between subcutaneous and oral action lies above 20.

In addition to the very high gestagenna activity in the test for continuation of the pregnancy, which for the most part even exceeds that excluded from the scope of formula (I) compounds proposed in the invention compounds of General formula (I), in contrast to the known connection 14,17-ethano-19-norpregna-4-ene-3,20-dione, however, for the most part after the introduction of oral show good gestagenna action. In the case of proposed according to the invention compounds of subcutaneous action differs from oral about 3-5 times. Proposed according to the invention compounds, therefore, differ from the known compounds 14, 17 ethano-19-norpregna-4-ene - 3,20-dione clearly improved spectrum of action.

On the basis of their high gestagenna activity new soy is for contraception. However, the new compounds can also be used in all other known today for gestagen the use cases.

Suitable dosages can be determined in the usual way, for example by determining bioequivalence with respect to well-known gestagen for a particular purpose, such as the number, which bioequivalence 30-150 μg levonorgestrel for contraception.

The dosage proposed according to the invention compounds in contraceptive preparations shall be preferably from 0.01 to 2 mg per day.

Gestagennoy estrogenic components of biologically active substances in contraceptive preparations are preferably administered together with oral. The daily dose is injected preferably once.

As estrogen is preferable to use a synthetic estrogen, as ethinylestradiol, 14,17-ethano-1,3,5(10)-estratrien-3,17-diol (international application 88/01275) or 14,17-ethano-1,3,5(10)-estratrien-3, 16,17-triol (international application 91/08219). Estrogen is administered in an amount which corresponds to 0.01-0.05 mg of ethinyl estradiol.

The new compounds of General formula (I) can also be used in preparations to treat ginekologicheskie the invention compounds are particularly well suited for the treatment of premenstrual ailments, such as headaches, depressive mood, water retention and mastodinia. The daily dose in the treatment of premenstrual ailments is about 1-20 mg

Finally, the new compounds can also be used as gestagenna components in the newly developed compositions for the control of female fertility, which are competitive antagonists of progesterone (H. B. Croxatto and A. M. Salvatierra in Female Contraception and Male Fertility Regulation, ed. Runnebaum, Rabe and Russ. name, volume 2, Advances in Gynecological and Obstetric Research Series, Parthenon Publishing Group -1991, S. 245).

Dosage lies already in the specified area; dosage form can be obtained as in the case of conventional OS-drugs. When you do this consistently, you can also enter additional, competitive antagonists of progesterone.

Dosage forms based on new connections get itself known due to the fact that the active substance, optionally in combination with estrogen, processed and transferred to the desired finished dosage form using conventional in galenical industry carriers, diluents, may improve the taste of the ingredients, etc.

For the preferred oral introduction the high application particularly suitable oil solutions, as, for example, solutions in sesame oil, castor oil and cottonseed oil. To improve the solubility can add agents dissolution, as, for example, benzyl benzoate or benzyl alcohol.

Compounds of General formula (I) can also be entered continuously due to intrauterine system release (IUD); the rate of release of active compounds (active compounds) are chosen so that daily disposable dose was the amount already in the specified area of the dosages.

Proposed according to the invention substances can also be entered in the transdermal system and thus to introduce them percutaneous.

First of all, to obtain the compounds of General formula (I) requires the parent compound synthesized according to scheme 1 synthesis pathway (see below).

According to scheme 1, for example, is in itself well-known compound of General formula (I) (see, for example, patent Germany 43 26 240 - 1) by attaching anion terminal alkyne can be translated in itself well-known compound of General formula (2). This connection by entering into interaction with the acid, such as sulfuric acid, hydrochloric acid, p-toluensulfonate, ant is tetrahydrofuran or dichloromethane, transferred in connection with the General formula (3) (see, for example, D. K. Phillips, P. P. Wickham, G. O. Potts and A. A. Arnold, J. Med.Chem., II, 924 (1968)). If desired, the compound of General formula (3) with the help of suitable nucleophiles, such as, for example, dialkylated compounds, with subsequent oxidation, for example, modified Saegusa-oxidation (see I. Minami and others, Tetrahedron, 42, 2971 (1986) or the European patent application 0299913), is converted into a compound of General formula (4), and then means an alkyl residue. Otherwise, means hydrogen.

The compound of General formula (4) then, using Atena under pressure and at elevated temperature under itself known methods cycloaddition can be converted into a compound of General formula (5). This compound is then the standard ways by hydrogenation of 171, 172- double bond (carbon atom 171accordingly 172denotes the carbon atom, which is the Deputy , respectively ) in the presence of a catalyst based on a noble metal, such as platinum or palladium, is transferred to the compound of General formula (6). Compounds of General formulas (5) and (6) in which R21means a hydrogen atom, can be alkilirovanii also according to standard methods, and so -C3)-alkyl group (see , for example, R. BIoch, Tetrahedron, 39, 639 (1983)). Compounds of General formula (5) can be detalizirovat standard methods to compounds of General formula (7), which in turn by Geri simulation can be converted into compounds of General formula (8). These compounds can also be obtained by in compounds of General formula (6). Thus instead of 1,2-atanderson(hydroxy)-protective group at the carbon atom 20 generally according to the invention is suitable also other well-known ketoamine groups, such as 2,2 - dimethyl-1,3-propanediylbis(hydroxy) group. Other protective groups which can be used in the present invention are described in the book "Protective groups in organic synthesis", Theodora W. Greene, Peter G. N. Wuts, ed. John Wiley and Sons, Inc., New York, 1991, S. 178-210.

Those compounds of General formulas (5) and (6) in which R13means ethyl group, and R21means a hydrogen atom or (C1-C3)-alkyl group, or R13means methyl group and R21means (C1-C3)-alkyl group, constitute the subject matter of this application as intermediate compounds of General formula (II):

< / BR>
where

R13means - C2H5; R21mean water3)-alkyl, and

and , independently of one another, mean hydrogen or (C1-C3)-alkyl;

and , each represent hydrogen or together form a bond.

All get by in compounds of General formulas (5), respectively (6) compounds of the General formulas (7) and (8) are new and also form the subject of the present invention, the intermediate compounds of General formula (III):

< / BR>
where

R13mean-CH3; -C2H5;

and independently of one another, mean hydrogen or (C1-C3)-alkyl;

and each represent hydrogen or together form a bond;

K means catalou protective group;

R21means hydrogen, (C1-C3)-alkyl.

According to scheme 2 (see the end of the description) the interaction of the compounds of General formula (4) with phenylenesulfonyl in inert solvents, also in itself known methods, leads to the compound of General formula (9) (J. R. Bull, and R. I. Thomson, S. Afr.J. Chem., 41, 87 (1991)). The recovery of this compound in the presence of metal as Raney Nickel or magnesium, in lower alcohols like methanol or ethanol, in turn, leads to compounds of General formulas (6) and (10), which by way of oxidation, respectively, vos is by using sodium borohydride or sociallyengaged, you can translate one into another.

Proposed according to the invention compounds that are substituted at positions 15 and/or 16, is produced by the interaction of the compounds of General formula (4) with suitable olefins, such as propene, 2-methylpropene, 2-butene, cyclopentene, cyclohexene or 2.5-dihydrofuran, and optionally, hydrogenation of the resulting 171, 172-double bond. Further transformations of the thus obtained compounds perform similarly to the further reaction of compounds of General formula (6).

To obtain proposed according to the invention compounds, which are in position 16 contain alkyl or alkanniny residue, the compound of General formula (4) also you can enter into interaction with the acrylic ester of the formula H2C=CH-Coolkid (where the alkyl means a (C1-C4)-alkyl) according to scheme 3 (see end of description).

The thus obtained compounds of General formula (II) once in ketogroup in position 20 and hydrogenation of the resulting 171, 172-double bond is converted into compounds of General formula (12), which by interaction with lithium - aluminohydrides can be turned into a 16-hydroxymethylene compounds of General formum., 46, 86 (1968)) can be translated into the corresponding 16-brometalia connection, which in terms of recovery Birju reduced to compounds with methyl group in position 16. It also restores the aromatic A-ring with the formation of 2,5 (10)-diene structure.

Compounds of General formula (13) by oxidation in itself known methods, for example, using pyridinediamine, can be transformed into the corresponding 16-aldehydes, which after interaction with the relevant phosphoramidate lead to proposed according to the invention compounds with alkenylphenol group at position 16, which in turn can be achieved by hydrogenation to translate in connection with the alkyl group in position 16.

16-Aldehydes by heating with arylhydrazines in itself known methods (see, for example, M. Pieper and others, Liebigs Ann.Chem., 1334 (1986)) can be translated in arylhydrazones that when processing bases in the sense of reaction Shapiro, respectively reaction Bamford-Stevens, split up to 16-eksootilisuse compounds. Alternative 16 - aldehydes by interacting with derivatives of sulfonic acids, such as, for example, galodamadruga sulphonic acids or anhydrides of sulfonic acids, rastvoritelyakh, as, for example, tetrahydrofuran, can be converted to esters of rolalbocaler, which in turn due to the recovery of cleavage, for example, by treatment with ammonium formate in the presence of catalytic amounts of a catalyst based on palladium(II), as, for example, acetate, palladium(II), in a suitable solvent, such as acetonitrile, turn in 16-eksootilisuse connection.

The compound of the General formula (11), (12) and (13) together with described in the text all derivatives are new and are the subject of the present invention as the intermediate compounds of General formula (IV):

< / BR>
where

R13means-CH3- 2H5;

R16means Coolkill, and alkyl is a (C1-C4)-alkyl residue, or-CH2HE, or CHO, or methylene;

and independently of one another, mean hydrogen or (C1-C3)-alkyl;

and , each represent hydrogen or together form a bond;

It means an oxygen atom or catalog protective group;

R21means hydrogen, (C1-C3)-alkyl.

Compounds of General formula (12) by alkaline hydrolysis can be converted to the corresponding carboxylic and acetate of copper(II) in toluene (see, for example, J. D. Bacha and J. K. Kochi, Tetrahedron, 24, 2215 (1968)) result derived from the 15,16-double bond.

14,17-C2- bridge derived from the 15,16-double bond are also other ways.

1. The interaction of compounds of General formula (4) with maleic anhydride in the formation of the product of the Diels-alder reaction followed by catalytic hydrogenation of the 171, 172-double bond, after heating with bystrogasjashchajasja Nickel in a suitable solvent, as diglyme, gives the corresponding derived from the 15,16-double bond (see, for example, K. Wiesner and others, Can. J. Chem., 52, 640 (1974)). Alternatively, based on the 171, 172-saturated anhydride using bases, such as aqueous sodium hydroxide solution, you can get 15,16-dicarboxylic acid, which through the double decarboxylation transferred to the appropriate derived from the 15,16-double bond (see , for example, S. M. Gimarusti and J. Wolinsky,J. Am.Chem.Soc., 90, 113 (1968)). For example, the dicarboxylic acid is heated with tetracetate lead in a suitable solvent, such as pyridine, at temperatures from 30 to 100oC.

Adduct Diels-alder reaction can also be used for the synthesis of other derivatives: restoring the product of the Diels-alder reaction to La is., 35, 3574 (1970)), oxidation of the resulting alcohol in the position 20, for example, using pyridinediamine and protection of the ketone as Catala after the restoration of the lactone by using suitable reducing agents, such as, for example, sociallyengaged leads to 15,16-bishydroxyethyl connection. Hydroxyl function, for example, in suitable conditions it is possible to condense to a simple cyclic ether. This condensation is preferably carried out in basic conditions, as, for example, by treatment with derivatives of sulfonic acids, as galodamadruga sulphonic acids or anhydrides of sulfonic acids, in the presence of bases, such as pyridine.

2. The interaction of compounds of General formula (4) with vinylnorbornene about the Diels-alder reaction with vinylnorbornene see, for example, Y. Shizuri, etc., J. Chem., Soc.,Chem. Commun., 292(1985); or G. H. Posnet and others,Tetrahedron Lett. 32, 5295 (1991)) by Diels-alder reaction according to scheme 4 (see below) leads to the product of the cycloaddition of the formula (14). After hydrogenation of the 171, 172-double bond with cleavage of cyclic carbonate by standard methods, such as the interaction of carbonate in a suitable solvent, such as methanol, with a base, such as, nab the gang.

For the conversion of vicinal diols into olefins specialist familiar with a number of commonly used methods (see for example, M. Ando, and other Chemistry Letters, 879 (1986)). For example, a diol of General formula (17) can enter into interaction with complex orthoevra, as, for example, triethylorthoformate, acid catalysis, for example, using pyridinedicarboxylate, in a suitable solvent, and as an example it should be called dichloromethane, or without solvent, to obtain the corresponding complex orthoevra, which when heated in a suitable solvent, as, for example, acetamiprid, into olefin of General formula (18).

Compounds of General formula 14, 15, 16, 17 and 18 together with described in the text all derivatives are new and are the subject of the present invention as the intermediate compounds of General formula (V):

< / BR>
where

R13means-CH3-C2H5;

R15and R16together form a cycle of partial formula:

< / BR>
< / BR>
or

< / BR>
where

where X and V are, independently from each other, each represent an oxygen atom or two hydrogen atoms; and

Rmmeans (C1-C3)-alkyl; or

R15and R16each as other, mean hydrogen or (C1-C3)-alkyl;

and each represent hydrogen or together form a bond;

It means an oxygen atom or catalog protective group;

R21means hydrogen or (C1-C3)-alkyl.

Other ways substitution in the D - ring 14, 17-C2-bridge steroids can be achieved, for example, based on the products of the Diels - alder reaction of the formula (19), we obtain due to the interaction of the diene of the General formula (4) with alkilany ether acetylanthranilic acid (alkyl means a (C1-C4)-alkyl) (scheme 5, see the end of the description).

Catalysate cycloaddition product of formula (19) leads to the compound of General formula (21). Selective recovery of 15,16-double bond is carried out using magnesium in a suitable solvent, preferably an alcohol, such as, for example, methanol, and obtain the connection formula (23), where R15then means a hydrogen atom. Reaction of 1,4-addition to compounds of the formula (21) exercise in itself known methods. For example, the interaction dimethylamide in a suitable solvent, such as tetrahydrofuran, gives compound of General formula (23), where R15then means methyl group. By kataliticheskogo stage, you cannot delete 171,127 - double bond. Ester function at the carbon in position 16 can be modified in various ways. Additionally to the already described for the implementation of the cycloaddition using alilovic esters of acrylic acid possibilities here should be mentioned the following:

, unsaturated esters, such as, for example, the compounds of the General formulas (23) and (24), after recovery using sociallyengaged, transferring the formed alcohol group to delete a group, such as ester Sul - facility, which, for example, obtained by the interaction with halogenerator sulfonic acids using suitable bases, such as pyridine, with or without an inert solvent, such as dichloromethane, and subsequent recovery by using suitable reducing agents, for example, as triethylborohydride lithium give derivatives with a methyl group in position 16.

, - unsaturated esters, such as, for example, the compounds of the General formulas (21) and (22), when treatment with suitable reducing agents, such as, for example, diisobutylaluminium, if necessary, using Lewis acids, such as zinc chloride, give 15,16-unsaturated 16 - the sulphonic acids, exercise in itself known methods. For example, allyl alcohol using acetylchloride in pyridine converted into the corresponding ester of acetic acid. Under the reaction conditions of Birha (Birch) then receive a corresponding 15,16-unsaturated derivative with a methyl group at position 16 (about recovery Birju of allylacetate see, for example, R. T. Jacbos and other J. Org.Chem., 55, 4051 (1990)). It also restores the A-ring with the formation of 2,5 (10)-diene structure.

Compounds of General formula(19), (20), (21), (22), (23) and (24) together with described in the text all derivatives are new and are the subject of the present invention as the intermediate compounds of General formula (VI):

< / BR>
where

R13means-CH3- 2H5;

R15and R16each represent hydrogen or together form a bond;

R15means hydrogen or (C1-C3)-alkyl;

R16means Coolkill, and alkyl is a (C1-C4)-alkyl residue, or CH2HE, or CHO, or (C1-C3)-alkyl residue;

and , independently of one another, mean hydrogen or a (C1-C3)-alkyl;

and , each represent hydrogen or together form SUB>-C3)-alkyl.

In the above compounds of formula (III), (IV), (V) and (VI) costs To, when it comes to Catalinas protective group, and means 1,2-atanderson(hydroxy) -, or 2,2-dimethyl-1,3-propanediyl-bis(hydroxy) group.

The restoration of the thus obtained compounds of the General formula(6), (7), (8) and (9), as well as the corresponding derivatives which are substituted in positions 15, 16, 171or 172that in itself known conditions recovery Birju (see, for example, J. Fried, J. A. Edwards, Organic reactions in the chemistry of steroids, Nostrand Reinhold Company, 1972, S. 1-60) leads to the corresponding 3 - methoxy - 2,5 (10)-derivative. By entering into interaction with diluted inorganic acids and, if necessary, subsequent oxidation of the 20-hydroxyl group by standard methods, such as using pyridinediamine, the above compounds can be turned into a 4-3-ketones of General formula (I). 3-Methoxy - 2,5 (10)-derivative, however, also be according to standard methods (see, for example, D. Burn, and V. Petrow, J. Chem.Soc., 364(1962)) can be transformed into a 5 (10)-3-ketones, which are synthesized by dihydrobromide and possible subsequent oxidation of the 20-hydroxyl group can be converted to a proposed according to the invention 4,9-3-ketones Catalysate 4,9-3-ketones standard methods leads to 5(10), 9 (11)-3-ketals, which in mild acidic conditions, for example, using an aqueous solution of acetic acid can be split up 5(10), 9(11)-3-ketones. Deconjugation 4,9-3-ketones can optionally also be accomplished by treatment with acids, such as aqueous hydrochloric acid, with the addition of a dissolving agent, such as acetone. Interaction obtained deconjugating of dienones with oxidizing agents (see, for example, patent Germany 2748250-2), as, for example, 2,3 - dichloro - 5,6-dicyano-p-benzoquinone, in a suitable solvent, such as dichloromethane, after you remove may still be available protective groups leads to 4,9,11-3-ketones of General formula (I).

The following stages are all rules of introduction of the residues R6, R6and R7. 6,7-Double bond is introduced via bromination simple dianalove ether and subsequent cleavage of bromovalerate (see for example, J. Fried, J. A. Edwards, Organic reactions in the chemistry of steroids Nostrand Reinhold Company, 1972, S. 265-374) or by interaction with chloranil or 2,3 - dichloro-5,6-dicyano-p-benzoquinone.

Bromination simple dianalove ether can be accomplished, for example, according to the methodology described in Steroids, I, 233 (1965). Removal bromoiodide spend putanyh solvents, as dimethylformamide, at temperatures of 50-150oC or, however, by the fact that 6-bromoaniline heated in collidine or lutidine.

For compounds with 6,7-methylene function of its introduction is carried out also on the basis of dienone due to the interaction with dimethylsulfoxide, and here, however, there is a mix - and-isomers (ratio depends on the used substrates and is approximately 1:1), which can be divided, for example, by column chromatography.

Compounds in which R7means alkyl, obtained from 4,6-Dien-3-ones by 1,6-addition according to known methods (J. Fried, J. A. Edwards, Organic reactions in the chemistry of steroids, Nostrand Reinhold Company, 1972, S. 75-82; A. Hosomi and H. Sakurai, J. Am.Chem. Soc., 99, 1673 (1977)). In this case, as a rule, the 7-alkyl function is injected with dialkyl-copper-lithium compounds.

Compounds in which R6means a chlorine atom, a R6and R7form General additional communication, are also based on 4,6-Dien-3-ones. For this purpose, first epoxidized 6,7-double bond in the application of organic nagkalat, as, for example, m-chlormadinone acid in dichloromethane, optionally in the presence of sodium hydrogen carbonate solution (see Inoi group exercise, for example, by introducing into the interaction with gaseous hydrogen chloride in glacial acetic acid (see, among other things, a patent application in Germany 11 58 966 and a patent application in Germany 40 06 165).

the 6-Methylene group can be entered, for example, based on 3-amino-3,5-diene derivative by introducing it into interaction with formalin in alcohol solutions in the formation of 6-hydroxymethylene group and subsequent removal of water under acidic conditions, for example, with a solution of hydrogen chloride in a mixture of dioxane and water. The removal of water, however, can also be implemented in such a way that first introduced the group that you want and then helps eliminate. As the deleted groups are suitable, for example, mesilate, toilet or benzoate (see patent application Germany 34 02 329, European patent application 150157, U.S. patent 4 584 288 (86); K. Nickisch, S. Beier, D. Bittler, W. EIger, H. Laurent, W. Losent, Y. Nishino, E. Schillinger, R. Wiechert, J. Med.Chem., 34, 2464 (1991)).

Another possibility of obtaining compounds with methylene group in position 6 is in direct interaction 4(5)- unsaturated 3-ketones with acetals of formaldehyde in the presence of sodium acetate, for example, using phosphorus oxychloride or pentachloride phosphorus in suitable solvents, such as chloroform (see , e.g shall her in making 4-3-ketone in a simple diagnolly ether, introduction in his interaction with dimethylformamide and phosphorus oxychloride to obtain aldehyde, and recovering the obtained aldehyde through a comprehensive borhydride with subsequent removal of water using inorganic acids in itself known methods (see international application 90/12027).

Connection with the methylene group in position 6 can be used to obtain the compounds of General formula (I) in which R6means methyl, a R6and R7together form an additional bond.

For this purpose, for example, described D. Burn, D. N. Kirk and V. Petrov in Tetrahedron, 21, 1619 (1965) method, according to which the isomerization of the double bond reached by heating compounds with a methylene group at position 6 in ethanol in the presence of 5% palladium-on-coal as a catalyst pre-treated with either hydrogen or by heating in a small amount of cyclohexene. The isomerization can be carried out using previously untreated catalyst if the reaction mixture is added a small amount of cyclohexene. The formation of minor amounts of hydrogenated products can be prevented due to the direct method (see, K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Liebigs Ann.Chem., 712 (1983)).

Compounds in which R6means-methyl function, can be obtained from the 6-methylene compounds by hydrogenation in a suitable environment. The best results (selective hydrogenation of the Exo-methylene function) reach through the transfer-hydrogenation (E. A. Brande, R. P. Linstead and P. W. D. Mitchell, J. Chem.Soc., 3578 (1954)). If 6-methylene derivative in a suitable solvent, such as ethanol, is heated in the presence of a hydrogen donor, such as, for example, cyclohexene, and catalyst based on a noble metal, such as platinum or palladium, you get very good outputs 6-methyl derivatives. Minor amounts of 6-methyl compounds can be isomerizate with acid (see, for example, D. Burn, D. N. Kirk, V. Petrow, Tetrahedron, 21, 1619 (1965)).

Alkylation of the 17-acetyl derivatives to homologous ketones can be done not only, as already described, when using compounds with aromatic A-ring, but also in the further course of the synthesis using suitable manner protected derivatives.

21-HE is the Deputy administered in a suitable way secured 20-catasetinae itself known methods such or turning enolate into the corresponding iodide, substitution of iodide acetate and hydrolysis of the acetate. Formed, if necessary, a mixture of diastereoisomers can be divided by chromatography.

After the introduction of all residues otscheplaut remaining protective groups in standard ways.

The compounds of General formula (I), where R3means oxygen, in a desirable way, by introducing into the interaction with hydroxylaminopurine in the presence of tertiary amines at temperatures between -20oC to +40oC, can be converted to the oxime (in General formula (I), where R3means N-OH, and a hydroxyl group can be in the SYN - or Antologiya).

The removal of the 3-carbonyl group to obtain the desired product of General formula (I), where R3means two hydrogen atoms can be carried out, for example, according to the methodology specified in the application for patent of Germany 2805490, by reductive cleavage of tickets.

The following examples serve for a closer explanation of the invention:

Example 1: 14,17-Ateno-19-norpregna-4-ene-3,20-dione

a) 3-Methoxy-19-norpregna-1,3,5(10),14,16-pentaen-20-he

84,2 g of 3-methoxy-19-nor-17-pregna-1,3,5(10), 15-tetraen-20-in-17-ol (J. Med. Chem. , 11, 924 (1968)) in 875 ml of 86% formic acid nausea precipitated solid is filtered off, dried and chromatographic on silica gel using mixtures of ethyl acetate with hexane. Get to 47.8 g of target compound 1 (a).

Melting point 152-155oC.

1H-NMR (deuterated chloroform (M. D.) = 1.22v (s, 3H, H-18); of 2.35 (s, 3H, H-21);of 3.78 (s, 3H, 3-och3);between 6.08 (m,1H,H-15); of 6.68 (d, J =3 Hz, 1H, H-4); 6,74 (DD, J=9,3 Hz, 1H, H-2); of 7.23 (d, J=9 Hz, 1H, H-1);7,27 (d, J 3 Hz, 1H, H-16).

b) 3-Methoxy-14,17-ateno-19-norpregna-1,3,5(10)-triene-20-he

A solution of 200 g described in example 1A) substances in 2.5 liters of benzene under pressure of ethylene to 300 bar heated for 240 hours at a temperature of 160oC. After cooling, the reaction mixture was concentrated and the residue chromatographic on silica gel using mixtures of ethyl acetate with hexane. Obtain 175 g of target compound 1B).

1H-NMR (deuterated chloroform) (M. D.)=0,91 (s, 3H, H-18); 2,22 (s, 3H, H-21); of 3.78 (s, 3H, 3-och3); 6,07 and 6.14 (2D, J = 6 Hz, 1H,H-171and H-172);of 6.65 (d, J = 3 Hz, 1H, H-4); of 6.73 (DD, J =9,3 Hz, 1H, H-2);7,22 (d, J = 9 Hz, 1H, H-1).

in) 20; 20[1,2-Atanderson (oxy)]-3-methoxy-14, 17-ateno-19 - norpregna-1,3,5 (10)-triene

To a solution of 25 g described in example 16) compounds in 175 ml of dichloromethane at room temperature and with stirring, add 75 ml of ethylene glycol, 63 ml of triethylorthoformate and 1.25 thrice washed with a concentrated solution of sodium bicarbonate. The organic phase is dried over potassium carbonate, filtered and concentrated. Obtain 31 g of target compound 1B).

1H-NMR (deuterated chloroform), (M. D.) = 0,98 (s, 3H, H-18); of 1.37 (s, 3H, H-21); of 3.78 (s, 3H, 3-och3); 3,95-of 4.05 (m,4H, 20-och2CH2O-); 5,97 and 6,01 (2D, J = 6 Hz, each 1H, H-171and H-172); of 6.65 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J = 9,3 Hz, 1H, H-2); 7,22 (d, J 9 Hz,1H, H-1).

g) 20,20-/1,2-Atanderson (hydroxy)/-3-methoxy-14,17-ateno-19 - norpregna-2,5(10)-Dien

For 2.2 l of liquid ammonia at -70oC add a solution of 31 g described in example 1B) compounds in a mixture of 400 ml of tetrahydrofuran and 70 ml of tert-butanol. To this mixture was added with stirring portions 16 g of lithium. Leave to warm to -40oC, after 5.5 hours added dropwise 350 ml of ethanol, then the mixture is left to warm to room temperature, diluted with water and extracted with ethyl acetate. The organic phase is washed with water and concentrated solution of sodium chloride, dried over sodium sulfate and concentrated in vacuo. Obtain 23.1 g of crystalline compound 1G), which without further purification enter into cooperation in the next stage.

1H-NMR (deuterated chloroform) (M. D.) = 0,96 (s, 3H, H-18); of 1.33 (s, 3H, H-21); 3,55 (with SUP>).

d) 14,17-Ateno-19-norpregna-4-ene-3,20-dione

A solution of 2.7 g described in example 1 g) compound in 30 ml of tetrahydrofuran and 150 ml of acetone with stirring, mixed with 7.8 ml of 4 n hydrochloric acid. Two hours later, the solvent is removed and the remainder will recrystallized from diisopropyl ether. Get 1,72 g of compound 1D). Melting point 139-143oC.

1H-NMR (deuterated chloroform): (M. D.)=0,92 (s, 3H, H-18); to 2.18 (s, 3H, H-21); 5,88 (ush.s, 1H, H-4); 6,04 (s, 2H, H-171and H-172).

Example 2: 14,17-Ateno-19-norpregna-4,6-diene-3,20-dione

a) 3-Ethoxy-14,17-ateno-19-norpregna-3,5-Dien-20-he

To a solution 2,02 g described in example 1D) compound in 80 ml of tetrahydrofuran was added with stirring to 6.1 ml of ethanol, 6,1 ml triethylphosphite and 145 mg of p-toluenesulfonic acid. After incubation for two hours at room temperature, add 2.5 ml of triethylamine, diluted with a solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic phase is washed with water and concentrated solution of sodium chloride, dried over sodium sulfate and concentrated. Gain of 3.3 g of compound 2A) as a colourless oil, which without further purification enter into cooperation in the next stage.

oC and under stirring with 890 mg of 1,3-dibromo-5,5-dimethylhydantoin. After 15 minutes the reaction mixture is poured into ice water and extracted with ethyl acetate. The organic phase is washed with concentrated sodium chloride solution, dried over sodium sulfate and filterout in a suspension of 2.4 g of lithium carbonate and 3.4 g of lithium bromide in 120 ml of dimethylformamide. The mixture is heated at 150oC during the distillation of ethyl acetate. After one hour, cooled, diluted the reaction mixture with water and extracted with ethyl acetate. The organic phase is washed with water and concentrated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The remainder chromatographic on silica gel using a mixture of n-hexane and ethyl acetate. Get 880 mg of compound 2B).

So pl. 150-152oC; []2D0= +172,3o(CHCl3; = 0,510).

1H-NMR (deuterated chloroform): (M. D.)=0,95 (s, 3H, H-18); are 2.19 (s, 3H, H-21); of 5.82 (ush.s, 1H, H-4); of 5.92 and 6,04 (2D, J = 6 Hz, each 1H, H-171and H-172); 6,20-6,32 (m, 2H, H-6 and H-7).

Example 3: 7-Methyl-14,17-ethano-19-norpregna-4-ene-3, 20-dione

A suspension of 1.9 g of copper iodide(I) in 25 ml of diethyl ether at 0oC dropwise mixed with 8.5 ml of a 1.6 M solution metallia in diethyl EFS was added dropwise to 1.23 ml epirate of boron TRIFLUORIDE and then was added dropwise a solution of 340 mg, described in example 2B) compound in 15 ml of tetrahydrofuran. Leave to heat up for 4 hours to room temperature, stirred for another 72 hours and the reaction mixture is poured into 100 ml of concentrated solution of ammonium chloride. The mixture is extracted four times with ethyl acetate, the combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated. After chromatography on silica gel using mixtures of ethyl acetate with hexane obtain 46 mg of compound 3).

So pl. 133-135oC.

1H-NMR (deuterated chloroform): (M. D.)= 0,94 (s, 3H, H-18); of 1.07 (d, J = 7.5 Hz, 3H, 7-CH3); of 2.20 (s, 3H, H - 21); of 5.83 (ush.s, 1H, H-4); 6,05 (s, 2H, H-171and H-172).

Example 4: 14, 17-Ateno-19-norpregna-4,9-diene-3,20-dione

a) 14, 17-Ateno-19-norpregna-5 (10)-ene-3,20-dione

To a suspension of 3.0 g described in example 1G) connection in 60 ml of acetone under stirring and at room temperature was added dropwise a solution of 2.1 g of oxalic acid dihydrate in 30 ml of water. After 2 hours, mixed with 150 ml of concentrated solution of sodium bicarbonate and extracted three times with ethyl acetate. The combined organic phases are washed with concentrated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The remainder chromatographer is 96-110oC; []2D0= +231,6o(CHCI3;- worn: 0.505)

1H-NMR (deuterated chloroform): (M. D.) = 1,03 (s, 3H, H-18); of 2.20 (s, 3H, H-21); 2,72 and 2.82 (ush. 2D, J = 20 Hz, each 1H, H-4); 6,04 and 6,10 (2D, J = 6 Hz, each 1H, H-171and H-172).

b) 14,17-Ateno-19-norpregna-4,9-diene-3,20-dione

A solution of 500 mg described in example 4A) connection 6.5 ml of pyridine with stirring, mixed with 530 mg pyridineboronic-perbromide, stirred for one hour at room temperature and then for another 2 hours at 50oC. After cooling, the reaction mixture is stirred in 20 ml of 6N hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are washed with water and concentrated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with hexane. Obtain 0.31 g of compound 4B).

So pl. 152-158oC; []2D0= -200o(CHCl3;= 0,496)

1H-NMR (deuterated chloroform); (M. D.) = 1,04 (s, 3H, H-18); of 2.20 (s, 3H, H-21); 5,72 (ush.s, 3H, H-4); 6,03 (s, 2H, H-171and H-172).

Example 5: 21-Hydroxy-14,17-ateno-19-norpregna-4-ene-3,20 - dione

(a) 3,3; 20,20-Bis[2,2-dimethyl-1,3-propanediylbis (oxy)]- 14,17-this is the type of 2.08 g of 2,2-DIMETHYLPROPANE-1,3-diol, 2,7 ml triethylorthoformate and 190 mg of p-toluenesulfonic acid. After 2 hours, mixed with 5 ml of triethylamine, diluted with ethyl acetate, washed five times with water and once with a concentrated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with hexane. Gain of 3.85 g of compound 5A) in the form of foam.

1H-NMR (deuterated chloroform): (M. D.) = 0,72;0,88; to 0.94;1.07 and 1,19(5s, 15H, ketal-CH3and H-18);of 1.43(s, 3H, H-21); 3,17-of 3.78 (m, 8H, ketal-OCH2);5,88 and 5,95 (2D, J = 6 Hz, each 1H, H-171and H-172).

b) 3,3-[2,2-Dimethyl-1,3-propanediylbis(oxy)]-14,17-ateno-19 - norpregna-5(10)-ene-20-he

A solution of 3.85 g described in example 5A) compound in 50 ml of dichloromethane is mixed with 11 g of silica gel (0,063-0.2 mm) and 1.1 ml of aqueous concentrated solution of oxalic acid and intensively stirred for 30 minutes. Add 100 ml of 1N solution of sodium hydroxide and 100 ml of dichloromethane, stirred for five minutes, allowed to settle, filtered, the residue washed with dichloromethane, washed the combined organic phases are concentrated solution of sodium chloride, dried over sodium sulfate, filtered and soedineniya 5B) in the form of a foam

1H-NMR (deuterated chloroform): (M. D.) = of 0.85 and 0.88 (-s, 6H, ketal-CH3); a 1.08 (s, 3H, H-18);to 2.18 (s, 3H, H-21);3,42 - 3,70 (m, 4H, ketal-OCH2); 5,98 and 6,07(2D, J = 6 Hz, each 1H, H-171and H-172).

C) 3,3-/2,2-Dimethyl-1,3-propanediylbis (hydroxy)/-21-iodine-14,17 - ateno-19-norpregna-5(10)-ene-20-he

To a solution of 1.9 ml of N-cyclohexylhydroxylamine in 10 ml of tetrahydrofuran at -40oC was added dropwise to 3.9 ml of a 1.6 M solution of n-utility in hexane. After stirring for 15 minutes, was added dropwise a solution of 1.93 g described in example 5B) of the substance in 15 ml of tetrahydrofuran. After stirring for 30 minutes at -30oC the solution is cooled to -50oC and then through a Teflon tube pump cooled to -50oC solution of 1.37 g of iodine in 10 ml of tetrahydrofuran. The reaction mixture for two hours, warmed to room temperature, then poured into a concentrated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed with concentrated sodium thiosulfate solution and a concentrated solution of sodium bicarbonate, dried over sodium sulfate and concentrated. Obtain 2.6 g of compound 5B) in the form of a light yellow resin, which without further purification enter in entries batch is with, 3H, H-18); 3,42-3,70(m, 4H, ketal-OCH2); 3.90 and 3,99 (2D, J = 12 Hz, each 1H, H-21); 6,07-6,18 (m, 2H, H-171and H-172).

g) 21-(atomic charges)-3,3-[2,2-dimethyl-1,3-propanediylbis (oxy)]-14,17-ateno-19-norpregna-5(10)-ene-20-he

A solution of 2.6 g described in example 5B) of the substance in 10 ml of dimethylformamide is mixed with 4.9 g of potassium acetate, stirred for 80 minutes at a temperature of 80oC, after cooling, poured into water and extracted with ethyl acetate. The organic phase is washed with concentrated sodium chloride solution, dried over sodium sulfate and concentrated. Get 1,99 g of compound 5g) as a colourless resin, which without further purification enter into cooperation in the next stage.

1H-NMR (deuterated chloroform): (M. D.) = 0,88 (s,6H, ketal-CH3); a 1.08 (s, 3H, H-18); 2,17 (s, 3H, atomic charges-CH3); 3,42 - and 3.72 (m, 4H, ketal-OCH2); 4,67 and 4,85 (2D, J = 15 Hz, each 1H, H-21);5.99 and 6,12 (2D, J = 6 Hz,each 1H, H-171and H-172).

d) 21(atomic charges)-14,17-ateno-19-norpregna-5(10)-ene-3,20-dione

A solution of 1.99 g described in example 5g) substance in 10 ml of tetrahydrofuran is mixed with 100 ml of 70% acetic acid and stirred for 60 minutes at room temperature and then for 60 minutes at a temperature of 40oC. Reactio the United organic phases are washed with a concentrated solution of sodium chloride, dried over sodium sulfate and concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with hexane. Get to 1.15 g of compound 5D).

So pl. 126-128oC []2D0= 199,6o(CHCl3); from = 0,500.

1H-NMR (deuterated chloroform): (M. D.) or = 0.90 (s, 3H, H-18); to 2.18 (s, 3H, atomic charges-CH3); 4,67 and 4,84 (2D, J = 16 Hz, each 1H, H-21); 6,02 and 6.14(2D, J = 6 Hz, each 1H, H-171and H-172).

e) 21-(atomic charges) -14,17-ateno-19-norpregna-4-ene-3,20-dione

A solution of 500 mg described in example 5D) substances in 25 ml of acetone is mixed with 1 ml of 4n hydrochloric acid, stirred for 30 minutes at room temperature and then concentrated to dryness. Receive 500 mg of compound 5e) in the form of foam, which without further purification enter into cooperation in the next stage.

1H-NMR (deuterated chloroform): (M. D. ) = 0,93 (s, 3H, H-18); to 2.18(s, 3H, acetoacet-CH3); 4,68 and a 4.83 (2D, J = 16 Hz, each 1H, H-21); 5,86 (ush.s, 1H, H-4); 6,02 and 6,10 (2D, J = 6 Hz, each 1H, H-171and H-172).

W) 21-Hydroxy-14,17-ateno-19-norpregna-4-ene-3,20-dione

A solution of 500 mg described in example 5e) substances in 15 ml of methanol is mixed with 1.8 ml of 10% aqueous potassium carbonate solution, stirred for 30 minutes primidi with ethyl acetate, the combined organic phases are washed with concentrated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with hexane. Obtain 282 mg of the compound I).

So pl. 160-163oC; []2D0= +162,3o(CHCl3; = 0,510).

1H-NMR (deuterated chloroform): (M. D.) = 0,95 (s, 3H, H-18); of 3.32( T, J = 5 Hz, 1H, HE); 4,23 and 4,42 (DD, J = 16 Hz and 5 Hz, each 1H, H-21); by 5.87(ush.s, 1H, H-4); by 5.87 and 6,10 (2D, J = 6 Hz, each 1H, H-171and H-172).

Example 6: 21-Hydroxy-14,17-ateno-19-norpregna-4,9-diene - 3,20-dione

a) 21-(atomic charges)-14,17-ateno-19-norpregna-4,9-diene-3,20-dione

540 mg, Described in example 5D) substances injected into the interaction as described in example 4B) technique. Get 292 mg of compound 6A).

So pl. 182-184oC; []2D0= -106,6o(CHCl3C = 0,495).

1H-NMR (deuterated chloroform): (M. D.) = 1,04 (s, 3H, H-18); are 2.19 (s, 3H, atomic charges-CH3); 4,69 and a 4.83 (2D, J = 16 Hz, each 1H, H-21); 5,72(ush.s, 1H, H-4); 6,02 and 6,10 (2D, J = 6 Hz,each 1H, H-171and H-172).

b) 21-Hydroxy-14,17-ateno-19 - norpregna-4,9-diene-3,20-dione

270 mg, Described in example BA) substances injected into the>C; []2D0= -171,4o(CHCl3; = worn: 0.505).

1H-NMR (deuterated chloroform): (M. D.) = 1,04 (s, 3H, H-18);3,33 (ush.s, 1H, HE); 4,24 and 4,43 (ush. 2D, J = 16 Hz, each 1H, H-21); 5,72 (ush. s, 1H, H-4); 5,95 and 6,10 (2D, J = 6 Hz, each 1H, H-171and H-172).

Example 7: 21-Methyl-14,17-ateno-19-norpregna-4-ene-3,20 - dione

a) 3-Methoxy-21-methyl-14, 17-ateno-19-norpregna-1,3,5 (10) - triene-20-he

To a solution of 1.5 ml of Diisopropylamine in 15 ml of tetrahydrofuran at -20oC was added dropwise and 6.6 ml of a 1.6 M solution of n-utility in hexane, and then stirred for further 30 minutes at 0oC, and then added dropwise at a temperature of -30oC solution of 2.4 g described in example 1B) substances and 0.78 ml of 1,3 - dimethylimidazole-2-it in 46 ml of tetrahydrofuran and stirred for further 30 minutes at -30oC. and Then added dropwise to 0.66 ml under the conditions and heated to 0oC. the Reaction mixture contribute with stirring to a concentrated solution of ammonium chloride, diluted with water, extracted three times with ethyl acetate, the combined organic phases are washed with concentrated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is crystallized from diisopropyl ether. Get 2,12 g of compound 7a).

So pl. 94o): (m D. ) = 0,89 (s, 3H, H-18); a 1.08(T, J = 7.5 Hz, 3H, H-22); 3,79 (s, 3H, 3-och3); 6,05 and 6,12 (2D, J = 6 Hz, each 1H, H-171and H-172); only 6.64 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J = 9,3 Hz, 1H, H-2); 7,22 (d, J = 9 Hz, 1H, H-1).

b) 21-Methyl-14,17-ateno-19-norpregna-4-EN-20-ol-3-one

1.9 grams Described in example 7a) substances injected into the interaction as described in example 1G) method. The crude product chromatographic on silica gel using mixtures of ethyl acetate with hexane. Receive 750 mg of the intermediate product, which transform as described in example 1D) technique. After chromatography on silica gel using mixtures of ethyl acetate with hexane obtain 317 mg of compound 7b).

1H-NMR(deuterated chloroform): (M. D.)=0,89 (0,92) (s, 3H, H-18); 1,05(1,03), (t, J = 7.5 Hz, 3H, H-22); 3,70(DD, J = 8 and 3 Hz ,1H, H-20); of 5.83(5,85)(ush. s, 1H, H-4);of 5.89 and 5,94 (5,96 and 6,02)(2a,J = 6 Hz, each 1H, H-171and H-172) (signals of the second diastereoisomer shown in brackets).

in) 21-Methyl-14, 17-ateno-19 - norpregna-4-ene-3, 20-dione

To a suspension 1,67 r pyridinediamine in 15 ml of dimethylformamide was added with stirring a solution of 300 mg described in example 76) compound in 40 ml of dichloromethane. The mixture is stirred for one hour at room temperature, then mixed with 50 ml of ethyl acetate, stirred next Coram sodium chloride, dried over sodium sulfate, filtered and concentrated. The residue is purified by high performance liquid chromatography (HPLC). Receive 100 mg of compound 7b).

So pl. 140-149oC;[]2D0= +147,0oC (CHCl3; = 0,510)

1H-NMR (deuterated chloroform): (M. D.) or=0.90 (s, 3H, H-18); Of 1.06 (T, J = 7.5 Hz, 3H, H-22); 5,86(ush.s, 1H, H-4);of 6.02(s,2H,H-171and H-172).

Example 8: 21-Methyl-14,17-ateno-19-norpregna-4,9-diene-3,20 - dione

a) 20,20-/1,2-Atanderson(hydroxy)/-3-methoxy-31-methyl-14,17 - ateno-19-norpregna-1,3,5(10)-triene

To a solution of 21.3 g described in example 7a) compound in 250 ml of toluene at room temperature and with stirring, add 62 ml of ethylene glycol, 52 ml of triethylorthoformate and 1.0 g of p-toluenesulfonic acid. Heated for 8 hours

at a temperature of 60oC. After cooling, add 15 ml of triethylamine and 250 ml of ethyl acetate and the mixture is washed three times with concentrated solution of sodium bicarbonate. The organic phase is dried over potassium carbonate, filtered and concentrated. Obtain 27 g of compound 8A), which without further purification enter into cooperation in the next stage.

1H-NMR (deuterated chloroform): (M. D.)= 0,94 (t, J = 7.5 Hz, 3H, H-22); 0,96(�4); 6,72(DD, J = 9,3 Hz, 1H, H-2); 7,21(d, J = 9 Hz, 1H, H-1).

b) 20,20-/1,2-Atanderson(hydroxy)/-3-methoxy-21-methyl-14, 17-ateno-19-norpregna-2,5(10)-Dien

27 g Described in example 8A) substances injected into the interaction as described in example 1G) method. Get to 18.9 g of compound 8b).

1H-NMR (deuterated chloroform): (m DV = 0,93 (t, J = 7.5 Hz, 3H, H-22); of 0.95 (s, 3H, H-18); of 3.56 (s, 3H, 3-OCH3); 3,93-4,10 (m, 4H, 20-och2CH2-O-); 4,62-of 4.67 (m, 1H, H-2); of 5.92 (s, 2H, H-171and H-172).

in) 20,20-[1,2-Atanderson(oxy)] -21-methyl-14,17 - ateno-19-norpregna-5(10)-EN-3-one

A solution of 18.2 g described in example 8b) substances in 700 ml of tetrahydrofuran with stirring, mixed with 250 ml of concentrated solution of ammonium chloride and 18 ml of concentrated solution of oxalic acid and stirred for 6 hours. Then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with concentrated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with hexane. Gain of 11.0 g of compound 8b) in the form of foam.

[]2D0= +169,6o(CHCl3; = 0,510)

1H-NMR (date the/SUB>CH2O-); by 5.87 is 5.98 (m,2H, H-171and H-172).

g) 21-Methyl-14,17-ateno-19-norpregna-4,9-diene-3,20-dione

11 g Described in example 8b) substances transform as described in example 4B) technique. Obtain 3.75 g of compound 8D)

So pl. 145-146oC; []2D0= -180,1o(CHCl3; = 0,510)

1H-NMR (deuterated chloroform): (M. D.) = 1,03(s,3H,H-18); a 1.08 (t, J= 7.5 Hz,3H,H-22);5,72(ush.s,3H,H-4);6,03(s, H-171and H-172).

Example 9: 21-Methyl-14,17-ateno-19-norpregna-4,9,11-triene - 3,20-dione

(a) 3,3-/2,2-Dimethyl-1,3-propanediylbis(hydroxy)/-21 - methyl-14,17-ateno-19-norpregna-5(10),9(11)-Dien-20-he

To a solution of 3.5 g described in example 8D) compound in 30 ml of dichloromethane with stirring 2,87 g of 2,2 - DIMETHYLPROPANE-1,3-diol, 1,4 ml triethylorthoformate and 100 mg p-toluenesulfonic acid. After 3 hours, diluted with dichloromethane, washed with water and concentrated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with hexane. Gain of 3.84 g of compound 9a) in the form of foam.

1H-NMR (deuterated chloroform); (M. D.) = 0,82 (2s, 6H, ketal-CH3); 1,09 (s, 3H, H-18);of 1.09 (t, J = 7.5 Hz, 3H, H-22); 3,42-to 3.52 (m, 2H, ketal-OCH

b) 21-Methyl-14,17-ateno-19-norpregna-5(10), 9(11)-the diene-3,20-dione

500 mg Described in example 9a) connection using ultrasound dissolved in 25 ml of 70% acetic acid and 5 ml of tetrahydrofuran and then stirred for 4 hours at room temperature. Thereafter, under stirring, neutralized with a concentrated solution of sodium bicarbonate, extract three times with ethyl acetate, the combined organic phases are washed with concentrated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Obtain 480 mg of compound 9b), which without further purification enter into cooperation in the next stage.

1H-NMR (deuterated chloroform): (M. D.) = 0,87 (s, 3H, H-18); a 1.08 (t,J = 7.5 Hz, 3H, H-22); 2.91 in(ush.s, 2H, H-4); of 5.53-the ceiling of 5.60 (m, 1H, H-11); 6,07 and 6,13 (2D, J = 6 Hz, each 1H, H-171and H-172).

in) 21-Methyl-14,17-ateno-19-norpregna-4,9,11-triene-3,20-dione

480 mg) Described in example 9b) compounds dissolved in 40 ml dichloromethane and mixed with 600 mg of 2,3-dichloro-5,6-dicyan-p-benzoquinone. Stirred for 4 hours at room temperature, filtered, the filtrate is washed with a concentrated solution of sodium bicarbonate, concentrated solution of sodium thiosulfate and again concentrated togetherbut on silica gel using mixtures of ethyl acetate with cyclohexane. Obtain 206 mg of compound 9b).

So pl. 117-119oC;

[]2D0= -278,8o(CHCl3With = 0,500).

1H-NMR (deuterated chloroform): (M. D.) = 0,97 (s, 3H, H-18); a 1.11 (t, J = 7.5 Hz, 3H, H-22); 5,80 (ush.s, 3H, H-4); 5.99 and between 6.08 (2D, J = 6 Hz, each 1H, H-171and H-172); 6,04 (d, J = 12 Hz, 1H, H-11) 6,44 (d, J = 12 Hz, 1H, H-12).

Example 10: 171-Methyl-14,17-ateno-19-norpregna-4-ene-3,20 - dione

a) 3-Methoxy-16-methyl-19-norpregna-1,3,5(10),14,16-pentaen-20-o

A suspension of 15.2 g of copper iodide-(1) in 50 ml of diethyl ether at 0oC dropwise mixed with 90 ml of a 1.6 M solution of methyl lithium in diethyl ether. After stirring for 30 minutes at -70oC was added dropwise 12 ml of triethylamine and then 11 ml of trimethylchlorosilane. Then was added dropwise a solution of 15 g described in example 1A) compounds in 220 ml of tetrahydrofuran. Stirred for further 2 hours at -70oC, then add 100 ml of concentrated solution of ammonium chloride, allowed to warm to room temperature, shaken with 400 ml of ethyl acetate, filtered off the solid components and the aqueous phase extracted again with ethyl acetate. The combined organic phases are washed four times policecontributing solution of ammonium chloride, dried over sulfate h the solution was added to 10.9 g of palladium acetate-(II) and heated for 20 hours at 80oC. After cooling, add 400 ml of ethyl acetate, filtered under vacuum through celite and concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with n-hexane. Get to 5.03 g of compound 10A).

So pl. 166-167oC;

[]2D0= +459,2o(CHCl3; = worn: 0.505).

1H-NMR (deuterated chloroform): (M. D.) = 1.22v (s, 3H, H-18); is 2.37 and 2.40 a (2s, 6H, 16-CH3and H-21); of 3.80 (s, 3H, 3-och3); of 5.92 (d, J = 2 Hz, 1H, H-15); of 6.68 (d, J = 3 Hz, 1H, H-4); to 6.75 (DD, J= 9,3 Hz, 1H, H-2); to 7.25(d, J=9 Hz, 1H, H-1).

b) 3-Methoxy-171-methyl-14,17-ateno-19-norpregna - 1,3,5(10)-triene-20-he

5.0 g Described in example 10A) make connections as described in example 1B) technique. Get to 3.38 g of compound 10B) in the form of foam.

1H-NMR (deuterated chloroform): (M. D.)= 0,85 (s, 3H, H-18); 1,74 (ush. s, 171-CH3); of 2.20 (s, 3H, H-21); 3,79 (s, 3H, 3-OCH3); 5,67 (ush.S., H-172); 6,66 (d, J = 3 Hz, 1H, H-4); of 6.73 (DD, J = 9,3 Hz, 1H, H-2); 7,22 (d, J 9 Hz, 1H, H-1).

in) 171-Methyl-14,17-ateno-19-norpregna-4-ene-3,20-dione

500 mg Described in example 10B) make connections as described in examples 1C), 1D) and 1D) methods. Obtain 344 mg of compound 10B).

So pl. 137oC; []2D0= +109,6o(CHCl2); of 5.84 (ush.s, 1H, H-4).

Example 11: 171-Methyl-14,17-ateno-19-norpregna-4,6-diene - 3,20-dione

250 mg Described in example 10B) make connections as described in examples 2A and 2B) methods. Obtain 102 mg of compound (11). So pl. 132-136oC.

1H-NMR (deuterated chloroform): (M. D.)= 0,89 (s, 3H, H-18); 1.69 in (ush.s, 171-CH3); 2,17 (s, 3H, H-21); 5,47 (ush.s, 1H, H-172); 5,80 (ush.s, 1H, H-4); 6,17-6,30 (m, 2H, H-6 and H - 7)

Example 12: (171R)-171-Methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione

a) 3-Meixi-171-methyl-14,17-ethano-19-norpregna-1,3,5(10)-triene-20-he

2,75 Described in example 10B connection with shaking dissolved in 125 ml of tetrahydrofuran. Add 765 mg of 10% palladium-on-charcoal, in the apparatus of the injected hydrogen and shaken until the cessation of hydrogen absorption. After filtering the solution through celite, the filtrate was concentrated in vacuo. Receive 2.9 g of compound 12 in the form of foam.

1H-NMR (deuterated chloroform): (M. D.) = 0,88 (0,92),(C, 3H, H-18) 0,99 (1,10) (d, J=7.5 Hz, 3H, 171-CH3); 2,08 (2,11) (c, 3H, H-21), 3,78 (c, 3H, 3-OCH3), 6,62 (d, J=3 Hz, 1H, H-4); 6.73 x DD, J=9,3 Hz, 1H, H-2); 7,22 (d, J=9 Hz, 1H, H-1) (signals of the second diastereoisomer shown in brackets).

b) (71R)-171-Methyl-1m in examples 1B), 1G) and 8b) methods. Obtain 209 mg of compound 12B), 310 mg of both C-171-epimeres 20,20-/1,2-atanderson(hydroxy)/-171-methyl-14,17-ethano-19-norpregna - 4-EN-3-one mixture with (171S)-171-methyl-14,17-ethano-19-norpregna-5(10)-ene-3,20 - dione and of 1.36 g both C-171-epimeres 20,20-/1,2-atanderson(hydroxy)/-171-methyl-14,17-ethano-19-norpregna-5(10) -EN-3-one

1H-NMR(deuteromony chloroform): (M. D.) or = 0.90 (c, 3H, H-18); of 1.07 (d, J = 7.5 Hz, 3H, 171-CH3); to 2.06 (c, 3H, H-21).

in) (171R)-171-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione 190 mg of compound 12B) transform as described in example 1D) technique. Obtain 105 mg of compound 12B).

1H-NMR (deuterated chloroform): (M. D.)= 0,95 (s,3H,H-18); of 1.05 (d, J = 7.5 Hz, 3H, 171-CH3); 2,07 (s, 3H, H-21); 5,81 (ush.s, 1H, H-4).

Example 13: (171S)-171-Methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione

300 mg Described in example 12B) a mixture of both C-171-epimeres 20,20-/1, 2-atanderson(hydroxy)/-171-methyl-14,17 - ethano-19-NOC-regn-4-EN-3-one (171S)-171-methyl-14,17-ethano-19 - norpregna-5(10)-ene-3,20-dione is administered in the interaction as described in example 1D) technique. Obtain 77 mg of compound 12B) and 122 mg of compound 13).

1H-NMR (deuterated chloroform): (M. D.) = 0"ptx2">

Examples 14 and 15:

14:(171R)-Methyl-14,17-ethano-19-norpregna-4,9-diene - 3,20-dione

15:(171S)-171-Methyl-14,17-ethano-19-norpregna-4,9-diene - 3,20 - dione

1.30 grams Described in example 12B) a mixture of both C-171- epimeres 20,20-/1,2-atanderson(hydroxy)/-171-methyl-14,17 - ethano-19-nor-pregn-5(10)-EN-3-it is injected into the interaction as described in examples 4B) and 1D) methods. Receive 200 mg of compound 14) and 120 mg of compound 15).

14):

1H-NMR (deuterated chloroform): (M. D.)= 1,04 (s,3H, H-18); of 1.06 (d, J = 7.5 Hz, 3H, 171-CH3); 2,07 (s, 3H, H-21); 5,65 (ush.s, 1H, H-4).

15):

1H-NMR (deuterated chloroform): (M. D.)= 0,76 (DD, J = 5 Hz and 12 Hz, 1H, H-172); of 0.95 (d, J = 7.5 Hz, 3H, 171-CH3); a 1.01 (s, 3H, H-18); of 2.09 (s, 3H, H-21); 5,66 (ush.s, 1H, H-4).

Example 16: 14, 17 Ethano-19-norpregna-4, 9-diene-3, 20-dione

a) 3-Methoxy-16-phenylsulfonyl-14,17-ateno-19-norpregna - 1,3,5(10)-triene-20-he

The mixture of 14.7 g described in example 1A) substances and 24.0 g of phenylenesulfonyl in 100 ml of benzene is heated for 10 days at a temperature of 155oC. After cooling, the reaction mixture was concentrated and the residue chromatographic on silica gel using first dichloromethane and then with a mixture of ethyl acetate with hexane. Obtain 14.9 g of compound 1, H, 3-OCH3); 4,58 (DD, J=8,4 Hz, 1H, H-16); 6,48 and 6.50 (2D, J= 5 Hz, each 1H, H-171and H-172); only 6.64 (d, J= 3 Hz, 1H, H-4); 6,72 (DD, J= 9,3 Hz, 1H, H-2); to 7.18 (d, J= 9 Hz, 1H, H-1); 7,52-7,87 (m, 5H, SO2C6H5).

b) 3-Methoxy-14,17-ethano-19-norpregna-1,3,5(10)-trien - 20-ol

120 g of Anhydrous Raney Nickel washed repeatedly with ethanol and finally suspended in 900 ml of ethanol. To this suspension add 6,95 g described in example 16A) substances and for 16 hours refluxed. After cooling, the Raney Nickel is removed by decanting the reaction mixture, optionally washed repeatedly with ethanol and the combined organic phases are concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with cyclohexane. Obtain 1.40 g of 3-methoxy - 14,17-ethano-19-norpregna-1,3,5 (10)-triene-20-she's so square 140-142oC and 2.70 g of compound 16B). So pl. 90-100oC.

1H-NMR (deuterated chloroform): (M. D.)= to 0.88 and 0.92 (2s, 3H, H-18); and 1,12 1,18 (2D, J = 6 Hz, 3H, H-21); of 3.78 (s, 3H, 3-OCH3); 3,95 (K, J= 6 Hz, 1H, H - 20); 6,63 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J= 9,3 Hz, 1H, H-2); 7,21 (d, J= 9 Hz, 1H, H-1).

b) 3-Methoxy-14,17-ethano-19-norpregna-2,5(10)-Dien-20-ol

5.50 g Described in example 16B) make connections as described in example 1G) method. Get 5.50 g is 21); 3,55 (s, 3H, 3-OCH3); a 3.87-3,98 (m, 1H, H-20); the 4.65 (m, 1H, H-2).

g) 14,17-Ethano-19-norpregna-5(10)-EN-20-ol-3-one

1.70 g Described in example 16B) make connections as described in example 4A) technique. Get 0,80 g of compound 16 g). So pl. 103-117oC.

1H-NMR (deuterated chloroform): (M. D.) = of 0.87 and 0.90 (2s, 3H, H-18); 1.11 and of 1.16 (2D, J = 6 Hz, 3H, H-21); 2.69 and 2,78 (2D, J = 20 Hz, each 1H, H-4); 3,85-3,98 (m,1H, H-20).

d) 14, 17 Ethano-19-norpregna-4,9-Dien-20-ol-3-one

To a solution of 0.16 ml of bromine in 10 ml of pyridine under ice cooling and with stirring was added dropwise a solution of 0.80 g described in example 16 g) compound in 10 ml of pyridine. After 3 hours the reaction mixture was poured into 2n hydrochloric acid and establish a pH value of 4-5. Extracted with ethyl acetate, the organic phase is washed with water and concentrated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. The remainder chromatographic on silica gel using mixtures of ethyl acetate with hexane. Get to 0.22 g of compound 16 d).

1H-NMR (deuterated chloroform): (M. D.)= a 1.01 and 1.07 (2s, 3H, H-18); of 1.12 and 1.15 (2D, J= 6 Hz, 3H, H-21); 3,88-4,00 (m, 1H, H-20); 5,67 (ush. s, 1H, H-4).

e) 14,17-Ethano-19-norpregna-4,9-diene-3,20-dione

To a solution of 220 mg described in example 16 d) the hours at room temperature and then filtered. The filtrate is concentrated and the residue chromatographic on silica gel using mixtures of ethyl acetate with hexane. Obtain 130 mg of the compound e) in the form of foam.

[]2D0= -255,3o(CHCl3;- 0,600).

1H-NMR (deuterated chloroform): (M. D.) = 1,04 (s, 3H, H-18); a 2.12 (s, 3H, H-21); 5,67 (ush.s, 3H, H-4).

Example 17: 14,17-Ethano-19-norpregna-4,6-diene-3,20-dione

a) 14,17-Ethano-19-norpregna-4-ene-3,20-dione

5.50 g Described in example 16B) make connections as described in examples 1D) and e) methods. Get 2,80 g of compound 17A). So pl. 140 - 145oC;

[]2D0= +67,6o(CHCl3; = 0,550).

1H-NMR (deuterated chloroform): (M. D.) = 0,94 (s, 3H, H-18); 2,10 (C, H-21); of 5.83 (ush.s, 1H, H-4).

b) 14,17-Ethano-19 - norpregna-4,6-diene-3, 20-dione

326 mg, Described in example 17A) make connections as described in examples 2A) and (26) methods. Receive 160 mg of compound 17B). So pl. 126-132oC;. []2D0= +31,8o(CHCl3; = 0,575).

1H-NMR (deuterated chloroform): (M. D.)= 0,96 (s, 3H, H-18); 2,11 (s, 3H, H-21); 5,78 (ush.s, 1H, H-4); 6,14-6,23 (m, 2H, H-6 and H-7).

Example 18: 21-Methyl-14,17-Ethano-19-norpregna-4-ene-3, 20-dione

a) 3-Methoxy-21-methyl-14,17-ethano-19-norpregna dobavlaut 13 g of 10% palladium-on-charcoal, placed in the apparatus with the atmosphere of hydrogen and shaken until the cessation of hydrogen absorption. After filtering the solution through celite, the filtrate concentrated. After crystallization from ethyl acetate to obtain 129 g of compound 18a). So pl. 146-147oC;

[]2D0= +66,7o(CHCl3; = 0,490)

1H-NMR (deuterated chloroform): (M. D.) or = 0.90 (s, 3H, H-18); of 2.23 (s, 3H, H-21); of 3.78 (s, 3H, 3-OCH3); 6,63 (d, J= 3 Hz, 1H, H-4); of 6.73 (DD, J = 9,3 Hz, 1H, H-2); 7,22 (d, J = 9 Hz, 1H, H-1).

b) 3-Methoxy-21-methyl-14,17-ethano-19-norpregna - 1,3,5(10)-triene-20-he

5,00 g Described in example 18a) make connections as described in example 7a) method. Obtain 4.4 g of compound 18b) in the form of foam.

[]2D0= +71,3o(CHCl3C = 0,545)

1H-NMR (deuterated chloroform): (M. D.) = 0,89 (s, 3H, H-18); of 1.03 (t, J= 7 Hz, 3H, H-22); 2,40-of 2.50 (m, 2H, H-21); of 3.78 (s, 3H, 3-OCH3); 6,63 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J= 9,3 Hz, 1H, H-2); 7,22 (d, J= 9 Hz, 1H, H-1).

b) 3-Methoxy-21-methyl-14, 17-ethano-19-norpregna-2,5(10) - Dien-20-ol

2.70 g Described in example 18b) make connections as described in example 1G) method. Get a 1.75 g of compound 18b).

So pl. 137-143oC.

1H-NMR (deuterated chloroform): (M. D.) = 0,86 (s, 3 he

356 mg, Described in example 18b) make connections according to the method described in example 1D). Receive 300 mg of the compound 18g).

1H-NMR (deuterated chloroform): (M. D.) = 0,91 (s, 3H, H-18); and 0.98 (t, J= 7 Hz, 3H, H-22); 3,55-3,63 (m, 1H, H-20); 5,81 (ush.s, 1H, H-4).

d) 21-Methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione

300 mg Described in example 18g) make connections as described in example 14) methodology. Receive 200 mg of the compound d).

So pl. 123-128oC; []2D0= +63,8o(CHCl3; = 0,525).

1H-NMR (deuterated chloroform): (M. D.) = 0,93 (s, 3H, H-18); and 1.00 (t, J = 7 Hz, 3H, H-22); of 5.82 (ush.s, 1H, H-4).

Example 19: 21-Methyl-14, 17-ethano-19-norpregna-4, 9-diene-3, 20-dione

770 mg, Described in example 18b) make connections as described in examples 4A), 4B) and e) methods. Obtain 170 mg of compound 19). So pl. 130oC;

[]2D0= -251,2o(CHCl3; = 0,470).

1H-NMR (deuterated chloroform): (M. D.) = 1,02 (t, J = 7 Hz, 3H, H-22); of 1.05 (s, 3H, H-18); 5,68 (ush.s, 1H, H-4).

Example 20: 21-Methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione

370 mg, Described in example 18g) make connections as shown in examples 2A), 2B) and e) methods. Get 120 mg Soeder (deuterated chloroform): (m D.) = 0,96 (s, 3H, H-18); of 1.02 (t, J = Hz, 3H, H-22); 5,78 (ush.s, 1H, H-4); 6,15 - 6,23 (m, 2H, H-6 and H-7).

Example 21: 21, 21-Dimethyl-14, 17-ethano-19-norpregna-4, 9 - diene-3,20-dione

(a) 3,3/2,2-Dimethyl-1,3-propanediylbis (hydroxy)/- 21-methyl-14,17-ethano-19-norpregna-5 (10),9(11)-Dien-20-he

18,3 g Described in example 18b) compounds injected into the interaction as specified in examples 4A), 46), (9a) and 7b) methods. Obtain 1.0 g of compound 21A).

1H-NMR (deuterated chloroform): (M. D.) = of 0.85 and 0.90 (2s, 6H, ketal-CH3);of 1.03 (t, J = 7 Hz, 3H, H-22); of 1.09 (s, 3H, H-18); 3,42-to 3.52 (m, 2H, ketal-OCH2); 3,57-3,68 (m, 2H, ketal-OCH2);5,50-of 5.55 (m,1H, H-11).

b) 21,21-Dimethyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione

210 mg, Described in example 21A) compounds injected into the interaction (turn) as specified in examples 7a) and 1D) methods. Obtain 108 mg of compound 21B).

1H-NMR (deuterated chloroform): (M. D.) = a 1.01 (d, J = 6 Hz, 6H, H-22', H-22);of 1.05 (s, 3H, H-18);5,68 (ush.s, 1H, H-4).

Example 22: 6-Methyl-14,17-ethano-19-norpregna-4,6-diene-3,20 - dione

a) 6-Methylene-14,17-ethano-19-norpregna-4-ene-3,20-dione

6,10 g Described in example 17A connections as described in example 2A) methodology is transformed into the corresponding simple diagnolly ether in the form of a crude product restauraut. An hour later, the reaction mixture was added dropwise to a concentrated solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with water and concentrated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. Get at 5.27 g of 6-formyl compound as crude product, which was dissolved in 14 ml of ethanol and 28 ml of dimethylformamide and portions mixed with 0.66 g of sodium borohydride. An hour later added dropwise 7.5 ml of 2 n sulfuric acid. After 15 minutes the reaction mixture is diluted with 120 ml of water, neutralized with a concentrated solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with water and concentrated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. Get or 4.31 g of compound 22A) in the form of a crude product.

1H-NMR (deuterated chloroform): (M. D. ) = 0,93 (s, 3H, H-18); a 2.12(s, 3H, H-21);4,94 and 5,18 (ush. 2C, each, 1H, 6 - = CH2); 6,11 (ush.s, 1H, H-4).

b) 6-Methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione

1,05 g of a 5% Palladium-on-coal in 50 ml of methanol for 30 minutes, refluxed and then mixed with a solution of 2.15 g described in example 22A) connection is tiravanija balance chromatographic on silica gel using mixtures of ethyl acetate with hexane. Obtain 88 mg of compound 22b).

1H-NMR (Deuteronomy chloroform): (M. D.) = 0,95 (s,3H,H-18); 1,83 (ush.s,1H,6-CH3);a 2.12 (s,3H,H-21);5,93 and of 5.99 (ush.2C,2H, H-4 and H-7).

Example 23: 6-Methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione

A solution of 2.15 g described in example 22A) compound in 30 ml of ethanol is mixed with 3 ml of cyclohexane and 0.25 g of 10% palladium-on-coal, and within 75 minutes refluxed. The catalyst is filtered off and the residue after concentration chromatographic on silica gel using mixtures of ethyl acetate with hexane. Obtain 140 mg of compound 23).

1H-NMR (deuterated chloroform): (M. D.) = 0,95 (s,3H,H-18); of 1.12 (d, J=7 Hz, 3H, 6-CH3); a 2.12 (s,3H,H-21);5,86 (ush.s,1H, H-4).

Example 24: 21-Hydroxy-14,17-ethano-19-norpregna-4-ene-3, 20-dione

4.9 g Described in example 17A) make connections as shown in examples 9a), 5B), 5C), 1D) and e) methods. Get 253 mg of compound 24).

[]2D0= +65,9o(CHCl3; = 0,525).

1H-NMR (deuterated chloroform): (M. D.) = 0,95 (s,3H, H-18); at 3.35 (t, J = 5 Hz, 1H,21-HE);4,24 and 4,27 (2D, J = 5 Hz, each 1H,H-21);5,27 (ush. s,1H,H-4).

Example 25: 21-Hydroxy-14, 17-ethano-19-norpregna-4,9-diene-3,20-dione

805 mg, Described in example I) connection []2D0= -232,8o(CHCl3; = 0,500).

1H-NMR (deuterated chloroform): (M. D.) = 1,04 (s,3H, H-18); of 3.32 (t, J = 5 Hz, 1H, 21-HE); 4,23 and 4,27 (2D, J = 5 Hz, each 1H, H-21);5,68 (ush.s,1H, H-4).

Examples 26 and 27:

26: (21R)-21-Hydroxy-21-methyl-14,17 - ethano-19-norpregna-4,9-diene-3,20-dione

27: (21S)-21-Hydroxy-21-methyl-14,17-ethano-19-norpregna-4,9 - diene-3,20-dione

2,00 g Described in example 21A) make connections as shown in examples 5B), 5C), 1D) and e) methods. Obtain 640 mg of a mixture of 21-ephemerol, which is shared by chromatography on silica gel using mixtures of ethyl acetate with hexane, getting 210 mg of compound 26) and 230 mg of the compound 27).

26: []2D0= -1,6o(CHCl3; = 0,495)

1H-NMR (deuterated chloroform): (M. D.) = 1,03 (s, 3H, H-18); of 1.32 (d, J= 6 Hz, 3H, H-22); of 3.60 (d, J= 6 Hz, 1H, 21-HE); 4,37-to 4.46 (m, 1H, H-21); 5,68 (ush.s, 1H, H-4).

27: []2D0= -1,0o(CHCl3; = value (0.475))

1H-NMR (deuterated chloroform): (M. D.) = 1,07 (s, 3H, H-18); of 1.29 (d, J= 6 Hz, 3H, H-22); 3,40 (d, J= 7 Hz, 1H, 21-HE); 4,33-of 4.44 (m, 1H, H-21); 5,68 (ush.s, 1H, H-4).

Example 28: 16-Methyl-14,17 - ethano-19-norpregna-4-ene-3, 20-dione

a) Methyl ester of 3-methoxy-20-oxo-14,17-ateno-19-norpregna - 1,3,5 (10)-triene-16-carboxylic acid

9.4 g Opiskelijat within 7 days @ 120oC. After cooling and removal of all volatile components under reduced pressure, the residue chromatographic on silica gel using a mixture of ethylacetate with hexane. Get 21,0 g of compound 28a).

So pl. 145-146oC; []2D0= +216,4o(CHCl3; = worn: 0.505)

1H-NMR (deuterated chloroform): (M. D.) =0,96 (s, 3H,H-18); to 2.29 (s, 3H, H-21);of 3.60 (s,3H,CO2CH3);of 3.78 (s,3H,3-och3); a-3.84 (DD, J = 9.5 and 4.5 Hz, H-16); 6,15 and 6,27 (2D, J = 6 Hz, each 1H,H-171and H-172);only 6.64 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J = 9 Hz and 3 Hz, 1H, H-2);7,19 (d, J = 9 Hz, 1H, H-1).

b) Methyl ether 20,20-/1,2-atanderson(hydroxy)/-3-methoxy- -14,17-ateno-19-norpregna-1,3,5 (10)-triene-16-carboxylic acid

20,8 g Described in example 28a) make connections as specified in example 1B) technique. Obtain 17.0 g of compound 28B). So pl. 128-130oC; []2D0= +141,2o(CHCl3; = worn: 0.505)

1H-NMR (deuteromony chloroform): (M. D.) = 1,03 (s, 3H, H-18); of 1.32 (s, 3H, H-21); to 3.38 (DD, J = 9.5 and 4.5 Hz, 1H, H-16); of 3.60 (s, 3H, CO2CH3); of 3.78 (s, 3H, 3-och3); 3,82-4,18 (m, 4H, 20-OCH2CH2O-); 6,00 and 6.23 (2D, J = 6 Hz, each 1H, H-171and H-172); 6,63 (d, J=3 Hz, 1H, H-4); of 6.71 (DD, J = 9 and 3 Hz, 1H, H-2); then 7.20 (d, J= 9 Hz, 1H, H-1).

in) 20,20-[1,2-Atanderson(oxy)] -3-methoxy-14,17 - these the uranium was added dropwise to a cooled to 0oC suspension 2,84 g sociallyengaged in 100 ml of tetrahydrofuran. After stirring for two hours at room temperature slowly mixed with 5 ml of water. Later the next 20 minutes, filtered through celite, optionally washed with dichloromethane, dried over sodium sulfate and concentrated. Gain of 7.1 g of compound 28C). For analytical purposes the product is crystallized from pentane.

So pl. 162-164oC []2D0= +104,2o(CHCl3;- 0,520)

1H-NMR (deuterated chloroform): (M. D.) = 1,05 (s, 3H, (H-18); to 1.48 (s, 3H, H-21); 3,18-3,44 (m, 2H, 16-C2IT); of 3.77 (s, 3H, 3-OCH3): 4,01-4,12 (m, 4H, 20-och2CH2O-); 5,95 and 6,04 (2D, J = 6 Hz, each 1H, H-171and H-172); 6,62 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J =9 and 3 Hz, 1H, H-2); 7,21 (d, J = 9 Hz, 1H, H-1).

g) 20,20-[1,2-Atanderson(oxy)]-3-methoxy-14,17-ethano-19- -norpregna-1,3,5 (10)-triene-16-methanol

7,8 g Described in example 28C) make connections as specified in example 16A) method. Gain of 7.4 g of compound 28G).

So pl. 190-193oC; []2D0= + 5,5o(CHCl3; = worn: 0.505).

1H-NMR (deuterated chloroform): (M. D.) = 1,05 (s,3H, H-18);of 1.43 (s,3H,H-21);of 3.54 (m,1H,16-CH2HE);3,37 (s,3H, 3-och3); 3,69-4,10 (m,5H,20-och2CH2-atanderson (oxy)]- 3-methoxy-14,17-ethano-19-norpregna-1,3,5 (10)-triene

6.8 g Described in example 28G) compounds of 7.2 g of tetrabromomethane and 5.7 of triphenylphosphine in 250 ml of dichloromethane is stirred for 16 hours at room temperature. After concentration the residue chromatographic on silica gel with the help of a mixture of ethyl acetate with hexane. Obtain 2.2 g of the compound d).

So pl. 176-177oC; []2D0= -21,7o(CHCl3; = worn: 0.505).

1H-NMR (Deuteronomy chloroform): (M. D.) = 1,02 (s,3H, H-18);of 1.30 (s, 3H, H-21); to 3.34 (DD, J 10 Hz and 12 Hz, 16-CH2Br); to 3.73 (s,3H,3-och3); 3,82-4,06 (m, 5H,20-och2CH2Oh - and 16-CH2Br); 6,63 (d, J = 3 Hz, 1H, H-4) of 6.71 (DD, J = 9 Hz and 3 Hz,1H,H-2); then 7.20 (d, J = 9 Hz, 1H, H-1).

e) 20,20-[1,2-Atanderson (oxy)]-3-methoxy-16 - methyl-14,17-ethano-19-norpregna-2,5(10)-Dien

1.78 g Described in example d) make connections as specified in example 1G) method. Obtain 1.1 g of the compound 28th).

So pl. 174-178oC; []2D0= +41,4o(CHCl3C = 0,50).

1H-NMR (deuterated chloroform): (M. D.) = 0,99 (s,3H, H-18); of 1.06 (d, J = 7 Hz, 16-CH3);1,25 (s, 3H, H-21); of 3.56 (s, 3H, 3-och3); 3,78-4,01 (m, 4H, 20-och3CH2O-);with 4.64 (m, 1H, H-2).

W)16-Methyl-14, 17-ethano-19-norpregna-4-ene-3,20-dione

1,05 g Described in example 28e) SOEDINENIYa>C; []2D0= +52,7o(CHCl3; = 0,485).

1H-NMR (deuterated chloroform): (M. D.) = 0,96 (s,3H, H-18);to 0.96 (d, J = 7 Hz,16-Snz);of 2.09 (s,3H,H-21);of 5.81 (t, J = 1 Hz,H-4).

Example 29: 16-Ethyl-14, 17-ethano-19-norpregna-4-ene-3, 20-dione

a) 20,20-[1,2-Atanderson(oxy)]-3-methoxy-14, 17 - ethano-19-norpregna-1,3,5 (10)-triene-16-carbaldehyde

2.7 g Described in example 28G) make connections as specified in example 7b) method. Obtain 2.4 g of compound 29A).

1H-NMR (deuterated chloroform): (M. D.) = 1,02 (s,3H,H-18); of 1.34(s, 3H, H-21); of 3.78 (s,3H,3-och3)3,82-4,16 (m,4H, 20-och2CH2O-);is 6.61 (d, J 3 Hz,1H,H-4);6,72 (DD, J = 9 Hz and 3 Hz,1H,H-2);then 7.20 (d, J = 9 Hz,1H,H-1); 9,88 (d, J = 2 Hz,CHO).

b) 20,20-/1,2-Atanderson (hydroxy)/-16-ethynyl-3-methoxy- - 14,17-ethano-19-norpregna-1,3,5(10)-triene

10.7 g of Methyltriphenylphosphonium suspended in 70 ml of tetrahydrofuran and, at 0oC dropwise mixed overall, with 18 ml of a 1.6 M solution of n-utility in hexane. After stirring for 20 minutes at a temperature of 0oC and for 1 hour at room temperature was added dropwise a solution of 2.6 g described in example 29A) compound in 40 ml of tetrahydrofuran. After 2 hours, filtered off the solid components and concentrate. The residue is partitioned between water ifecom sodium, filtered and canceryou. After chromatography on silica gel using mixtures of ethyl acetate with hexane obtain 1.6 g of compound 29b).

[]2D0= +13,7o(CHCl3; = 0,510).

1H-NMR (deuterated chloroform): (M. D.) = 1,03 (s, 3H, H-18);to 1.38 (s, 3H, H-21);of 3.78(s, 3H, 3-och3);3,84-a 4.03 (m,4H, 20-och2CH2O-);4,96-5,08 (m, 2H, vinyl-CH2);6,02-of 6.17 (m, 1H, vinyl-CH); 6,62 (d, J = 3 Hz, 1H, H-4); of 6.71 (DD, J = 9 and 3 Hz, 1H, H-2); 7,21 (d, J= 9 Hz, 1H, H-1).

in) 20,20-[1,2-Atanderson(oxy)]-16-ethyl-3-methoxy-14, 17-ethano-19-norpregna-1,3,5(10) -triene

1.0 g Described in example 29b) make connections as specified in example 16A) method. Obtain 1.0 g of compound 29b).

1H-NMR (deuterated chloroform): (M. D.) = 0,91 (t, J = 7 Hz, 3H, 16-ethyl-CH3); and 1.00 (s, 3H, H-18); of 1.30 (s, 3H, H-21); of 3.77 (s, 3H, 3-OCH3); 3,70-was 4.02 (m, 4H, 20-och2CH2O-); is 6.61 (d, J = 3 Hz, 1H, H-4); of 6.71 (DD, J =9 and 3 Hz, 1H, H-2); 7,21 (d, J= 9 Hz, 1H, H-1).

g) 20,20-[1,2-Atanderson (oxy)] -16 ethyl-3-methoxy-14,17- -ethano-19-norpregna-2,5 (10) -Dien

1.0 g Described in example 29b) make connections as specified in example 1G) method. Obtain 1.07 g of the compound 29g), which is injected into the interaction further as crude product.

1H-NMR (Tatarinova-ethano-19-norpregna-4-ene-3,20-dione

0.97 g Described in example 29g) make connections as specified in example 1D) technique. After chromatography on silica gel using mixtures of ethyl acetate with hexane obtain 0.56 g of the compound g), which crystallized from diisopropyl ether.

So pl. 145-147oC; []2D0= +42,9o(CHCl3; = 0,515)

1H-NMR (deuterated chloroform): (M. D.) = 0,96 (t, J = 7 Hz, 3H, 16-ethyl-CH3); to 0.96 (s, 3H, H-18); of 2.10 (s, 3H, H-21); of 5.81 (t, J= 1 Hz, 1H, H-4).

Example 30: 16-Ethynyl-14, 17-ethano-19-norpregna-4-ene-3,20-dione

a) 20,20-[1,2-Atanderson(oxy)]-16-ethynyl-3-methoxy-14, 17-ethano-19-norpregna-2,5(10)-Dien

0.5 g Described in example 29b) make connections as described in example 1G) method. Get 0.5 g of compound 30A), which without treatment is injected into the interaction further.

1H-NMR (deuterated chloroform): (M. D.) = 1,02 (s, 3H, H-18); of 1.23 (s, 3H, H-21); of 3.56 (s, 3H, 3-OCH3); 3,82-was 4.02 (m, 4H, 20-OCH2CH2O-); with 4.64 (m, 1H, H-2); 4,93 is 5.07 (m, 2H, vinyl-CH2); between 6.08 (m, 1H, vinyl-CH)

b) 16 Ethynyl-14,17-ethano-19-norpregna-4-ene-3,20-dione

0,49 g of Compound 30A) transform as described in example 1D) technique. After chromatography on silica gel using mixtures of ethyl acetate with hexane obtain 0.27 g is connected to tarirovannyjj chloroform): (M. D.) = 1,00 (s, 3H, H-18); of 2.08 (s, 3H, H-21); 5,03-5,13 (m, 2H, vinyl-CH); 5,72-by 5.87 (m, 2H, vinyl-CH and N-4).

Example 31: 16-Methylene-14, 17-ethano-19-norpregna-4-ene-3, 20 - dione

a) 20,20-/1,2-Atanderson(hydroxy)/-3-methoxy-16-methylene-14, 17-ethano-19-norpregna-1,3,5(10)-triene

27,86 g Described in example 29A) compounds dissolved in 268 ml of tetrahydrofuran and at a temperature of ABOUToWith a mix from 26.6 g hexamethyldisilazide potassium. After 1 hour was added dropwise to 17.8 ml nonafflicted (1,1,2,2,3,3,4,4,4-nonattribute-sulfonyl fluoride). After stirring for three hours at room temperature, the reaction mixture was partitioned between water and ethyl acetate and the organic phase is washed with a concentrated solution of sodium bicarbonate and sodium chloride solution. After drying the organic phase over sodium sulfate filtered, concentrated and the residue is treated 546 ml of dimethylformamide. After adding 111,5 ml of triethylamine, 2.0 g of bis-(triphenylphosphine)-palladium-(II)-chloride and 19.5 ml of formic acid is heated for 7 hours at 80oC and then incubated overnight at room temperature. After distribution between ethyl acetate and water, the organic phase is washed with concentrated sodium chloride solution, dried over sodium sulfate, from the m Get 5,33 g of compound 31A).

[]2D0= +21,1o(CHCl3; = 0,530).

1H-NMR (deuterated chloroform): (M. D.) = 0,99 (s, 3H, H-18); the 1.44 (s, 3H, H-21); of 3.78 (s, 3H,3-och3,); a 3.87-4,07 (m, 4H, 20-OCH2CH2O-); 4,90 (ush. s, 1H, 16-methylene); 5,15 (ush.s, 1H, 16-methylene); 6,63 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J= 9 and 3 Hz, 1H, H-2); of 7.23 (d, J = 9 Hz, 1H, H-1).

b) 16-Methylene-14,17-ethano-19-norpregna-4-ene-3,20-dione

510 mg, Described in example 31 (a) make connections as described in examples 1G and 1D) methods. Obtain 440 mg of compound 31B), which insist with diisopropyl ether.

1H-NMR (deuterated chloroform): (M. D.) = 1,09 (s, 3H, H-18); 2,22 (s, 3H, H-21); a 4.83 (ush.s, 1H, 16-methylene); 4,90 (ush.s, 1H, 16-methylene); of 5.82 (ush.s, 1H, H-4).

Example 32: 16-Methylene-14, 17-ethano-19-norpregna-4,9-diene-3,20-dione

a) 20,20-/1,2-Atanderson(hydroxy)/-16-methylene-14,17 - ethano-19-norpregna-5(10)-EN-3-one

6.8 g Described in example 31A) make connections as described in examples 1D) and 8b) methods. After chromatography on silica gel using mixtures of ethyl acetate with hexane obtain 4.9 g of compound 32A). In addition, receive 600 mg 20,20-/1,2-atanderson(hydroxy)/-16-methylene-14, 17-ethano-19-norpregna-4-EN-3-one.

1H-NMR (deuterated chlorof the SUB>2O-); 4,89 (ush.s, 1H, 16-methylene); 5,12 (ush.s, 1H, 16-methylene);

1H-NMR (deuterated chloroform) for 20,20-/1,2-ethandiyl-bis(hydroxy)/-16-methylene-14, 17-ethano-19-norpregna-4-EN-3-one: (M. D.) = 1,00 (s, 3H, H-18); of 1.42 (s, 3H, H-21); 3,84-Android 4.04 (m, 4H, 20-och2CH2O) 4,88 (ush.s, 1H, 16-methylene); 5,13 (ush. s, 1H, 16-methylene); of 5.82 (ush.s, 1H, H-4).

b) 16-Methylene-14, 17-ethano-19 - norpregna-4, 9-diene-3,20-dione

4.9 g Described in example 32A) make connections as described in examples 4B) and 1D) methods. After chromatography on silica gel using mixtures of ethyl acetate with hexane and infusion product with diisopropyl ether obtain 1.52 g of compound 32b).

So pl. 141oC (decomposition); []2D0= -358,8o(CHCl3; = 0,515)

1H-NMR (deuterated chloroform): (M. D.) = 1,19 (s, 3H, H-18); 2,22 (s, 3H, H-21); 4,84 (ush.s, 1H, 16-methylene); 4,90 (ush.s, 1H, 16-methylene); 5,68 (ush.s, 1H, H-4).

Example 33: 16-methylene-14,17-ethano-19-norpregna-4,6-diene-3,20-dione

600 mg 20,20-/1,2-Atanderson(hydroxy)/-16-methylene-14,17 - ethano-19-norpregna-4-EN-3-one from example 32A) transform as described in examples 2A), 26) and 1D) methods. After chromatography on silica gel using mixtures of ethyl acetate with hexane and crystallization from diisopropyl ether get 70 mg when len);4,92 (ush.s,1H, 16-methylene);5,78 (ush.s, 1H,H-4);6,10-of 6.26 (m,2H,H-6 and H-7).

Example 34: 16-Methyl-14,17-ethano-19-norpregna-4,6-diene - 3, 20-dione

a) 20,20-[2-Atanderson(oxy)] -3-methoxy-16 /[(methylsulphonyl)oxy] methyl/-14,17-ethano-19-norpregna-1, 3,5(10)-triene

11,7 g Described in example 28B) compounds dissolved in a mixture of 15 ml of pyridine and 110 ml of dichloromethane, at a temperature of 0oC slowly mixed with 4.7 ml of the acid chloride of methansulfonate. After conditioning for 24 hours at room temperature is mixed with a concentrated, cooled with ice with a solution of sodium bicarbonate. The organic phase is washed three times with concentrated, chilled ice sodium hydrogen carbonate solution, dried over sodium sulfate and filtered. Under reduced pressure to remove all volatile components. Obtain 14.3 g of compound 34a), which enter into interaction without further purification.

1H-NMR (deuterated chloroform): (M. D.) = 1,11 (s, 3H, H-18); of 1.31 (s, 3H, H-21); to 3.02 (s, 3H, SO2CH3);3,68 (s,3H,3-och3); 3,82 - 4,06 (m, 4H, 20-OCH2CH2O-); of 4.12 (DD, J =9 and 10 Hz, 1H, 16-CH2); 4,80 (DD, J = 4 and 10 Hz, 1H, 16-CH2); 6,62 (d, J = 3 Hz, 1H, H-4); 6,70 (DD, J = 9 and 3 Hz, 1H, H-2); then 7.20 (d, J = 9 Hz, 1H, H-1).

b) 20,20-[1,2-Atanderson(oxy)] -3-methoxy-16-methyl-furane and mixed with 150 ml of 1M solution of triethylborohydride lithium in tetrahydrofuran. After heating for 5.5 hours in an argon atmosphere leave to stand for 15 hours at room temperature and distributed between ethyl acetate and concentrated solution of ammonium chloride. The organic phase is washed with a concentrated solution of sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. After chromatography on silica gel using mixtures of ethyl acetate with hexane obtain 6.0 g of compound 34B). So pl. 132 - 134oC.

1H-NMR (deuterated chloroform): (M. D.) = 1.01 (s,3H,H-18); to 1.19 (d, J = 7.5 Hz,16-CH3);of 1.30 (s,3H,H-21);of 3.78 (s,3H,3 - OCH3); 3,83-Android 4.04 (m, 4H, 20-OCH2CH2O-); 6,62 (d, J = 3 Hz, 1H, H - 4);of 6.71 (DD, J = 9 and 3 Hz, 1H, H-2); 7,22 (d, J=9 Hz, 1H, H-1).

b) 3-Methoxy-16 /methyl-14,17-ethano-19-norpregna-1,3,5 (10) - triene-20-he

5,96 g Described in example 34B) make connections as described in example 1D) technique. Get to 5.58 g of compound 34B) in the form of a crude product.

So pl. 115-116oC; []2D0+51,3o(CHCl3; = 0,530).

1H-NMR (deuterated chloroform): (M. D.) = 0,93 (s,3H,H-18); 0,99 (d, J = 7.5 Hz,16-CH3);2,11 (s,3H,H-21);of 3.78 (s,3H,3-och3);6,62 (d, J = 3 Hz,1H,H - 4);of 6.71 (DD, J =9 and 3 Hz, 1H, H-2); 7,21 (d, J = 9 Hz, 1H, H-1).

g) 3-Methoxy-16-methyl-14,17-canola and 130 ml of dichloromethane and portions mixed with 2,37 g of sodium borohydride. After incubation for two hours at room temperature, mixed with water, acidified with 2n hydrochloric acid and the aqueous phase is extracted twice with dichloromethane. After washing the organic phase with water, concentrated sodium hydrogen carbonate solution and concentrated solution of sodium chloride it is dried over sodium sulfate, filtered and concentrated. After chromatography on silica gel using mixtures of ethyl acetate with hexane get to 4.28 g of compound 34 g).

1H-NMR (deuterated chloroform): (M. D.) = 0,98 (s,3H, H-18);1,04 (1,13) (d, J = 7.5 Hz, 16-CH3), 1,24 (1,22) (d, J = 6.5 Hz, 3H, H-21); of 3.78 (s, 3H, 3-och3); 3,88 - 3,98 (m, 1H, H-20);6,62 (d, J = 3 Hz, 1H, H-4); of 6.71 (DD, J = 9 and 3 Hz, 1H, H-2); 7,21(d, J = 9 Hz, 1H, H-1) (signals of the second diastereoisomer shown in brackets).

d) 3-Methoxy-16-methyl-14, 17-ethano-19-norpregna-2,5(10)- Dien-20-ol

4.26 deaths g Described in example 34 (d) make connections as described in example 1G) method. Get of 4.45 g of compound 34B) in the form of a crude product.

1H-NMR (deuterated chloroform): (M. D.) = 0,94 (s, 3H, H-18); of 1.02 (d, J = 7.5 Hz, 16-CH3); of 1.20 (d, J = 6.5 Hz, 3H, H-21); of 3.53 (s, 3H, 3-och3); 3,84-of 3.96 (m, 1H, H-20); with 4.64 (ush.s, 1H, H-2), (NMR data are presented only for the main diastereoisomer).

So pl. 165o; []2D0= +16,4o(CHCl3; = 0,525).

1H-NMR (deuterated chloroform); (M. D.) = 0,98 (c,3H, H-18);and 1.00 (d, J = 7.5 Hz, 3H, 16-CH3); 2,11 (s, 3H, H-21); 5,78 (ush.s, 1H, H-4); between 6.08 and to 6.22 (m, 2H, H-6 and H-7).

Example 35: 16-Methyl-14,17-ethano-19-norpregna-4,9-diene - 3,20-dione

2.5 g Described in example d) make connections as described in examples 4A),4B) and 7b) methods. Obtain 410 mg of compound 35).

So pl. 125-126oC; []2D0= -300,7o(CHCl3; = 0,530).

1H-NMR (deuterated chloroform): (M. D.) = 0,98 (d, J = 7.5 Hz, 3H, 16-CH3);of 1.07 (s, 3H, H-18); 2,11 (s, 3H, H-21); 5,68 (ush. s, 1H, H-4).

Example 36: 16 21-Dimethyl-14-17-ethano-19 - norpregna-4,9-diene - 3,20-dione

3.2 g Described in example d) make connections as described in examples 4A),4B),9a),7a),7b) and 1D) methods. Obtain 308 mg of compound 36).

[]2D0= -274,3o(CHCl3; = 0,535).

1H-NMR (deuterated chloroform): (M. D.) = 0,99 (d, J = 7.5 Hz, 3H, 16-CH3); the 1.04 (t, J = 7 Hz, 3H, H-22); a 1.08 (s,3H,H - 18); 5,69 (ush.s,1H,H-4).

Example 37: 21-Hydroxy-16-methyl-14, 17-ethano-19-noben-4-ene-3,20-dione

1,25 g Described in example 343 mg of compound 37).

[]2D0= +is 56.4o(CHCl3; = 0,250).

1H-NMR (deuterated chloroform): (M. D.) = 0,97 (d, J = 7.5 Hz, 3H, 16-CH3);and 0.98 (s, 3H, H-18);4,22 (ush.s, 2H, H-21); of 5.82 (ush.s, 1H, H-4).

Example 38: 172-Methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione

a) 17-Ethinyl-3-methoxy-15-methylestra-1,3,5(10), 15-tetraen-17-ol.

At a temperature of 0oC for 30 minutes in 500 ml of tetrahydrofuran miss acetylene. Then added dropwise 230 ml of a 1.6 M solution of n-utility in hexane. After the next 30 minutes was added dropwise a solution of 12.1 g of 3-methoxy-15-methyl-östra-1,3,5(10), 15 - tetraen-17-it (see patent application Germany 4326240-1) in 250 ml of tetrahydrofuran. After 30 minutes the reaction mixture was partitioned between Polynesians solution of sodium chloride and ethyl acetate, the organic phase is washed polysystem and a saturated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated. When this substance crystallizes. Overall get of 12.12 g of compound 38A).

[]2D0= -191,4o(CDCl3; = 0,500).

1H-NMR (deuterated chloroform): (M. D.) = 0,95 (s,3H,H-18);1,90 (ush. s, 3H, 15-CH3); to 2.66 (s,1H,17-ethinyl);3,79 (s,3H,3-och3);5,40 (ush.s,1H, H-16);only 6.64 (d, J=3 Hz,1H,H-4);of 6.73 (DD, J = 9 and 3 Hz, 1H, H-2)sledge in example 38A) make connections as described in examples 1A) and 1B) methods. Get of 8.95 g of compound 38b).

So pl. to 123.5-125oC; []2D0= -207,5o(CHCl3; = 0,520).

1H-NMR (deuterated chloroform): (M. D.) = 0,86 (s,3H,H-18);1,88 (ush.c,3H,172-CH3);2,21 (c,3H,H-21);3,79 (s,3H,3-och3); 5,66 (ush.s,1H,H-171); 6,63 (d, J = 3 Hz,1H,H-4);of 6.73 (DD, J = 9 Hz and 3 Hz,1H,H-2);7,22 (d, J = 9 Hz,1H,H-1).

in) 20,20-/1,2-Atanderson(hydroxy)/-3-methoxy-172- methyl-14,17-ateno-19-norpregna-2,5(10)-Dien

1.50 g Described in example 38b) make connections as described in examples 1B) and 1D) methods. Gain of 1.65 g of the crude compound 38b).

1H-NMR (deuterated chloroform): (M. D.) = 0,92 (s,3H,H-18);of 1.32 (s, 3H, H-21);1,80 (ush.s,3H,172-CH3);to 3.56 (s,3H,3-och3); 3,83 -4,02 (m,4H,20-och2CH2O-);4,65 (ush.s,1H,H-2);of 5.53 (ush.s,1H,H-171).

g) 172-Methyl-14,17-ateno-19-norpregna-4-ene-3, 20-dione

270 mg, Described in example 38b) make connections as described in example 1D) technique. Get (according to HPLC) 126 mg of compound 38 g).

1H-NMR (deuterated chloroform): (M. D.) or = 0.90 (s,3H,H-18);1,82 (ush.s,3H,172-CH3);to 2.18 (s,3H,H-21);5,63 (ush.s,1H, H-171);5,85 (ush.s,1H,H-4).

Example 39: 172-Methyl-14,17-ateno-19-norpregna-4,9-diene-3,20-dione

1,41 g Described in section the connection 39).

[]2D0= -306,2o(CHCl3; = 0,510).

1H-NMR (deuterated chloroform): (M. D.) = 0,98 (s,3H,H-18);1,73 (ush. s, 3H, 172-CH3);to 2.18 (s,3H,H-21);5,67 and 5,73 (ush.2s,each 1H,H-4 and H-171).

Example 40: (172R)-172-Methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione

a) (172R)-3-Methoxy-17-methyl-14,17-ethano-19-norpregna - 1,3,5(10)-triene-20-he

of 7.95 g Described in example 38b) make connections as described in example 12A) method. Get 6,97 g of compound 40A). So pl. 107,5 - 109,5oC.

1H-NMR (deuterated chloroform): (M. D.) = 0,94 (s,3H,H-18);of 1.07 (d, J = 7.5 Hz,3H,172-CH3);2,11 (s,3H,H-21);of 3.78 (s,3H,3-och3);is 6.61 (d, J 3 Hz, 1H,H-4);6,72 (DD, J = 9 and 3 Hz,1H,H-2);of 7.23 (d, J= 9 Hz,1H,H-1).

b) (172R)-20,20-/1,2-Atanderson(hydroxy)/-3-methoxy-172- methyl-14,17-ethano-19-norpregna-2, 5 (10) -Dien

3.5 g Described in example 40A) make connections as described in examples 1B) and 1D) methods. Obtain 4.0 g of the crude compound 40B), which without treatment is injected into the interaction further.

1H-NMR (deuterated chloroform): (M. D.) = 0,99 (s,3H,H-18);0,99 (d, J = 7.5 Hz,3H,172-CH3);2,11 (s,3H,H-21);3,55 (s, 3H,3-och3);3, 83-4,00 (m, 4H, 20-och2CH2O-); with 4.64 (ush.s,1H, H-2).

in) (172the public hearing described in example 1D) technique. Obtain 0.14 g

connection 40V).

1H-NMR (deuterated chloroform): (M. D.) = 0,95 (s,3H,H-18);of 1.05 (d, J = 7.5 Hz,3H,172-CH3);is 2.05 (s,3H,H-21);5,79 (ush.s,1H,H-4).

Example 41: (172R)-172-Methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione

1.1 g Described in example 40B) make connections as described in examples 1D), 2A) and 2B) methods. Obtain 0.21 g of compound 41).

[]2D0= +117,3o(CHCl3; = 0,450).

1H-NMR (deuterated chloroform): (M. D.) = 0,98 (d, J = 7.5 Hz,3H, 172-CH3);0,99 (s,3H,H-18);of 2.08 (s,3H,H - 21);5,68 (ush.s,1H,H-4);6,11-6,27 (m, 2H,H-6 and H-7).

Example 42: (172R)-172-Methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione

1.4 g Described in example 40B) make connections as described in examples 4A and 4B) methods. Obtain 0.56 g of compound 42).

So pl. 118-120oC; []2D0= -270,5o(CHCl3; = 0,495).

1H-NMR (deuterated chloroform): (M. D.) = 1,06 (s,3H,H-18); of 1.09 (d, J= 7.5 Hz,3H,172-CH3);is 2.09 (s,3H,H-21);5,66 (ush.s, 1H,H-4).

Example 43: (172R)-172, 21-Dimethyl-14,17-ethano-19 - norpregna-4,9-diene-3,20-dione

a) (172R)-172, 21-Dimethyl-20,20- [1,2-atanderson(oxy)]-14,17-ethano-19-norpregna-5(10)-EN-3-on
2R)-172, 21-dimethyl-20,20-/1,2-atanderson(hydroxy)/ -14,17-ethano-19-norpregna-4-EN-3-one.

1H-NMR (deuterated chloroform): (M. D.) = 0,86 (t, J = 7.7 Hz,3H, H-22); 0,99 (s,3H,H-18);and 1.00 (d, J = 7.5 Hz,3H,177- CH3); to 2.67 and 2,78 (d, J = 20 Hz, each 1H, H-4);3,90-4,08 (m,4H,20-och2CH2O-).

b) (172R)-172,21-Dimethyl-14,17-ethano-19-norpregna-4,9 - diene-3,20-dione

2,33 g Described in example 43A) make connections as described in examples 4B) and 1D) methods. Obtain 0.8 g of the compound 43B) and along with him to 0.48 g (172R)- 172,21 - dimethyl-14,17-ethano-19-norpregna-5(10),9(11)-the diene-3,20-dione

[]2D0to connect 43B):-285,4o(CHCl3; = 0,515).

1H-NMR (deuterated chloroform) to connect 43B): (M. D.) = 1,00 (T, J= 7.5 Hz,3H,H-22);of 1.05 (s,3H,H-18);a 1.08 (d, J = 7.5 Hz,3H,172-CH3);5,67 (ush.s,1H,H-4).

1H-NMR (deuterated chloroform) to (172R)-172,21-dimethyl - 14,17-ethano-19-norpregna-5(10), 9(11)-the diene-3,20-dione: (M. D.) = 0,86 (s,3H,H-18); and 1.00 (t, J = 7.5 Hz,3H,H-22);the 1.04 (d, J = 7.5 Hz,3H,172-CH3);2,88 (ush.s,2H, H-4);5,59-of 5.68 (m,1H,H-11).

Example 44: (172R)-172,21-Dimethyl-14,17-ethano-19 - norpregna-4,9,11-triene-3,20-dione

0.45 g Described in exampl described in example 9b) method.

Obtain 0.16 g of compound 44).

[]2D0= -48,1o(CHCl3; = 0,455).

1H-NMR (deuterated chloroform): (M. D.) = 1,00 (s,3H,H-18); of 1.02 (d, J = 7.5 Hz,3H,172-CH3);of 1.03 (t, J = 7.5 Hz,3H,H-22); 5,76 (ush.s,3H,H-4);6,44 (d, J = 12 Hz,1H,H-11);6,48 (d, J = 12 Hz,1H,H-12).

Example 45: (172R)-172, 21-Dimethyl-14,17-ethano-19 - norpregna-4,6-diene-3,20-dione

0,62 g Described in example 43A) of the compound (172R)- 172,21-dimethyl-20,20-/1,2-atanderson (hydroxy)/-14, 17 ethano-19-norpregna 4-EN-3-make it as described in examples 2A), 2B) and 1D) methods. Gain of 0.13 g of compound 45).

1H-NMR (deuterated chloroform): (M. D.) = 0,93-of 1.02 (m,9H, 172-CH3H-18 and H-22);5,76 (ush.s,1H,H-4);6,12-6,24 (m,2H,H-6 and H-7).

Example 46: 14, 17 Ethano-19-norpregna-4, 15-diene-3, 20 - dione

a) 15,16-Dihydro-3-methoxy/1,3/dioxolo/4',5';15,16/-14,17-ateno-19-norpregna-1,3,5(10)-trien-2',20-dione

56 g Described in example 1A) compounds mixed with 90,5 ml vinylnorbornene and 50 mg of hydroquinone and maintained under an argon atmosphere at a bath temperature of 170oC for 18 hours. After removal of all volatile components under high vacuum, the residue chromatographic on silica gel using mixtures of ethyl acetate with hexane. After crystallization from a mixture of Hai is D0= -219,8o(CHCl3; = 0,495).

1H-NMR (deuterated chloroform): (M. D.) = 0,94 (s,3H,H-18);of 2.30 (s, 3H, H-21); 3,79 (s,3H,3-och3);4.99 and USD 5.76 (2H, J = 8 Hz,H-15 and H-16);of 6.31 and 6,40 (2D, J = 6 Hz,each 1H,H-171and H-172);6,66(d, J = 3 Hz,1H,H-4);6,72 (DD,J = 9,3 Hz,1H, H-2);to 7.18 (d, J = 9 Hz,1H,H-1).

b) 15,16-Dihydro-3-methoxy/1,3/dioxolo/4',5':15,16/-14, 17-ethano-19-norpregna-1,3,5(10)-trien-2' 20-dione

56 g Described in example 46a) make connections as described in example 12A) method. Obtain 56 g of compound 46B).

So pl. p.223-224oC; []2D0= -111,2o(CHCl3; = 0,515).

1H-NMR (deuterated chloroform): (M. D.) = 0,94 (s,3H,H-18);of 2.20 (s, 3H,H-21);of 3.78 (s,3H,3-och3);4,68 and 5,48 (DD, J = 1.5 and 9 Hz,each 1H,H-171and H-172); only 6.64(d,J = 3 Hz,1H,H-4); of 6.73(DD, J = 9,3 Hz,1H,H-2),19 (d, J = 9 Hz,1H,H-1).

in) 15,16-Dihydroxy-3-methoxy-14,17-ethano-19 - norpregna-1,3,5(10)-triene-20-he

50 g Described in example 46B) connection together with 26 g of potassium carbonate in a mixture of 250 ml of methanol, 500 ml of tetrahydrofuran and 150 ml of water to the boil for 6 hours. After subsequent removal of the solvent poured into 2 l of ice water, filtered off under vacuum and the residue on the filter is washed with 1 l of water. Get 45,80 g of compound V).

1H S IS P> and H-172); 6,63 (d, J = 3 Hz,1H,H-4); 6,72 (DD, J = 9,3 Hz,1H,H-2);7,21 (d, J = 9 Hz,1H,H-1).

g) 3-Methoxy-14,17-ethano-19-norpregna-1,3,5(10),15-tetraen-20-o

of 45.7 g Described in example V) compounds are dissolved in 1.5 l of dichloromethane and at 0oC is mixed with 150 ml of triethylorthoformate, and 6 g pyridinedicarboxylate. After incubation for 6 hours at room temperature the mixture is filtered through a column of silica gel and the filtrate concentrated. The residue after evaporation is treated with 1 l of acetanhydride and boiled for 5 hours. After concentration the residue is partitioned between concentrated solution of sodium bicarbonate and dichloromethane. After washing the organic phase with a concentrated solution of sodium chloride it is dried over sodium sulfate, filtered and concentrated; the residue chromatographic on silica gel using mixtures of ethyl acetate with hexane. Get to 6.75 g of compound g). All polar fractions after chromatography are combined and concentrated. The remainder, together with 20 g of potassium carbonate in 800 ml of methanol is boiled for three hours and poured into 2 l of ice water, filtered off under vacuum and the residue on the filter is washed with 0.5 l of water. Receive 27.5 g described in example/SUP>D0= +0,5o(CHCl3; = worn: 0.505).

1H-NMR (deuterated chloroform): (M. D.) = 0,91 (s,3H,H-18);of 2.23 (s, 3H, H-21);3,79 (s,3H,3-och3);6,62 and 6,13 (2D, J = 6 Hz, each 1H,H-15 and H-16); of 6.66 (d, J = 3 Hz,1H,H-4);of 6.73 (DD, J = 9,3 Hz,1H,H-2);7,21 (d, J=9 Hz, 1H,H-1).

d) 20,20-/1,2-Atanderson(hydroxy)/-3-methoxy-14,17 - ethano-19-norpregna-2,5(10),15-triene

4.5 g Described in example g) make connections as described in examples 1B) and 1D) methods. Get 5,33 g of crude compound d).

1H-NMR (deuterated chloroform): (M. D.) = 0,98 (s,3H,H-18);of 1.32 (s, 3H,H-21);of 3.56 (s,3H,3-och3);3,93-4,07 (m,4H,20-och2CH2O-);4,65 (ush.s,1H, H-2);5,94-6,03 (2D, J = 6 Hz,each 1H,H-15 and H-16).

e) 14,17-Ethano-19-norpregna-4, 15-diene-3,20-dione

2.0 g Described in example d) make connections as described in example 1D) technique. Get 1,32 g of crude compound e).

So pl. 131-133o; []2D0= +32,0oC (CHCl3; = worn: 0.505).

1H-NMR (deuterated chloroform): (M. D.) = 0,93 (s,3H,H - 18);of 2.20 (s, 3H, H-21); 5,85 (ush.s,1H,H-4);6,05 and to 6.19 (2D, J = 6 Hz,each 1H,H-15 and H-16).

Example 47: 14, 17 Ethano-19-norpregna-4,6,15-triene-3,20 - dione

1.2 g Described in example e) make connections as described in examples 2A) and (26) methods. Get the ptx2">

1H-NMR (deuterated chloroform): (M. D.) = 0,94 (s,3H,H-18);of 2.21 (s, 3H,H-21);5,79 (ush.s,1H,H-4);6,14-6,34 (m,4H,H-6, H-7,H-15 and H-16).

Example 48: 14,17-Ethano-19-norpregna-4,9-15-triene-3,20 - dione

3.33 g Described in example d) make connections as described in examples 8b and 4B) methods. Get a 1.08 g of compound 48).

[]2D0= -272,4o(CHCl3; = value (0.475)).

1H-NMR (deuterated chloroform): (M. D.) = a 1.01 (s,3H,H-18);of 2.21 (s, 3H,H-21);5,70 (ush.s,1H,H-4);6,06 and 6.23 (2D, J =6 Hz, 2H,H-15 and H-16).

Example 49: 21-Hydroxy-14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione

(a) 3,3-/1,2-Atanderson(hydroxy)/-14,17-ethano-19 - norpregna-5(10),9 (11), 15-trien-20-he

1.0 g Described in example 48) make connections as described in example 1B) technique. Get to 0.29 g of compound 49A), and 0.7 g of the corresponding 3,20-baskets.

1H-NMR (deuterated chloroform): (M. D.) = 0,82 (s,3H,H-18);2,22 (s, 3H,H-21);of 4.00 (s,4H,3-och2CH2O-);5,51 (ush.s,1H, H-11);6,04 and 6,22 (2D, J = 6 Hz,2H,H-15 and H-16).

b) 21-Hydroxy - 14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione

0.28 g Described in example 49A) make connections as described in examples 5B), 5C), 1D) and e) methods. Get 11 mg of compound b).

1H-NMR (deuterated chlorof the l-14,17-ethano-19-norpregna-4, 15-diene - 3,20-dione

a) 20,20-/1,2-Atanderson(hydroxy)/-21-methyl-14,17 - ethano-19-norpregna-4,15-Dien-3-one

6.6 g Described in example g) make connections as described in examples 7a), 8A), 1G) and 8b) methods. Get 0,605 g of compound 50A), as well as 3,70 g of 20,20-/1,2 - atanderson(hydroxy)/-21-methyl-14,17-ethano-19-norpregna-5(10), 15-Dien-3-one.

12H-NMR (deuterated chloroform) to connect 50A): (M. D.) = 0,93 (t, J = 7 Hz,3H,H-22);0,99 (s, 3H,H-18);3,98-to 4.15 (m,4H,20-och2CH2O-);of 5.83 (ush.s,1H,H-4);5,96 (s,2H,H-15 and H-16).

1H-NMR (deuterated chloroform) for 20,20-/1,2-atanderson(hydroxy)/-21-methyl-14, 17-ethano-19-norpregna-5(10),15-Dien-3-one: (M. D.) = 0,94 (t, J = 7 Hz, 3H, H-22); of 0.96 (s, 3H, H-18); 2.70 and 2,80 (2D, J = 20 Hz, 2H, H-4); 3,96-to 4.14 (m, 4H, 20-OCH2CH2O-); 5,94 and 6,01 (2D, J = 6 Hz, 2H, H-15 and H-16).

b) 21-Methyl-14,17-ethano-19-norpregna-4,15-diene-3,20-dione

142 mg, Described in example 50A) make connections as described in example 1D) technique. Obtain 127 mg of the compound 50B). So pl. 140-141oC;

[]2D0= +25,4oC (CHCl3; = 0,495).

1H-NMR (deuterated chloroform): (M. D.) or = 0.90 (s,3H,H - 18);of 1.07 (t, J = 7 Hz,3H,H-22);5,85 (ush.s,1H,H-4)6,05 and of 6.20 (2D, J = 6 Hz,2H,H-15 and H-16).

Example 51: 21-Methyl-14, 17-ethano-19-norpregna-4,6,15 - triene-3,20-dione

460 mg of Opisaniya 51).

So pl. 153,5-154,5oC

[]2D0= -37,9o(CHCl3; = 0,490)

1H NMR (deuterated chloroform): (M. D.) = 0,93 (s, 3H, H-18); a 1.08 (t, J= 7 Hz, 3H, H-22); 5,80 (ush.s, 1H, H-4); 6,16-6,36 (m, 4H, H-6 and H-7 and H-15 and H-16).

Example 52: 21-Methyl-14, 17-ethano-19-norpregna-4,9-15-triene - 3,20-dione

3.7 g 20,20-/1,2-Atanderson(hydroxy)/-21-methyl-14,17 - ethano-19-norpregna-5(10), 15-Dien-3-one from example 50A) transform as described in examples 4B) and 1D) methods. Obtain 2.1 g of compound 52).

1H-NMR (deuterated chloroform): (M. D.)= 1,00 (s, 3H, H-18); a 1.08 (t, J - 7 Hz, 3H, H - 22); 5,70 (ush.s, 1H, H-4); 6,06 and 6,24 (2D, J= 6 Hz, 2H, H-15 and H - 16).

Examples 53 and 54:

53: (21R)-21-Hydroxy-21-methyl-14, 17 - ethano-19-norpregna-4,9,15-triene-3,20-dione

54: (21S) -21-Hydroxy-21-methyl-14, 17-ethano-19-norpregna-4, 9, 15-triene-3,20-dione

1,72 g Described in example 52) make connections as described in examples 9a), 5B), 5C), 1D) and e) methods. Obtain 198 mg of compound 53) and 250 mg of compound 54).

53: []2D0= -290,0o(CHCl3; = 0,520)

1H-NMR (deuterated chloroform): (M. D.) = 0,95 (s, 3H, H-18); to 1.38 (d, J= 7 Hz, 3H, H-22); 4,43-4,56 (m, 1H, H-21); 5,68 (ush.s, 1H, H-4); 6,15 and 6,22 (2D, J= 6 Hz, 2H, H-15 and H-16).

54: []2D0= -218,4o(CHCl3; = 0,515).

6,18 (2D, J = 6 Hz, 2H, H-15 and H-16)

Example 55: 16-Methyl-14, 17-ethano-19-norpregna-4, 15-diene - 3,20-dione

a) Methyl ester of 3-methoxy-20-oxo-14,17-ateno-19-norpregna - 1,3,5 (10) 15-tetraen-16-carboxylic acid

20 g Described in example 1A) compound, 20 ml of methyl ester propionovoi acid and 50 mg of hydroquinone is kept in a sealed tube in an argon atmosphere for 34 hours at a bath temperature of 110oC. After cooling, removal of volatile components and chromatography of the residue on silica gel using mixtures of ethyl acetate with hexane get 12,66 g of compound 55A).

So pl. 149-149,5oC; []2D0= -8,3o(CHCl3; = worn: 0.505)

1H-NMR (deuterated chloroform): (m DV = 1,30 (s, 3H, H-18; of 2.28 (s, 3H, H-21); to 3.73 and of 3.78 (2s, each 3H, 3-och3and CO2CH3); of 6.65 (d, J=3 Hz, 1H, H-4); of 6.73 (DD, J = 9 and 3 Hz, 1H, H-2); 6,76 and 7,02 (2D, J = 6 Hz, each 1H, H-171and H-172); then 7.20 (d, J = 9 Hz, 1H, H-1); 7,58 (s, 1H, H-15)

Methyl ester

b) 20,20-[1,2-atanderson (oxy)]-3 - methoxy-14,17-ateno-19-norpregna-1,3,5 (10),15-tetraen-16 - carboxylic acid

10,83 g Described in example 55A) make connections as described in example 1B) technique. Get 11,46 g connection street, 55A).

So pl. 147-147,5oC; []2D0= -14,7o(CHCl3; 3 and CO2CH3); 3,95-4,11 (m, 4H, 20-OCH2CH2O-); only 6.64 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J =9 and 3 Hz, 1H, H-2); 6,67 and 6.80 (2D, J - 6 Hz, each 1H, H-171and H-172); 7,21 (d, J = 9 Hz, 1H, H-1); to 7.50 (s, 1H, H-15).

C) Methyl ether 20,20-[1,2-atanderson (oxy)]-3-methoxy-14,17-ethano-19-norpregna-1,3,5(10),15 - tetraen-16-carboxylic acid

2.50 g Described in example street, 55A) compounds in a mixture of 250 ml of methanol and 250 ml of ethyl acetate in the presence of 100 mg of 10% palladium-on-coal hydronaut at normal pressure until the absorption of 1 equivalent of hydrogen. After filtering off the catalyst, concentration and chromatography on silica gel using mixtures of ethyl acetate with hexane get 1,99 g of compound 55V).

1H-NMR (deuterated chloroform): (M. D.) = 0,97 (s, 3H, H-18); and 1.54 (s, 3H, H-21); to 3.73 and of 3.78 (2s, each 3H, 3-och3and CO2CH3); 3,90-4,06 (m, 4H, 20 - och2CH2O-); only 6.64 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J= 9 and 3 Hz, 1H, H-2); 6,92 (s, 1H, H-15); 7,21 (d, J= 9 Hz, 1H, H-1).

g) 20,20/1,2-Atanderson(hydroxy)/-3-methoxy-14,17 - ethano-19-norpregna-1,3,5(10),15-tetraen-16-methanol

2,52 g Described in example 55V) compounds dissolved in 40 ml of tetrahydrofuran, mixed with 157 mg of zinc chloride. At a temperature of -78oC was added dropwise 24 ml of a 1.2 M solution of diisobutylaluminium in hkomnatnoy and extracted with ethyl acetate, the organic phase is washed with concentrated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After chromatography on silica gel using mixtures of ethyl acetate with hexane gain of 1.46 g of compound 55 g).

1H-NMR (deuterated chloroform): (M. D.) = 0,98 (s, 3H, H-18);of 1.39 (s, 3H, H-21); 3,24-of 3.32 (m, 1H, 16-CH2); of 3.78 (s, 3H, 3-och3); 3,94 is 4.13 (m, 4H, 20-och2CH2O-); 4,18-4.26 deaths (m, 1H, 16-CH2); 6,00 (ush.s, 1H, H-15); only 6.64 (d, J = 3 Hz, 1H, H-4);of 6.71 (DD, J=9 and 3 Hz, 1H, H-2); then 7.20 (d, J= 9 Hz, 1H, H-1).

d) 16-/(atomic charges)-methyl/-20,20-/1,2-atanderson(hydroxy)/- -3-methoxy-14,17-ethano-19-norpregna-1,3,5(10),15-tetraen

1,475 g Described in example 55) compound in 60 ml of pyridine at a temperature of 0oC dropwise mixed with 1.3 ml of acetylchloride. After incubation for 1.5 hours at room temperature, poured into ice concentrated solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed successively with concentrated solution of sodium bicarbonate and sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Obtain 1.85 g of crude compound 55 d).

1H-NMR (deuterated chloroform): (M. D.)= 0,97 (s, 3H, H-18); of 1.33 (s, 3H, H-21); of 2.09 (s, 5 (ush. s, 1H, H-15); only 6.64 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J =9 and 3 Hz, 1H, H-2); then 7.20 (d, J= 9 Hz, 1H, H-1).

e) 16-Methyl-14,17-ethano-19-norpregna-4,15-diene-3, 20-dione

1.73 g of Crude compound 55 d transform as described in examples 1G and 1D) methods. Obtain 34 mg of the compound a) and 92 mg, described in example 31 (b) connection.

1H-NMR (deuterated chloroform): (M. D.) = 0,96 (s, 3H, H-18); 1.77 in (ush. s, 3H, 16-CH3); 2,17 (s, 3H, H-21); 5,62 (ush.s, 1H, H-15); of 5.84 (ush.s, 1H, H-4).

Example 56: 15,16-Dimethyl-14,17-ateno-19-norpregna-4 - ene - 3,20-dione

a) Methyl ether 20,20-/1,2-atanderson(hydroxy)/- 3-methoxy-15-methyl-14,17-ateno-19-norpregna-1,3,5(10)-triene - 16-carboxylic acid

To 30,47 g of copper iodide-(1) in 420 ml of diethyl ether at a temperature of 0oC was added dropwise 200 ml of 1.6 M solution metallice in diethyl ether. After keeping for 30 minutes at this temperature, diluted with 500 ml of tetrahydrofuran. After cooling to -50oC was added dropwise a solution of 7.0 g described in example street, 55A) compound in 200 ml of tetrahydrofuran. After warming to 0oC was incubated for 4 hours at this temperature. After adding a concentrated solution of chloride ammonia at a temperature of -20oC, the reaction mixture was partitioned between water and ethyl acetate, Altria, dried over sodium sulfate, filtered, concentrated and the residue chromatographic on silica gel using mixtures of ethyl acetate with hexane, get 5,47 g of compound 56a).

1H-NMR (deuterated chloroform): (M. D.) = 1,18 (d, J = 7 Hz, 3H, 15-CH3); of 1.20 (s, 3H, H-18); of 1.30 (s, 3H, H - 21); 3,14 (d, J= 5 Hz, 1H, H-16); 3,62 (s, 3H, CO2CH3); of 3.78 (s, 3H, 3-och3); 3,79 is 4.13 (m, 4H, 20-och2CH2O-); 5,98 and 6,30 (2D, J= 6 Hz, each 1H, H-171and H-172); only 6.64 (d, J = 3 Hz, 1H, H-4); 6,72 (DD, J = 9 and 3 Hz, 1H, H-2); then 7.20 (d, J = 9 Hz, 1H, H-1).

b) 15,16-Dimethyl-14,17-ateno-19-norpregna-4-ene-3,20 - dione

2.0 g Described in example 56a) make connections as described in the examples 28V), 34a), 34B), 1G and 1D) methods. Get 303 mg connection b). []2D0= +99,8o(CHCl3; = 0,510)

1H-NMR (deuterated chloroform): (M. D.)= 0,88 and 1.05 (2D, J = 7 Hz, each 3H, 15-CH3and 16-CH3); the 1.04 (s, 3H, H-18); and 2.14 (s, 3H, H-21) 5,85 (ush.s, 1H, H-4); and 6,01 of 6.20 (2D, J = 6 Hz, each 1H, H-171and H-172).

Example 57: 15,16-Dimethyl-14,17-ethano-19-norpregna-4-ene-3,20-dione

1.48 g Described in example 56a) make connections as described in the examples 28V), 34a), 34B) 55V), 1G and 1D) methods.

Obtain 223 mg of compound 57).

So pl. 212-214oC; []23and 16-CH3); a 1.08 (s, 3H, H-18); of 2.09 (s, 3H, H-21); of 5.82 (ush.s, 1H, H-4).

Example 58: 2', 5' 15,16-tetrahydrofuro/3',4'; 15,16/-14,17-ateno-19-norpregna-4-ene-3, 20-dione,

a) 15,16-Dihydro-3-methoxy/2H,5H/furo/3', 4', 15,16/- 14,17-ateno-19-norpregna-1,3,5(10)-trien-2',5',20-Trion

10.0 g Described in example la) compounds and 10.0 maleic anhydride is stirred for 18 hours in an argon atmosphere at a temperature of 95oC. After removal of excess maleic anhydride in a high vacuum, the residue is crystallized from diisopropyl ether. Gain of 9.8 g of compound 58A).

So pl. 186 - 187oC (decomposition); []2D0= +197,0o(CHCl3; = 0,500)

1H-NMR (deuterated chloroform): (M. D.) = 1,00 (s, 3H, H-18); of 2.35 (s, 3H, H-21); 3.57 and 4,47 (2D, J = 8 Hz, each 1H, H-15 and H-16); 3,79 (s, 3H, 3-och3); 6,41 and of 6.49 (2D, J = 6 Hz, each 1H, H-171and H-172); 6,66 (d, J= 3 Hz, 1H, H-4); of 6.73 (DD, J= 9 and 3 Hz, 1H, H-2); to 7.18 (d, J = 9 Hz, 1H, H-1),

b) 20,20-/1,2-Atanderson(hydroxy)/-14, 17-ateno-19-norpregna-1,3,5(10)-triene - 15,16-dimethanol

the 5.45 g Described in example 58A) make connections as shown in the examples 34g), 7b), 1B) and 28V) methods. Get 4,13 g of crude compound b).

1H-NMR (deuterated chloroform): (M. D.) = a 1.01 (s, 3H, H-18); of 1.42 (s, 3H, H-21): 3,48-3.58 and, = 6 Hz, each 1H, H-171and H - 172); 6,63 (d, J= 3 Hz, 1H, H-4); 6,72 (DD, J = 9 and 3 Hz, 1H, H-2); 7,19 (d, J = 9 Hz, 1H, H-1).

in) 20,20-/1,2-Atanderson(hydroxy)/-3-methoxy-2',5', 15,16-tetrahydrofuro/3',4': 15,16/-14,17-ateno-19-norpregna-1,3,5(10)-triene

4.1 g Described in example b) compounds in a mixture of 70 ml of dichloromethane and 14 ml of pyridine is cooled to 0oC dropwise and mixed in with General 3,34 ml of the acid chloride of methansulfonate. After stirring for three hours at room temperature, the reaction mixture is mixed with a concentrated solution of sodium bicarbonate. After 20 minutes partitioned between water and ethyl acetate, the organic phase is washed with a concentrated solution of sodium bicarbonate and sodium chloride solution, dried over sodium sulfate, filtered, concentrated and chromatographic on silica gel using mixtures of ethyl acetate with hexane. Get 0,81 g of compound 58B).

So pl. 148-150oC; []2D0= +135,0oC (CHCl3; from = to 0.480)

1H-NMR (deuterated chloroform); (M. D.)= 1,19 (s, 3H, H-18); of 1.30 (s, 3H, H-21); 3,34-a 3.83 (m, 4H, 15-CH2and 16-CH2); 3,79 (s, 3H, 3-och3); 3,85-4,08 (m, 4H, 20-och2CH2O-); 6, 12 and 6,18 (2D, J= 6 Hz, each 1H, H-171and H-172); 6,63 (d, J= 3 Hz, 1H, H-4); 6,72 (DD, J= 9 and 3 g Described in example 58B) make connections as described in examples 1G and 1D) methods. Get to 0.23 g of compound g). So pl. 163 - 165oC; []2D0= +149,8o(CHCl3; = 0,485)

1H-NMR (deuterated chloroform) (M. D.) = 1,08 (s, 3H, H-18); 2,17 (s, 3H, H-21); to 3.33-3.46 in and of 3.60 is 3.76 (2m, each 2H, 15-CH2and 16-CH2); 5,88 (ush.s, 1H, H-4); 6,21 and 6,27 (2D, J = 6 Hz, each 1H, H-171and H-172).

Example 59: 2',5', 15,16-Tetrahydrofuro/3',4':15,16/-14, 17-ethano-19-norpregna-4-ene-3,20-dione

0.4 g Described in example 58B) make connections as shown in the examples 55V), 1G and 1D) methods. Get 0,234 g of compound 59).

So pl. 187-189oC; []2D0= +72,8o(CHCl3; = 0,520).

Example 60: 14,17-Ethano-18a-Homo-19-norpregna-4,15-diene-3,20-dione

a) 3-Methoxy-14,17-ethano-18a-Homo-19-norpregna-1,3,5(10)- tetraen-20-he

34,0 g of 3-methoxy-15-methyl-18a-gamestro-1,3,5(10), 15 - tetraen-17-it (see patent application Germany A1 - 3710728) transform as described in the examples 38A), 1A), 58A) and (18a) methods and then treated with 2n sodium hydroxide solution in tetrahydrofuran. 2.0 g of the Obtained dicarboxylic acid crude product was dissolved in 20 ml of pyridine, mixed with 2.2 g of leads to compounds, which lead and heated for 10 hours at 70oC. After the reaction mixture contribute in 4 n hydrochloric acid. On the Receive 90 mg of compound 60A)

1H-NMR (deuterated chloroform): (M. D.) = 0,62 (t,J =7 Hz, 3H, H-18); of 2.25 (s, 3H, H-21); of 3.78 (s, 3H, 3-och3); 6,10 and 6.26 (2D, J = 6 Hz, each 1H, H-15 and H-16); of 6.65 (d, J= 3 Hz, 1H, H-4); 6,72 (DD, J = 9,3 Hz, 1H, H-2); 7,19 (d, J = 9 Hz, 1H, H-1).

b) 14,17-Ethano-18a-Homo-19-norpregna-4,15-diene-3,20-dione

115 mg, Described in example 60A) make connections as described in examples 1C), 1D) and 1D) methods. Obtain 18 mg of the compound 60B).

1H-NMR (deuterated chloroform): (M. D.) = 0,63 (t, J = 8 Hz, 3H, H-18); of 2.23 (s, 3H, H-21); 5,86 (ush.s, 1H, H-4); 6,03 and 6,24 (2D, J= 5 Hz, each 1H, H-15 and H-16).

1. 14,17-C2-bridged steroids of General formula I

< / BR>
where R3means an oxygen atom;

R6means a hydrogen atom or located in or position (C1-C4)-alkyl residue, and then R6and R7represents a hydrogen atoms, or R6means a hydrogen atom or a (C1-C4)-alkyl residue, and then R6and R7together form an additional bond;

R7means located in or permanent position (C1-C4)-alkyl residue, and then R6and R6represent hydrogen atoms, or

R9and R10each mean is brisout communication;

R13means a methyl or ethyl group;

R15means a hydrogen atom or a (C1-C3)-alkyl residue;

R16and R16independently from each other mean a hydrogen atom, (C1-C3)-alkyl residue, or (C2-C4)-alkanniny residue or together denote (C1-C3)-alkylidene group;

R15and R16together form a bond, and R16means a hydrogen atom or a (C1-C3)-alkyl residue, or R15and R16together form a cycle of partial formula

< / BR>
where n = 1, and X means an oxygen atom, and R16means a hydrogen atom;

means a hydrogen atom or a (C1-C3)-alkyl residue;

means a hydrogen atom, (C1-C3)-alkyl residue;

and each means a hydrogen atom or together form a bond;

R21means a hydrogen atom or a (C1-C3)-alkyl residue;

R21means a hydrogen atom, (C1-C3)-alkyl residue or a hydroxyl group;

except for the connection 14,17-ethano-19-norpregna-4-ene-3,20-dione.

2. 14,17-C2-bridged steroids of General formula I on p. 1, wherein R6oz the
and R7mean hydrogen atoms.

3. 14,17-C2-bridged steroids of General formula I on p. 1, wherein R6means a hydrogen atom or a (C1-C4)-alkyl residue, when R6and R7together form an additional bond.

4. 14,17-C2-bridged steroids of General formula I on p. 1, wherein R16and R16each mean a hydrogen atom, methyl group, or one of these two substituents means (C1-C4)-alkyl or vinyl group, and the other of these two substituents means a hydrogen atom, or both Deputy together imply (C1-C3)-alkylidene group.

5. 14,17-C2-bridged steroids of General formula I on p. 1, characterized in that means a hydrogen atom or a (C1-C3)-alkyl residue, a represents a hydrogen atom, (C1-C3)-alkyl residue, or (C2-C4)-alkanniny residue, and each mean a hydrogen atom or together form an additional bond.

6. 14,17-C2-bridged steroids of General formula I on p. 1, wherein R21means a hydrogen atom or a (C1-C3)-alkyl residue, and R21means atomawashi fact, which the alkyl residue in the value of R6, R7, R15, R16, R16, , , R21and/or R21means a methyl or ethyl residue.

8. 14,17-C2-bridged steroids of General formula I on p. 1, wherein (C2-C4)-alkanniny the remainder in the value of R16, R16is a vinyl residue.

9. 14,17-C2-bridged steroids of General formula I on p. 1 representing:

14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

14,17-ethano-19-norpregna-4,15-diene-3,20-dione;

14,17-ethano-19-norpregna-4,6,15-triene-3,20-dione;

14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4,15-diene-3,20-dione;

21-methyl-14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione;

4,17-ateno-19-norpregna-4-ene-3,20-dione, example 1D;

14,17-ateno-19-norpregna-4,6-diene-3,20-dione, example 2B;

21-methyl-14,17-ateno-19-norpregna-4-ene-3,20-dione;

21-methyl-14,17-ateno-19-norpregna-4,9-diene-3,20-dione;

21-methyl-14,17-ateno-19-norpregna-4,9,11-triene-3,20-dione;

21-hydroxy-14,17-ATEE. 47;

171-methyl-14,17-ateno-19-norpregna-4-ene-3,20-dione;

171-methyl-14,17-ateno-19-norpregna-4,6-diene-3,20-dione;

172-methyl-14,17-ateno-19-norpregna-4-ene-3,20-dione, is an example 38g, page 82;

172-methyl-14,17-ateno-19-norpregna-4,9-diene-3,20-dione;

15, 16-dimethyl-14,17-ateno-19-norpregna-4-ene-3,20-dione;

6-methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

6-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

15, 16-dimethyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-methyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

16-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

16,21-dimethyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

21-hydroxy-16-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-ethyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-ethynyl-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-methyl-14,17-ethano-19-norpregna-4,15-diene-3,20-dione;

(171R)-171-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione, example 12, page 57;

(171S)-171-methyl-14,17-ethano-19-norpregna-4-ene-3,20-dione, example 13, page 57;

(171R)-171-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione, example 14, the data page 58;

(171S)-171-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione, example 15, the data page 58;

(172R)-17
(172R)-172-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

(172R)-172,21-dimethyl-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

(172R)-172,21-dimethyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

(172R)-172,21-dimethyl-14,17-ethano-19-norpregna-4,9,11-triene-3,20-dione;

16-methylene-14,17-ethano-19-norpregna-4-ene-3,20-dione;

16-methylene-14,17-ethano-19-norpregna-4,6-diene-3,20-dione;

16-methylene-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

21-hydroxy-14,17-ethano-19-norpregna-4-ene-3,20-dione;

21-hydroxy-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

21-hydroxy-14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione, is an example b, page 90;

(21R)-21-hydroxy-21-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione;

(21S)-21-hydroxy-21-methyl-14,17-ethano-19-norpregna-4,9-diene-3,20-dione, example 27, the data page 67 (middle);

(21R)-21-hydroxy-21-methyl-14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione;

(21S)-21-hydroxy-21-methyl-14,17-ethano-19-norpregna-4,9,15-triene-3,20-dione, example 54, the data page 93;

14,17-ethano-18a-Homo-19-norpregna-4-ene-3,20-dione;

14,17-ethano-18a-Homo-19-norpregna-4,15-diene-3,20-dione.

10. Pharmaceutical drug with gestagenna action based activitiesthese substances and common purpose additives, characterized in that act as well as pharmaceutically acceptable carrier.

11. 14,17-C2-bridged steroids of General formula I on p. 1 with gestagennami action.

 

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The invention relates to the field of chemical processing of birch bark (outer layer of birch bark)

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

The invention relates to covered bridge in position 1417thestratriene General formula I

< / BR>
where

if OR3is set tothen

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

if OR3is in "beta", then

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

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

The invention relates to organic chemistry, specifically to a method for producing triterpene glycopeptides derived glycyrrhizic acid (GA) using unprotected glycoside (carboxy-component) and free amino acids or dipeptides (aminoquinones AK)

The invention relates to new steroid, namely steroid with a 17-spermatocelectomy group having the General formula I, where R1is O, (H, H), (H, or), or NOR, and R is selected from H, (1-6C) alkyl and (1-6C) acyl; R2is H, (1-6C)akilam arbitrarily substituted with halogen, (2-6C)alkenyl arbitrarily substituted with halogen, (2-6C)quinil arbitrarily substituted with halogen, or halogen; R2is H; or R'2together with R2is (1-6C)alkylidene group or (2-6C)allenylidene group; or R'2together with R3are bond; R3is N, if R'2is not a bond; R4is (1-6C)alkyl; one of R5and R6is hydrogen and the other is hydrogen or (1-6C) alkyl; X is (CH2)nor (CnH2n-2), where n is 2 or 3, which is arbitrarily substituted with hydroxyl, halogen, (1-6C)alkyl, (1-6C)acyl, (7-9C)phenylalkyl, phenyl group which may be substituted (1-6C)alkyl, (1-6C)alkoxyl, hydroxyl or halogen; Y is O or (H, HE) and dashed lines show a random link, and at least one of the links 4-5, 5-10 and 9-10 is a double bond

The invention relates to novel condensed polycyclic heterocyclic compounds of the formula I and the way they are received
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