Derivatives of vitamin-d compounds, pharmaceutical composition, a therapeutic agent, the method of treatment

 

(57) Abstract:

The invention relates to a derivative of vitamin D formula (1):

Formula 1

where X = -O - or-S- ; m = 1, 2, 3; R1and R2-H or alkyl; R4-H; R5Is H, OH or R4and R5together form a double 16, 17 connection, R3- YR8where Y is-O - or-S-,

R8-H, alkyl, possibly substituted by F or cycloalkyl, or-NR9R10where R9and R10 -H, alkyl, possibly substituted by F or cycloalkyl, R6-OH, possibly substituted, R7-H or a protective group. Compounds 1 are useful as therapeutic agents for the treatment of skin diseases such as psoriasis, and they have a reduced hypercalcemic effect. 11 N. and 14 C.p. f-crystals, 46 PL.

The scope of the invention

The present invention relates to a derivative of vitamin D, and more particularly to a derivative of vitamin D, which are useful as medicines (i.e., therapeutic agents for the treatment of skin diseases such as psoriasis).

Background of the invention

In vivo, vitamin D3or 24R,25-dihydroxyvitamin D3in the kidneys as a result of hydroxylation of 1 - or 24-position, respectively. Among these metabolites, as you know, 1,25-dihydroxyvitamin D3and its synthetic analogues have a broad spectrum of physiological activities, including the activity of regulating calcium metabolism, activity, inhibitory growth or differentiation of tumor cells, or the like, and immunoregulatory activity.

With vitamin D3is this a problem that he, apparently, causes hypercalcemia, if it is continuously used for a long period of time. To solve this problem, attempts were made to synthesize various derivatives of vitamin D; proposed some derivatives of vitamin D, which have a reduced hypercalcemic effect (for example, in JP 7-330714 A and JP 10-231284 A).

The aim of the present invention is to provide derivatives of vitamin D, which have excellent physiological activities as medicines, particularly as therapeutic agents for the treatment of skin Scania inventions

In such circumstances, the authors of the present invention have focused on compounds with ester or amide structures in their side chains, and made extensive and intensive efforts to obtain derivatives of vitamin D, which differ reduced hypercalcemic effect. The authors found that the desired goal can be achieved by using a derivative of vitamin D formula (1):

where X represents an oxygen atom or a sulfur atom;

m represents a number from 1 to 3;

R1and R2each represents a hydrogen atom or alkyl group;

R4and R5each represents a hydrogen atom or hydroxyl group, or R4and R5together form a double bond between the 16 - and 17-positions;

R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched alkyl group which may be substituted by one or more fluorine atoms or a cyclic alkyl group, or a cyclic alkyl group which may be substituted by one or newset a hydrogen atom, straight or branched alkyl group which may be substituted by one or more fluorine atoms or a cyclic alkyl group, or a cyclic alkyl group which may be substituted by fluorine atom, or R9and R10may form a ring together with the nitrogen atom, if R4and R5together form a double bond between the 16 - and 17-positions);

R6represents a hydrogen atom or-OR11(where R11represents a hydrogen atom or a protective group);

R7represents a hydrogen atom or a protective group;

and thus the authors have carried out one aspect of the present invention.

So, in the present invention proposed a derivative of vitamin D formula (1).

In the formula (1) preferably, when X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 3, R1and R2each represents a hydrogen atom or1-C4alkyl group, R4and R5each represents a hydrogen atom or hydroxyl group, or R4and R5together form a double bond between the 16 - and 17-OST">8represents a hydrogen atom, a straight or branched C1-C15alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C10alkyl group, or a cyclic3-C15alkyl group which may be substituted by one or more fluorine atoms), or-NR9R10(where R9and R10each represents a hydrogen atom, a straight or branched C1-C15alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C10alkyl group, or a cyclic3-C15alkyl group which may be substituted by one or more fluorine atoms, or R9and R10form a 3-10-membered ring together with the nitrogen atom, if R4and R5together form a double bond between the 16 - and 17-positions), R6represents a hydrogen atom or hydroxyl group, and R7represents a hydrogen atom.

Preferably also, if in the formula (1), X represents an oxygen atom or atom seryu group, R4and R5at the same time represent a hydrogen atom, or R4represents a hydrogen atom when R5 represents a hydroxyl group, or R4and R5together form a double bond between the 16 - and 17-positions, R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched C1-C10alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C8alkyl group, or a cyclic3-C12alkyl group which may be substituted by one or more fluorine atoms), or-NR9R10(where R9and R10each represents a hydrogen atom, a straight or branched C1-C10alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C8alkyl group, or a cyclic3-C12alkyl group which may be substituted by one or more fluorine atoms, or R9 is form a double bond between the 16 - and 17-positions), R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched C1-C8alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C8alkyl group, or a cyclic3-C8alkyl group which may be substituted by one or more fluorine atoms), or-NR9R10(where R9and R10each represents a hydrogen atom, a straight or branched C1-C8alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH9and R10form a 3-8-membered ring together with the nitrogen atom, if R4and R5together form a double bond between the 16 - and 17-positions), R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched C1-C8alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C6alkyl group, or a cyclic3-C8alkyl group which may be substituted by one or more fluorine atoms), R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents the atom bodoro R1and R2each represents a hydrogen atom or methyl group, R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R3is-NR9R10(where R9and R10each represents a hydrogen atom, a straight or branched C1-C8alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C6alkyl group, or a cyclic3-C8alkyl group which may be substituted by one or more fluorine atoms, or R9and R10form a 3-6-membered ring together with the nitrogen atom, if R4and R5together form a double bond between the 16 - and 17-positions), R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R3pridinol group), R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom or a sulfur atom, m represents 1 or 2, R1and R2each represents a hydrogen atom or methyl group, R3is-SR8(where R8is branched C3-C8alkyl group), R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom or a sulfur atom, m represents 1, R1and R2each represents a hydrogen atom or methyl group, R3is-NR9R10(where R9represents a hydrogen atom or a straight or branched C1-C4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R3is-OR8(where R8is branched C6-C8alkyl group), R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or a methyl group, provided that one of R1and R2must represent a methyl group,8alkyl group), R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom, m represents 1, R1and R2each represents a hydrogen atom or a methyl group, provided that one of R1and R2must represent a methyl group,R3is-NR9R10(where R9represents a hydrogen atom or methyl group, R10is a straight or branched C1-C4alkyl group which may be substituted by one or more fluorine atoms), R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

In the formula (1) preferably, when X represents an oxygen atom, m represents 1, R1and R2each represents a hydrogen atom or a methyl group, provided that one of R1R10(where R9represents a hydrogen atom, R10is sawn group which may be substituted by one or more fluorine atoms), R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

Preferred derivatives of vitamin D of the present invention include:

1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19),16-tetraen,

1,3-dihydroxy-20(S)-(1-isopropyl-2-methylpropanesulfonate)-9,10-scoprega-5,7,10(19),16-tetraen,

1,3-dihydroxy-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraen,

1,3-dihydroxy-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraen,

1,3-dihydroxy-20(S)-{2-(1-ethyl-1-methylpropanesulphonic)ethoxy}-9,10-scoprega-5,7,10(19),16-tetraen,

{(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide and

1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19)-triene.

In another aspect the present invention provides FA the present invention provides a therapeutic agent for the treatment of skin diseases, which contains as an active ingredient the above-mentioned derivative of vitamin D. Skin disease is preferably psoriasis.

In another aspect the present invention provides the use of the above derivative of vitamin D to obtain a therapeutic agent for the treatment of skin diseases. Therapeutic agent for the treatment of skin diseases is preferably a therapeutic agent for the treatment of psoriasis.

In another aspect of the present invention, a method for treatment of skin diseases using the above derivative of vitamin D, for example a method that includes a step of introducing a therapeutically effective amount of a derivative of vitamin D in need of such treatment to the patient. Skin disease is preferably psoriasis.

In addition, in the present invention proposed a convenient method for obtaining compounds that can be used as an intermediate connection when receiving the above-mentioned derivative of vitamin D. namely, in the present invention, a method for carbonylation of compounds of formula (2)

where R12and R13cadastrale, in the presence of alyuminiiorganicheskikh reagent and a palladium catalyst in an atmosphere of carbon monoxide, to obtain the compounds of formula (3):

where R12and R13have indicated in the formula (2) values, and R15represents alkyl group, aryl group, alkenylphenol group or alkylamino group.

In the above method alyuminiiorganicheskikh reagent preferably has the formula (4):

where n is an integer from 1 to 3, R15represents alkyl group, aryl group, alkenylphenol group or alkylamino group, and W represents a halogen atom.

The preferred embodiment of the invention

Further information will be disclosed variants of the embodiment of the present invention and methods of obtaining derivative of vitamin D formula (1) in accordance with the present invention and containing the pharmaceutical composition. This application claims priority based on Japanese patent applications No. 2000-179251, 2000-351412 and 2000-375024, the content of which is included here for your reference in its entirety.

In the sense used here, the term "alkyl group" is usually S="POST">3-C15alkyl group, unless otherwise noted. Alkyl groups, such as R1and R2preferably contain from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms. Specific examples include methyl, ethyl, n-butyl, with methyl preferred. Straight or branched alkyl groups, such as R8, R9and R10preferably contain from 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms. Most preferably, if R8is branched C6-C8alkyl group, and R9and R10each is a straight or branched C1-C4alkyl group. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, tert-pentyl, 1-ethyl-1-methylpropyl, 1-isopropyl-2-methylpropyl, 1,1-diethylpropion, 1,1-dimethylbutyl, 1,1-dimethylpentyl, n-hexyl, n-heptyl, n-octyl, nonyl and decanoyl. The preferred methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, tert-pentyl, 1-ethyl-1-methylpropyl, 1-isopropyl-2-methylpropyl, 1,1-diethylpropion, 1,1-dimethylbutyl and 1,1-diethylhexyl and b is Il, 1,1-dimethylbutyl and 1,1-diethylhexyl. The most preferred R8include 1-ethyl-1-methylpropyl or 1,1-diethylhexyl, R9is methyl, and R10represents n-propyl.

Examples of cyclic alkyl groups generally include those which contain from 3 to 15 carbon atoms, preferably from 3 to 12 carbon atoms and more preferably from 3 to 8 carbon atoms. In particular, cyclic C3-C6an alkyl group is preferable as the substituent is straight or branched alkyl groups. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecane, cyclododecane and cyclopentadienyl.

Straight or branched alkyl group which may be substituted by one or more fluorine atoms or a cyclic alkyl group, or a cyclic alkyl group which may be substituted by one or more fluorine atoms, usually called straight, branched or cyclic alkyl groups, such as the ones listed above, in which at least one of hydrogen atoms substituted by fluorine atom or a cyclic alkyl group. RA is respectfully 3-15 fluorine atoms, more preferably 3-12 fluorine atoms and most preferably 3 to 8 fluorine atoms.

Protective group, such as R7, R11, R12and R13may be the same or different, and examples include an acyl group, an optionally substituted alkyl group and a substituted silyl group. Specific examples include methyl, methoxymethyl, methylthiomethyl, tert-butylthioethyl, (phenyldimethylsilane)methoxymethyl, benzoyloxymethyl, p-methoxybenzyloxy, p-chlorobenzoyloxy, (4 methoxyphenoxy)methyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloromethyl, 2-(trimethylsilyl)ethoxymethyl, phenylthiomethyl, cyclopropylmethyl, tetrahydropyranyl, tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxyestradiol, 4-methoxycarbonylaminophenyl, 4-methoxycarbonylaminophenyl, S,S-dioxide, 1,4-dioxane-2-yl, tetrahydrofuranyl, tetrahydrofuranyl, pencil, p-bromfenac, 1-ethoxyethyl, methoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methylbenzylamine, 1-methyl-1-benzyloxy-2-foretel, 2,2,2-trichloroethyl, 2-trimethylsilylmethyl, 2,2-dichloro-1,1-dottorati, allyl, tert-butyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, 3,4-d is vensil, 4-(dimethylaminoethyl)benzyl, 2-picolyl, 4-picolyl, diphenylmethyl, p,p'-dinitrobenzamide, 5-dibenzosuberyl, triphenylmethyl, p-methoxyphenylalanine, di(p-methoxyphenyl)phenylmethyl, three(p-methoxyphenyl)methyl, 9-antrel, 1,3-benzodithiol-2-yl, benzisothiazole, S,S-dioxide, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylazobenzene, diethylenediamine, dimethylhexylamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-silisili, triphenylsilane, diphenylmethylsilane, tert-butylmethacrylate, formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, methoxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl, substituted, cyclohexanecarbonyl, benzoyl, 4-nitrobenzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, Naftoli, toluoyl, 9-fluorocarbons, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzenesulfonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichlorocyanuric, 2-(trimethylsilyl)etoxycarbonyl, 2-(methylthiomethyl)etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, ISO-butoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, p-nitrophenylacetylene, 3,4-dimethoxyphenylacetone, o-nitrobenzenesulfenyl and phenylenecarbonyl. Preferred substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylazobenzene, diethylenediamine, dimethylhexylamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylamine, three-p-silisili, triphenylsilane, diphenylmethylsilane and tert-butylmethacrylate, or acyl groups such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, methoxyacetyl, triphenylmethyl, phenoxyacetyl, propionyl, butyryl, isobutyryl, 4-(methylthiomethyl)butyryl, pivaloyl, substituted, cyclohexanecarbonyl, benzoyl, 4-nitrobenzoyl, 4-chlorobenzoyl, 2-iodobenzoyl, 4-methoxybenzoyl, p-phenylbenzyl, Naftoli, toluoyl and 9-fluorocarbons. More preferred triethylsilyl, triisopropylsilyl, dimethylazobenzene, diethylenediamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilane, diphenylmethylsilane, acetyl, pivaloyl, benzoyl and 4-methoxybenzoyl.

Examples tseplyaesh groups, such as R14include halogen atoms such as chlorine atoms, bromine and iodine, sulfonyloxy, such as tripterocalyx, pentafluoroethanesulfonyl, nonatherosclerotic, methanesulfonic is lexi, diethylphosphonate, diphenylphosphoryl, preferably bromine atoms, iodine, tripterocalyx, nonatherosclerotic.

Upon receipt of the compounds of the formula (3) according to the method of the present invention, the solvent for use in the carbonylation process, you can choose accordingly, but the preferred organic solvents. The term organic solvent is used to denote a liquid substance that is inert to the substrate of the reaction, and examples include N,N-dimethylacetamide, N,N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, tert-butyl methyl ether, ethyl ether, isopropyl ether, acetone, methyl ethyl ketone, ethyl acetate, methylene chloride, 1,2-dichloroethane, toluene, benzene, and chlorobenzene. Preferred N,N-dimethylacetamide, N,N-dimethylformamide and 1,3-dimethyl-2-imidazolidinone and the preferred N,N-dimethylacetamide.

Upon receipt of the compounds of formula (3) according to the method of the present invention, the term alyuminiiorganicheskikh reagent refers to a compound of formula (4):

where n represents the integer 1, 2 or 3;

R15represents an alkyl group, articleno1-C15alkyl group or cyclic WITH3-C15alkyl group, the term aryl group means a phenyl group which may have substituents, such as alkyl, halogen or nitro, the term Alchemilla group means a straight or branched C2-C15Deputy containing a double bond, and the term Alchemilla group means a straight or branched C2-C15Deputy containing a triple bond; W represents a halogen atom such as chlorine, bromine or iodine.

Examples include trimethylaluminum, dimethylammoniumchloride, dimethylaminopropyl, diethylaluminium, methylaluminoxane, methylaluminoxane, methylacetanilide, triethylaluminium, diethylaluminium, diethylaluminium, diethylaluminium, ethylaminoethanol, ethylaluminum, ethylaminomethyl, tri-n-Propylamine, di-n-propylalanine, di-n-propylalanine, di-n-propylaminoethyl, n-properlyinstalled, n-propylaminosulfonyl, n-propylaminoethyl, tri-n-butylamine, di-n-butylaminoethyl, di-n-butylaminoethyl, di-n-butylaminoethyl, n-butylimidazole, n-Buti is, fenilalaninei, vanillymandelic, phenylalaninamide and phenylalaninamide. Preferred trimethylaluminum, dimethylammoniumchloride, methylaluminoxane, triethylaluminium, diethylaluminium, ethylaminoethanol, tri-n-Propylamine, di-n-propylalanine, n-properlyinstalled, tri-n-butylamine, di-n-butylaminoethyl, n-butylimidazole, triphenylamine, diphenylalanine and vanillymandelic. More preferred dimethylammoniumchloride, diethylaluminium, di-n-propylalanine, di-n-butylaminoethyl and diphenylalanine.

The term palladium catalyst refers to zero - or bivalent compound of palladium, which can have a corresponding ligand. Examples include tetrakis (triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichloro[1,3-bis(diphenylphosphino)propane]palladium, dichloro[1,2-bis (diphenylphosphino)ethane]palladium, bis(dibenzylideneacetone) palladium and Tris(dibenzylideneacetone)dipalladium, preferably tetrakis(triphenylphosphine)palladium.

The following table 1-44 demonstrate limitiruyuschie examples of derivatives of vitamin D formula (1) of the present invention.8; and in tables 25-44 R3is NR9R10.

Derivatives of vitamin D formula (1) of the present invention can be obtained as follows. However, obtaining derivatives are not strictly limited to these methods, and synthesis can be used in other procedures.

I. Obtaining derivatives of vitamin D formula (1) in which X represents an oxygen atom

Derivatives of vitamin D formula (1), where X represents an oxygen atom, R6represents a hydroxyl group, and R7represents a hydrogen atom, can be obtained as follows, based on the compounds of formula (A) described in JP 61-267550 A or E. Murayama e

(Stage 1) preparation of hydrazone

The compound (A) in a suitable solvent is treated with arylsulfonamides or alkylsulfonamides to obtain compound (B).

Examples of arylsulfonamides or alkylsulfonamides suitable for use in this reaction includes benzosulfimide, p-toluensulfonate, m-toluensulfonate, o-toluensulfonate, 4-ethylbenzaldehyde, 2-mesitylenesulfonic, 4-chlorobenzenesulfonamide, 4-isopropylbenzaldehyde, 2,4,6-triisopropylbenzenesulfonyl, methysulfonylmethane, 2-methyl-2-propanesulfonate, 2-propanesulfonate and acanaloniidae. Preferred benzosulfimide, p-toluensulfonate and 2,4,6-triisopropylbenzenesulfonyl and more preferred 2,4,6-triisopropylbenzenesulfonyl.

Examples of solvents suitable for use in this reaction include solvents based on hydrocarbons, ethers, Halogens, esters, amides, alcohols, sulfoxidov and NITRILES. Specific examples include hexane, benzene, toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy the Etat, methyl acetate, propyl, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, methanol, ethanol, isopropanol, dimethyl sulfoxide, acetonitrile and propionitrile. The preferred toluene, diethyl ether, tetrahydrofuran, dichloromethane and ethyl acetate and the preferred tetrahydrofuran and ethyl acetate.

The reaction can be conducted at any temperature at which it can flow, preferably at a temperature of from 0°C to 100°C, more preferably at room temperature.

(Stage 2) Alkylation

Then the compound (B) in an appropriate solvent is treated with a base, then formaldehyde (or its equivalent, such as 1,3,5-trioxane and paraformaldehyde or acetone to obtain the compound (C).

Examples of bases suitable for use in the above reaction include n-utility, second-utility, tert-utility, motility, finality, methylacrylamide, methylaniline, methylmagnesium, isopropylacrylamide, Diisopropylamine, sitedisability, lithium bis (trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidine, litigated, sodium hydride, sodium bis(trimethylsilyl)ATI and sitedisability and more preferred n-utillity and second-utility.

In the above reaction, after the reaction with base, you can add the appropriate metal salt. Examples of metal salts include the chloride of cerium, magnesium bromide, magnesium chloride, zinc chloride, titanium tetrachloride, corticosteroid, samarium chloride and chloride India, preferably the chloride of cerium.

Examples of solvents suitable for use in the above reaction include solvents based on hydrocarbons and ethers. Specific examples include pentane, hexane, benzene, toluene, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and anisole. Preferred hexane, diethyl ether and tetrahydrofuran, and more preferred hexane and tetrahydrofuran.

This reaction can also be maintained in the presence of compounds amide or amine. Examples of the amide compounds or amine include 1,4-diazabicyclo[2,2,2]octane, N,N,N',N'-tetramethylethylenediamine, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphorotriamide. Preferred N,N,N',N'-tetramethylethylenediamine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and hexamethylphosphorotriamide and more predpochtite and which the reaction proceeds, preferably at a temperature of from -100°C to 50°C, more preferably at a temperature of from -80°C to 20°C

Reaction with formaldehyde (or its equivalents, such as 1,3,5-trioxane, paraformaldehyde or acetone can be conducted at any temperature at which this reaction proceeds preferably at a temperature of from -100°C to 50°C, more preferably at a temperature of from -80°C to 20°C

In that case, if R1and R2each represents a hydrogen atom and R4and R5together form a double bond between the 16 - and 17-positions, the compound (C) can also be synthesized as follows.

(Stage 1') Epoxidation

The compound (A) in an appropriate solvent treated salt trimethylsilane or salt trimethylsulfoxonium in the presence of a base to obtain compound (D).

Examples of salts trimethylsilane or trimethylsulfoxonium suitable for use in this reaction include trimethylsulfonium, trimethylsulfonium, trimethylacetylchloride, trimethylsilyltriflate, trimethylsilylamodimethicone, trimethylsulfonium, trimethylsilylamodimethicone and trimethylsulfoxonium, preferably trimethylsulfonium and trimethylsulfoxonium.

Examples of bases suitable for use in this reaction include n-utility, second-utility, tert-utility, motility, finality, methylacrylamide, methylaniline, methylanisole, isopropylacrylamide, sitedisability, lithium bis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidine, litigated, sodium hydride, sodium bis(trimethylsilyl)amide, potassium hydride, potassium bis(trimethylsilyl)amide, sodium hydroxide and potassium hydroxide.

The preferred sodium hydride, potassium hydride, n-utility, second-utility, tert-utility, sodium hydroxide and potassium hydroxide and the preferred sodium hydride and potassium hydride.

Examples of solvents suitable for use in this reaction include solvents based on hydrocarbons, ethers, amides and sulfoxidov. Specific examples include pentane, hexane, benzene, toluene, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, anisole, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and dimethylsulfoxide, moreover, the solvents on the basis of simple ether (for example, with tetrahydrofuran).

The reaction can be conducted at any temperature at which this reaction can take place, preferably at a temperature of from -20°C to 20°C

(Stage 2') ring-opening of epoxide

The compound (D) in an appropriate solvent is treated with acid to obtain the compound (C).

Examples of acids suitable for use in this reaction include hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, trimethoxy aluminum, triethoxy aluminum, triisopropyl aluminum, tri-tert-piperonyl aluminium, aluminium chloride, zinc chloride, tin chloride(II) chloride tin(IV) chloride titanium(IV), tetramethoxy titanium, tetraethoxy titanium and tetraisopropoxide titanium. Preferred trimethoxy aluminum, triethoxy aluminum, triisopropoxide aluminum and tri-tert-piperonyl aluminum and the preferred triisopropoxide aluminum.

Examples of solvents suitable for use in this reaction include solvents based on hydrocarbons, ethers, halides, and amides. Specific examples include pentane, hexane, benzene, 1,2-dichlorobenzene, toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane, tert-butyl, 2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and dimethylsulfoxide. The preferred benzene, 1,2-dichlorobenzene and toluene, and more preferred is 1,2-dichlorobenzene.

This reaction can be conducted at any temperature at which this reaction can take place, preferably at a temperature of from 0°C to 200°C, more preferably at a temperature of from 80°C to 180°C

The above reaction can be carried out using a base instead of acid. Examples of bases include n-utility, second-utility, tert-utility, motility, finality, methylacrylamide, methylaniline, methylanisole, isopropylacrylamide, litigating, sitedisability, lithium bis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidine, lithium amide, sodium hydride, sodium bis(trimethylsilyl)amide, potassium hydride, potassium bis(trimethylsilyl)amide, diethylaminopropylamine, diethylaluminium-2,2,6,6-tetramethylpiperidine, sodium hydroxide and potassium hydroxide. Preferred litigational, Diisopropylamine, sitedisability, lithium bis(trimethylsilyl)amide, lithium 2,2,6,6-tetramethylpiperidine, lithium amide, sodium hydride, sodium beini 2,2,6,6-tetramethylpiperidine and more preferred litigational.

Examples of solvents suitable for use in the reaction with the base, include solvents based on hydrocarbons, ethers, halides, and amides. Specific examples include pentane, hexane, benzene, 1,2-dichlorobenzene, toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, diglyme, 1,2-dimethoxyethane, 1,4-dioxane, anisole, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and dimethylsulfoxide, preferably benzene, toluene, diethyl ether and tetrahydrofuran.

The reaction with the base can be conducted at any temperature at which this reaction may proceed, preferably at temperatures from -40°C to 200°C, more preferably at a temperature from -0°C to 100°C

(Stage 3) the Introduction of the side chain

For the introduction of the side chain of the compound (C) obtained in the above stage (1) and (2) or stages (1') and (2'), is subjected to the interaction with the alkylating agent, the corresponding side chain, in the presence of a base, resulting in a receive connection (E).

Suitable for use autaut alkylating agents, represented by the formula corresponding to the side chain R3:

Z-(CH2)m-COR3

where Z represents tsepliaeva group such as halogen atom, methyloxirane, tosyloxy or triftormetilfullerenov, or

CH2=CH-COR3

(JP 6-72994 A. T. Mikami, T. Iwaoka, M. Kato, H. Watanabe and N. Kubodera, Synth. Commun. 27(14), 1997, 2363-2369).

Examples of Z-(CH2)m-COR3include tert-butylbromide, N-tert-butylbromide and N-tert-butyl-N-methylpropanamide.

Examples CH2=CH-COR3include acrylic acid, methyl acrylate, acrylate, n-propylacetate, isopropylacetate, butyl acrylate, tert-butyl acrylate, acrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-ethylacetamide, N,N-diethylacrylamide and N-tert-butylacrylamide.

Examples of bases include hydrides of alkali metals, alkoxides of alkali metals, dialkylamide metals and alkali metals. The preferred sodium hydride, potassium hydride, tert-piperonyl potassium, sitedisability, liebestraumereien, motility, n-utility and ethylmagnesium, and more preferred sodium hydride and potassium hydride.

Examples of solvents include solvents based uglevodorodov, ethers and amides. Specific examples include benzene, toluene, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Preferred tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide and 1,3-dimethyl-2-imidazolidinone and more preferred tetrahydrofuran.

The reaction is carried out at a temperature, which varies depending on the type of substrate, typically at temperatures from -40°C to the boiling point or decomposition temperature of the used solvent, preferably at a temperature of from 0°C to 200°C, more preferably in the temperature range from room temperature up to about 120°C

The method of introducing the side chain is not specifically limited to the above method, and this introduction can be done in other ways known to the specialists.

(Stage 4) removing the protective groups

The protective group of the compound (E) is removed by conventional means, receiving as a result, the compound (F).

Examples of reagents for removal of the protective groups include chlorite is, hydrogen fluoride/pyridine, hydrogen fluoride/triethylamine and hydrofluoric acid, preferably an acidic ion-exchange resin, tetrabutylammonium and hydrogen fluoride/pyridine.

Removal of protective groups is usually carried out in solvents on the basis of simple ether, preferably tetrahydrofuran. The reaction temperature for the removal of the protective groups varies depending on the type of substrate, but it is generally preferable to carry out the removal of the protective groups at temperatures in the range from room temperature to 65°C

(Stage 5) Photoreactive and thermoisomerization

The compound (F) is subjected to the expression and thermoisomerization conventional methods, resulting in the compound (G).

Stage 3, 4 and 5 are not always performed in this order. These stages can be performed in the following order: stage 3 stage 5 stage 4 or stage 5 stage 3 stage 4, provided that the stage 4 should not be preceded by Phase 3.

At each stage if necessary, you can modify the side chain of the known methods, such as solvolysis (including hydrolysis - esterification/amidation, the exchange reaction of ester (transesterification) (Larock, R. C., Comprehensive Ohdate as the compounds of formula (C), to start processing with stage 3 to 5.

This connection can be found in JP 61-267550 A or E, Murayama, K. Miyamoto, N. Kubodera, T. Mori and I. Matsunaga, Chem. Pharm. Bull. 34(10), 1986, 4410-4413.

This connection can be found in JP 6-86626 A and N. Kubodera, H. Watanabe, K. Miyamoto and M. Matsumoto, Bioorg, Med. Chem. Lett. 3(9), 1993, 1869-1872.

These compounds can be found in JP 10-231284 A.

II. Synthesis of derivatives of vitamin D formula (1), where X represents a sulfur atom

Derivatives of vitamin D formula (1), where X represents a sulfur atom, R6represents a hydroxyl group, and R7represents a hydrogen atom, can be obtained as follows, based on the compound (C) obtained in the above stages 1, 2 and so on

(Stage 3') Introduction functional structuresa group

The compound (C) is subjected to, for example, the following two reactions, resulting in a receive connection (I):

where Z represents tsepliaeva group such as chlorine atom, bromine atom, iodine atom, methysulfonylmethane or toluensulfonate.

The compound (C) can be converted into the compound (M) containing tsepliaeva group, by conventional means (Larock, R. C. Comprehensive Organic TraB POS="POST">1and R2each represents a hydrogen atom, and R4and R5together form a double bond between the 16 - and 17-positions, other cases can be treated similarly.

Then the compound (M) in an appropriate solvent is treated by a salt of the metal thiocarbonates or dithiocarbonic acid, resulting in a receive connection (I).

Examples of metal salts thiocarbonate or dithiocarbonate acids include thioacetate sodium, thioacetal potassium, thiopental sodium, thiobenzoate potassium, dithioacetate sodium, dithioacetate potassium, dithiobenzoate sodium and dithiobenzoate potassium, and preferred thioacetate potassium.

Examples of solvents include solvents based on hydrocarbons, ethers, halogen, ketone/ester/amides, sulfoxidov and NITRILES. Specific examples include hexane, benzene, toluene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, carbon tetrachloride, acetone, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, dimethylsulfoxide and acetonitrile. Preferred diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, is d, and more preferred tetrahydrofuran, acetone and dimethyl sulfoxide. In addition, these solvents can be used in combination.

The reaction can be conducted at any temperature at which this reaction can occur, usually at a temperature of from -50°C to 100°C, preferably at temperatures from 0°C to room temperature.

Two of the above reaction can be performed continuously, i.e. after conversion of the hydroxyl group in tsepliaeva group, compound (M) without allocation can be processed metal salt thiocarbonate or dithiocarbonic acid.

(Stage 4') Alkaline solvolysis and S-alkylation

The compound (I) is subjected to solvolysis in alkaline conditions simultaneously with S-alkylation, obtaining the compound (J).

Examples of bases suitable for use on stage alkaline solvolysis and S-alkylation include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and tert-piperonyl potassium, preferably sodium hydroxide, potassium hydroxide and sodium methoxide.

Examples of solvents suitable for use include water and alcohol solvents. So, for example, methanol, ethanol, propanol and burgertron, 1,2-dimethoxyethane, 1,4-dioxane or diglyme.

Suitable for use alkylating agent may correspond to the side chain, as described in section I to Stage 3.

The reaction is usually conducted at temperatures from -40°C to 100°C, preferably at temperatures from 0°C to 50°C, more preferably at room temperature.

(Stage 5') Removal of protective groups

The protective group of the compound (J) is removed by conventional means, receiving the connect ().

Examples suitable for use reagents for the removal of the protective groups include hydrochloric acid, sulfuric acid, acetic acid, acidic ion exchange resins, tetrabutylammonium, hydrogen fluoride/pyridine, hydrogen fluoride/triethylamine and hydrofluoric acid, preferably an acidic ion-exchange resin and tetrabutylammonium.

Removal of protective groups is usually carried out in solvents on the basis of simple ether, preferably tetrahydrofuran. The reaction temperature for the removal of the protective groups varies depending on the type of substrate, but it is generally preferable to carry out the removal of the protective groups at temperatures between room tempera is treacly and thermoisomerization conventional methods, getting in the compound (L).

Stage 3', 4' 5' is not always performed in this order. These stages can be performed in any order, provided that the stage 4' and stage 5' must not precede stage 3'.

In addition, any of the following compounds, which can be found in JP 10-231284 A, can be used as the compounds of formula (I) to start the reaction with stage 4'.

In addition, any of the following compounds, which can be found in JP 10-231284 And can be used as the compounds of formula (I) to start the reaction with stage 4'. In this case, stage 6' can be omitted.

At appropriate stages previously presented schemes of synthesis I and II corresponding intermediate compounds and final products can be purified and to allocate standard methods, such as chromatographic processing on a column of silica gel, thin layer chromatography and recrystallization.

The present invention provides a convenient obtaining the compounds represented by formula (3), which can be used as intermediates in obtaining the derivatives of vitamin D formula (1) we shall use tetramethylol and dimethylzinc. However, first requires improved method for reasons of toxicity and reactivity, because of its low reactivity leads to side reactions that occur simultaneously with the desired reaction, while the latter requires improvement of the way of the considerations of reactivity, so its high reactivity leads to the preferred course of adverse reactions compared with the desired response.

On the contrary, if obtaining the compound (3) of the present invention use alyuminiiorganicheskikh reagent, this reagent causes few adverse reactions that ensures the flow of the desired reaction with high selectivity, which results in an increase in yield of the reaction product. Additionally, the reagent of low toxicity. Therefore, the present invention achieves a more comfortable obtaining the compounds of formula (3) in comparison with previously known methods. This means that the present invention is also more advantageous to obtain the compounds of formula (1), rather than getting the usual ways, as advantages for obtaining compounds (3), if it is used for connection (1) leads to an increased in the groups for R12and R13include acetyl group, and tert-butyldimethylsilyloxy group. Examples tsepliaeva group R14include a bromine atom, an iodine atom, triftormetilfullerenov and nonatherosclerotic. The compound of the formula (2) can be obtained, for example, by way of example 24 below.

Then the compound of the formula (2) can be carbanilate using carbon monoxide in an organic solvent (such as N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, toluene) in the presence of alyuminiiorganicheskikh reagent of formula (4) and palladium catalyst to obtain the desired compounds of formula (3).

Examples alyuminiiorganicheskikh reagents include dimethylammoniumchloride, diethylaluminium, di-n-propylalanine, di-n-butylaminoethyl and diphenylalanine.

Examples of palladium catalysts include tetrakis (triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichloro[1,3-bis(diphenylphosphino)propane]palladium, dichloro[1,2-bis(diphenylphosphino)ethane]palladium, bis(dibenzylideneacetone) palladium and Tris(dibenzylideneacetone)dipalladium.

In sposobnymi as triphenylphosphine, tributylphosphine, tricyclohexylphosphine or three-tert-butylphosphine, to achieve higher catalytic activity or a higher selectivity of the reaction.

The carbonylation reaction is conducted at temperatures from 0°C to 150°C in an atmosphere of carbon monoxide at a pressure of from normal to high (up to about 20 ATM) for from about 10 minutes to about 12 hours.

Thus obtained compound (3) can be used as intermediate compounds for the synthesis of a derivative of vitamin D formula (1) of the present invention.

The compound of formula (1) can be obtained from the compounds of formula (3), for example, by the method of example 25 below.

In the formula (3) R12and R13have the meanings specified for formula (2), and R15represents alkyl groups such as methyl, ethyl, propyl and butyl, aryl groups such as phenyl, alkeline groups such as vinyl, or alkyline groups, such as ethinyl.

Thus obtained derivative of vitamin D formula (1) is a pharmaceutically useful compound which has a reduced hypercalcemic effect, as shown in the examples below.

In that case, if therapeutic agent for the treatment of skin diseases, comprising as active ingredient a derivative of vitamin D of the present invention, is used to treat reactions of psoriasis or similar, this agent can be obtained in a unit dosage form, suitable for outdoor use, such as ointments, creams or lotions.

The dose of therapeutic agent containing as an active ingredient a derivative of vitamin D of the present invention, can be determined in accordance with the type subject to treatment of the disease, condition, physical data, diathesis, age and sex of the patient, the proposed method of administration or dosage forms, etc. Usually the agent is used in amount of active ingredient are from 0.001 to 10000 μg/day, preferably 0.01 to 1000 mg/day for oral administration, in the amount of from 0.01 to 1 is but from 10 to 5000 μg/day for external use, moreover, these doses can be entered as a lump sum or divided into separate portions, twice or three times a day.

In that case, if therapeutic agent for the treatment of skin diseases, comprising as active ingredient a derivative of vitamin D of the present invention, used in the reaction of psoriasis or similar, this agent preferably using surface application, such as an external application, but in some cases it may be administered systemically, such as orally or parenterally.

Examples

The present invention is further described by the following examples, which are offered only for the purpose of illustration and should not be construed as limiting the scope of invention.

In these examples, each of the NMR spectra obtained in CDCl3if there are no other indications, and used as an internal standard tetramethylsilane or chloroform. Each mass spectrum (MC) obtained by the EI (electron impact) when the voltage ionization 70 eV. Each ultraviolet absorption spectrum (UV=UV) measured in ethanol solution.

Chromatography on a column and preparative thin-layer chromatography carried out using a silica compound is.

Example 1

Getting 17-acetyltributyl-1,3-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triens

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-17-(2,4,6-triisopropylbenzenesulfonyl)androsta-5,7-Dien

1,3-bis(tert-butyldimethylsilyloxy)-17-oxoandrosta-5,7-diene (1.64 g, is 3.08 mmol) and 2,4,6-triisopropylbenzenesulfonyl (1.01 g, 3,39 mmol) is dissolved in ethyl acetate (6 ml) and stirred at room temperature for 16 hours. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (hexane:ethyl acetate = 15:1), obtaining mentioned in the title compound (1.86 g, 75%).

1NNMR : 7,15 (s, 2H), 6,98 (Shir.s, 1H), 5,58 (d, J=5.8 Hz, 1H), 5.40 to-5,33 (m, 1H), 4,28-4,20 (m, 2H), 4,18-3,93 (m, 1H), 3,70-3,63 (m, 1H), 2,95-to 2.74 (m, 2H), 1,30-1,22 (m, 24H), to 0.88 (s, 9H), of 0.85 (s, 9H), of 0.68 (s, 3H), and 0.09 (s, 3H), to 0.06 (s, 3H), of 0.04 (s, 3H), of 0.03 (s, 3H). IR (KBr): 3232, 2956, 2860, 1600, 1462, 1426, 1384, 1372, 1362, 1328, 1254, 1214, 1194, 1166, 1154, 1102, 1038, 1006, 968, 952, 938, 928, 916, 878, 834, 774, 716, 666, 548 cm-1.

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triens

A solution of 1,3-bis(tert-butyldimethylsilyloxy)-17-(2,4,6-triisopropylbenzenesulfonyl)androsta-5,7-diene (32,7 M53 M n-utility (0,106 ml, 0,161 mmol). The reaction mixture was stirred at -78°C for 2 hours and then heated to 0°C and stirred for 15 minutes. After adding paraformaldehyde (10 mg, 0.33 mmol), the reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 1 hour. An aqueous solution of sodium chloride added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate and evaporated to remove solvent. The resulting residue is purified through column chromatography (hexane:ethyl acetate = 6:1), obtaining specified in the header connection (to 13.6 mg, 62%).

(3) Obtaining 17-acetyltributyl-1,3-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triens

To a solution of 1,3-bis(tert-butyldimethylsilyloxy)-17-hydroxymethyl)androsta-5,7,16-triens (4,00 g, 7,34 mmol) in tetrahydrofuran (70 ml), add triethylamine (4,10 ml, 29.4 mmol) and then dropwise add methanesulfonanilide (1.70 ml of 22.0 mmol) at -10°C, followed by stirring for 20 minutes. After heating to room temperature, to the reaction mixture add a solution of thioacetate potassium (of 3.73 g, 29.4 mmol) in dimethyl sulfoxide (70 ml). The reaction mixture is stirred for 30 minutes, diluted with Sri removal of the solvent, the obtained residue is purified on a chromatographic column with silica gel (hexane:ethyl acetate = 15:1), getting listed in the title compound (3,91 g, 88%) as a colourless oil.

IR (net): 2954, 2929, 2897, 2856, 1695, 1471, 1462, 1371, 1360, 1254, 1099 cm-1.1H NMR : 0,05 (s, 1H), 0,07 (s, 3H), of 0.07 (s, 3H), of 0.11 (s, 3H), of 0.82 (s, 3H), from 0.88 (s, 18H), were 0.94 (s, 3H), of 2.34 (s, 3H), 2,79-2,90 (m, 1H), 3,52-3,68 (m, 2H), 3,68-to 3.73 (m, 1H), 3,98-4,12 (m, 1H), 5,35-5,41 (m, 1H), 5,57-5,64 (m, 2H). MC m/z: 602 (M+), 413(100%). UVmaxnm: 234, 261, 271, 281, 294.

Example 2

Stage (1) and (2) in example 1, substitute the following stages (1) and (2).

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)androsta-5,7-diene(17S)-Spiro-2'-oxirane

Sodium hydride (60% in oil, 0,2821 g, 7,06 mmol) are added to a dimethyl sulfoxide (13 ml) and stirred at 80°C for 1 hour. The resulting suspension is cooled to 0°C and diluted with tetrahydrofuran (19 ml), then it is added dropwise a solution of trimethylsulfonium (1,33 g of 6.50 mmol) in dimethyl sulfoxide (9 ml) and stirred at 0°C for 35 minutes. Then add a solution of 1,3-bis(tert-butyldimethylsilyloxy)-17-oxoandrosta-5,7-diene (1.0 g, 1.88 mmol) in tetrahydrofuran (7 ml) and stirred at room temperature for 14 hours. The reaction mixture was poured into a saturated aqueous solution of ameriglide, extracted with ethyl acetate, tion under reduced pressure to remove the solvent the residue is purified through column chromatography (hexane:ethyl acetate = 6:1), getting listed in the title compound (0,93 g, 91%) as a white foam.

1H NMR : 0,05 (s, 3H), 0,06 (s, 3H), of 0.07 (s, 3H), of 0.11 (s, 3H), 0.88 to (s, 3H), 0,89 (s, 3H), 2,65 (d, J=4.9 Hz, 1H), 2,93 (d, J=4.9 Hz, 1H), 3,71 (Shir.s, 1H), 3,98-4,12 (m, 1H), 5,35-5,43 (m, 1H), 5,57-5,64 (m, 1H).

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triens

To a solution of 1,3-bis(tert-butyldimethylsilyloxy)androsta-5,7-diene(17S)-Spiro-2'-oxirane (20 g, to 36.7 mmol) in 1,2-dichlorobenzene (130 ml) in an argon atmosphere add isopropoxide aluminum (22 g, 108 mmol) and stirred at 130°C for 1.5 hours. To the reaction mixture is added aqueous Rochelle salt solution and then extracted with ethyl acetate (twice), then washed with water and dried over anhydrous sodium sulfate. After evaporation under reduced pressure to remove solvent, the residue is purified through column chromatography (hexane:ethyl acetate = 6:1), obtaining mentioned in the title compound (10 g, 50%) as a solid white color.

IR (net): 3392, 2954, 2929, 2856, 1462, 1254, 1097, 1082 cm-1.1H NMR : 0,05 (s, 3H), of 0.07 (s, 6H), of 0.11 (s, 3H), 0.88 to (s, 3H), 0,89 (s, 3H), 3,71 (Shir.s, 1H), 4.00 points (Shir.s, 1H), 4,22 (s, 2H), 5.40 to (Shir.s, 1H), 5,57-to 5.66 (m, 2H). MC m/z: 544 (M+) 355(100%). UVmaxnm: 270, 281, 293.

After steps (1) and (2) of example 1 instead of stage (3) should be presented to the next stage.

To a solution of 1,3-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triens (100 mg, 0,183 mmol), triphenylphosphine (96.0 mg, 0,366 mmol) and imidazole (49,8 mg, 0,732 mmol) in dichloromethane (2 ml) at 0°C add N-bromosuccinimide (of 65.1 mg, 0,366 mmol) and stirred at room temperature. After 1 hour the reaction mixture hexane, then washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solvent is removed under reduced pressure, obtaining a mixture (150 mg) containing 1,3-bis(tert-butyldimethylsilyloxy)-17-(methyl bromide)androsta-5,7,16-triene. This mixture is dissolved in acetone (1.5 ml) followed by the addition of thioacetate potassium (to 31.4 mg, 0,275 mmol) and stirred for 30 minutes. The reaction mixture was diluted with hexane and filtered. The resulting filtrate is evaporated under reduced pressure to remove solvent, and the residue purified using preparative thin-layer chromatography (plate 0.5 mm × 2, hexane:ethyl acetate = 20:1, show once), getting listed at the beginning of the connection (to 70.2 mg, 64%) as a colourless oil.

Example 4

(1) preparation of 1,3 .3m-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregn-5,7,16-triens (400 mg, to 0.72 mmol) in tetrahydrofuran (7.2 ml) is added sodium hydride (60% in oil, 46 mg, 1.15 mmol) and stirred at room temperature for 30 minutes in a stream of nitrogen. After adding N,N-dimethylacrylamide (308 mg, 3.11 mmol) the reaction mixture is additionally stirred at the same temperature for 3 hours, poured into saturated aqueous ammoniacal, extracted with ethyl acetate (three times) and washed with saturated aqueous sodium chloride and water. The organic layer is dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (hexane:ethyl acetate = 2:1), obtaining mentioned in the title compound (459 mg, 96.9 percent) as a colorless oil.

IR (net): 2954, 2929, 2895, 2856, 1655, 1462, 1389, 1371, 1254, 1149, 1097 cm-1.1H NMR : 0,05 (s, 3H), 0.06 to (C, 6N), of 0.11 (s, 3H), 0.88 to (s, 21H), were 0.94 (s, 3H), of 1.30 (d, J=6.6 Hz, 3H), 2,60 (t, J=6.9 Hz, 2H), 2,78-2,90 (m, 1H), equal to 2.94 (s, 3H), to 3.02 (s, 3H), 3,57-of 3.80 (m, 3H), 3,90-4,11 (m, 2H), 5,35-5,43 (m, 1H), 5,57-5,64 (m, 2H). MC m/z: 540 (M+-HO(CH2)2CONMe2), 73(100%). UVmaxnm: 271, 282, 294.

(2) Obtaining 1,3-dihydroxy-20(S)-(N,N-dimethylaminocarbonylmethyl)pregna-5,7,16-triens

To a solution of 1,3-bis(tert-butylal) add 1M tertrahydrofuran ring solution of Tetra-n-butylammonium (1.5 ml) and stirred at 50°C for 1 hour in a stream of nitrogen. After cooling to room temperature the reaction mixture was diluted with ethyl acetate, washed successively with 0.5 n hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified using preparative thin-layer chromatography (plate 1.0 mm × 2, chloroform:methanol = 10:1), obtaining mentioned in the title compound (45 mg, 70,3%) as a colourless foam.

IR (net): 3359, 2970, 2935, 2918, 2873, 2837, 1624, 1417, 1361, 1257, 1196, 1151, 1097, 1053 cm-1.1H NMR : of 0.87 (s, 3H), of 0.97 (s, 3H), of 1.29 (d, J=6.3 Hz, 3H), at 2.59 (t, J=6.9 Hz, 2H), 2,73-to 2.85 (m, 1H), 2,93 (s, 3H), to 3.02 (s, 3H), 3,53-3,66 (m, 1H), 3,69-3,81 (m, 2H), 3,92 is 4.13 (m, 2H), 5.40 to-5,48 (m, 1H), the ceiling of 5.60 (Shir.s, 1H), 5,70-USD 5.76 (m, 1H). MC m/z: 312 (M+-HO(CH2)2CONMe2), 72 (100%). UVmaxnm: 271, 282, 293.

(3) Obtaining 1,3-dihydroxy-20(S)-(N,N-dimethylaminocarbonylmethyl)-9,10-scoprega-5,7,10(19),16-tetraene

1,3-dihydroxy-20(S)-(N,N-dimethylaminocarbonylmethyl) pregna-5,7,16-triene (60 mg, 0.14 mmol) dissolved in ethanol (200 ml). When bubbling argon at 0°C under stirring the resulting solution was irradiated with a reflux condenser for 2 hours. After cooling to room temperature the reaction mixture is evaporated under reduced pressure to remove solvent, and the resulting residue purified using preparative thin-layer chromatography (plate 0.5 mm × 3, dichloromethane:ethanol = 20:1, are three; plate 0.5 mm × 2, hexane:ethyl acetate:ethanol = 3:7:0,5, show three times; and then the plate is 0.5 mm × 1, hexane:ethyl acetate:ethanol = 2:8:0,5, show three times), getting listed in the title compound (5,333 mg, 8,9%) as a colourless oil.

IR (net): 3400, 2930, 2848, 1633, 1628, 1103, 1055 cm-1.1H NMR : 0,77 (s, 3H), of 1.29 (d, J=6.6 Hz, 3H), at 2.59 (t, J=6.9 Hz, 2H), 2,74-of 2.86 (m, 1H), 2,93 (s, 3H), to 3.02 (s, 3H), 3,52-the 3.65 (m, 1H), 3,68-of 3.80 (m, 1H), 3,94 (kV, J=6,6 Hz, 1H), 4,17-the 4.29 (m, 1H), 4,39-4,48 (m, 1H), 5,01 (Shir.s, 1H), 5,33 (Shir.s, 1H), 5,57 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 429(M+), 118(100%). UVmaxnm: 264.

Example 5

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(N,N-dimethylaminocarbonylmethyl)pregna-5,7,16-triens

1,3-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregn-5,7,16-triene (316 mg, or 0.57 mmol) is treated with N,N-dimethylacrylamide (175 mg, 1.77 mmol) and sodium hydride (60% in oil, 36 mg, of 0.91 mmol) in tetrahydrofuran (5.7 ml) by the method of example 4 (1) (0°C for the column chromatography (hexane:ethyl acetate = 2:1), getting listed in the title compound (352 mg, 93.9 per cent) as a colourless oil.

IR (net): 3280, 2954, 2929, 2885, 2856, 1628, 1464, 1402, 1373, 1255, 1097 cm-1.1H NMR : 0,05 (s, 3H), 0,07 (C, 6N), of 0.11 (s, 3H), or 0.83 (s, 3H), from 0.88 (s, 18H), were 0.94 (s, 3H), 1,32 (d, J=6.3 Hz, 3H), 2.63 in (t, J=6.9 Hz, 2H), 2,79-2,90 (m, 1H), equal to 2.94 (s, 3H), 3,01 (s, 3H), 3,66-with 3.79 (m, 3H), of 3.96-4.09 to (m, 2H), 5,34-5,42 (m, 1H), 5,56-to 5.66 (m, 2H). MC m/z: 540 (M+-HO(CH2)2CONMe2), 73(100%). UVmaxnm: 271, 282, 294.

(2) Obtaining 1,3-dihydroxy-20(R)-(N,N-dimethylaminocarbonylmethyl)pregna-5,7,16-triens

1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(N,N-dimethylaminocarbonylmethyl)pregna-5,7,16-triene (100 mg, 0.15 mmol) is treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (1.5 ml) in tetrahydrofuran (6.0 ml) by the method of example 4 (2) (at room temperature for 30 minutes and then at 50°C for 1.5 h) followed by treatment and purification via preparative thin-layer chromatography (plate 0.5 mm × 2, chloroform:methanol = 10:1), obtaining mentioned in the title compound (52 mg, 83,0%) as a colourless foam.

IR (net): 3390, 2962, 2933, 2875, 1624, 1456, 1398, 1373, 1267, 1157, 1097, 1057 cm-1.1H NMR : 0,84 (s, 3H), and 0.98 (s, 3H), 1,32 (d, J=6.6 Hz, 3H), 2,60 (t, J=7,3 Hz, 2H), POS="POST">+-HO(CH2)2CONMe2), 72(100%). UVmaxnm: 271, 281, 293.

(3) Obtaining 1,3-dihydroxy-20(R)-(N,N-dimethylaminocarbonylmethyl)-9,10-scoprega-5,7,10(19),16-tetraene

1,3-dihydroxy-20(R)-(N,N-dimethylaminocarbonylmethyl) pregna-5,7,16-triene (50 mg, 0.12 mmol) is treated in ethanol (200 ml) by the method of example 4 (3) (irradiated with light for 4 minutes and 45 seconds, refluxed for 2 hours), followed by purification using preparative thin layer chromatography (plate 0.5 mm × 2, dichloromethane:ethanol = 20:1, show three times, and then the plate is 0.5 mm × 1, hexane:ethyl acetate:ethanol = 2:8:0,5, show three times), getting mentioned in the title compound (3,427 mg, 6,9%) as a colourless oil.

IR (pure): 3400, 2929, 1633, 1055 cm-1.1H NMR : 0,73 (s, 3H), of 1.31 (d, J=6.6 Hz, 3H), at 2.59 (t, J=7,3 Hz, 2H), 2,75-to 2.85 (m, 1H), equal to 2.94 (s, 3H), to 3.02 (s, 3H), and 3.72 (t, J=7,3 Hz, 2H), 3,99 (kV, J=6,6 Hz, 1H), 4,18-4,30 (m, 1H), 4,39-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), 5,33 (Shir.s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,10 (d, J=11,6 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 429(M+), 72(100%). UVmaxnm: 265.

Example 6

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-17-(N,N-dimethylaminocarbonylmethyl)androsta-5,7,16-triens

1,3-bis(tert-ω (540 mg, 5,44 mmol) and sodium hydride (60% in oil, 105 mg, 2,62 mmol) in tetrahydrofuran (17.5 ml) by the method of example 4 (1) (5°C for 14 h) with subsequent processing and purification through column chromatography (hexane:ethyl acetate = 2:1), obtaining specified in the header of the connection (of 1.05 g of 92.7%) as a yellow oil.

IR (net): 2954, 2929, 2895, 2856, 1653, 1462, 1398, 1371, 1254, 1097, 1074 cm-1.1H NMR : 0,05 (s, 3H), 0,06 (m, 6N), of 0.11 (s, 3H), of 0.82 (s, 3H), 0,877 (s, 9H), 0,881 (s, 9H), were 0.94 (s, 3H), 2,62 (t, J=6.6 Hz, 2H), 2,80-2,90 (m, 1H), equal to 2.94 (s, 3H), to 3.02 (s, 3H), 3,70 (Shir.s, 1H), 3,76 (t, J=6.6 Hz, 2H), 3.96 points-of 4.12 (m, 4H), 5,34-5,42 (m, 1H), 5,55-5,67 (m, 2H). MC m/z: 644 (M+-1), 73(100%). UVmaxnm: 271, 281, 293.

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-17-(N,N-dimethylaminocarbonylmethyl)-9,10-secondrate-5,7,10(19),16-tetraene

1,3-bis(tert-butyldimethylsilyloxy)-17-(N,N-dimethylaminocarbonylmethyl)androsta-5,7,16-triene (300 mg, 0.47 mmol) is treated in ethanol (350 ml) by the method of example 4 (3) (irradiated light for 13 min and 30 s, heated at the boil under reflux for 2 hours and then evaporated under reduced pressure to remove the solvent, resulting in receive yellow oil (300 mg) containing the target product.

(3) Obtaining 1,3-digib example 6 (2) (300 mg), dissolved in tetrahydrofuran (30 ml) and methanol (30 ml), then it is added AMBERLYST 15 (11.1 g) and stirred in the dark at room temperature for 4 h in a stream of nitrogen. Insoluble products is filtered off on CELITE and washed with methanol. To the filtrate add sodium bicarbonate and stirred for 5 min, followed by repeated filtration. The filtrate is concentrated under reduced pressure and the resulting residue purified using preparative thin-layer chromatography (1.0 mm × 3 plates, dichloromethane:ethanol = 20:1, show three times and then 0.5 mm × 3 plates, hexane:ethyl acetate:ethanol = 2:8:0,5, show three times), getting mentioned in the title compound (10,282 mg, 5,5%) as a colourless oil.

IR (net): 3400, 2929, 2875, 2850, 1633, 1500, 1402, 1159, 1059 cm-1.1H NMR : 0,72 (s, 3H), 2,62 (t, J=6.6 Hz, 2H), 2,54-of 2.66 (m, 1H), 2,75-of 2.86 (m, 1H), equal to 2.94 (s, 3H), to 3.02 (s, 3H), 3,68-of 3.78 (m, 2H), 3.96 points-4.09 to (m, 2H), 4,18-the 4.29 (m, 1H), 4,39-4,48 (m, 1H), 5,00 (Shir.s, 1H), 5,33 (Shir.s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,09 (d, J=11,6 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H). MC m/z: 298 (M+-HO(CH2)2CONMe2), 72(100%). UVmaxnm: 264.

Example 7

Obtaining 1,3-dihydroxy-20(S)-(N,N-dimethylaminocarbonylmethyl)-9,10-scoprega-5,7,10(19)-triens

1,3-b is in ethanol (200 ml) by the method of example 4 (3) (irradiated with light for 12 min, refluxed for 2 h and then evaporated under reduced pressure to remove solvent. The obtained residue (210 mg) was treated in tetrahydrofuran (20 ml) and methanol (20 ml) and AMBERLYST (7,4 g) by the method of example 6 (3) (at room temperature for 5 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 7 plates, dichloromethane:ethanol = 20:1, show three times; 0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 2:8:0,5, show three times; and then 0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, are twice), getting mentioned in the title compound (7,202 mg, 5.1 percent after 2 stages) as a colourless oil.

IR (net): 3400, 2927, 2873, 1633, 1628, 1446, 1417, 1149, 1095, 1059 cm-1.1H NMR : 0,51 (s, 3H), of 1.16 (d, J=5,9 Hz, 3H), 2,75-is 2.88 (m, 1H), 2,93 (s, 3H), to 3.02 (s, 3H), 3,20-to 3.33 (m, 1H), 3,51-3,63 (m, 1H), 3,80-to 3.92 (m, 1H), 4,17-4,27 (m, 1H), to 4.38-4,47 (m, 1H), 4,99 (Shir.s, 1H), 5,32 (Shir.s, 1H), 6,02 (d, J=11.2 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H). MC m/z: 296 (M+-HO(CH2)2CONMe2-N2O), 72(100%). UVmaxnm: 264.

Example 8

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(tert-butoxycarbonylmethyl)pregna-5,7,16-triens

A solution of 1,3-bis(tert-butylimide is 0681 mmol) in tetrahydrofuran (1 ml) is stirred at ambient temperature for 72°C for 1 hour, then to this add tert-butylbromide (0.05 ml, 0,336 mmol) at room temperature and further stirred at an external temperature of 72°C for 5 hours and 15 minutes and Then the reaction mixture was diluted with ethyl acetate, are added dropwise water while cooling with ice. After washing with saturated aqueous sodium chloride the organic layer is dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 10:1, show once), getting mentioned in the title compound (55,1 mg, 82%) as a colourless oil.

IR (net): 2928, 2856, 1748, 1088, 832 cm-1.1H NMR : 0,05 (s, 3H), by 0.06 (s, 6H), of 0.10 (s, 3H), 0,86 (s, 3H), from 0.88 (s, 18H), were 0.94 (s, 3H), of 1.36 (d, J=6.3 Hz, 3H), of 1.46 (s, 9H), and 2.79-2.91 in (m, 1H), 3,69 (Shir.s, 1H), 3,82 (d, J=16.5 Hz, 1H), 3,94 (d, J=16.5 Hz, 1H), 3,98-to 4.15 (m, 2H), 4.09 to (kV, J=6.3 Hz, 1H), 5,35-5,43 (m, 1H), 5,57-to 5.66 (m, 2H). UVmaxnm: 271, 282, 294.

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(tert-butoxycarbonylmethyl)-9,10-scoprega-5,7,10(19),16-tetraene

1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(tert-butoxycarbonylmethyl)pregna-5,7,16-triene (52,2 mg, 0,0775 mmol) is treated in ethanol is 2 hours, followed by purification using preparative thin layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 20:1, are twice), getting a mixture of 16.6 mg) containing specified in the header of the connection.

(3) 20(S)-(tert-butoxycarbonylmethyl)-1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraene

The mixture obtained in example 8 (2) (16.6 mg), dissolved in tetrahydrofuran (2.5 ml), then to this add hydrogen fluoride/pyridine (70%, 1 ml) and stirred at room temperature for 30 minutes, the Reaction mixture was diluted with ethyl acetate, washed successively with water (twice), saturated aqueous sodium bicarbonate (three times) and saturated aqueous sodium chloride (once), dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to remove solvent. The resulting residue is purified using preparative thin-layer chromatography (0.25 mm × 1 plate, dichloromethane:ethanol = 20:1, show three times; 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are five times; and then 0.25 mm × 1 plate, dichloromethane:ethyl acetate = 3:1, are three times), getting mentioned in the title compound (1.77 mg, 5% over 2 stages) as a colourless oil.

IR (net): 3400, 2976, 2932, 1746, 1122 cm-1.1H NMR : 0,77 (s, 3H), of 1.36 (d, J=6.4 Hz, 3H), of 1.47 (s, 9H), is 2.37 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 312 (M+-HOCH2CO2C(CH3)3), 57(100%). UVmaxnm: 263.

Example 9

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(tert-butoxycarbonylmethyl)pregna-5,7,16-triens

1,3-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregn-5,7,16-triene (158 mg, 0,283 mmol) is treated with sodium hydride (60% in oil, 77 mg, 1,925 mmol), tetrahydrofuran (6 ml), 15-crown-5 (67 mg, 0,304 mmol) and tert-butylbromide (0.25 ml, 1,679 mmol) by the method of example 8 (1) (at an external temperature of 85°C for 11 hours and 40 min) and then treated. The resulting residue is purified through column chromatography (hexane:ethyl acetate = 10:1) and preparative thin-layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 20:1, are twice), getting mentioned in the title compound (142,6 mg, 75%) as a colourless oil.

IR (net): 2932, 2856, 1748, 1100, 834 cm-1.1H NMR : 0,05 (s, 3H), of 0.07 (s, 6H), of 0.11 (s, 3H), of 0.85 (s, 3H), from 0.88 (s, 18H), were 0.94 (s, 3H), of 1.37 (d, J=6.6 Hz, 3H), of 1.47 (s, 9H), 2,78-only 2.91 (m, 1H), 3,70 (Shir.s, 1H), 3,86 (d, J=16.4 Hz, 1H), 3.96 points (d, J=16.4 Hz, 1H), 3,98 is 4.13 (m, 1H), 4,15 (kV, J=6,6 Hz, 1H), 5,35-5,46 (m, 1H), 5,61 (d, J=5.4 Hz, 1H), 5,66 (Shir.s, 1H). UVmaxnm: 271, 282, 29,7,10(19),16-tetraene

1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(tert-butoxycarbonylmethyl)pregna-5,7,16-triene (108,3 mg, 0,161 mmol) is treated in ethanol (200 ml) by the method of example 4 (3) (irradiated light for 6.5 minutes, refluxed for 1.5 hours), followed by purification using preparative thin layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 20:1, are twice) to give compound (25.6 mg), containing specified in the header of the connection.

(3) 20(R)-(tert-butoxycarbonylmethyl)-1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraene

The mixture obtained in example 9 (2) (25.6 mg), treated in tetrahydrofuran (2.5 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.35 ml, 0.35 mmol) by the method of example 4 (2) (at an external temperature of 47.5°C for 4 h) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, dichloromethane:ethanol = 15:1, are four times; 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, show three times; and then 0.25 mm × 1 plate, dichloromethane:ethyl acetate = 3:1, are three times), getting mentioned in the title compound (3,169 mg, 4% over 2 stages) as a colourless oil.

+-HOCH2C(O)OC(CH3)3), 57(100%). UVmaxnm: 263.

Example 10

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-17-(tert-butoxycarbonylmethyl)androsta-5,7,16-triens

A solution of 1,3-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triens (1.0 g, of 1.84 mmol), sodium hydride (60% in oil, 220 mg of 5.50 mmol), 15-crown-5 (400 mg, 1.82 mmol) and tert-butylbromide (0,55 ml of 3.69 mmol) in tetrahydrofuran (20 ml) was stirred at an external temperature of 88°C for 1 hour and 15 minutes, the Reaction mixture was diluted with ethyl acetate and filtered through CELITE. To the filtrate is added dropwise to water while cooling with ice, followed by washing with saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (hexane:ethyl acetate = 20:1), obtaining specified in the header connection (946,6 mg, 78%) as a colourless oil.

IR (net): 2952, 2928, 2892, 94 (with, 3H), of 1.48 (s, 9H), 2,79 of 2.92 (m, 1H), 3,70 (Shir.s, 1H), 3,95 (s, 2H), 4,13 (s, 2H), 3,97-4,20 (m, 1H), 5,35-5,43 (m, 1H), ceiling of 5.60 (d, J=5.4 Hz, 1H), 5,69 (s, 1H). MC m/z: 526 (M+-HOCH2CO2C(CH3)3), 57(100%). UVmaxnm: 271, 281, 294.

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-17-(tert-butoxycarbonyloxyimino)-9,10-secondrate-5,7,10(19),16-tetraene

1,3-bis(tert-butyldimethylsilyloxy)-17-(tert-butoxycarbonylmethyl)androsta-5,7,16-triene (168 mg, 0,255 mmol) is treated in ethanol (200 ml) by the method of example 4 (3) (irradiated with light for 10 min, refluxed for 1.5 hours), followed by purification using preparative thin layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 15:1, are twice), getting a mixture of (a 35.8 mg), containing specified in the header of the connection.

(3) Obtaining 1,3-dihydroxy-17-(tert-butoxycarbonyloxyimino)-9,10-secondrate-5,7,10(19),16-tetraene

The mixture obtained in example 10 (1) (a 35.8 mg), treated in tetrahydrofuran (1 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.35 ml, 0.35 mmol) by the method of example 4 (2) (at an external temperature of 45°C for 2 h) and then treated. The resulting residue is purified n times; 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, show three times; 0.25 mm × 1 plate, dichloromethane:ethanol = 20:1, show twice, and dichloromethane:ethanol = 15:1, show twice, then 0.25 mm × 1 plate, dichloromethane:ethyl acetate = 3:1, are twice), getting mentioned in the title compound (0,649 mg, 0.6% over 2 stages) as a colourless oil.

IR (net): 3352, 2928, 1744, 1452, 1368, 1226, 1162, 1130, 1056 cm-1.1H NMR : 0,74 (s, 3H), of 1.48 (s, 9H), 2,53-to 2.67 (m, 1H), 2,75-2,89 (m, 1H), 3,95 (s, 2H), 4,12 (Shir.s, 2H), 4,17-4,30 (m, 1H), 4,39-4,50 (m, 1H), free 5.01 (s, 1H), 5,33 (s, 1H), 5,65 (s, 1H), 6,09 (d, J=11.5 Hz, 1H), 6,37 (d, J=11.5 Hz, 1H). MC m/z: 430 (M+), 57 (100%). UVmaxnm: 263.

Example 11

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraene

1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregn-5,7,16-triene (1.0 g, to 1.79 mmol) is treated in ethanol (270 ml) by the method of example 4 (3) (irradiated with light for 1 hour, refluxed for 2 hours, followed by separation using chromatographic column (hexane:dichloromethane:ethyl acetate = 9:1:0.5), and obtaining a fraction containing the target product as a colorless foam (250 mg).

(2) Obtaining 1,3-dihydroxy-20(S)-(tert-butoxy the STI)-20(S)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraen, obtained in example 11 (1) (40 mg), treated with sodium hydride (60% in oil, 4.5 mg, 0.11 mmol), tetrahydrofuran (0.7 ml) and tert-butyl acrylate (55 mg, 0.43 mmol) under the conditions of example 4 (1) with the subsequent processing and secretion using preparative thin-layer chromatography (0.5 mm × 3 plates, hexane:dichloromethane:ethanol = 9:1:0.5), and receiving a colorless oily fraction (42 mg) containing the target product. This fraction (42 mg) is treated then in tetrahydrofuran (2.4 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.6 ml) by the method of example 4 (2) (for 1.5 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 20:1, are twice; 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are four times; and then 0.5 mm × 1 plate, dichloromethane:ethyl acetate = 1:3, are four times), getting mentioned in the title compound (3,276 mg, 1,22% for 3 stages) as a colourless oil.

IR (net): 3383, 2976, 2931, 2869, 2850, 1732, 1448, 1367, 1255, 1159, 1105, 1054 cm-1.1H NMR : 0,78 (s, 3H), of 1.28 (d, J=6.6 Hz, 3H), 1,45 (s, 9H), 2,46 (t, J=6.6 Hz, 2H), 2,56-to 2.65 (m, 1H), was 2.76-2,87 (m, 1H), 3.45 points is 3.57 (m, 1H), 3,60-and 3.72 (m, 1H), 3,92 (kV, J=6,6 Hz, 1H), 4,18-or 4.31 (m, 1H), 4,39-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,34 P CLASS="ptx2">Example 12

Obtaining 1,3-dihydroxy-20(R)-(N,N-dimethylaminocarbonylmethyl)-9,10-scoprega-5,7,10(19)-triens

1,3-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregn-5,7-diene (100 mg, 0.18 mmol) is treated in ethanol (200 ml) by the method of example 4 (3) (irradiated with light for 5 min and 45 sec, refluxed for 2 hours, followed by separation using preparative thin layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 5:1) to give oily fraction yellow, containing the desired product (18 mg). This fraction is treated then N,N-dimethylacrylamide (9.8 mg, 0,099 mmol) and sodium hydride (60% in oil, 2 mg, 0,047 mmol) in tetrahydrofuran (0,32 ml) by the method of example 4 (1) (0°C for 2 h and then at room temperature for 24 hours) with subsequent processing and separation using preparative thin layer chromatography (0.5 mm × 2 plates, ethyl acetate) to give colorless oily fraction, containing the desired product (11 mg). This fraction (11 mg) is treated later in tetrahydrofuran (2 ml) and methanol (2 ml), AMBERLYST 15 (1.3 g) by the method of example 6 (3) (at room temperature for 5 hours), followed by processing and purification via preparative tonkel is, toluene:ethyl acetate = 1:9, are five times), getting mentioned in the title compound (1,261 mg, 1,62%) as a colourless oil.

IR (net): 3429, 2925, 2871, 1628, 1103, 1057 cm-1.1H NMR : 0,55 (s, 3H), of 1.09 (t, J=5,9 Hz, 3H), 2,78-2,89 (m, 1H), 2,93 (s, 3H), to 3.02 (s, 3H), 3.25 to 3,37 (m, 1H), 3,54-3,66 (m, 1H), 3,79-3,90 (m, 1H), 4,16-the 4.29 (m, 1H), to 4.38-4,48 (m, 1H), 5,00 (Shir.s, 1H), 5,32 (Shir.s, 1H), of 5.99 (d, J=11.2 Hz, 1H), 6,38 (d, J=11.2 Hz, 1H). MS m/z: 431 (M+), 118 (100%). UVmaxnm: 264.

Example 13

Obtaining 1,3-dihydroxy-20(S)-(N-tert-butyl-N-methylaminoquinoline)-9,10-scoprega-5,7,10(19),16-tetraene

The fraction containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 11(1) (100 mg), treated with sodium hydride (60% in oil, 86 mg, 2.14 mmol), tetrahydrofuran (4.8 ml), 15-crown-5 (80 mg, 0.36 mmol) and N-tert-butyl-N-methylpropanamide (446 mg, 2.14 mmol) according to the method of example 8 (1) with the subsequent processing and selection using preparative thin layer chromatography (0.5 mm × 4 plates, hexane:ethyl acetate = 10:1, are four times) to give a colorless oily fraction containing the target product (63 mg). This fraction (63 mg) is treated later in tetrahydrofuran (6.0 ml) 1M tetrahydrofuranyl solution of tet is omashu preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 20:1, show four times and then 0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:5:1, are five times), getting mentioned in the title compound (10,683 mg, 2.35 per cent for stage 3) in the form of a colorless oil.

IR (net): 3390, 2974, 2931, 2850, 1651, 1633, 1446, 1392, 1365, 1211, 1140, 1053 cm-1.1H NMR : 0,76 (s, 3H), of 1.35 (d, J=6.6 Hz, 3H), of 1.40 (s, 9H), 2,54-to 2.67 (m, 1H), 2,87 (s, 3H), with 3.89 (d, J=a 13.9 Hz, 1H), 3,99-to 4.14 (m, 2H), 4,18-or 4.31 (m, 1H), 4,40-to 4.52 (m, 1H), 5,01 (Shir.s, 1H), 5,33 (Shir.s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 312 (M+-HOCH2CON(Me) - t-Bu), 57 (100%). UVmaxnm: 264.

Example 14

Obtaining 1,3-dihydroxy-20(S)-(N-tert-butylaminoethyl)-9,10-scoprega-5,7,10(19),16-tetraene

The fraction containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 11(1) (100 mg), treated with sodium hydride (60% in oil, 43 mg, 1.07 mmol), tetrahydrofuran (1.9 ml), N,N-dimethylformamide (80 mg, 1.9 mmol) and N-tert-butylbromide (208 mg, 1.07 mmol) according to the method of example 8 (1) with subsequent processing and selection using preparative thin layer chromatography (0.5 mm × 4 plates, hexane:ethyl acetate = 10:1, are three times), getting oily fraction is l) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,78 ml) by the method of example 4 (2) (for 2 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 20:1, show three times and then 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are five times), getting mentioned in the title compound (5,267 mg, 1,20% for 3 stages) as a colourless oil.

IR (net): 3400, 3323, 2968, 2931, 2850, 1666, 1531, 1456, 1365, 1227, 1109, 1055 cm-1.1H NMR : 0,79 (s, 3H), of 1.36 (d, J=6.6 Hz, 3H), of 1.37 (s, 9H), 2,19-2,47 (m, 3H), 2,55-to 2.65 (m, 1H), 2.77-to is 2.88 (m, 1H), 3,69 (d, J=15.2 Hz, 1H), 3,81 (d, J=15.2 Hz, 1H), 3,98 (kV, J=6.3 Hz, 1H), 4,17-to 4.33 (m, 1H), 4,40-a 4.53 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H), 6,44 (Shir.s, 1H). MC m/z: 312 (M+-HOCH2CONHt-Bu), 57 (100%). UVmaxnm: 263.

Example 15

Obtaining 1,3-dihydroxy-20(S)-(isopropoxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraene

The fraction containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 11(1) (100 mg), treated with sodium hydride (60% in oil, 43 mg, 1.07 mmol), tetrahydrofuran (4.8 ml), 15-crown-5 (80 mg, 0.36 mmol) and isopropylmalate (388 mg, 2.14 mmol) by the method of example 8 (1) with subsequent processing and selection using preparative thin layer chromatography (0.5 mm × 4 plates, hexane:ethyl acetate = 10:1) to give colorless maslanik the M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,46 ml) by the method of example 4 (2) (for 2 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 20:1, are twice; 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are four times; and then 0.5 mm × 1 plate, dichloromethane:ethyl acetate = 1:3, are four times), getting mentioned in the title compound (1,386 mg, 0.32 per cent for stage 3) in the form of a colorless oil.

IR (net): 3386, 2978, 2931, 2850, 1747, 1444, 1373, 1286, 1207, 1126, 1105, 1052 cm-1.1H NMR : 0,78 (s, 3H), 1,25 (d, J=6.3 Hz, 6H), to 1.37 (d, J=6.6 Hz, 3H), 2,55-of 2.66 (m, 1H), 2.77-to 2,87 (m, 1H), 3,89 (d, J=16.5 Hz, 1H), was 4.02 (d, J=16.2 Hz, 1H), 4,07 (kV, J=6.3 Hz, 1H), 4,19-4,30 (m, 1H), 4,40-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,03-of 5.15 (m, 1H), 5,34 (Shir.s, 1H), 5,61 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 430 (M+), 133 (100%). UVmaxnm: 264.

Example 16

(1) preparation of 17-acetyltributyl-1,3-dihydroxy-9,10-secondrate-5,7,10(19),16-tetraene

1,3-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl) androsta-5,7,16-triene (750 mg, 1.38 mmol) is treated in ethanol (600 ml) by the method of example 4 (3) (irradiated with light for 30 minutes, refluxed for 2 hours), followed by purification through column chromatography (hexane:ethyl acetate = 10:1) to give a fraction containing specified in the title compound (550 mg). This fraction is then treated with methanesulfonamide is) in dimethyl sulfoxide (5 ml) according to the method of example 1 (3) (exercise metilirovanie for 15 minutes, diacetylpyridine within 30 minutes), followed by processing and purification via preparative thin-layer chromatography (1.0 mm × 7 plates, hexane:ethyl acetate = 10:1, show once), obtaining a fraction containing specified in the title compound (430 mg). This fraction is treated later in tetrahydrofuran (40 ml) and methanol (40 ml), AMBERLYST 15 (18 g) by the method of example 6 (3) with further processing and purification via preparative thin-layer chromatography (1.0 mm × 7 plates, hexane:ethyl acetate:ethanol = 5:5:1, showing once), getting mentioned in the title compound (30 mg) as a colourless oil.

1H NMR : 0,72 (s, 3H), of 2.33 (s, 3H), 3,50-3,68 (m, 2H), 4,10 (Shir.s, 1H), 4,43 (Shir.s, 1H), 5,00 (s, 1H), 5,33 (s, 1H), to 5.57 (s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,34 (d, J=11.2 Hz, 1H).

(2) Obtaining 17-(tert-butoxycarbonylmethylene)-1,3-dihydroxy-9,10-secondrate-5,7,10(19),16-tetraene

To a solution of 17-acetyltributyl-1,3-dihydroxy-9,10-secondrate-5,7,10(19),16-tetraene (10 mg, 0,0267 mmol) in tetrahydrofuran (0.5 ml) is added tert-butylbromide (10 mg, 0,0513 mmol) under nitrogen atmosphere and stirred at room temperature for 5 minutes. Add a 1M methanol solution of potassium hydroxide (0.5 ml) and then stirred at room temperatur sodium and then dried over anhydrous sodium sulfate. After evaporation under reduced pressure to remove solvent residue purified using preparative thin-layer chromatography (0.25 mm × 1 plate, ethyl acetate:toluene = 1:1, are twice), getting mentioned in the title compound (0,479 mg, 4%) as a colourless oil.

IR (net): 2924, 2848, 1722, 1564, 1367, 1294, 1259, 1124, 1053 cm-1.1H NMR : 0,76 (s, 3H), of 1.48 (s, 9H), is 3.08 (s, 2H), 3,28-of 3.31 (m, 2H), 4,22 (Shir.s, 1H), 4,46 (Shir.s, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), 5,59 (s, 1H), 6,10 (d, J=10,9 Hz, 1H), 6,37 (d, J=10,9 Hz, 1H). MC m/z: 389 (M+-(CH3)3C), 57 (100%). UVmaxnm: 264.

Example 17

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(tert-butoxycarbonylmethyl)-9,10-scoprega-5,7,10(19),16-tetraene

To a solution of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraene (848 mg, of 1.52 mmol) in tetrahydrofuran (25 ml) is added sodium hydride (60% in oil, 374 mg, 9,34 mmol) and stirred at room temperature for 15 minutes in a stream of nitrogen. Then added dropwise a solution of 15-crown-5 (335 mg, of 1.52 mmol) and tert-butylbromide (1,82 g, 9,34 mmol) in tetrahydrofuran (8 ml), followed by boiling under reflux for 4 hours and 30 minutes. The reaction mixture by pouring the major aqueous sodium bicarbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (n-hexane:ethyl acetate = 20:1) to give compound (1.47 g), containing specified in the title compound as a colourless oil.

(2) Obtaining [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(tert-butoxycarbonylmethyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 17 (1) (1.47 g), dissolved in tetrahydrofuran (30,0 ml). To this solution was added 1M methanol solution of sodium methoxide (11 ml) and stirred at room temperature for 30 minutes. Then add 1M aqueous sodium hydroxide (11 ml) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane, poured into saturated aqueous sodium dihydrophosphate, extracted with dichloromethane and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (dichloromethane:ethanol = 20:1), obtaining mentioned in the title compound (651 mg, 69% over 2 stages) in the form Bestway : 0,04-0,09 (m, 12H), to 0.78 (s, 3H), from 0.88 (s, 18H), of 1.40 (d, J=6.4 Hz, 3H), 2,78-is 2.88 (m, 1H), 3,93 (d, J=16,3 Hz, 1H), 4,01-of 4.25 (m, 3H), 4,34-4,43 (m, 1H), 4,87 (d, J=2.1 Hz, 1H), 5,20 (d, J=1.7 Hz, 1H), 5,64 (Shir.s, 1H), 6,10 (d, J=11,4 Hz, 1H), 6,23 (d, J=11.2 Hz, 1H). MS m/z: 616 (M+-1), 73 (100%). UVmaxnm: 264.

(3) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19),16-tetraene

To a solution of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (326 mg, of 0.53 mmol) in tetrahydrofuran (5.3 ml) is added 3-methyl-3-pentanol (87 mg, 0.85 mmol), N,N'-dicyclohexylcarbodiimide (175 mg, 0.85 mmol) and 4-(dimethylamino)pyridine (65 mg, of 0.53 mmol) and stirred at room temperature for 17 hours in a stream of nitrogen. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (hexane:ethyl acetate = 20:1) to give compound (319 mg) containing specified in the title compound as a colourless oil.

(4) to Obtain 1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19),16-tetraene

The mixture, with tetraen, obtained in example 17 (3) (319 mg), dissolved in tetrahydrofuran (10 ml). To this solution was added 1M tertrahydrofuran ring solution of Tetra-n-butylammonium (4,55 ml) and stirred at 50°C for 2 hours in a stream of nitrogen. The reaction mixture was poured into water, extracted with ethyl acetate and then washed sequentially with saturated aqueous ammoniacloridegas, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (dichloromethane:ethanol = 20:1) and then using preparative thin layer chromatography (0.5 mm × 3 plates, dichloromethane:ethanol = 20:1, are three times), getting mentioned in the title compound (125,3 mg, 50% over 2 stages) as a colourless oil.

IR (net): 3400, 2973, 2931, 2883, 2850, 1745, 1727, 1459, 1373, 1218, 1122, 1052 cm-1.1H NMR : 0,77 (s, 3H), of 0.85 (t, J=7,6 Hz, 6H), of 1.36 (d, J=6.6 Hz, 3H), 2,56-of 2.66 (m, 1H), 2.77-to 2,87 (m, 1H), 3,84 (d, J=16.5 Hz, 1H), 3.96 points (d, J=16,3 Hz, 1H), 4,08 (kV, J=6,4 Hz, 1H), 4,19-the 4.29 (m, 1H), 4,40-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,59 (Shir.s, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,1 Hz, 1H). MC m/z: 472 (M+), 85 (100%). UVmaxnm: 263.

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (26 mg, 0,042 mmol) is treated with 2-methyl-2-pentanol (0.1 ml, 1,208 mmol), N,N'-dicyclohexylcarbodiimide (14 mg, 0,067 mmol) and 4-(dimethylamino)pyridine (5 mg, 0,042 mmol) in tetrahydrofuran (1.0 ml) by way of example 17 (3) (at room temperature for 18 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 6:1, show once), obtaining a mixture (20 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 18 (1) (20 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (1.0 ml) in tetrahydrofuran (1.0 ml) by the method of example 17 (4) (at an external temperature of 45°C for 1 hour) with further processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:10:1, are twice), receiving the specified 1369, 1218, 1122, 1052 cm-1.1H NMR : 0,77 (s, 3H), of 0.91 (t, J=7.0 Hz, 3H), of 1.36 (d, J=6.2 Hz, 3H), 2,56-of 2.66 (m, 1H), 2.77-to 2,89 (m, 1H), 3,82 (d, J=16.5 Hz, 1H), 3,93 (d, J=16.5 Hz, 1H), 4,08 (kV, J=6.2 Hz, 1H), 4,19-4,30 (m, 1H), 4,40-is 4.93 (m, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), ceiling of 5.60 (s, 1H), 6,11 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC (ESI) m/z: 495 (M++Na). UVmaxnm: 263.

Example 19

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (50,7 mg, 0,0822 mmol) is treated with 2-methyl-2-heptanol (0.1 ml, 0,936 mmol), N,N'-dicyclohexylcarbodiimide (27 mg, 0,131 mmol) and 4-(dimethylamino)pyridine (0.01 g, 0,0822 mmol) in dichloromethane (1.0 ml) by way of example 17 (3) (at room temperature for 18 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 6:1, are twice), obtaining a mixture (30 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-dimethylacetophenone solution of Tetra-n-butylammonium (1.0 ml) in tetrahydrofuran (1.0 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1 hour), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 5:5:1, are twice), getting mentioned in the title compound (7,414 mg, 18% over 2 stages) as a colourless oil.

IR (net): 2929, 2852, 1745, 1727, 1625, 1562, 1450, 1369, 1122, 1052 cm-1.1H NMR : 0,77 (s, 3H), 0.88 to (so J=7,0 Hz, 3H), of 1.36 (d, J=6.5 Hz, 3H), 2,56-to 2.65 (m, 1H), 2.77-to 2,87 (m, 1H), 3,82 (d, J=16.5 Hz, 1H), 3,92 (d, J=16.5 Hz, 1H), 4,07 (kV, J=6,5 Hz, 1H), 4,21-the 4.29 (m, 1H), 4,40-of 4.49 (m, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), 5,59 (s, 1H), 6,11 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC m/z: 482 (M+- H2O), 57(100%). UVmaxnm: 264.

Example 20

(1) preparation of 1-ethyl-1-methylpropylamine

To a solution of akriloilkhlorida (5.0 g, 55.2 mmol) and 3-methyl-3-pentanol (7,6 ml of 60.8 mmol) in dichloromethane added triethylamine (23 ml, 166 mmol) at room temperature under nitrogen atmosphere. After stirring at room temperature for 14 hours, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous sodium chloride. The organic layer is dried over anhydrous sodium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (hexane:ethyl acetate = 10:1), obtaining specified in the header of the connection (the 5.45 g, 63%) as a colourless m is 6,24 (DD, J=17,3, 1.7 Hz, 1H).

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-20(S}-(2-(1-ethyl-1-methylpropanesulphonic)ethoxy)-9,10-scoprega-5,7,10(19),16-tetraene

To a solution of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraene (50 mg, 0,0894 mmol) and 1-ethyl-1-methylpropylamine (0.1 g, 0,640 mmol) in tetrahydrofuran (1.0 ml) is added sodium hydride (60% in oil, 3.4 mg, of 0.085 mmol) at 0°C in nitrogen atmosphere. After stirring at 5°C for 18 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammoniacloridegas and water. The organic layer is dried over anhydrous sodium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 10:1, show once), obtaining a mixture (77,3 mg) containing specified in the header of the connection.

(3) Obtaining 1,3-dihydroxy-20(S)-{2-(1-ethyl-1-methylpropanesulphonic)ethoxy}-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-{2-(1-ethyl-1-methylpropanesulphonic)ethoxy}-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 20 (2) (77,3 mg), treated with 1M tetrapro external temperature of 50°C for 1 hour), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 4 plates, hexane:ethyl acetate:ethanol = 5:5:1, are twice), getting mentioned in the title compound (15.8 mg, 36% over 2 stages) as a colourless oil.

IR (net): 2973, 2931, 2881, 2850, 1727, 1461, 1444, 1367, 1263, 1195, 1056 cm-1.1H NMR : 0,77 (s, 3H), of 0.85 (t, J=7,6 Hz, 6H), of 1.28 (d, J=6.5 Hz, 3H), of 1.37 (s, 3H), 2,48 (t, J=6,8 Hz, 2H), 2,55-of 2.66 (m, 1H), was 2.76-is 2.88 (m, 1H), 3,44 of 3.56 (m, 1H), 3,57-3,71 (m, 1H), 3,92 (kV, J=6,5 Hz, 1H), 4,19-to 4.28 (m, 1H), 4,40-of 4.49 (m, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), to 5.57 (s, 1H), 6,10 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC m/z: 486 (M+), 312 (100%). UVmaxnm: 264.

Example 21

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-isopropyl-2-methylpropanesulfonate)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (30 mg, 0,049 mmol), 2,4-dimethyl-3-pentanol (17 mg, 0.15 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (19 mg, 0,099 mmol), 4-(dimethylamino)pyridine (18 mg, 0.15 mmol) and dichloromethane (1 ml) mixed and stirred over night at room temperature, followed by separation using preparative thin layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 5:1, showing once) to give compound (22 mg) containing the target product is 9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-isopropyl-2-methylpropanesulfonate)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 21 (1) (22 mg, 0,031 mmol), is treated in tetrahydrofuran (0,62 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,31 ml) by the method of example 17 (4) (at an external temperature of 50°C for 2 hours) with further processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, are twice), getting mentioned in the title compound (9,336 mg, 39% over 2 stages) as a colorless glass.

IR (net): 3370, 2966, 2933, 2877, 2850, 1751, 1464, 1203, 1122, 1053 cm-1.1H NMR : 0,78 (s, 3H), 0,83-of 0.91 (m, N), to 1.38 (d, J=6.4 Hz, 3H), 2,56-to 2.65 (m, 1H), 2.77-to 2,87 (m, 1H), 3,98 (d, J=16,7 Hz, 1H), 4,08 (d, J=16,7 Hz, 1H), 4.04 the-4,16 (m, 1H), 4,18 is 4.36 (width, 1H), 4,40-4,50 (width, 1H), 4,67 (t, J=6.3 Hz, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,4 Hz, 1H). MC m/z: 312 (M+-HOCH2CO2CH(i-Pr)2), 57 (100%). UVmaxnm: 264.

Example 22

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide

[{1,3-bis(tert-butylbiphenyl (41 mg, 0.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.11 mmol), monohydrate, 1-hydroxybenzotriazole (8 mg, 0,052 mmol) and dichloromethane (0,55 ml) are mixed and stirred over night at room temperature, followed by separation using preparative thin layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 5:1, showing once), receiving (29 mg) the mixture containing the target product as a colorless foam.

(2) Obtain {[1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl]oxy}-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide, obtained in example 22 (1) (29 mg, 0,039 mmol), is treated in tetrahydrofuran (0,78 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,39 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1.5 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, showing once and then 0.5 mm × 2 plates, dichloromethane:acetonitrile = 1:1, show once), getting mentioned in the title compound (9,603 mg, 33% for 2 is SUP>.1H NMR : 0,79 (s, 3H), of 1.36 (d, J=6.6 Hz, 3H), 2,55-to 2.65 (m, 1H), 2.77-to 2,87 (m, 1H), 3,86 (d, J=15,5 Hz, 1H), was 4.02 (d, J=15,5 Hz, 1H), 3,91-4.09 to (m, 3H), 4,19-4,30 (m, 1H), to 4.41 figure-4.49 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,11 (d, J=11.2 Hz, 1H) 6,36 (d, J=11.2 Hz, 1H), 6,85-6,97 (m, 1H). MS m/z: 519 (M+), 91 (100%). UVmaxnm: 264.

Example 23

(1) preparation of 1-ethyl-1-methylpropylamine

To a solution of 3-methyl-3-pentanol (10.6 g, 103 mmol) in dichloromethane (49 ml) is added N,N-dimethylaniline (15.0 g, 124 mmol) and bromoacetamide (25,0 g, 124 mmol) and stirred at room temperature for 2 hours in a stream of nitrogen. The reaction mixture was poured into water, extracted with tert-butylmethylamine ether, washed sequentially with saturated aqueous potassium bisulfate and saturated aqueous sodium bicarbonate and then dried over sodium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified by vacuum distillation (5 mm RT. Art. 71°C-72°C) receiving specified in the title compound (20.4 g, 89%) as a colourless oil.

IR (net): 2975, 2942, 2883, 1731, 1461, 1382, 1290, 1180, 1133, 1108 cm-1.1H NMR : 0,88 (t, J=7.5 Hz, 6H) of 1.41 (s, 3H), 1.70 to 1,99 (m, 4H), 3,76 (s, 2H).

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-a(S)-hydroxypregn-5,7-diene (5,00 g, 8,91 mmol) in tetrahydrofuran (90 ml) is added sodium hydride (60% in oil, 2.14 g, of 53.5 mmol), 15-crown-5 (1.77 ml, 8,91 mmol) and 1-ethyl-1-methylpropylamine (11.9 g, of 53.5 mmol), followed by boiling under reflux for 16 hours in an argon atmosphere. After cooling to room temperature the reaction mixture was poured into saturated aqueous ammoniacal and extracted with ethyl acetate (twice). The combined organic layers washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified on a chromatographic column (hexane:tert-butyl methyl ether = 30:1 and then hexane:toluene = 2:1) to give compound (5.9 g), containing specified in the header of the connection.

(3) Obtaining 1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)pregna-5,7-Dien

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethyl-1-methylpropionamidine)pregna-5,7-diene obtained in example 23 (2) (5,59 g), 1M tertrahydrofuran ring solution of Tetra-n-butylammonium (79,5 ml of 79.5 ml) and acetic acid (2 ml) are mixed and stirred at an external temperature of 65°C for 17 hours. After cooling to a potassium atom, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (hexane:ethyl acetate:ethanol = 5:5:0,3), receiving specified in the header connection (2,43 g, 57% over 2 stages) in the form of foam pale yellow color.

IR (net): 3369, 2968, 2939, 2875, 1751, 1722, 1460, 1375, 1294, 1209, 1132, 1055, 1032 cm-1.1H NMR : 0,62 (s, 3H), of 0.85 (t, J=7.5 Hz, 6H), were 0.94 (s, 3H), 1,20 (d, J=6,1 Hz, 3H), of 1.40 (s, 3H), 2,27-to 2.41 (m, 1H), 2,48 at 2.59 (m, 1H), 2,66-and 2.79 (m, 1H), 3,39 (m, 1H), 3,76 (Shir.s, 1H), 3,93 (d, J=16.0 Hz, 1H), 4,01 (d, J=16.0 Hz, 1H), 4,07 (m, 1H), are 5.36-of 5.45 (m, 1H), 5,69-USD 5.76 (m, 1H). MC m/z: 474 (M+), 315 (100%). UVmaxnm: 271, 282, 294.

(4) to Obtain 1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19)-triens

1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)pregna-5,7-diene (2,42 g, 5,10 mmol) is treated in tetrahydrofuran (650 ml) by the method of example 4 (3) except that the light irradiation is continued for 2 hours and 15 minutes, followed by purification through column chromatography (hexane:ethyl acetate:ethanol = 7:3:0.3, and then dichloromethane: ethyl acetate:ethanol = 6:1:0,1), receiving UCA, 1296, 1213, 1128, 1057 cm-1.1H NMR : 0,53 (s, 3H), of 0.85 (t, J=7.5 Hz, 6H), 1,19 (d, J=6.0 Hz, 3H), of 1.39 (s, 3H), 2,25-is 2.37 (m, 1H), 2,55-to 2.65 (m, 1H), 2.77-to is 2.88 (m, 1H), 3,36 (m, 1H), 3,92 (d, J=16.0 Hz, 1H), 4.00 points (d, J=16.0 Hz, 1H), 4,17-4,29 (width, 1H), 4,39-4,48 (width, 1H), 4,99 (m, 1H), 5,32 (m, 1H), 6,03 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC m/z: 474 (M+), 134 (100%). UVmaxnm: 264.

Example 24

Synthesis of (1,3)-1,3-bis((tert-butyl)dimethyl)silyl)oxy)pregna-5,7,16-triene-20-she

(1) Synthesis of (1,3)-1,3-bis((tert-butyl(dimethyl)silyl)oxy) androsta-5,7,16-triene-17-intraformational

(1,3)-1,3-bis((tert-butyl(dimethyl)silyl)oxy)androsta-5,7-Dien-17-one (21,0 g) dissolved in tetrahydrofuran (140 ml), to this add 2-(N,N-bis(trifloromethyl)amino)pyridine (19,1 g) at room temperature. After the reaction mixture was cooled to -78°C, and thereto is added dropwise a 1.0 M tertrahydrofuran ring solution of sodium bis(trimethylsilyl)amide (48,3 ml). Then stirring is continued at -78°C for 30 minutes, the reaction mixture is added saturated aqueous sodium bicarbonate, then extracted with a mixture of hexane/ethyl acetate = 5/1. Extracted solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove solvent. The resulting residue isH-NMR (270 MHz, CDCl3) : 5,64-to 5.58 (m, 2H), 5,43 lower than the 5.37 (m, 1H), 4,12-3,98 (m, 1H), 3,74-3,68 (m, 1H), 2,96-2,84 (m, 1H), 2,48-of 2.26 (m, 5H), 2.00 in to 1.42 (m, 1H), 0,97 (s, 3H), of 0.95 (s, 3H), of 0.89 (s, 18H), 0,12 (s, 3H), 0,107 (s, 6H), to 0.06 (s, 3H).

(2) Synthesis of (1,3)-1,3-bis((tert-butyl(dimethyl)silyl)oxy) pregna-5,7,16-triene-20-she

(1,3)-1,3-bis((tert-butyl(dimethyl)silyl)oxy)androsta-5,7,16-triene-17-intraformational (40,3 g) dissolved in dimethylacetamide (203 ml) followed by addition of tetrakis (triphenylphosphine)palladium(0) (703 mg). The resulting mixture was kept under reduced pressure and then placed in an atmosphere of carbon monoxide. This procedure is then repeated twice. To this mixture 0,98 M hexane solution dimethylammoniumchloride (74,4 ml) at room temperature and then stirred at room temperature for 20 minutes. After heating to 58°C and stirring for 2 hours to the reaction mixture, water is added, then extracted with a mixture of hexane/ethyl acetate = 1/1. Extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtaining specified in the header connection (34,0 g, yield 100%).

1H-NMR (300 MHz, benzene-d6) : 6,01 (DD, J=2.5 and 2.7 Hz, 1H), 5,72 (d, J=5.8 Hz, 1H), 5,43 and 5.36 (m, 1H), to 4.38-to 4.23 (m, 1H), to 3.58-3,51 (m, 1H), 3,09-of 2.97 (m, 1H), 2,02 (s, 3H).

Example 25

Synthesis of 1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19),16-tetraene

(1) Synthesis of (1,3,20 S)-1,3-bis((tert-butyl(dimethyl)silyl)oxy)pregna-5,7,16-trien-20-ol

(1,3)-1,3-bis((tert-butyl(dimethyl)silyl)oxy)pregna-5,7,16-triene-20-he, synthesized in example 24 (45,0 g), dissolved in toluene (240 ml) and then cooled to -20°C, followed by stirring for 30 minutes. To the resulting solution was added to the complex of borane-dimethyl sulfide (22.9 ml) at -20°C and stirred for 5 minutes. Then to the solution was added 1M toluene solution of (R)-2-methyl-CBS-oxazaborolidine (22.9 ml) at -20°C and stirred for 1 hour. To the reaction mixture is added methanol, then extracted with ethyl acetate. Extracted solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove solvent. The obtained residue is purified on a chromatographic column with silica gel (liquid phase: hexane/ethyl acetate = 9/1), getting mentioned in the title compound (23.3 g, yield 89%).

1H-NMR (300 MHz, benzene-d6) : 5,71 (d, J=4.9 Hz, 1H) 5,49 (Shir.s, 2H), 4,40-to 4.15 (m, 2H), 3,59 (Shir.s, 1H), 3,13-3,03 (m, 1H), 2,61 (s, 1H), 2,59 (s, 1H), 2,46-is 2.37 (m, 1H), 2,20-of 1.92 (m, 4H), 1.85 to about 1.47 (m, 4H), shall ethylpropyl -(((( 1,3, 20S)-1,3-bis(tert-butyl(dimethyl)silyl)oxy)pregna-5,7,16-triene-20-yl)oxy)acetate

(1,3,20 S)-1,3-Bis((tert-butyl(dimethyl)silyl)oxy) pregna-5,7,16-trien-20-ol (210 mg) and 60% sodium hydride (90 mg) was dissolved in tetrahydrofuran (3,7 ml). To the resulting solution was added 15-crown-5-ether (83 μl) and then 1-ethyl-1-methylpropylamine (502 mg) at room temperature followed by heating to 60°C. After stirring at 60°C for 12 hours to the solution was added methanol, and then extracted with tert-butylmethylamine ether. Extracted solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove solvent. The obtained residue is purified on a chromatographic column with silica gel (liquid phase:hexane:diethyl ether = 10/1) and then through column chromatography with silica gel (liquid phase:hexane/methylene chloride = 1/2), getting mentioned in the title compound (244 mg, yield 93%).

1H-NMR (300 MHz, benzene-d6) : 5,70 (d, J=6,9 Hz, 1H), 5.56mm (Shir.s, 1H), 5,49-5,41 (m, 1H), to 4.38-4.25 in (m, 1H), 4,21 (kV, J=6.3 Hz, 1H), 3,99 (d, J=16.2 Hz, 1H), 3,92 (d, J=16.2 Hz, 1H), 3,63-3,55 (m, 1H), 3,10-3,00 (m, 1H), 2,64 of $ 2.53 (m, 1H), 2,47-of 2.36 (m, 1H), 2,23-of 1.44 (m, 12H), of 1.41 (d, J=6.3 Hz, 3H), of 1.31 (s, 3H), was 1.04 (s, 9H), and 0.98 (s, 3H), were 0.94 (s, 9H), to 0.89 (s, 3H), 0,76 (t, J=7.4 Hz, 6H), of 0.18 (s, 3H), 0,16 (s, 3H), of 0.13 (s, 3H), 0,06 x2">1-Ethyl-1-methylpropyl((((1,3,20 S)-1,3-bis(tert-butyl(dimethyl)silyl)oxy)pregna-5,7,16-triene-20-yl)oxy)acetate (203 mg) was dissolved in 1.0 M tertrahydrofuran ring solution tetrabutylammonium (3.0 ml) followed by addition of acetic acid (75 mcg). The resulting solution was heated to 60°C, stirred for 12 hours and then extracted with ethyl acetate. Extracted solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove solvent. The obtained residue is purified on a chromatographic column with silica gel (liquid phase: hexane/ethyl acetate = 2/3), getting mentioned in the title compound (132 mg, yield 97%).

1H-NMR (300 MHz, acetone-d6) : 5,66-5,59 (m, 2H), 5,45 of 5.39 (m, 1H), 4,14 (kV, J=6,6 Hz, 1H), 4.09 to 3,95 (m, 1H), 3,95 (d, J=16.2 Hz, 1H), 3,86 (d, J=16.2 Hz, 1H), 3,80-3,70 (m, 1.5 H), 3,64-3,50 (m, 0.5 H), 2,49-2,39 (m, 1H), 2,38-2,17 (m, 4H), 2,12-to 2.06 (m, 1H), 1,96-of 1.62 (m, 8H), 1,54-of 1.42 (m, 1H), 1,37 (s, 3H), of 1.30 (d, J=6.6 Hz, 3H), of 0.95 (s, 3H), of 0.90 (s, 3H), of 0.85 (t, J=7.4 Hz, 6H).

(4) Synthesis of 1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19),16-tetraene

1-Ethyl-1-methylpropyl-(((1,3,20 S)-1,3-dihydroxypregna-5,7,16-triene-20-yl)oxy)acetate (132 mg) was dissolved in tetrahydrofuran (500 ml). This solution is cooled to 18°C in a stream of argon and irradiated At NTA application No. 10-188880, WO 00/01477). Then the solution is refluxed for 2 hours and evaporated under reduced pressure to remove solvent. The obtained residue is purified on a chromatographic column with silica gel (liquid phase: methylene chloride:ethyl acetate = 6/4) to give specified in the header of the connection (by 34.2 mg, yield 26%). The spectrum thus obtained compounds coincides with the spectrum of the compound obtained in example 17 (4).

Example 26

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-diethylpyrocarbonate)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (31 mg, 0.05 mmol) is treated with 3-ethyl-3-pentanol (9 mg, 0.08 mmol), N,N'-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) and 4-(dimethylamino)pyridine (6 mg, 0.05 mmol) in dichloromethane (0.5 ml) by way of example 17 (3) (at room temperature for 17 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 10:1, are twice) to give compound (27.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S-(1,1-S)-(1,1-diethylpyrocarbonate)-9,10-scoprega-5,7,10(19),16-tetraen from example 26 (1) (27 mg), treated in tetrahydrofuran (1.7 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,57 ml) by the method according to example 17 (4) (at an external temperature of 50°C for 2 hours) and then treated. The resulting residue is purified preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 20:1, are twice; 0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:5:1, show three times; and then 0.25 mm × 2 plates, dichloromethane:ethyl acetate = 3:1, are twice) to obtain specified in the connection header (of 2.966 mg, yield of 12.2% over 2 stages) as a colourless oil.

IR (net): 3386, 2969, 2931, 2881, 2852, 1745, 1727, 1457, 1288, 1214, 1122, 1052 cm-1.1H NMR : 0,78 (s, 3H), 0,81 (t, J=7,3 Hz, 9H), of 1.36 (d, J=6.3 Hz, 3H), 1,84 (kV, J=7,3 Hz, 6H), 2,18-2,47 (m, 3H), 2,54-to 2.67 (m, 1H), was 2.76-is 2.88 (m, 1H), 3,85 (d, J=16.5 Hz, 1H), 3,97 (d, J=16.5 Hz, 1H), Android 4.04 is 4.13 (m, 1H), 4,19-4,30 (m, 1H), 4,39-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,59 (Shir.s, 1H), 6,11 (d, J=11.5 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 312 (M+NON2COOCEt3), 57 (100%). UVmaxnm: 263.

Example 27

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclohexyloxycarbonyloxy)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-testexecution (10 mg, 0,0518 mmol) and 4-(dimethylamino)pyridine (4 mg, 0,0324 mmol) in dichloromethane (1.0 ml) by the method of example 17 (3) (at room temperature for 2 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 5:1, showing once) to give a mixture (26,7 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(cyclohexyloxycarbonyloxy)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclohexyloxycarbonyloxy)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 27(1) (26,7 mg), treated in tetrahydrofuran (0.7 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.3 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 5:5:1, are twice), getting mentioned in the title compound (4,134 mg, 25% over 2 stages) as a colourless oil.

IR (net): 3326, 2927, 2852, 2358, 2321, 1749, 1627, 1558, 1448, 1218, 1122, 1053 cm-1.1H NMR : 0,77 (s, 3H), of 1.36 (d, J=6.5 Hz, 3H), 2,55-to 2.65 (m, 466 (M+-H2O), 55 (100%). UVmaxnm: 263.

Example 28

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-protivotoksicheskoe)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (20 mg, 0,0324 mmol) is treated with 4-heptanol (7 μl, 0,0518 mmol), N,N'-dicyclohexylcarbodiimide (10 mg, 0,0518 mmol) and 4-(dimethylamino)pyridine (4 mg, 0,0324 mmol) in dichloromethane (1.0 ml) by the method of example 17 (3) (at room temperature for 2 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 5:1, showing once), getting a mixture of 21.7 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-protivotoksicheskoe)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-protivotoksicheskoe)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 28 (1) (21,7 mg), treated in tetrahydrofuran (0.7 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.3 ml) by the method of example 17 (4) (at an external temperature of 50°C in terapii (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 5:5:1, are twice) and then perform another loop using preparative thin layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:10:1, are twice), getting mentioned in the title compound (4,266 photo mg, 27% over 2 stages) as a colourless oil.

IR (net): 3390, 3325, 2956, 2931, 2852, 1749, 1627, 1448, 1203, 1122, 1053 cm-1.1H NMR : 0,77 (s, 3H), of 0.90 (t, J=7.0 Hz, 6H), to 1.37 (d, J=6.2 Hz, 3H), 2,53-to 2.65 (m, 1H), was 2.76-is 2.88 (m, 1H), a 3.87-4,17 (m, 3H), 4,19-the 4.29 (m, 1H), 4,39-of 4.49 (m, 1H), 4.92 in-of 5.05 (m, 2H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,11 (d, J=11,1 Hz, 1H), 6,38 (d, J=11,1 Hz, 1H). MC m/z: 450 (M+-2H2O), 57 (100%). UVmaxnm: 263.

Example 29

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methyl-1-protivotoksicheskoe)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (20 mg, 0.03 mmol) is treated with 4-methyl-4-heptanol (6.3 mg, 0,048 mmol), N,N'-dicyclohexylcarbodiimide (9,9 mg, 0,048 mmol) and 4-(dimethylamino)pyridine (3.7 mg, 0.03 mmol) in dichloromethane (0.3 ml) by way of example 17 (3) (at room temperature for 15 hours, followed by processing and purification via preparative is,0 mg), containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-methyl-1-protivotoksicheskoe)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methyl-1-protivotoksicheskoe)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 29 (1) (14 mg), treated in tetrahydrofuran (0.5 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.2 ml) by the method of example 17 (4) (at an external temperature of 50°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.25 mm × 2 plates, dichloromethane:ethanol = 20:1, are three times), getting mentioned in the title compound (6,351 mg of 42.3% over 2 stages) as a colourless oil.

IR (net): 3417, 2960, 2931, 2873, 1747, 1467, 1373, 1213, 1122, 1052 cm-1.1H NMR : 0,77 (s, 3H), of 0.90 (t, J=7,3 Hz, 6N), of 1.36 (d, J=6.6 Hz, 3H), of 1.40 (s, 3H), 2,17-2,47 (m, 3H), 2,56-of 2.66 (m, 1H), was 2.76-is 2.88 (m, 1H), 3,81 (d, J=16.5 Hz, 1H), 3,94 (d, J=16.5 Hz, 1H), was 4.02 is 4.13 (m, 1H), 4,19-the 4.29 (m, 1H), 4,40-4,51 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,59 (Shir.s, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,1 Hz, 1H). MC m/z: 312 (M+-HOCH2COOC(CH3)(C3H7)2), 71 (100%). UVmaxnm: 264.

is dimetoxy)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (20 mg, 0,0324 mmol) is treated with 1-methylcyclohexanol (7 μm, 0,0518 mmol), N,N'-dicyclohexylcarbodiimide (10 mg, 0,0518 mmol) and 4-(dimethylamino)pyridine (4 mg, 0,0324 mmol) in dichloromethane (1.0 ml) by the method of example 17 (3) (at room temperature for 14 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 7:1, show once), getting a mixture of 14.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S-(1-methylcyclohexanecarboxylic)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methylcyclohexanecarboxylic)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 30(1) (14,0 mg), treated in tetrahydrofuran (0.7 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.3 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 5:5:1, are the (net): 3446, 2931, 2852, 1747, 1446, 1211, 1124, 1053, 962 cm-1.1H NMR : 0,78 (s, 3H), of 1.37 (d, J=6.8 Hz, 3H), 1,49 (s, 3H), 2,56-of 2.66 (m, 1H), 2.77-to 2,89 (m, 1H), 3,85 (d, J=16.5 Hz, 1H), 3,98 (d, J=16.5 Hz, 1H), 4.09 to (kV, J=6,8 Hz, 1H), 4,19-the 4.29 (m, 1H), to 4.41 figure-4.49 (m, 1H), 5,02 (s, 1H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11,6 Hz, 1H), 6,38 (d, J=11,6 Hz, 1H). MC m/z: 466 (M+-H2O), 55 (100%). UVmaxnm: 263.

Example 31

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclobutanedicarboxylate)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (20 mg, 0,0324 mmol) is treated with cyclododecanol (9 μl, 0,0518 mmol), N,N'-dicyclohexylcarbodiimide (10 mg, 0,0518 mmol) and 4-(dimethylamino)pyridine (4 mg, 0,0324 mmol) in dichloromethane (1.0 ml) by the method of example 17 (3) (at room temperature for 14 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 7:1, show once) receiving a mixture of 21.6 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(cyclobutanedicarboxylate)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy in tetrahydrofuran (0.7 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.3 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 5:5:1, showing once), getting mentioned in the title compound (4,971 mg, 28% over 2 stages) as a colourless oil.

IR (net): 3446, 2931, 2850, 1748, 1471, 1446, 1205, 1124, 1053 cm-1.1H NMR : 0,77 (s, 3H), 2,56-of 2.66 (m, 1H), 2.77-to 2,87 (m, 1H), 3,90 (d, J=16.5 Hz, 1H), was 4.02 (d, J=16.5 Hz, 1H), 4.09 to (kV, J=6,5 Hz, 1H), 4,19-the 4.29 (m, 1H), to 4.41 figure-4.49 (m, 1H), free 5.01 (s, 1H), 5,04-of 5.15 (m, 1H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,10 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC m/z: 518 (M+-2H2O), 55 (100%). UVmaxnm: 263.

Example 32

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methylcyclopentadienylmanganese)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (30 mg, 0,048 mmol) is treated with 1-methylcyclopentanol (4,8 mg, 0,048 mmol), N,N'-dicyclohexylcarbodiimide (9,9 mg, 0,048 mmol) and 4-(dimethylamino)pyridine (3.7 mg, 0.03 mmol) in dichloromethane (0.3 ml) by the method of example 17 (3) (at room temperature for 15 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:this is(2) Obtaining 1,3-dihydroxy-20(S)-(1-methylcyclopentadienylmanganese)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methylcyclopentadienylmanganese)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 32(1) (20 mg), treated in tetrahydrofuran (0.5 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,29 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1.5 hours and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 20:1, are three times), getting mentioned in the title compound (7,666 mg, 54,3% over 2 stages) as a colourless oil.

IR (net): 3392, 2965, 2933, 2873, 2850, 1747, 1444, 1375, 1222, 1180, 1122, 1052 cm-1.1H NMR : 0,77 (s, 3H), of 1.36 (d, J=6.4 Hz, 3H), 2,19 is 2.51 (m, 3H), 2,56 of 2.68 (m, 1H), 2.77-to 2,89 (m, 1H), 3,83 (d, J=16,3 Hz, 1H), 3,95 (d, J=16,3 Hz, 1H), was 4.02-to 4.14 (m, 1H), 4,21-or 4.31 (m, 1H), to 4.41-4,51 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,1 Hz, 1H). MC m/z: 470 (M+), 312 (M+-HOCH2COOC6H11), 83 (100%). UVmaxnm: 263.

Example 33

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclooctatetraene)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy the g 0,109 mmol), N,N'-dicyclohexylcarbodiimide (24,0 mg, 0,116 mmol) and 4-(dimethylamino)pyridine (10.0 mg, 0,082 mmol) in dichloromethane (0.3 ml) by the method of example 17 (3) (at room temperature for 15 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 15:1, are twice), getting a mixture of 16.6 mg) containing specified in the header connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(cyclooctatetraene)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclooctatetraene)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 33(1) (16,5 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.25 ml) by the method of example 17 (4) (at an external temperature of 45°C for 30 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 15:1, show twice, and then 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are four times), getting mentioned in the title compound (3.5 mg, 20% over 2 stages) as a colourless oil.

IR (net): 3392, 2928, 2856, 1744, 1468, 1204, 1124, 1052 cm+-H2O), 69 (100%). UVmaxnm: 263.

Example 34

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-butylmethoxdibezoylmethane)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (22,0 mg, being 0.036 mmol) is treated with nonan-5-I (14,0 mg, 0,097 mmol), N,N'-dicyclohexylcarbodiimide (24,0 mg, 0,116 mmol) and 4-(dimethylamino)pyridine (10.0 mg, 0,082 mmol) in dichloromethane (0.3 ml) by the method of example 17 (3) (at room temperature for 15 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 15:1, are twice), getting a mixture of 17.4 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-butylmethoxdibezoylmethane)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-butylmethoxdibezoylmethane)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 34 (1) (16.4 mg), treated with 1M tetrahydrofurane 30 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 15:1, are twice; 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are four times; 0.25 mm × 1 plate, toluene:ethyl acetate = 1:1, are twice; and then 0.25 mm × 1 plate, dichloromethane:ethyl acetate = 3:1, showing once), getting listed in the title compound (1.7 mg, 10% over 2 stages) as a colourless oil.

IR (net): 3384, 2932, 2860, 1746, 1444, 1370, 1204, 1124, 1054 cm-1.1H NMR : 0,77 (s, 3H), of 0.87 (t, J=6.9 Hz, 3H), from 0.88 (t, J=6.9 Hz, 3H), of 1.37 (d, J=6.6 Hz, 3H), 2,56-of 2.66 (m, 1H), 2,78-2,89 (m, 1H), 3,93 (d, J=16.5 Hz, 1H), Android 4.04 (d, J=16.5 Hz, 1H), 4,08 (kV, J=6,6 Hz, 1H), 4,20-4,30 (m, 1H), 4,40-4,50 (m, 1H), 4,96 (Quint., J=6.3 Hz, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,10 (d, J=11.5 Hz, 1H), 6,38 (d, J=11.5 Hz, 1H). MC m/z: 312 (M+-CH3CO2CH(CH2CH2CH2CH3)2), 57 (100%). UVmaxnm: 263.

Example 35

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-demethylepipodophyllotoxin)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (13,0 mg, 0,021 mmol) obrabatyvaimym (3.0 mg, of 0.025 mmol) in dichloromethane (0.2 ml) by the method of example 17 (3) (at room temperature for 1 hour), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 15:1, are twice), getting a mixture of 9.2 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1,1-demethylepipodophyllotoxin)-9,10-scoprega-5,7,10(19),16 tetraena

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-demethylepipodophyllotoxin)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 35(1) (10.0 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.15 ml) by the method of example 17 (4) (at an external temperature of 45°C for 40 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 1 plate, dichloromethane:ethanol = 15:1, show once, dichloromethane:ethanol = 10:1, show once), getting mentioned in the title compound (3.6 mg, 34% over 2 stages) as a colourless oil.

IR (net): 3392, 2972, 2932, 2848, 1744, 1444, 1370, 1220, 1122, 1054 cm-1.1H NMR : 0,77 (s, 3H), of 0.87 (t, J=7.4 Hz, 3H), of 1.36 (d, J=6.5 Hz, 3H), USD 1.43 (s, 6H), 2,55-of 2.66 (m, 1H), was 2.76-2,87 (m, 1H), 3,82 (d, J=16,3 Hz, 1H), 3,94 (d,Hz, 1H). MC m/z: 312 (M+-CH3CO2C(CH3)2CH2CH3), 71 (100%). UVmaxnm: 263.

Example 36

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(adamantane-2-rockstarunlock)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (30 mg, 0,048 mmol) is treated with 2-adamantanol (12 mg, 0,0768 mmol), N,N'-dicyclohexylcarbodiimide (16 mg, 0,0768 mmol) and 4-(dimethylamino)pyridine (6 mg, 0,048 mmol) in dichloromethane (1.0 ml) by the method of example 17 (3) (at room temperature for 14 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 6:1, show once), getting a mixture of 15.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(adamantane-2-rockstarunlock)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(adamantane-2-rockstarunlock)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 36 (1) (15,0 mg), treated in tetrahydrofuran (1.0 ml) of 1M tetrahydrofurane is 1 hour), followed by processing. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:10:1, are twice), getting mentioned in the title compound (1,024 mg, 4% over 2 stages) as a colourless oil.

IR (net): 3325, 2927, 2850, 1626, 1576, 1448, 1122, 1045 cm-1.1H NMR : 0,78 (s, 3H), 2,56-to 2.67 (m, 1H), 2.77-to 2,87 (m, 1H), 3,92-4,17 (m, 3H), 4,20-4,30 (m, 1H), 4,40-4,50 (m, 1H), 4,98-5,04 (m, 2H), of 5.34 (s, 1H), 5,62 (Shir.s, 1H), 6,11 (d, J=11,6 Hz, 1H), 6,38 (d, J=11,6 Hz, 1H). MC m/z: 504 (M+- H2O), 135 (100%). UVmaxnm: 263.

Example 37

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (26 mg, 0,042 mmol) is treated with 2-methyl-2-hexanol (0.1 ml, 0,699 mmol), N,N'-dicyclohexylcarbodiimide (14 mg, 0,067 mmol) and 4-(dimethylamino)pyridine (5 mg, 0,042 mmol) in tetrahydrofuran (1.0 ml) by way of example 17 (3) (at room temperature for 14 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 6:1, show once), getting a mixture of 15.0 m is carbonyloxy)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 37 (1) (15,0 mg), treated in tetrahydrofuran (1.0 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (1.0 ml) by the method of example 17 (4) (at an external temperature of 45°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:10:1, are twice), getting mentioned in the title compound (1,784 mg, 9% over 2 stages) as a colourless oil.

IR (net): 3323, 2927, 2852, 1749, 1626, 1558, 1448, 1254, 1209, 1122, 1053 cm-1.1H NMR : 0,78 (s, 3H), of 0.90 (t, J=7.0 Hz, 3H), of 1.36 (d, J=6.8 Hz, 3H), 2,55-of 2.66 (m, 1H), 2.77-to is 2.88 (m, 1H), 3,82 (d, J=16.2 Hz, 1H), 3,94 (d, J=16.2 Hz, 1H), 3,99-4,12 (m, 1H), 4,20-the 4.29 (m, 1H), to 4.41-4,50 (m, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC m/z: 468 (M+- H2O), 57 (100%). UVmaxnm: 262.

Example 38

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1,2-trimethylhexamethylene)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]expida (18,0 mg, 0,087 mmol) and 4-(dimethylamino)pyridine (6.8 mg, 0,056 mmol) in dichloromethane (1.0 ml) by the method of example 17 (3) (at room temperature for 16 h) followed by treatment and purification via preparative thin-layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 15:1, are once) to give compound (6.6 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1,1,2-trimethylhexamethylene)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy-20(S)-(1,1,2-trimethylhexamethylene)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 38 (1) (6.0 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.1 ml) by the method of example 17 (4) (at an external temperature of 45°C for 20 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 1 plate, dichloromethane:ethanol = 15:1, show once), getting mentioned in the title compound (1.6 mg, 10% over 2 stages) as a colourless oil.

IR (net): 3384, 2972, 2932, 2852, 1744, 1444, 1372, 1218, 1124, 1054 cm-1.1H NMR : 0,77 (s, 3H), 0,89 (d, J=7.2 Hz, 6H), of 1.36 (d, J=6,7 Hz, 3H), of 1.41 (s, 3H), of 1.42 (s, 3H), 2,54-of 2.66 (m, 1H), was 2.76-2,87 (m, 1H), 3,82 (d, J=16,H), 6,37 (d, J=11.0 cm Hz, 1H). MC m/z: 387 (M+-CH(CH3)2CH(CH3)2), 85 (100%). UVmaxnm: 263.

Example 39

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethylcyclohexylamine)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (27 mg, 0,044 mmol) is treated with 1-ethylcyclohexane (17 mg, 0.133 mmol), N,N'-dicyclohexylcarbodiimide (18 mg, 0,087 mmol) and 4-(dimethylamino)pyridine (16 mg, 0,131 mmol) in dichloromethane (0.4 ml) by the method of example 17 (3) (at room temperature for 15 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 5:1, showing once) obtaining a mixture (25 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-ethylcyclohexylamine)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethylcyclohexylamine)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 39 (1) (25 mg), treated in tetrahydrofuran (0,66 ml) 1M tertrahydrofuran ring 1.5 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (7,157 mg, 33% over 2 stages) as a colorless glass.

IR (net): 3380, 2931, 2852, 1745, 1448, 1211, 1122, 1053 cm-1.1H NMR : 0,78 (s, 3H), of 0.82 (t, J=7,6 Hz, 3H), of 1.37 (d, J=6.4 Hz, 3H), 2.57 m-2,62 (m, 1H), 2,78-2,84 (m, 1H), 3,86 (d, J=16,3 Hz, 1H), 3,99 (d, J=16,3 Hz, 1H), 4.09 to-4,20 (m, 1H), 4,20-4,30 (m, 1H), 4,40-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,4 Hz, 1H). MC m/z: 312 (M+-HOCH2CO2C8H15), 69 (100%). UVmaxnm: 264.

Example 40

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methylcyclohexanecarboxylic)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (19 mg, 0,031 mmol) is treated with 1-methylcyclopentanol (13 mg, 0,091 mmol), N,N'-dicyclohexylcarbodiimide (13 mg, 0,063 mmol) and 4-(dimethylamino)pyridine (11 mg, 0,090 mmol) in dichloromethane (0.3 ml) by the method of example 17 (3) (at room temperature for 15 hours), followed by processing and purification via preparative(15 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-methylcyclohexanecarboxylic)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methylcyclohexanecarboxylic)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 40 (1) (15 mg), treated in tetrahydrofuran (0,46 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,23 ml) by the method of example 17 (4) (at an external temperature of 60°C for 1.5 hours and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (5,527 mg, 35% over 2 stages) as a colourless foam.

IR (net): 3390, 2927, 2852, 1743, 1448, 1373, 1205, 1115, 1053 cm-1.1H NMR : 0,77 (s, 3H), of 1.36 (d, J=6.4 Hz, 3H), 2.57 m) 2.63 in (m, 1H), 2,79-2,84 (m, 1H), 3,81 (d, J=16,3 Hz, 1H), 3,94 (d, J=16,3 Hz, 1H), 4.04 the-4,16 (m, 1H), 4,20-4,30 (m, 1H), 4,40-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 312 (M+-HOCH2CO2C9H17), 69 (100%). UVmaxnm: 263.

Example 41

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-{4-methyl-1-(3-methylb and)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (26 mg, 0,042 mmol) is treated with 2,8-dimethyl-5-nonanol (0.1 g, 0,580 mmol), N,N'-dicyclohexylcarbodiimide (14 mg, 0,067 mmol) and 4-(dimethylamino)pyridine (5 mg, 0,042 mmol) in dichloromethane (1.0 ml) by the method of example 17 (3) (at room temperature for 14 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 6:1, show once) to give compound (30.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-{4-methyl-1-(3-methylbutyl)ventilatsioonikambri}-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-{4-methyl-1-(3-methylbutyl)ventilatsioonikambri}-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 41 (1) (30.0 mg), treated in tetrahydrofuran (1.0 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.8 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1 hour) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:methanol = 10:10:1, are twice), getting mentioned in the title compound (8,820 mg, 39% over 2 stages) in the form of colorless Mac H) 0,86 (t, J=6.4 Hz, 12H), to 1.37 (d, J=6.5 Hz, 3H), 2,54-to 2.67 (m, 1H), was 2.76-2,90 (m, 1H), 3,93 (d, J=17.6 Hz, 1H), Android 4.04 (d, J=17.6 Hz, 1H), 4.09 to (kV, J=6,8 Hz, 1H), 4,20-the 4.29 (m, 1H), to 4.41 figure-4.49 (m, 1H), a 4.86-to 4.98 (m, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,11 (d, J=10,8 Hz, 1H), 6,38 (d, J=10,8 Hz, 1H). MC m/z: 524 (M+-H2O), 57 (100%). UVmaxnm: 264.

Example 42

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1,2,2-tetramethylpropylenediamine)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (26 mg, 0,042 mmol) is treated with 1,1,2,2-tetramethylbiphenyl (0.1 g, 0,861 mmol), N,N'-dicyclohexylcarbodiimide (14 mg, 0,067 mmol) and 4-(dimethylamino)pyridine (5 mg, 0,042 mmol) in dichloromethane (1.0 ml) by the method of example 17 (3) (at room temperature for 14 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 6:1, show once) to give compound (25.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1,1,2,2-tetramethylpropylenediamine)-9,10-scoprega-5,7,10(19),Catrina

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1,2,2-tetramethylspiro is hydrofuran (1.0 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.8 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:10:1, are twice), getting mentioned in the title compound (1,558 mg, 8% over 2 stages) as a colourless oil.

IR(net): 2960, 2929, 2850, 1747, 1724, 1371, 1120, 1053 cm-1.1H NMR : 0,77 (s, 3H), of 0.96 (s, 9H), of 1.36 (d, J=6.5 Hz, 3H), 2,54-of 2.66 (m, 1H), 2,75-is 2.88 (m, 1H), 3,81 (d, J=16.2 Hz, 1H), 3,94 (d, J=16.2 Hz, 1H), 4,08 (kV, J=5,9 Hz, 1H), 4,19-4,30 (m, 1H), 4,40-of 4.49 (m, 1H), 5,02 (s, 1H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC m/z: 387 (M+-C7H15), 57 (100%). UVmaxnm: 264.

Example 43

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethylcyclopentadienyl)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (22,0 mg, being 0.036 mmol) is treated with 1-ethylcyclopentane (11.3 mg, 0,099 mmol), N,N'-dicyclohexylcarbodiimide (13.1 mg, 0,064 mmol) and 4-(dimethylamino)pyridine (4,7 mg 0,039 mmol) in dichloromethane (0.5 ml) according to example 17 (3) (at room temperature for 4 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 3 platine.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-ethylcyclopentadienyl)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethylcyclopentadienyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 43 (1) (12.5 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.2 ml) by the method of example 17 (4) (at an external temperature of 45°C for 20 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 15:1, are twice), getting mentioned in the title compound (4.2 mg, 26% over 2 stages) as a colourless oil.

IR (net): 3400, 2932, 2876, 1742, 1446, 1370, 1218, 1120, 1054 cm-1.1H NMR : 0,77 (s, 3H), of 0.85 (t, J=7.4 Hz, 3H), of 1.36 (d, J=6.6 Hz, 3H), 2,55-of 2.64 (m, 1H), was 2.76-2,89 (m, 1H), 3,84 (d, J=16,3 Hz, 1H), 3.96 points (d, J=16,3 Hz, 1H), 4,08 (kV, J=6,6 Hz, 1H), 4,19-4,30 (m, 1H), 4,40-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,59 (Shir.s, 1H), 6,10 (d, J=11,1 Hz, 1H), 6,37 (d, J=11,1 Hz, 1H). MC m/z: 484 (M+), 55 (100%). UVmaxnm: 263.

Example 44

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-cyclopropyl-1 metiletilketoksim)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyl-2-propanol (29 mg, 0,290 mmol), N,N'-dicyclohexylcarbodiimide (39 mg, 0,189 mmol) and 4-(dimethylamino)pyridine (35 mg, 0,286 mmol) in dichloromethane (0.95 ml) by the method of example 17 (3) (at room temperature for 15 hours), followed by processing and purification via preparative thin-layer chromatography (hexane:ethyl acetate = 10:1) to give compound (54 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-cyclopropyl-1 metiletilketoksim)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-cyclopropyl-1 metiletilketoksim)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 44 (1) (49 mg), treated in tetrahydrofuran (1.4 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.7 ml) by the method of example 17 (4) (at an external temperature of 60°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 4 plates, hexane:ethyl acetate:ethanol = 10:10:1, showing once and then 0.5 mm × 2 plates, toluene:ethyl acetate = 5:6, show once), getting mentioned in the title compound (3,561 mg, 9% over 2 stages) as a colourless foam.

IR (pure): 3388, 2972, 2m, 1H), 3,81 (d, J=16,3 Hz, 1H), 3,93 (d, J=16,3 Hz, 1H), 4,03-4,22 (m, 1H), 4,20-4,30 (m, 1H), 4,40-4,50 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,10 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC m/z: 312 (M+-HOCH2CO2C6H11), 83 (100%). UVmaxnm: 264.

Example 45

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1,2-trimethylhexamethylene)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (to 43.1 mg, 0,070 mmol) is treated with 2,4-dimethyl-2-pentanol (0.1 g, 0,861 mmol), N,N'-dicyclohexylcarbodiimide (23 mg, 0,112 mmol) and 4-(dimethylamino)pyridine (10 mg, 0,070 mmol) in dichloromethane (1.0 ml) by way of example 17 (3) (at room temperature for 14 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 6:1, are twice), getting a mixture of 28.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1,1,2-trimethylhexamethylene)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1,2-trimethylhexamethylene)-9,10-scoprega solution of Tetra-n-butylammonium (1.0 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 5:5:1, showing once) and then perform another loop using preparative thin layer chromatography (0.5 mm × 1 plate, dichloromethane:methanol = 20:1, show once), getting mentioned in the title compound (2,195 mg, 7% over 2 stages) as a colourless oil.

IR (net): 2952, 2929, 1747, 1456, 1369, 1215, 1124, 1053 cm-1.1H NMR : 0,77 (s, 3H), of 0.93 (d, J=6.5 Hz, 6H), of 1.36 (d, J=6.8 Hz, 3H), 2,56-of 2.66 (m, 1H), 2.77-to 2,87 (m, 1H), 3,80 (d, J=16.2 Hz, 1H), 3,92 (d, J=16.2 Hz, 1H), 4,07 (kV, J=6.2 Hz, 1H), 4,20-4,30 (m, 1H), 4,40-4,50 (m, 1H), 5,02 (s, 1H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11,1 Hz, 1H), 6,38 (d, J=11,1 Hz, 1H). MC m/z: 468 (M+- H2O), 57 (100%). UVmaxnm: 264.

Example 46

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methylcyclohexanecarboxylic)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (to 29.4 mg, 0,048 mmol) is treated with 1-methylcyclopentanol (11.3 mg, 0,088 mmol), N,N'-dicyclohexylcarbodiimide (29.0 mg, 0,141 mmol) and 4-(dimethylamino)pyridine (6.9 mg, 0,056 mmol) in dichloromethane (0.6 ml) in ways paratively thin-layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 15:1, are twice) to give compound (10.4 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-methylcyclohexanecarboxylic)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-methylcyclohexanecarboxylic)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 46 (1) (9,3 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.15 ml) by the method of example 17 (4) (at an external temperature of 48°C for 20 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 15:1, show twice, and then 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are twice), getting mentioned in the title compound (3.0 mg, 14% over 2 stages) as a colourless oil.

IR (net): 3376, 2928, 2852, 1744, 1444, 1372, 1220, 1122, 1050 cm-1.1H NMR : 0,77 (s, 3H), of 1.36 (d, J=6.5 Hz, 3H), 2,54-to 2.65 (m, 1H), 2,75-2,87 (m, 1H), 3,83 (d, J=16.5 Hz, 1H), 3,95 (d, J=16.5 Hz, 1H), 4,08 (kV, J=6,5 Hz, 1H), 4,19-the 4.29 (m, 1H), 4,40-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,10 (d, J=12.1 Hz, 1H), 6,37 (d, J=12.1 Hz, 1H). MC m/z: 387 (M+-C8H15), 67 (100%). UV[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (30 mg, 0,049 mmol) is treated with 2,2,6,6-tetramethylheptane-4-I (26 mg, 0,156 mmol), N,N'-dicyclohexylcarbodiimide (16 mg, 0,078 mmol) and 4-(dimethylamino)pyridine (6.0 mg, 0,049 mmol) in dichloromethane (0.5 ml) by way of example 17 (3) (at room temperature for 2 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 10:1, show once) to give compound (20.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-{3,3-dimethyl-1-(2,2-dimethylpropyl)butoxycarbonylmethyl}-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-{3,3-dimethyl-1-(2,2-dimethylpropyl)butoxycarbonylmethyl}-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 47 (1) (20 mg), treated in tetrahydrofuran (0,52 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,26 ml) by the method of example 17 (4) (at an external temperature of 60°C for 2 hours) and then treated. The obtained residue cleaned the t twice), getting listed in the title compound (12,122 mg, 45.6 percent for stage 2) in the form of a colorless oil.

IR (net): 3390, 2952, 2869, 2852, 1747, 1727, 1367, 1191, 1126, 1051 cm-1.1H NMR : 0,76 (s, 3H), of 0.91 (s, 6H), to 0.92 (s, 6H), to 1.37 (d, J=6.4 Hz, 3H), 2,17-2,47 (m, 3H), 2,55-of 2.66 (m, 1H), was 2.76-is 2.88 (m, 1H), 3,84 (d, J=16,7 Hz, 1H), 3.96 points (d, J=16.5 Hz, 1H), 4.09 to (kV, J=6,4 Hz, 1H), 4,18-4,30 (m, 1H), to 4.41 figure-4.49 (m, 1H), 5,01 (Shir.s, 1H), 5,16 at 5.27 (m, 1H), 5,34 (Shir.s, 1H), 5,58 (Shir.s, 1H), 6,10 (d, J=11,4 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 527 (M+-Me), 57 (100%). UVmaxnm: 264.

Example 48

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1,3,3-tetramethylbutylamine)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (63,1 mg, is 0.102 mmol) is treated with 2,4,4-trimethylpentane-2-I (21,5 mg, 0,165 mmol), N,N'-dicyclohexylcarbodiimide (34,0 mg, 0,165 mmol) and 4-(dimethylamino)pyridine (12.5 mg, is 0.102 mmol) in dichloromethane (1.5 ml) by way of example 17 (3) (at room temperature for 15 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 4 plates, hexane:ethyl acetate = 15:1, are twice) to give compound (7.7 mg) containing specified in the header of the connection.

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1,3,3-tetramethylbutylamine)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 48 (1) (7.7 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.1 ml) by the method of example 17 (4) (at an external temperature of 43°C for 30 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 1 plate, dichloromethane:ethanol = 15:1, show once), getting mentioned in the title compound (2.0 mg, 4% over 2 stages) as a colourless oil.

IR (net): 3400, 2932, 1744, 1444, 1368, 1220, 1112, 1054 cm-1.1H NMR : 0,77 (s, 3H), 0,99 (s, 9H), of 1.36 (d, J=6.6 Hz, 3H), of 1.52 (s, 6H), 1,80 (s, 2H), 2,55-of 2.66 (m, 1H), 2.77-to is 2.88 (m, 1H), 3,79 (d, J=16,3 Hz, 1H), 3,91 (d, J=16,3 Hz, 1H), 4,07 (kV, J=6,6 Hz, 1H), 4,19-4,30 (m, 1H), 4,39-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,59 (Shir.s, 1H), 6,10 (d, J=11,1 Hz, 1H), 6,37 (d, J=11,1 Hz, 1H). MC m/z: 482 (M+- H2O), 57 (100%). UVmaxnm: 263.

Example 49

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-tert-butyl-2,2-demethylepipodophyllotoxin)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (18.7 mg, 0,030 mmol) obrabecim the 0,048 mmol) and 4-(dimethylamino)pyridine (4.0 mg, 0,033 mmol) by the method of example 17 (3) (at room temperature for 17 hours). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 15:1, are twice), getting a mixture of 23.4 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-tert-butyl-2,2-demethylepipodophyllotoxin)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-tert-butyl-2,2-demethylepipodophyllotoxin)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 49 (1) (23,0 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.3 ml) by the method of example 17 (4) (at an external temperature of 42°C for 30 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 1 plate, dichloromethane:ethanol = 15:1, are twice), getting mentioned in the title compound (7,1 mg, 46% over 2 stages) as a colourless oil.

IR (net): 3384, 2932, 1750, 1478, 1444, 1370, 1226, 1124, 1054 cm-1.1H NMR : 0,78 (s, 3H), 0,99 (s, 9H), and 1.00 (s, 9H), to 1.38 (d, J=6.3 Hz, 3H), 2,54-to 2.65 (m, 1H), 2,75-is 2.88 (m, 1H), 3,98 (d, J=16,8 Hz, 1H), 4.09 to (d, J=16,8 Hz, 1H), 4,07-4,16 (m, 1H), 4,16-4,30 (m, 1H), 4,39-4,50 (m, 1H), 4,66 (s, 1H), 5,01 (Shir.s,S="POST">maxnm: 264.

Example 50

(1) preparation of 1,3-bis( tert-butyldimethylsilyloxy)-20(S)-(1,1-diethyl-2-methylpropanesulfonate)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-Bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (600 mg, 0.97 mmol) is treated with 3-ethyl-2-methyl-3-pentanol (380 mg, of 2.92 mmol), N,N'-dicyclohexylcarbodiimide (602 mg, of 2.92 mmol) and 4-(dimethylamino)pyridine (357 mg, of 2.92 mmol) in dichloromethane (9.7 ml) by way of example 17 (3) (at room temperature for 15 hours), followed by processing and purification via column chromatography (hexane:ethyl acetate = 20:1) to give the crude product (460 mg), 100 mg of which is further purified through preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 10:1, show once) to give compound (6.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1,1-diethyl-2-methylpropanesulfonate)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1,1-diethyl-2-methylpropanesulfonate)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 50 (1) (6 mg), treated with 1 M tetrahydrofurane the e 1.5 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 20:1, show twice, and then 0.25 mm × 2 plates, dichloromethane:ethanol = 20:1, are twice), getting mentioned in the title compound (2,189 mg, 2,07% over 2 stages) as a colourless oil.

IR (net): 3390, 2969, 2931, 2883, 2850, 1745, 1727, 1461, 1371, 1288, 1209, 1122, 1052 cm-1.1H NMR : 0,77 (s, 3H), 0,83-and 0.98 (m, 12H), to 1.37 (d, J=6.6 Hz, 3H), 2,55-of 2.66 (m, 1H), was 2.76-is 2.88 (m, 1H), 3,86 (d, J=16.5 Hz, 1H), 3,99 (d, J=16.5 Hz, 1H), 4,05-4,16 (m, 1H), 4,19-or 4.31 (m, 1H), 4,40-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,59 (Shir.s, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11.0 cm Hz, 1H). MC m/z: 387 (M+-C(Et)2(i-Pr)), 57 (100%). UVmaxnm: 264.

Example 51

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2,2-dimethylpropyl)ndimethylacetamide

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (15 mg, 0,0243 mmol) is treated with 2,2-dimethylpropylene (11 mg, 0,126 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodykitstore.com (23 mg, 0,120 mmol) and the monohydrate of 1-hydroxybenzotriazole (3 mg, 0,024 mmol) in dichloromethane (1.5 ml) according to the method of example 22 (1) (at room temperature for 13 h is lastine, hexane:ethyl acetate = 2:1, showing once) to give compound (14 mg) containing the target product as a colorless oil.

(2) Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(2,2-dimethylpropyl) ndimethylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2,2-dimethylpropyl)ndimethylacetamide, obtained in example 51 (1) (13 mg), treated in tetrahydrofuran (0.2 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.2 ml) by the method of example 17 (4) (at an external temperature of 55°C for 1 hour) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, show once), getting mentioned in the title compound (4,174 mg, 40% over 2 stages) as a colorless glass.

IR (net): 3421, 2931, 2852, 1670, 1541, 1367, 1055 cm-1.1H NMR : 0,80 (s, 3H), of 0.93 (s, 9H), of 1.36 (d, J=6.3 Hz, 3H), 2,20-of 2.45 (m, 3H), 2,55-of 2.64 (m, 1H), 2,78-2,90 (m, 1H), 3,05 is 3.15 (m, 2H), 3,79-4,08 (m, 3H), 4,20-4,30 (width, 1H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), 5,35 (s, 1H), 5,61 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H), 6,70 (Shir.s, 1H). MC m/z: 312 (M+-HOCH2CONHCH2C(CH3)3), 57 (100%). UV[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (15 mg, 0,0243 mmol) is treated with 1-ethylpropylamine (11 mg, 0,126 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (23 mg, 0,120 mmol) and the monohydrate of 1-hydroxybenzotriazole (3 mg, 0,024 mmol) in dichloromethane (1.5 ml) according to the method of example 22 (1) (at room temperature for 13 hours), followed by processing and selection using preparative thin layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 2:1, showing once) to give compound (15 mg) containing the target product as a colorless oil.

(2) Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(1-ethylpropyl)ndimethylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(1-ethylpropyl)ndimethylacetamide, obtained in example 52 (1) (14 mg), treated in tetrahydrofuran (0.2 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.2 ml) by the method of example 17 (4) (at an external temperature of 55°C for 1 hour) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = Le.

IR (net): 3401, 2964, 2931, 2875, 2850, 1662, 1533, 1458, 1107, 1057 cm-1.1H NMR : 0,80 (s, 3H), of 0.90 (t, J=7,3 Hz, 3H), of 1.35 (d, J=6.3 Hz, 3H), 2,18-2,47 (m, 3H), 2,58-2,62 (m, 1H), 2,79-2,84 (m, 1H), 3,80-4,08 (m, 4H), 4,24 (Shir.s, 1H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), 5,35 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37-6,38 (m, 2H). MC m/z: 312 (M+-HOCH2CONHCH(C2H5)CH2CH3), 58 (100%). UVmaxnm: 264.

Example 53

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-isopropyl-N-methylacetamide

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (14,2 mg, is 0.023 mmol) is treated with isopropylbenzylamine (8,4 mg, 0,115 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (22 mg, 0,115 mmol) and the monohydrate of 1-hydroxybenzotriazole (3.5 mg, is 0.023 mmol) in dichloromethane (0.4 ml) by the method of example 22 (1) (at room temperature for 13 hours), followed by processing and selection using preparative thin layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 2:1, showing once) to give compound (7 mg) containing the target product as a colorless oil.

(2) Obtaining {(1,3-dihydroxy-9,10 butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-isopropyl-N-methylacetamide, obtained in example 53 (1) (6 mg), treated in tetrahydrofuran (0,18 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,09 ml) by the method of example 17 (4) (at an external temperature of 55°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, show once), getting mentioned in the title compound (2,330 mg, 27% over 2 stages) as a colorless glass.

IR (net): 3408, 2970, 2931, 2875, 2850, 1628, 1367, 1101, 1054 cm-1.1H NMR : 0,77 (s, 3H), of 1.09 (d, J=6.6 Hz, 3H), 1,13-to 1.38 (m, 6H), and 2.79 (d, J=6.6 Hz, 3H), 3,90-4,30 (m, 5H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,10 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MS m/z: 312 (M+-HOCH2CON(CH3) (i-Pr)), 58 (100%). UVmaxnm: 264.

Example 54

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(1-propinball)ndimethylacetamide

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (20.0 mg, 0.03 mmol) is treated with 4-heptylamine (14 mg, 0.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodykitstore.com (23 mg, 0.12 mmol) and monohydrate 1 hydroxybenzoic) with subsequent processing and selection using preparative thin layer chromatography (0.5 mm × 2 plates, hexane: ethyl acetate = 2:1, are twice) to give compound (18 mg) containing the target product as a colorless oil.

(2) Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(1-propinball) ndimethylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(1-propinball)ndimethylacetamide, obtained in example 54 (1) (18 mg), treated in tetrahydrofuran (0.5 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.25 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1.5 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, show three times; 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are four times; and then 0.5 mm × 1 plate, dichloromethane:ethanol = 20:1, are twice), getting mentioned in the title compound (7,089 mg, 48.7 percent for stage 2) in the form of a colorless oil.

IR (net): 3401, 2956, 2931, 2871, 1666, 1533, 1440, 1106, 1054 cm-1.1H NMR : 0,80 (s, 3H), of 0.91 (t, J=6.8 Hz, 6H), 2,18-2,48 (m, 3H), 2,54-to 2.67 (m, 1H), 2.77-to 2,89 (m, 1H), 3,80 (d, J=15.2 Hz, 1H), 3,92 (d, J=15.2 Hz, 1H), 3.95 to 4,07 (m, 2H), 4,19-the 4.29 (m, 1H), to 4.41 ñ 4.50 (m, 1H), 5,01 (Shir.s, 1H), 5,35 (lat.) - Rev. B>nm: 264.

Example 55

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2-ethylbutyl)ndimethylacetamide

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (to 21.9 mg, 0.035 mmol) is treated with 2-ethylbutylamine (18 mg, 0,178 mmol) 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (13 mg, 0,068 mmol) and the monohydrate of 1-hydroxybenzotriazole (5 mg, 0,033 mmol) in dichloromethane (0.4 ml) by the method of example 22 (1) (at room temperature for 5 hours) with subsequent processing and selection using preparative thin layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 3:1, showing once) to give compound (20 mg) containing the target product as a colorless oil.

(2) Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(2-ethylbutyl)ndimethylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2-ethylbutyl)ndimethylacetamide, obtained in example 55 (1) (15 mg), treated in tetrahydrofuran (0,42 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,21 ml) by the method of example 17 (4) (at an external temperature of 60°C in techenie (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (6,954 mg, 55% over 2 stages) as a colourless foam.

IR (net): 3419, 2962, 2929, 2875, 1668, 1540, 1446, 1106, 1055 cm-1.1H NMR : 0,79 (s, 3H), of 0.90 (t, J=7,3 Hz, 6H), 2,20-2,47 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1H), 3,19-of 3.27 (m, 2H), of 3.77-was 4.02 (m, 3H), 4,20-4,30 (width, 1H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,59 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H), 6,58 (Shir.s, 1H). MS m/z: 471 (M+), 160 (100%). UVmaxnm: 263.

Example 56

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraene

1,3-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregn-5,7,16-triene (5,24 g, 9,37 mmol) is treated in tetrahydrofuran (500 ml) by the method of example 25 (4) (irradiated light for 7 hours and 45 minutes, heat will isomerized at 25°C for 10 days) and evaporated under reduced pressure to remove solvent. The resulting residue is purified through column chromatography (hexane:ethyl acetate = 10:1) to give a colorless foam fraction containing specified in the header connection (1,95 g).

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(tert-butoxycarbonylmethyl)-9,10-scoprega-5,7,10(19),16-tetraene

(3) Obtaining [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(R)-yl}oxy]acetic acid

The fraction containing 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(tert-butoxycarbonylmethyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 56 (2) (0,90 g), is treated in tetrahydrofuran (10,2 ml) 1M methanol solution of sodium methoxide (10,2 ml) and water (0,26 ml) by the method of example 17 (2) (at room temperature for 30 minutes and then at room temperature for 10 minutes) with further processing and purification through column chromatography (dichloromethane:methanol = 15:1), obtaining mentioned in the title compound (482 mg, 18% over 3 stages) as a colourless foam.

1H NMR : of 0.07 (s, 6H), to 0.74 (s, 3H), from 0.88 (s, 9H), to 0.88 (s, 9H), of 1.39 (d, J=6.6 Hz, 3H), 2 1H).

(4) to Obtain 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(1-ethylpropylamine)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(R)-yl}oxy]acetic acid (35,3 mg) is treated with 3-pentanol (15 mg, 0,170 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodykitstore.com (22 mg, 0,115 mmol) and 4-(dimethylamino)pyridine (21 mg, 0,172 mmol) in dichloromethane (0.6 ml) by the method of example 21 (1) (at room temperature for 5 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 10:1, show once) to give compound (28 mg) containing specified in the header of the connection.

(5) Obtaining 1,3-dihydroxy-20(R)-(1-ethylpropylamine)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(1-ethylpropylamine)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 56 (4) (20 mg), treated in tetrahydrofuran (0,58 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,29 ml) by the method of example 17 (4) (at an external temperature of 60°C for 2 hours) and then treated. The resulting residue is purified pomodon times and then 0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 8:8:1, show once), getting mentioned in the title compound (4,302 mg, 23% over 2 stages) as a colorless glass.

IR (net): 3392, 2968, 2933, 2879, 2850, 1749, 1371, 1286, 1203, 1126, 1055 cm-1.1H NMR : 0,76 (s, 3H), from 0.88 (t, J=7,1 Hz, 6H), to 1.37 (d, J=6.6 Hz, 3H), 2.21 are of 2.50 (m, 3H), 2.57 m-2,62 (m, 1H), 2,78-2,84 (m, 1H), 3.96 points (d, J=16,3 Hz, 1H), 4,05 (d, J=16,3 Hz, 1H), 4.09 to-4,20 (m, 1H), 4,20-4,30 (m, 1H), 4,40-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,65 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 458 (M+), 133 (100%). UVmaxnm: 264.

Example 57

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy}-N-(2,2,2-triptorelin)ndimethylacetamide

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (36 mg, 0,058 mmol) is treated with 2,2,2-triptoreline (29 mg, 0,293 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (22 mg, 0,115 mmol) and the monohydrate of 1-hydroxybenzotriazole (9 mg, 0,047 mmol) in dichloromethane (0,58 ml) by the method of example 22 (1) (at room temperature for 10 minutes), followed by processing and selection using preparative thin layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 2:1, showing once), getting koprivna-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(2,2,2-triptorelin) ndimethylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2,2,2-triptorelin)ndimethylacetamide, obtained in example 57 (1) (33 mg), treated in tetrahydrofuran (0,94 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,47 ml) by the method of example 17 (4) (at an external temperature of 65°C for 1.5 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (17,305 mg, 73% over 2 stages) as a colorless glass.

IR (net): 3415, 2933, 2850, 1682, 1533, 1279, 1163, 1115, 1055 cm-1.1H NMR : 0,79 (s, 3H), of 1.36 (d, J=6.6 Hz, 3H), 2.21 are to 2.41 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-and 2.83 (m, 1H), 3,82-of 4.05 (m, 5H), 4,20-the 4.29 (m, 1H), 4,39-4,50 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H), 6,93 (Shir.s, 1H). MC m/z: 312 (M+-HOCH2CONHCH2CF3), 91 (100%). UVmaxnm: 263.

Example 58

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclobutanecarbonyl)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]xdieguitoamv (31 mg, rate £ 0.162 mmol) and 4-(dimethylamino)pyridine (30 mg, 0,246 mmol) in dichloromethane (0.8 ml) by the method of example 21 (1) (at room temperature for 2 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 5:1, showing once) to give compound (53 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(cyclobutanecarbonyl)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclobutanecarbonyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 58 (1) (53 mg) is treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,79 ml) by the method of example 17 (4) (at an external temperature of 50°C for 2.5 hours and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, are twice; 0.5 mm × 1 plate, dichloromethane:ethanol = 10:1, are twice; and then 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (1,718 mg, 5% over 2 stages) as a colorless glass.

IR (pure): 3400, 2929, H), a 3.87-4,19 (m, 3H), 4,20-4,30 (width, 1H), 4,40-4,49 (width, 1H), 5,01 is 5.07 (m, 2H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,10 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,4 Hz, 1H). MC m/z: 312 (M+-HOCH2CO2C4H7), 55 (100%). UVmaxnm: 264.

Example 59

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethylpropylamine)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (53 mg, 0,086 mmol) is treated with 3-pentanol (23 mg, 0,258 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodykitstore.com (33 mg, 0,172 mmol) and 4-(dimethylamino)pyridine (32 mg, 0,258 mmol) in dichloromethane (0.9 ml) by the method of example 21 (1) (at room temperature for 2 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 5:1, showing once) to give compound (51 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(1-ethylpropylamine)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethylpropylamine)-9,10-scoprega-5,7,10(19),16-tetraen obtained in Primavera 17 (4) (at an external temperature of 50°C for 2.5 hours and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (12,126 mg, 35% over 2 stages) as a colorless glass.

IR (net): 3390, 2970, 2931, 2879, 2850, 1749, 1458, 1205, 1124, 1053 cm-1.1H NMR : 0,77 (s, 3H), 0.88 to (dt, J=7,4, 2,1 Hz, 6H), to 1.37 (d, J=6.4 Hz, 3H), 2.21 are of 2.45 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1H), 3,91 is 4.13 (m, 3H), 4,20-4,30 (width, 1H), 4,40-4,50 (width, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,11 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 312 (M+-HOCH2CO2CH(C2H5)2), 71 (100%). UVmaxnm: 263.

Example 60

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclopentanecarbonyl)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (from 65.1 mg, 0,106 mmol) is treated with Cyclopentanone (30.0 mg, 0,348 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (40,0 mg, 0,209 mmol) and 4-(dimethylamino)pyridine (40,0 mg, 0,327 mmol) in dichloromethane (0.8 ml) by the method of example 21 (1) (at room temperature for 1 hour and 30 minutes), followed by purification with the aid of aluca mixture of 50.4 mg), containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-cyclopentanecarboxylate)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclopentanecarbonyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 60 (1) (23,7 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.35 ml) by the method of example 17 (4) (at an external temperature of 47°C for 50 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 1 plate, dichloromethane:ethanol = 20:1, show three times and then 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are three times), getting mentioned in the title compound (4,1 mg, 23% over 2 stages) as a colourless oil.

IR (net): 3392, 2932, 2872, 1746, 1440, 1370, 1208, 1122, 1052 cm-1.1H NMR : 0,77 (s, 3H), of 1.36 (d, J=6.6 Hz, 3H), 2,54-to 2.65 (m, 1H), was 2.76-of 2.86 (m, 1H), 3,89 (d, J=16.2 Hz, 1H), 4.00 points (d, J=16.2 Hz, 1H), 4,06 (kV, J=6,6 Hz, 1H), 4,20-4,30 (m, 1H), 4,40-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,19-of 5.29 (m, 1H), 5,34 (Shir.s, 1H), 5,61 (Shir.s, 1H), 6,10 (d, J=a 10.6 Hz, 1H), 6,37 (d, J=a 10.6 Hz, 1H). MC m/z: 438 (M+- H2O), 69 (100%). UVmaxnm: 264.

Example 61

(1) preparation of 1,3-bis(tert-butyldimethylsilyl is metilcellulose)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (31,3 mg, 0,051 mmol) is treated with cyclopropylmethanol (11.0 mg, 0,153 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (20.0 mg, 0.104 g mmol) and 4-(dimethylamino)pyridine (20.0 mg, 0,164 mmol) in dichloromethane (0.4 ml) by the method of example 21 (1) (at room temperature for 16 hours), followed by purification using preparative thin layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 20:1, show once, hexane:the ethyl acetate = 10:1, show once) to give compound (25.6 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-cyclopropanecarboxylate)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclopropanecarboxylate)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 61 (1) (24,0 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.4 ml) by the method of example 17 (4) (at an external temperature of 47°C for 50 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 1 plate, dichloromethane:ethanol = 20:1, show twice, and then 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are three times), getting listed in the header with the-1.1H NMR : 0,25-0,33 (m, 2H), 0,52-and 0.61 (m, 2H), 0,78 (s, 3H), 1,38 (d, J=6,7 Hz, 3H), 2,54-to 2.65 (m, 1H), was 2.76-is 2.88 (m, 1H), 3.96 points (d, J=16,3 Hz, 1H), 4,08 (d, J=16,3 Hz, 1H), 4,08 (kV, J=6,7 Hz, 1H), 4,18-to 4.28 (m, 1H), to 4.41-4,48 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,62 (Shir.s, 1H), 6,10 (d, J=10.3 Hz, 1H), 6,37 (d, J=10.3 Hz, 1H). MC m/z: 442 (M+), 55 (100%). UVmaxnm: 264.

Example 62

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclohexyloxycarbonyloxy)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (31 mg, 0,050 mmol) is treated with cyclohexanol (15 mg, 0,150 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (19 mg, 0,099 mmol) and 4-(dimethylamino)pyridine (18 mg, 0,148 mmol) in dichloromethane (2 ml) according to the method of example 21 (1) (at room temperature for 3 days) followed by treatment and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 5:1, showing once) to give compound (27 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(cyclohexyloxycarbonyloxy)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(cyclohex triuranium solution of Tetra-n-butylammonium (0,37 ml) by the method of example 17 (4) (at an external temperature of 50°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (5,218 mg, 24% over 2 stages) as a colourless foam.

IR (net): 3390, 2933, 2856, 1747, 1448, 1203, 1120, 1053 cm-1.1H NMR : 0,78 (s, 3H), of 1.37 (d, J=6.6 Hz, 3H), 2.21 are of 2.45 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1H), 3,88-4,12 (m, 3H), 4,20-4,30 (width, 1H), 4,40-4,50 (width, 1H), 4,79-of 4.90 (m, 1H), 5,01 (Shir.s, 2H), of 5.34 (s, 1H), 5,61 (Shir.s, 1H), 6,10 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,4 Hz, 1H). MC m/z: 470 (M+), 55 (100%). UVmaxnm: 264.

Example 63

(1) preparation of 1-[[(1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy]acetyl] piperidine

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (31 mg, 0,050 mmol) is treated with piperidine (13 mg, 0,150 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodykitstore.com (19 mg, 0,099 mmol) and 4-(dimethylamino)pyridine (18 mg, 0,148 mmol) in dichloromethane (2 ml) according to the method of example 21 (1) (at room temperature for 3 days) followed by treatment and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 1:1, showing one of the and-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}acetyl]piperidine

A mixture containing 1-[[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetyl]piperidine obtained in example 63 (1) (22 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,32 ml) by the method of example 17 (4) (at an external temperature of 50°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, show once), getting mentioned in the title compound (7,499 mg, 34% over 2 stages) as a colourless foam.

IR (net): 3384, 2933, 2854, 1630, 1446, 1254, 1053 cm-1.1H NMR : 0,78 (s, 3H), of 1.35 (d, J=6.4 Hz, 3H), 2,20-of 2.44 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1H), 3,35-3,61 (m, 4H), 3,93-to 4.14 (m, 3H), 4,20-4,30 (width, 1H), 4,40-4,49 (width, 1H), 5,01 (Shir.s, 2H), of 5.34 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,4 Hz, 1H). MC m/z: 312 (M+-HOCH2COC5H10N), 144 (100%). UVmaxnm: 264.

Example 64

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(adamantane-1-rockstarunlock)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (40 mg, 0,065 mmol) is treated ethylamino)pyridine (24 mg, 0,196 mmol) in dichloromethane (0,65 ml) by the method of example 21 (1) (at room temperature for 15 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 5:1, showing once) to give compound (18 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(adamantane-1-rockstarunlock)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(adamantane-1-rockstarunlock)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 64 (1) (17 mg) in tetrahydrofuran (0,46 ml), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,23 ml) by the method of example 17 (4) (at an external temperature of 60°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (7,471 mg, 23% over 2 stages) as a colorless glass.

IR (net): 3380, 2916, 2852, 1745, 1456, 1209, 1122, 1053 cm-1.1H NMR : 0,77 (s, 3H), of 1.36 (d, J=6.3 Hz, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1H), 3,82 (d, J=16,3 Hz, 1H), 3,92 (d, J=16,3 Hz, 1H), 4.04 the->+), 135 (100%). UVmaxnm: 264.

Example 65

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(1-ethyl-1-methylpropanesulphonic)methoxy-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(R)-yl}oxy]acetic acid (34 mg, by 0.055 mmol) is treated with 3-methyl-3-pentanol (28 mg, 0,275 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodykitstore.com (21 mg, 0,110 mmol) and 4-(dimethylamino)pyridine (20 mg, 0,164 mmol) in dichloromethane (0,55 ml) by way of example 21 (1) (at room temperature for 5 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 10:1, show once), obtaining a mixture (10 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(R)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(R)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 65 (1) (9 mg), treated in tetrahydrofuran (0.1 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.2 ml) by the method of example 17 (4) (when NR is active thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, show once), getting mentioned in the title compound (3,102 mg, 13% over 2 stages) as a colorless glass.

IR (net): 3380, 2971, 2929, 2850, 1747, 1460, 1373, 1213, 1124, 1055 cm-1.1H NMR : 0,76 (s, 3H), of 0.85 (t, J=7.4 Hz, 6H), 1,25 (s, 3H), of 1.36 (d, J=6.6 Hz, 3H), of 1.39 (s, 3H), 2,20-2,49 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1H), a 3.87 (d, J=16,3 Hz, 1H), 3,95 (d, J=16,3 Hz, 1H), 4,08-4,16 (m, 1H), 4,20-4,30 (m, 1H), 4,40-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,63 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 312 (M+-HOCH2CO2C(C2H5)2CH3), 85 (100%). UVmaxnm: 265.

Example 66

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-methoxy-N-methylacetamide

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-ml}oxy]acetic acid (13.5 mg, 0,0219 mmol), N-methoxy-N-methylaminopropane (11 mg, 0,109 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (21 mg, 0,110 mmol), monohydrate, 1-hydroxybenzotriazole (3 mg, 0,024 mmol), triethylamine (22 mg, 0,217 mmol) and dichloromethane (0.4 ml) are mixed and stirred at room temperature for 15 hours. The reaction mixture is distributed meidum aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue is separated via preparative thin layer chromatography (0.5 mm × 2 plates, hexane: ethyl acetate = 2:1, showing once) to give compound (13 mg) containing the target product as a colorless oil.

(2) Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-methoxy-N-methylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-methoxy-N-methylacetamide obtained in example 66 (1) (12 mg), treated in tetrahydrofuran (0,36 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,18 ml) by the method of example 17 (4) (at an external temperature of 55°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, show once), getting mentioned in the title compound (3,800 mg, 44% over 2 stages) as a colorless glass.

IR (net): 3399, 2933, 2850, 1668, 1436, 1052 cm-1.1H NMR : 0,78 (s, 3H), 1,38 (d, J=6.6 Hz, 3H), 2,18-2,47 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1H), 3,18 (s, 3H), 3,66 (s, 3H), 4,07-4,27 (m, 4H), 4,39-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), 5,34 S="POST">3), 91 (100%). UVmaxnm: 264.

Example 67

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-methoxyacetate

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (13,6 mg, 0,0220 mmol) is treated with N-methoxyacetanilide (9 mg, to 0.108 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (21 mg, 0,110 mmol), monohydrate, 1-hydroxybenzotriazole (3 mg, 0,024 mmol) and triethylamine (22 mg, 0,217 mmol) in dichloromethane (0,88 ml) by way of example 66 (1) (at room temperature for 15 hours), followed by processing and selection using preparative thin layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 2:1, showing once) to give compound (12 mg) containing the target product as a colorless oil.

(2) Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-methoxyacetate

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-methoxyacetate obtained in example 67 (1) (11 mg), treated in tetrahydrofuran (0,34 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.17 ml) is to purify using preparative thin layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, show once), getting mentioned in the title compound (3,189 mg, 38% over 2 stages) as a colorless glass.

IR (net): 3384, 2929, 2850, 1674, 1441, 1117, 1053 cm-1.1H NMR : 0,78 (s, 3H), of 1.34 (d, J=6.6 Hz, 3H), 2,18 is 2.46 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-and 2.83 (m, 1H), 3,81 (s, 3H), 3,81-4,07 (m, 3H), 4,20-4,30 (m, 1H), to 4.41-4,48 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,59 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H), 8,92 (Shir.s, 1H). MC m/z: 312 (M+-HOCH2CONHOMe), 91 (100%). UVmaxnm: 264.

Example 68

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(ethoxycarbonylmethoxy)-9,10-scoprega-5,7,10(19),16-tetraene

To a solution of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (43,0 mg, 0.07 mmol) in dichloromethane (0.8 ml) at room temperature under nitrogen atmosphere add ethanol (5 mg, 0.1 mmol), 2-chloro-1,3-dimethylimidazolidine (17 mg, 0.1 mmol) and pyridine (17 mg, 0.21 mmol) and then stirred for 15 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, aqueous sodium chloride and water, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure on the mm × 2 plates, hexane:ethyl acetate = 10:1, show once), getting a mixture of 28.0 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(ethoxycarbonylmethoxy)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(ethoxycarbonylmethoxy)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 68 (1) (28 mg), treated in tetrahydrofuran (2.0 ml) 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0,65 ml) by the method of example 17 (4) (at an external temperature of 50°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 20:1, show twice, and then 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are three times), getting mentioned in the title compound (3,167 mg, up 10.9% over 2 stages) as a colourless oil.

IR (net): 3347, 2975, 2931, 2848, 1751, 1442, 1369, 1288, 1203, 1124, 1052 cm-1.1H NMR : 0,78 (s, 3H), of 1.27 (t, J=7,3 Hz, 3H), of 1.37 (d, J=6.3 Hz, 3H), 2,19-2,48 (m, 3H), 2,55-of 2.66 (m, 1H), 2,78-2,87 (m, 1H), 3,93 (d, J=16.2 Hz, 1H), 4,05 (d, J=16.2 Hz, 1H), 4,03-4,12 (m, 1H), 4,15-4,30 (m, 3H), 4,39-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,62 (Shir.s, 1H), 6,11 (d, J=11.5 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 416 (M+),C)-20(S)-(isopropoxycarbonyl}-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (641 mg, 1,039 mmol) is treated with isopropanol (0,641 ml, 9,350 mmol), 2-chloro-1,3-dimethylimidazolidine (263 mg, 1,558 mmol) and pyridine (260 μl, 3,117 mmol) in dichloromethane (10 ml) according to the method of example 68 (1) (at room temperature for 2 hours) with further processing and purification through column chromatography (hexane:ethyl acetate = 10:1) to give a mixture (669 mg) containing specified in the header of the connection.

(2) Obtaining 1,3-dihydroxy-20(S)-(isopropoxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(isopropoxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 69 (1) (669 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (5.0 ml) according to the method of example 17 (4) (at an external temperature of 50°C for 3 hours) and then treated. The resulting residue is purified through column chromatography (dichloromethane:methanol = 10:1) to give a mixture containing 1,3-dihydroxy-20(S)-(isopropoxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraen, (246 mg) and [{1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic cyclotech)-9,10-scoprega-5,7,10(19),16-tetraen, purify using preparative thin layer chromatography (0.5 mm × 8 plates, hexane:ethyl acetate:ethanol = 5:5:1, showing once) to give 1,3-dihydroxy-20(S)-(isopropoxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraen (169 mg, 37% over 2 stages) as a colourless oil. Spectra IR, Mass,1NNMR and UV this connection coincide with the spectra of compounds obtained in example 15.

For [{1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid:

1H NMR : 0,79 (s, 3H), of 1.39 (d, J=6.8 Hz, 3H), 2,53-to 2.65 (m, 1H), 2,75-2,87 (m, 1H), 3,92 (d, J=16.5 Hz, 1H), 4,03-4,16 (m, 2H), 4,21-the 4.29 (m, 1H), to 4.41 ñ 4.50 (m, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), 5,64 (Shir.s, 1H), 6,11 (d, J=11.3 Hz, 1H), 6,36 (d, J=11.3 Hz, 1H). MC m/z: 388(M+), 91(100%). UV maxnm: 264.

Example 70

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2-methylpropyl)ndimethylacetamide

[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (60 mg, 0,097 mmol) is treated with 2-methylpropylamine (0.1 ml, 0,970 mmol), 2-chloro-1,3-dimethylimidazolidine (25 mg, 0,146 mmol) and pyridine (80 μl, 0,970 mmol) in dichloromethane (1.0 ml) by the method of example 68 (1) (at room temperature for 2 stiny, hexane:ethyl acetate:ethanol = 5:1, showing once) to give compound (10.0 mg) containing specified in the header of the connection.

(2) Obtaining [{1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2-methylpropyl) ndimethylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-(2-methylpropyl " ndimethylacetamide, obtained in example 70 (1) (10 mg) is treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (1.0 ml) by the method of example 17 (4) (at an external temperature of 40°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol=5:5:1, showing once), getting mentioned in the title compound (0,859 mg, 2% over 2 stages) as a colourless oil.

IR (net): 3421, 2956, 2850, 1668, 1541, 1437, 1369, 1107, 1055 cm-1.1H NMR : 0,79 (s, 3H), of 0.93 (d, J=6.8 Hz, 6H), of 1.35 (d, J=6.8 Hz, 3H), 2,50-of 2.66 (m, 1H), 2,74-is 2.88 (m, 1H), 3,02-3,20 (m, 2H), 3,64-4,06 (m, 3H), 4,13-4,30 (m, 1H), 4,34-of 4.49 (m, 1H), free 5.01 (s, 1H), 5,35 (s, 1H), ceiling of 5.60 (Shir.s, 1H), 6,10 (d, J=10,8 Hz, 1H), 6,36 (d, J=10,8 Hz, 1H), 6,58-of 6.71 (m, 1H). MC m/z: 425 (M+- H2O), 57 (100%). UVmaxnm: 263.

Example 71

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (60 mg, 0,097 mmol) is treated with Isopropylamine (0.1 ml, 0,970 mmol), 2-chloro-1,3-dimethylimidazolidine (25 mg, 0,146 mmol) and pyridine (80 μl, 0,970 mmol) in dichloromethane (1.0 ml) by the method of example 68 (1) (at room temperature for 2 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 5:1, showing once), getting a mixture of 44.0 mg), containing specified in the header of the connection.

(2) Obtaining [{1,3-hydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-isopropylacrylamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]-N-isopropylacetate obtained in example 71 (1) (44 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (1.0 ml) by the method of example 17 (4) (at an external temperature of 40°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 5:5:1, showing once), getting mentioned in the title compound (13,17 mg, 31% over 2 stages) as a colourless oil.

IR (net): 3406, 2972, 2931, 2850, 1662, 1531, 1446, 1367, 1109, 1055 cm-1.+), 118 (100%). UVmaxnm: 264.

Example 72

(1) Obtaining {1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxyacetic

A solution of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (15,0 mg, 0,024 mmol) in tetrahydrofuran (0.6 ml) cooled to 0°C in nitrogen atmosphere. After adding triethylamine (18.3 mg, 0.18 mmol) and ethylchloride (15.6 mg, 0.14 mmol), the reaction mixture is stirred for 30 minutes and further stirred for 20 minutes, barbotine while gaseous ammonia. The reaction mixture is filtered and evaporated under reduced pressure to remove solvent, followed by separation using preparative thin layer chromatography (0.5 mm × 1 plate, dichloromethane:methanol = 10:1, show once), getting a mixture of 14.5 mg) containing the target product as a colorless oil.

(2) Receive {1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxyacetic

A mixture containing {1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxyacetic obtained in example 72(1) (14,5 mg), treated in tet (4) (at an external temperature of 50°C for 2 hours) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.25 mm × 2 plates, dichloromethane:methanol = 10:1, show three times, and then 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:2, are twice), getting mentioned in the title compound (5,249 mg, 56.4 per cent for stage 2) in the form of a colorless oil.

IR (net): 3353, 2960, 2931, 2873, 1727, 1681, 1457, 1288, 1118, 1056 cm-1.1H NMR : 0,79 (s, 3H), of 1.35 (d, J=6.4 Hz, 3H), 2,18-2,47 (m, 3H), 2,55-of 2.66 (m, 1H), was 2.76-is 2.88 (m, 1H), 3,78 (d, J=15,5 Hz, 1H), 3.96 points (d, J=15.6 Hz, 1H), 3.96 points-4,06 (m, 1H), 4,19-4,30 (m, 1H), 4,40-of 4.49 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,52 (Shir.s, 1H), 5,61 (Shir.s, 1H), 6,11 (d, J=11.2 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H), 6,56 (Shir.s, 1H). MC m/z: 387 (M+), 312 (100%). UVmaxnm: 264.

Example 73

(1) preparation of 1,3-dihydroxy-20(S)-(1-trifluoromethyl-2,2,2-tripterocalyx)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (9.6 mg, of 0.025 mmol) is treated with 1,1,1,3,3,3-hexamer-2-propanol (420 mg, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (19 mg, 0.10 mmol) and 4-(dimethylamino)pyridine (12 mg, 0.10 mmol) in dichloromethane (0.25 ml) by the method of example 21 (1) (at room temperature for 4 hours), followed by processing and is given twice), getting listed in the title compound (2,867 mg, 22%) as a colorless glass.

IR (net): 3360, 2931, 2850, 1803, 1386, 1290, 1234, 1203, 1113 cm-1.1H NMR : 0,77 (s, 3H), 1,38 (d, J=6.6 Hz, 3H), 2,20-to 2.41 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1H), 4,05-4,30 (m, 4H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,63 (Shir.s, 1H), 5,75 of 5.84 (m, 1H), 6,11 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,4 Hz, 1H). MC m/z: 312(M+-HOCH2CO2CH(CF3)2), 83(100%). UVmaxnm: 264.

Example 74

Obtaining 1,3-dihydroxy-20(S)-(isopropylidenedioxy)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (15 mg, 0,0386 mmol) is treated with 2-propandiol (36 μm, 0,386 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodykitstore.com (74 mg, 0,386 mmol) and 4-(dimethylamino)pyridine (47 mg, 0,386 mmol) in dichloromethane (0.5 ml) according to the method of example 21 (1) (at room temperature for 2 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:methanol = 5:5:1, showing once), getting mentioned in the title compound (1,157 mg, 7%) as a colourless oil.

IR (net): 3356, 2927, 2850, 1682, 1442, 1367, 1254, 1128, 1051 see<1H), 4,37-4,50 (m, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), 5,63 (Shir.s, 1H), 6,10 (d, J=11,1 Hz, 1H), 6,37 (d, J=11,1 Hz, 1H). MC m/z: 428(M+-H2O), 55(100%). UVmaxnm: 263.

Example 75

Obtaining 1,3-dihydroxy-20(S)-(tert-butyldimethylsiloxy)-9,10-scoprega-5,7,10(19),16-tetraene

[{1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]acetic acid (15 mg, 0,0386 mmol) is treated with 2-methyl-2-propandiol (44 microns, 0,386 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodykitstore.com (74 mg, 0,386 mmol) and 4-(dimethylamino)pyridine (47 mg, 0,386 mmol) in dichloromethane (0.5 ml) according to the method of example 21 (1) (at room temperature for 2 hours, followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 5:5:1, showing once) and then carry out a second cycle using preparative thin layer chromatography (0.5 mm × 1 plate, toluene:ethyl acetate = 1:1, show once), getting mentioned in the title compound (0,236 mg, 1%) as a colourless oil.

IR (net): 2927, 2852, 1676, 1456, 1363, 1126, 1051 cm-1.1H NMR : 0,78 (s, 3H), of 1.39 (d, J=6.5 Hz, 3H), 2,52-of 2.66 (m, 1H), 2,74-is 2.88 (m, 1H), 3,84 (d, J=15,9 Hz, 1H), 3,93-4,08 (m, 2H), 4,19-the 4.29 (m, 1H), 4,37 figure-4.49 (m, 1H), free 5.01 (s, 1H), of 5.34 (s, 1H), 5,62 (Shi is

Example 76

(1) preparation of tert-butyl [{1,3-bis(tert-butyldimethylsilyloxy)pregna-5,7-Dien-20(S)-yl}oxy]acetate

1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregn-5,7-diene (150 mg, 0,267 mmol) is treated in tetrahydrofuran (2.7 ml) sodium hydride (60% in oil, 65 mg, 1,625 mmol), 15-crown-5 (16 mg, 0,268 mmol) and tert-butylbromide (316 mg, of 1.62 mmol) by the method of example 17 (1) (refluxed for 17 hours) with subsequent processing and selection using preparative thin layer chromatography (0.5 mm × 5 plates, hexane:ethyl acetate = 5:1, showing once and then 0.5 mm × 2 plates, hexane:ethyl acetate = 7:1, are twice), getting mentioned in the title compound (30 mg, 17%) as a colourless foam.

1H NMR : 0,05 (s, 3H), by 0.06 (s, 6H), of 0.11 (s, 3H), and 0.61 (s, 3H), of 0.89 (s, 18H), 1,20 (d, J=5,9 Hz, 3H), of 1.48 (s, N), 2,73-to 2.85 (m, 1H), 3,32-of 3.46 (m, 1H), 3,64 is 4.13 (m, 4H), from 5.29-5,38 (width, 1H), 5,55-5,61 (width, 1H).

(2) Obtaining 1,3-dihydroxy-20(S)-(tert-butyloxycarbonyl)-9,10-scoprega-5,7,10(19)-triens

Tert-butyl [{1,3-bis(tert-butyldimethylsilyloxy)pregna-5,7-Dien-20(S)-yl}oxy]acetate (110 mg, 0,267 mmol) is treated in tetrahydrofuran (200 ml) by the method of example 4 (3) (irradiated with light for 6 minutes and 15 seconds, boil with Obrist tetrahydrofuran (5 ml) and hydrogen fluoride/pyridine (70%, 2,31 g), then treated according to the method of example 8 (3) (at room temperature for 30 minutes with subsequent processing and selection using preparative thin layer chromatography (0.5 mm × 3 plates, dichloromethane:ethanol = 10:1, showing once and then 0.5 mm × 2 plates, hexane:ethyl acetate:ethanol = 10:10:1, are twice), getting mentioned in the title compound (6,252 mg, 9%) as a colourless foam.

IR (net): 3380, 2929, 2875, 1749, 1369, 1223, 1128, 1055 cm-1.1H NMR : 0,54 (s, 3H), of 1.18 (d, J=6,1 Hz, 3H) of 1.47 (s, 9H), 2,31 (DD, J=13,4, 6.4 Hz, 1H), 2.57 m) 2.63 in (m, 1H), 2,80-of 2.86 (m, 1H), 3,31-to 3.41 (m, 1H), 3,90 (d, J=16.0 Hz, 1H), 3,98 (d, J=16.0 Hz, 1H), 4,21-4,30 (width, 1H), 4,40-4,49 (width, 1H), 4,99 (Shir.s, 1H), 5,33 (s, 1H), 6,03 (d, J=11,4 Hz, 1H), 6,36 (d, J=11,4 Hz, 1H). MC m/z: 446 (M+), 57 (100%). UVmaxnm: 264.

Example 77

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)pregna-5,7-Dien-20(S)-yl}oxy]acetic acid

To a solution of tert-butyl [{1,3-bis(tert-butyldimethylsilyloxy)pregna-5,7-Dien-20(S)-yl}oxy]acetate (9 mg, of 0.013 mmol) in tetrahydrofuran (0,13 ml) is added 1M methanol solution of sodium methoxide (0,13 ml) and stirred at room temperature for 20 minutes. Then add water (0,26 ml) and stirred at room temperature for 30 minuet over anhydrous sodium sulfate. The solvent is removed under reduced pressure, obtaining mentioned in the title compound (6 mg, 73%) as a colourless solid.

1H NMR : 0,05 (s, 3H), of 0.07 (s, 6H), of 0.11 (s, 3H), and 0.61 (s, 3H), from 0.88 (s, 9H), to 0.89 (s, 9H), 2.26 and-to 2.42 (m, 2H), 2,74-to 2.85 (m, 1H), 3,40-3,55 (m, 1H), 3,65-to 3.73 (width, 1H), 3,91-is 4.21 (m, 3H), 5,31 lower than the 5.37 (width, 1H), 5,54-5,61 (m, 1H).

(2) Obtaining 1-ethylpropyl [{1,3-bis(tert-butyldimethylsilyloxy)pregna-5,7-Dien-20(S)-yl}oxy}acetate

[{1,3-bis(tert-butyldimethylsilyloxy)pregna-5,7-Dien-20(S)-yl}oxy]acetic acid (91 mg, 0.147 mmol) is treated with 3-pentanol (39 mg, 0,443 mmol), N,N'-dicyclohexylcarbodiimide (61 mg, 0,296 mmol) and 4-(dimethylamino)pyridine (54 mg, 0,443 mmol) in dichloromethane (1.5 ml) according to the method of example 17 (3) (at room temperature for 15 hours) with further processing and purification via preparative thin-layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 5:1, showing once), getting mentioned in the title compound (37 mg, 37%) as a colourless oil.

1H NMR : 0,05 (s, 3H), by 0.06 (s, 6H), of 0.11 (s, 3H) and 0.61 (s, 3H), of 0.89 (s, 18H), to 1.21 (d, J=5,9 Hz, 3H), 2,29-5 to 2.41 (m, 2H), 2,73-to 2.85 (m, 1H), 3,35-of 3.48 (m, 1H), 3,66-to 3.73 (width, 1H), 3,94-4,16 (m, 3H), 4,78-4,91 (m, 1H), 5,30 lower than the 5.37 (width, 1H), 5,54-5,63 (m, 1H).

(3) Obtaining 1,3-dihydroxy-20(S)-(1-ethylpropylamine the-5,7-Dien-20(S)-yl}oxy]acetate (35 mg, 0,051 mmol) is treated in tetrahydrofuran (200 ml) by the method of example 4 (3) (irradiated with light for 4 minutes and 45 seconds, refluxed for 2 hours and then evaporated to remove solvent. To the obtained residue, add tetrahydrofuran (2 ml) and hydrogen fluoride/pyridine (70%, 0.51 g), then treated according to the method of example 8 (3) (at room temperature for 1 hour), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, showing once and then 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:10:1, show once), getting listed in the title compound (2,506 mg, 11%) as a colorless glass.

IR (net): 3390, 2931, 2877, 1751, 1458, 1375, 1286, 1203, 1055 cm-1.1H NMR : 0,54 (s, 3H), from 0.88 (t, J=7.4 Hz, 6H), 1,20 (d, J=6,1 Hz, 3H), 2,31 (DD, J=13,4, 6.4 Hz, 1H), 2.57 m) 2.63 in (m, 1H), 2,80-of 2.86 (m, 1H), 3,35-of 3.43 (m, 1H), was 4.02 (d, J=16.2 Hz, 1H), 4,10 (d, J=16.2 Hz, 1H), 4,21-4,30 (width, 1H), 4,40-4,49 (width, 1H), 4,79-4,88 (m, 1H), 4,99 (Shir.s, 1H), 5,33 (s, 1H), 6,03 (d, J=11,4 Hz, 1H), 6,36 (d, J=11,4 Hz, 1H). MC m/z: 460 (M+), 55 (100%). UVmaxnm: 265.

Example 78

(1) preparation of [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(R)-yl}oxy]-N-(tert-butyl) - acetone is srabatyvayut in tetrahydrofuran (0.7 ml) sodium hydride (60% in oil, 18 mg, 0.44 mmol), 15-crown-5 (16 mg, 0,073 mmol) and 2-bromo-N-(tert-butyl)ndimethylacetamide (85 mg, 0.44 mmol) according to the method of example 17 (1) (refluxed for 6 hours with subsequent processing and selection using preparative thin layer chromatography (0.5 mm × 3 plates, only dichloromethane, show once) to give compound (33 mg), containing the target product in the form of oil pale yellow color.

(2) Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(R)-yl)oxy-N-(tert-butyl)ndimethylacetamide

The mixture containing [{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(R)-yl}oxy]-N-(tert-butyl)ndimethylacetamide, obtained in example 78 (1) (31 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.5 ml) according to the method of example 17 (4) (at an external temperature of 60°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:ethanol = 10:1, show once), getting mentioned in the title compound (10,028 mg, 33% over 2 stages) as a colorless glass.

IR (net): 3400, 2968, 2931, 1662, 1533, 1365, 1103, 1057 cm-1.1H NMR : 0.75 in (s, 3H), of 1.37 (s, 9H), 2,20-of 2.44 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-2,84 (m, 1(Shir.with, 1H). MC m/z: 443(M+), 57(100%). UVmaxnm: 263.

Example 79

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(ethoxycarbonylmethoxy)-9,10-scoprega-5,7,10(19),16-tetraene

1,3-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxy-9,10-scoprega-5,7,10(19),16-tetraen (USD 147.4 mg, 0,264 mmol) is treated with sodium hydride (60% in oil, 112,0 mg, 2,800 mmol), 15-crown-5 (580,0 mg, 2,633 mmol) and 4-bromo-1,1,1-trimethoxymethane (346,0 mg, 1,523 mmol) in tetrahydrofuran (0.5 ml) according to the method of example 17 (1) (at an external temperature of 68°C for 17 hours and 30 minutes) and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 15:1, showing once and then 0.5 mm × 1 plate, hexane:ethyl acetate = 20:1, show once), getting a mixture of 43.1 mg) containing specified in the header of the connection.

(2) Obtaining 4-[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]butyric acid

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(ethoxycarbonylmethoxy)-9,10-scoprega-5,7,10(19),16-tetraen (21,8 mg, 0,033 mmol), treated with 2M aqueous sodium hydroxide (0.2 ml) in methanol (0.2 ml) and tetrahydrofuran (0.5 ml) spout using preparative thin layer chromatography (0.25 mm × 1 plate, dichloromethane:ethanol = 30:1, are twice), getting mentioned in the title compound (6.9 mg, 49%) as a colourless oil.

IR (net): 2936, 1712, 1462, 1362, 1252, 1214, 1166, 1080 cm-1.1H NMR : 0,06 (s, 6H), of 0.07 (s, 3H), 0.76 to (s, 3H), from 0.88 (s, 18H), of 1.30 (d, J=6.3 Hz, 3H), 2,16-of 2.28 (m, 2H), 2,34 is 2.55 (m, 2H), 2,75-2,87 (m, 1H), 3.25 to 3,39 (m, 1H), 3,44 of 3.56 (m, 1H), a 3.87-3,98 (m, 1H), 4,14-of 4.25 (m, 1H), 4,35-and 4.40 (m, 1H), 4,88 (Shir.s, 1H), 5,20 (Shir.s, 1H), 5,57 (Shir.s, 1H), 6,10 (d, J=11.0 cm Hz, 1H), 6,23 (d, J=11.0 cm Hz, 1H). UVmaxnm: 263.

(3) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(tert-butoxycarbonylamino)-9,10-scoprega-5,7,10(19),16-tetraene

4-[{1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl}oxy]butyric acid (7.5 mg, 0.012 mmol) is treated with tert-butanol (288,0 mg, 3,886 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodykitstore.com (70.0 mg, 0,365 mmol) and 4-(dimethylamino)pyridine (71,0 mg, 0,581 mmol) in dichloromethane (0.05 ml) by way of example 21 (1) (at room temperature for 30 minutes. The reaction mixture was purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 15:1, show twice, dichloromethane:ethanol = 10:1, are twice), getting mentioned in the title compound (3.5 mg, 43%) as a colourless Mac is>1H NMR : 0,06 (s, 6H), of 0.07 (s, 6H), 0.76 to (s, 3H), of 0.87 (s, 9H), to 0.88 (s, 9H), of 1.28 (d, J=6.6 Hz, 3H), of 1.44 (s, 9H), was 2.76-of 2.86 (m, 1H), 3,20-to 3.34 (m, 1H), 3,34-of 3.48 (m, 1H), 3,86 (kV, J=6,6 Hz, 1H), to 4.15-4.26 deaths (m, 1H), 4,34 was 4.42 (m, 1H), 4,88 (Shir.s, 1H), 5,18 (Shir.s, 1H), 5,55 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6.35mm (d, J=11.2 Hz, 1H). MC m/z: 700 (M+), 73 (100%). UVmaxnm: 263.

(4) to Obtain 1,3-dihydroxy-20(S)-(tert-butoxycarbonylamino)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing 1,3-bis(tert-butyldimethylsilyloxy)-20(S)-(tert-butoxycarbonylamino)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 79 (3) (5,8 mg), treated with 1M tetrahydrofuranyl solution of Tetra-n-butylammonium (0.1 ml) by the method of example 17 (4) (at an external temperature of 43°C for 20 minutes). The reaction mixture was purified using preparative thin-layer chromatography (0.25 mm × 1 plate, dichloromethane:ethanol = 15:1, are twice), getting mentioned in the title compound (1.1 mg, 10% over 2 stages) as a colourless oil.

IR (net): 3388, 2928, 2852, 1728, 1446, 1368, 1252, 1156, 1106, 1058 cm-1.1H NMR : 0,77 (s, 3H), of 1.28 (d, J=6.6 Hz, 3H), of 1.44 (s, 9H), 2,30 (t, J=7,3 Hz, 2H), 2,56-to 2.65 (m, 1H), 2,78-is 2.88 (m, 1H), 3,22-to 3.33 (m, 1H), 3,35-of 3.48 (m, 1H), 4,19-4,30 (m, 1H), 4,40-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,55 (Shir.s, 1H), 6,10 (d, J=11.3 Hz, 1H), 6,37 (d, J=11.3 Hz, 1H). MC m/z: 47 the pet-butyldimethylsilyloxy)-17-methylandrosta-5,7,17-triens and 4-phenyl-1,2,4-triazoline-3,5-dione

To a solution of the adduct of 1,3-bis(tert-butyldimethylsilyloxy)-17-oxoandrosta-5,7-diene and 4-phenyl-1,2,4-triazoline-3,5-dione (70,0 g, 99 mmol) in tetrahydrofuran (300 ml) is added tert-piperonyl potassium (14,50 g, 129 mmol) and then methyltriphenylphosphonium (46,05 g, 129 mmol), followed by boiling under reflux for 2 hours. After cooling to room temperature the reaction mixture is distributed between ethyl acetate and aqueous sodium chloride. The organic layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove solvent. The obtained residue was stirred in acetonitrile (250 ml) at room temperature for 30 minutes and filtered. The obtained solid product is again washed with acetonitrile and dried, obtaining specified in the header connection (61,78 g, 89%) as a colourless solid.

1H NMR : 0,06 (s, 3H), and 0.08 (s, 3H), and 0.09 (s, 3H), of 0.13 (s, 3H), of 0.87 (s, 9H), to 0.89 (s, 9H), 2,35-of 2.72 (m, 5H), 3,23-3,30 (m, 1H), 3,85 (Shir.s, 1H), 4,70 (s, 2H), 4,70 of 4.83 (m, 1H), 6,23 (d, J=7.9 Hz, 1H), to 6.39 (d, J=7.9 Hz, 1H), 7.23 percent-7,46 (m, 5H).

(2) Obtaining 1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-17-methylandrosta-5,7,17-triens

To a suspension of selenium dioxide (4,87 g and 43.9 mmol) in dichloromethane (300 ml) is added tert-mutilor adduct of 1,3-bis(tert-butyldimethylsilyloxy)-17-methylandrosta-5,7,17-triens and 4-phenyl-1,2,4-triazoline-3,5-dione (61,75 g, 87,7 mmol) in dichloromethane (300 ml) and stirred at 30°C for 15 hours. The reaction mixture was washed with 2M aqueous sodium hydroxide and aqueous sodium chloride, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to remove solvent. The resulting residue is purified through column chromatography (hexane:dichloromethane:acetone=5:5:1) to give the product 1,3-bis-(tert-butyldimethylsilyloxy)-16-hydroxy-17-methylandrosta-5,7,17-triens and 4-phenyl-1,2,4-triazoline-3,5-dione (41,73 g) as colorless solids. This solid substance added 1,3-dimethyl-2-imidazolidinone (810 ml) and stirred at 160°C for 50 minutes. After cooling to room temperature the reaction mixture was separated between ethyl acetate and aqueous sodium chloride. The organic layer is washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then evaporated under reduced pressure to remove solvent. The resulting residue is purified through column chromatography (hexane:ethyl acetate = 9:1), obtaining specified in the header connection (12,30 g, 39% over 2 stages) in the form of a slightly yellowish solid substance and 1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-17-methylandrosta-5,7,17-triene (14,35 g, 45% of androsta-5,7,17-triens:

1H NMR : 0,05 (s, 3H), 0,06 (s, 3H), of 0.07 (s, 3H), of 0.11 (s, 3H), of 0.87 (s, 9H), to 0.88 (s, 9H), to 0.92 (s, 3H), were 0.94 (s, 3H), 2,78-is 2.88 (m, 1H), 3,71 (Shir.s, 1H), 4,00-to 4.15 (m, 1H), 4,60 (Shir.s, 1H), 4,94 (d, J=1.7 Hz, 1H), 5,09 (d, J=1.3 Hz, 1H), are 5.36 of 5.39 (m, 1H), 5,59 (d, J=5.6 Hz, 1H).

For 1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-17-methylandrosta-5,7,17-triens:

1H NMR : 0,06 (s, 3H), of 0.07 (s, 6H), of 0.11 (s, 3H), 0.74 and (s, 3H), from 0.88 (s, 9H), to 0.89 (s, 9H), to 0.92 (s, 3H), 2,80-only 2.91 (m, 1H), 3,68-3,75 (width, 1H), 3,98-to 4.14 (m, 1H), 4,67 was 4.76 (m, 1H), 4,93 (Shir.s, 1H), 5,11 (Shir.s, 1H), 5,33 of 5.39 (m, 1H), 5,56-5,62 (m, 1H).

(3) Receive {1,3-bis(tert-butyldimethylsilyloxy)}-16-hydroxy-17-methyl-9,10-secondrate-5,7,10(19),17-tetraen

1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-17-methylandrosta-5,7,17-triene (2.00 g, to 3.67 mmol) is treated in ethanol (650 ml) by the method of example 4 (3) (irradiated light for 2.5 hours, refluxed for 2 hours) with subsequent processing and purification through column chromatography (hexane:dichloromethane = 2:3 and then hexane:ethyl acetate = 9:1) and preparative thin-layer chromatography (0.5 mm × 3 plates, hexane:ethyl acetate = 9:1, show three times, receiving a fraction of a colorless foam containing specified in the title compound (0.40 g).

(4) to Obtain 1,3-bis(tert-butyldimethylsilyloxy)-17-methyl is hydroxy-17-methyl-9,10-secondrate-5,7,10(19),17-tetraen, obtained in example 80 (3) (400 mg), dissolved in dichloromethane (20 ml). To this solution was added molecular sieves 4A (2 g) and then treated with ultrasound for 1 minute. To the reaction mixture are added manganese dioxide (2,40 g) and stirred at room temperature for 10 minutes. Then the insoluble product is filtered off, the solvent is removed under reduced pressure, and the residue purified through column chromatography (hexane:ethyl acetate = 9:1) to give a fraction containing specified in the title compound (342 mg).

(5) 17-acetyltributyl-1,3-bis(tert-butyldimethylsilyloxy)-16-oxo-9,10-secondrate-5,7,10(19)-triene

The fraction containing 1,3-bis(tert-butyldimethylsilyloxy)-17-methyl-16-oxo-9,10-secondrate-5,7,10(19),17-tetraen obtained in example 80 (4) (340 mg), dissolved in dichloromethane (5 ml). To this solution was added pyridine (0.6 ml), then rinsed with argon. To this solution add teoksessa acid (480 mg, 6.3 mmol) and stirred at room temperature for 10 minutes. After evaporation under reduced pressure to remove solvent, the obtained residue is purified through column chromatography (hexane:ethyl acetate = 10:1) to give a fraction containing specified in the header connection (2n

The fraction containing the 17-acetyltributyl-1,3-bis(tert-butyldimethylsilyloxy)-16-oxo-9,10-secondrate-5,7,10(19)-triene obtained in example 80 (5) (285 mg), dissolved in tetrahydrofuran (15 ml), to this add then 1M tertrahydrofuran ring solution of tri-tert-butoxycarbonylamino (0,92 ml) and stirred at room temperature for 30 minutes. After adding hexane (50 ml) and saturated aqueous ameriglide (0.5 ml) the reaction mixture is stirred for 30 minutes and filtered to remove insoluble products. The filtrate is concentrated under reduced pressure and purified through column chromatography (hexane:ethyl acetate = 9:1) to give a fraction containing specified in the title compound (220 mg).

(7) 17-acetyltributyl-1,3,16-trihydroxy-9,10-secondrate-5,7,10(19)-triene

The fraction containing the 17-acetyltributyl-1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-9,10-secondrate-5,7,10(19)-triene obtained in example 80 (6) (220 mg), treated with AMBERLYST 15 (1.5 g) in methanol (3 ml) and tetrahydrofuran (3 ml) according to the method of example 6 (3) (at room temperature for 2 hours and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, only uh what about the glass.

1H NMR : 0,71 (s, 3H), of 2.36 (s, 3H), 2,54-of 2.66 (m, 1H), 2,80-to 2.94 (m, 2H), 3,07-up 3.22 (m, 1H), 4,05-4,47 (m, 4H), 4,99 (Shir.s, 1H), 5,32 (Shir.s, 1H), 6,04 (d, J=11.5 Hz, 1H), 6,36 (d, J=11.5 Hz, 1H).

(8) Obtaining 17-tert-butyloxycarbonyl-1,3,16-trihydroxy-9,10-secondrate-5,7,10(19)-triens

17-acetyltributyl-1,3,16-trihydroxy-9,10-secondrate-5,7,10(19)-triene (5 mg, of 0.013 mmol) is treated with 1M methanolic potassium hydroxide solution (0,13 ml) and tert-butylbromide (76 mg, 0,390 mmol) in tetrahydrofuran (2 ml) according to the method of example 16 (2) (at room temperature for 16 hours and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:acetonitrile = 3:2, show once), getting mentioned in the title compound (3,056 mg, 52%) as a colorless glass.

IR (net): 3400, 2933, 2838, 1716, 1296, 1257, 1053 cm-1.1H NMR : 0,67 (s, 3H), of 1.48 (s, 9H), 2.57 m) of 2.92 (m, 5H), and 3.16 (d, J=15,5 Hz, 1H), 3,24 (d, J=15,5 Hz, 1H), 4,20-4,30 (m, 1H), to 4.38-4,60 (m, 2H), 4,99 (Shir.s, 1H), 5,31 (s, 1H), equal to 6.05 (d, J=11.2 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H). MC m/z: 464 (M+), 57 (100%). UVmaxnm: 263.

Example 81

(1) preparation of 1,3-bis(tert-butyldimethylsilyloxy)-16-oxo-9,10-scoprega-5,7,10(19),(17E)-tetraene

1,3-bis(tert-b is (100 ml), molecular sieves 4A (10 g) and manganese dioxide (12 g, 138,1 mmol) by the method of example 80 (4) at room temperature for 10 minutes), followed by processing and purification through column chromatography (hexane:ethyl acetate = 30:1), obtaining mentioned in the title compound (1.56 g, 78%) as a white foam.

1H NMR (C6D6) : 0,78 (s, 3H), USD 1.43 (d, J=7,6 Hz, 3H), 2,69-2,82 (m, 1H), 4,18-the 4.29 (m, 1H), 4,39-4,47 (m, 1H), 5,02 (Shir.s, 1H), 5,28 (Shir.s, 1H), and 6.25 (d, J=11,6 Hz, 1H), 6,41 (d, J=11,6 Hz, 1H), 6,66 (kV, J=7,6 Hz, 1H).

(2) 20(S)-acetylthio-1,3-bis(tert-butyldimethylsilyloxy)-16-oxo-9,10-scoprega-5,7,10(19)-triens

1,3-bis(tert-butyldimethylsilyloxy)-16-oxo-9,10-scoprega-5,7,10(19), (17E)-tetraen (1.56 g, 2,80 mmol) is treated in dichloromethane (50 ml), pyridine (2,27 ml of 28.0 mmol) and teoksessa acid (2,01 ml of 28.0 mmol) by the method of example 80 (5) at room temperature for 1.5 hours), followed by processing and purification through column chromatography (hexane:ethyl acetate = 10:1, twice), receiving the compound (1.20 g), containing specified in the header of the connection.

(3) 20(S)-acetylthio-1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-9,10-scoprega-5,7,10(19)-triens

A mixture containing 20(S)-acetylthio-1,3-bis(tert-butyldimethylsilyloxy)-16-oxo-9,10-scoprega-5,7,10(19)-triene, palucca (3.8 ml) in tetrahydrofuran (45 ml) by the method of example 80 (6) at room temperature for 1 hour), followed by processing and purification through column chromatography (hexane:ethyl acetate = 10:1), getting a mixture of 1.02 g) containing specified in the header of the connection.

(4) to Obtain 1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-20(S)-(tert-butoxycarbonylmethyl)-9,10-scoprega-5,7,10(19)-triens

A mixture containing 20(S)-acetylthio-1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-9,10-scoprega-5,7,10(19)-triene obtained in example 81 (3) (20 mg), dissolved in tetrahydrofuran (0.2 ml), then to this add methanol (0.2 ml) and 2M aqueous sodium hydroxide (0.16 ml) in an argon atmosphere. After stirring at room temperature for 30 minutes to the reaction mixture of tert-butylbromide (0,046 ml) and then stirred at room temperature for 1 hour. To the reaction mixture are added ethyl acetate, then washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered to remove the solid phase. After evaporation under reduced pressure to remove solvent, the obtained residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate = 6:1, show once), getting mentioned in the title compound (12 mg) as a colourless oil.

1H NMR : 0,06 (s, 6H), of 0.07 (s, 6H), is 0.84 (s, 3H), of 0.87 (s, 9H), to 0.88 (s, 9H), 1,, H).

(5) Obtaining 1,3,16-trihydroxy-20(S)-(tert-butoxycarbonylmethyl)-9,10-scoprega-5,7,10(19)-triens

To a solution of 1,3-bis(tert-butyldimethylsilyloxy)-16-hydroxy-20(S)-(tert-butoxycarbonylmethyl)-9,10-scoprega-5,7,10(19)-triens (16 mg, 0,0228 mmol) in tetrahydrofuran (0.5 ml), under nitrogen atmosphere add 1M tertrahydrofuran ring solution of Tetra-n-butylammonium (0.5 ml) and stirred at room temperature for 2 days. The reaction mixture was poured into water, extracted with ethyl acetate and then washed sequentially with 0.5 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer is dried over anhydrous sodium sulfate and filtered to remove the solid phase. After evaporation under reduced pressure to remove solvent, the obtained residue is purified using preparative thin-layer chromatography (0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 5:5:1, showing once), getting mentioned in the title compound (5,821 mg, 53%) as a colourless oil.

IR (net): 2925, 2863, 2358, 2332, 1699, 1647, 1296, 1128, 1053 cm-1.1H NMR : 0,85 (s, 3H), of 1.47 (s, 9H), 2.77-to 2,87 (m, 1H), 3,09 (d, J=14,0 Hz, 1H), 3,22-to 3.35 (m, 2H), 4,18-the 4.29 (m, 1H), to 4.38 figure-4.49 (m, 2H), free 5.01 (s, 1 the example 82

(1) Obtaining {1,3-bis(tert-butyldimethylsilyloxy)}-20(S)-(tert-butyloxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraene

Mix {1,3-bis(tert-butyldimethylsilyloxy)}-20(S)-phenoxycarbonyl-9,10-scoprega-5,7,10(19),16-tetraen (20 mg, 0,0220 mmol), tetrahydrofuran (0,34 ml) and methanol (0,34 ml), to this add in an argon atmosphere 2M aqueous sodium hydroxide (0.17 ml) and then tert-butylbromide (56 mg, in 0.288 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove solvent. The resulting residue is separated via preparative thin layer chromatography (0.5 mm × 2 plates, hexane:ethyl acetate = 100:9, show once), obtaining a mixture (10 mg) containing the target product as a colorless oil.

(2) Obtaining 1,3-dihydroxy-20(S)-(tert-butyloxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraene

A mixture containing {1,3-bis(tert-butyldimethylsilyloxy)}-20(S)-(tert-butyloxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 82 (1) (10 mg) is treated in tetrahedr the external temperature of 50°C for 1 hour and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:acetonitrile = 3:2, are once; 0.5 mm × 1 plate, toluene:ethyl acetate = 9:11, show twice, and then 0.5 mm × 1 plate, hexane:ethyl acetate:ethanol = 8:8:1, show once), getting mentioned in the title compound (1,754 mg, 13% over 2 stages) as a colorless glass.

IR (net): 3379, 2929, 2850, 1724, 1367, 1292, 1132, 1055 cm-1.1H NMR : 0,81 (s, 3H), of 1.42 (d, J=7,3 Hz, 3H), of 1.46 (s, 9H), 2,22 is 2.43 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-and 2.83 (m, 1H), 3,12 (s, 2H), 4,20-4,30 (width, 1H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,64 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MS m/z: 460 (M+), 57 (100%). UVmaxnm: 264.

Example 83

(1) preparation of 1,3-dihydroxy-20(S)-phenoxycarbonyl-9,10-scoprega-5,7,10(19),16-tetraene

{1,3-bis(tert-butyldimethylsilyloxy)}-20(S)-phenoxycarbonyl-9,10-scoprega-5,7,10(19),16-tetraen (55 mg, 0,0791 mmol) is treated in tetrahydrofuran (5 ml) and methanol (5 ml), AMBERLYST 15 (2 g) by the method of example 6 (3) (at room temperature within 3 hours), followed by processing and purification via preparative thin-layer chromatography (0.5 mm × 3 plates, dichloromethane:ethanol = 10:1, show once), OYe, 3H), 1,58 (d, J=6.9 Hz, 3H), 2,54-of 2.66 (m, 1H), 2.77-to is 2.88 (m, 1H), 4,12 (kV, J=7,3 Hz, 1H), 4,19-the 4.29 (m, 1H), 4,40-4,48 (m, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,74 (Shir.s, 1H), 6,11 (d, J=10,9 Hz, 1H), 6,37 (d, J=10,9 Hz, 1H), 7,12-7,41 (m, 5H).

(2) Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)thio}-N-(tert-butyl)ndimethylacetamide

1,3-Dihydroxy-20(S)-phenoxycarbonyl-9,10-scoprega-5,7,10(19),16-tetraen (6 mg, 0,0129 mmol) is treated with 1M methanolic potassium hydroxide solution (0.5 ml) and 2-bromo-N-(tert-butyl)ndimethylacetamide (10 mg, 0,0515 mmol) by the method of example 16 (2) (at room temperature for 15 hours and then treated.

The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:acetonitrile = 3:2, show once), getting mentioned in the title compound (3,874 mg, 66%) as a colorless glass.

IR (net): 3340, 2964, 2931, 1653, 1525, 1454, 1223, 1057 cm-1.1H NMR : or 0.83 (s, 3H), of 1.36 (s, 9H), 2,22-to 2.42 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-and 2.83 (m, 1H), of 3.07 (s, 2H), 3.33 and-of 3.48 (m, 1H), 4,20-4,30 (width, 1H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,63 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H), 6,72 (Shir.s, 1H). MC m/z: 459 (M+), 57 (100%). UVmaxnm: 263.

Example 84

Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)thio}-N-(tert-is 7 mmol) is treated with 1M methanolic potassium hydroxide solution (0.5 ml) and 2-bromo-N-(tert-butyl)-N-methylacetamide (10 mg, 0,0481 mmol) by the method of example 16 (2) (at room temperature for 15 hours and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.5 mm × 2 plates, dichloromethane:acetonitrile = 2:1, are twice), getting mentioned in the title compound (3,102 mg, 61%) as a colorless glass.

IR(net): 3380, 2927, 2850, 1630, 1367, 1211, 1093, 1057 cm-1.1H NMR : 0,82 (s, 3H), of 1.41 (s, 9H), of 1.46 (d, J=6.9 Hz, 3H), 2.21 are to 2.42 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-and 2.83 (m, 1H), equal to 2.94 (s, 3H), 3,19-3,29 (m, 2H), to 3.58-3,66 (m, 1H), 4,20-4,30 (width, 1H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,66 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 473 (M+), 57 (100%). UVmaxnm: 263.

Example 85

Obtaining {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)thio}-N-methoxy-N-methylacetamide and {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)thio}-N-methylacetamide

1,3-Dihydroxy-20(S)-phenoxycarbonyl-9,10-scoprega-5,7,10(19),16-tetraen (5 mg, 0,0107 mmol) is treated with 1M methanolic potassium hydroxide solution (0.5 ml) and 2-bromo-N-methoxy-N-methylacetamide (10 mg, 0,0549 mmol) by the method of example 16 (2) (at room temperature for 15 hours and then treated. The resulting residue is purified using preparative tone is 215; 1 plate, dichloromethane:acetonitrile = 1:1, show once), getting {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)thio}-N-methoxy-N-methylacetamide (0,847 mg, 18%) as a colourless glass and {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)thio}-N-methylacetamide (0,839 mg, 19%) as a colorless glass.

For {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)thio}-N-methoxy-N-methylacetamide:

IR (net): 3401, 2922, 2850, 1647, 1446, 1055 cm-1.1H NMR : or 0.83 (s, 3H), of 1.44 (d, J=6.9 Hz, 3H), 2,22-2,39 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-and 2.83 (m, 1H), 3,20 (s, 3H), 3,24-to 3.38 (m, 2H), 3,66-to 3.73 (m, 1H), of 3.73 (s, 3H), 4,20-4,30 (width, 1H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), of 5.34 (s, 1H), 5,67 (Shir.s, 1H), 6,10 (d, J=10,9 Hz, 1H), 6,37 (d, J=10,9 Hz, 1H). MC m/z: 429 (M+-H2O), 91 (100%). UVmaxnm: 263.

For {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)thio}-N-methylacetamide:

IR (net): 3326, 2924, 2850, 1653, 1417, 1122, 1055 cm-1.1H NMR : 0,81 (s, 3H), of 1.41 (d, J=6.9 Hz, 3H), 2,20-of 2.36 (m, 3H), 2.57 m-2,62 (m, 1H), 2,79-of 2.86 (m, 1H), 2,85 (d, J=4.9 Hz, 3H), and 3.16 (s, 2H), 3,42-to 3.49 (m, 1H), 4,20-4,30 (width, 1H), 4,39-4,49 (width, 1H), 5,01 (Shir.s, 1H), 5,35 (s, 1H), 5,62 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,36 (d, J=11.2 Hz, 1H). MC m/z: 399 (M+-H2O), 91 (100%). UVmaxnm: 264.

Example 86

Obtaining 1,3-dihydroxy-20 is about-9,10-scoprega-5,7,10(19),16-tetraen (8,7 mg, 0,0186 mmol) is treated with 1M methanolic potassium hydroxide solution (0.04 ml) and tert-butyl acrylate (120,0 mg, 0,936 mmol) by the method of example 16 (2) (at room temperature for 30 minutes and then treated. The resulting residue is purified using preparative thin-layer chromatography (0.25 mm × 1 plate, dichloromethane:ethanol = 15:1, show three times and then 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, show three times, getting mentioned in the title compound (3.6 mg, 40%) as a colorless glass.

IR (net): 3400, 2928, 1728, 1450, 1368, 1252, 1152, 1056 cm-1.1H NMR : 0,82 (s, 3H), of 1.41 (d, J=6.9 Hz, 3H), 1,45 (s, 9H), 2,75-is 2.88 (m, 1H), 3.46 in (kV, J=6,9 Hz, 1H), 4,20-4,30 (m, 1H), 4,40-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,61 (Shir.s, 1H), 6,10 (d, J=11,4 Hz, 1H), 6,37 (d, J=11,4 Hz, 1H). MC m/z: 474 (M+), 57 (100%). UVmaxnm: 263.

Example 87

Obtaining 1,3-dihydroxy-20(S)-tert-butoxycarbonylamino-9,10-scoprega-5,7,10(19),16-tetraene

1,3-Dihydroxy-20(S)-phenoxycarbonyl-9,10-scoprega-5,7,10(19),16-tetraen (6.2 mg, 0,0133 mmol) is treated with 2M aqueous sodium hydroxide (65 ml) and tert-butyl 4-bromobutyrate (155,0 mg, 0,695 mmol) by the method of example 16 (2) (at room temperature for 30 minutes and then treated. The obtained OST show once, dichloromethane:ethanol = 10:1, are once; 0.25 mm × 1 plate, dichloromethane:ethyl acetate = 3:1, show once, dichloromethane:ethyl acetate = 1:1, showing once; and then 0.25 mm × 1 plate, hexane:ethyl acetate:ethanol = 10:5:1, are twice), getting mentioned in the title compound (2.9 mg, 45%) as a colourless oil.

IR (net): 3384, 2968, 2928, 2848, 1728, 1448, 1368, 1240, 1160, 1056 cm-1.1H NMR : 0,82 (s, 3H), of 1.41 (d, J=7,0 Hz, 3H), of 1.44 (s, 9H), of 1.84 (t, J=7,3 Hz, 2H), 2,32 (t, J=7,3 Hz, 2H), 2,45 (dt, J=3.3, which is 7.3 Hz, 2H), 2,55-to 2.65 (m, 1H), 2,75-of 2.86 (m, 1H), 3,44 (kV, J=7,0 Hz, 1H), 4,19-4,30 (m, 1H), 4,40-4,50 (m, 1H), 5,01 (Shir.s, 1H), 5,34 (Shir.s, 1H), 5,58 (Shir.s, 1H), 6,10 (d, J=11.2 Hz, 1H), 6,37 (d, J=11.2 Hz, 1H). MC m/z: 470 (M+-H2O), 57 (100%). UVmaxnm: 263.

Test example 1

Eight male mice of the strain Balb/c mice subcutaneously injected with active vitamin D3(1, 25(OH)2D3, 125 μg/ml in ethanol) or compounds 1-5 (derivatives of vitamin D, obtained in the above examples, 500 μg/ml in ethanol) or ethanol (as a control). These samples are applied once on the skin in the back (about 1.5×2.0 cm2) the mouse in a volume of 2 ml/kg, Then each of the mice, fixed with the help of "hard" collar to avoid execution ven the mice take blood and examine the levels of ionized calcium by the method of ion-selective electrodes. The analysis carried out for groups of 3 mice. Table 45 presents the results obtained. The levels of ionized calcium in the table are expressed as average values.

Test example 2

The keratinocytes of the foreskin of a newborn baby (Clonetics) were seeded in 96-well plates (COSTAR 3595) at a density of cells 2×103/well. Then in wells placed certain concentration of active vitamin D3(1,25(OH)2D3or compounds 1-5, followed by incubation in KGM-2 medium at a density of cells 2×103cells/200 µl/well for 3 days at a temperature of 37°C in an atmosphere consisting of 5% CO2and 95% air. To each well add [3H]thymidine (with 7.4 kBq/well) and the plates further incubated for 1 day. Each well once washed with phosphate buffer containing calcium and magnesium (Dulbecco's PBS(-), Nissui, code, 05913, pH 7.3 7,65) and treated with 0.25% trypsin for purification of cells. Included in cell number [3H]thymidine was determined by liquid scintillation counter (1450 MicroBeta, Wallac). Table 45 presents the results obtained. The growth inhibition of keratinocytes expressed in the table as inhibition = (IR50(mol/l) of active vitamin D3)/(IR50(mol/l) of each connection).

Connection 1 is 20(S)-(tert-butoxycarbonylmethyl)-1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 8 (3). Compound 2 represents 1,3-dihydroxy-20(S)-(N-tert-butyl-N-methylaminoquinoline)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 13. The connection 3 is 1,3-dihydroxy-20(S)-(tert-butoxycarbonylamino)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 11 (2). The connection 4 is 1,3-dihydroxy-20(S)-(N-tert-butylaminoethyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 14. Compound 5 is 1,3-dihydroxy-20(S)(isopropoxycarbonyl)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 15.

Test example 3

Repeat the test method of example 1 to analyze the levels of ionized calcium in the blood of mice except that, as a derivative of vitamin D use connections 6-12. Table 46 presents the results obtained. The levels of ionized calcium in the table are presented as average values.

Test example 4

The keratinocytes of the skin of an adult (Cl certain concentration of active vitamin D3(1,25(OH)2D3or compounds 6-12, followed by incubation in KGM-2 medium at a density of cells 1×103cells/200 µl/well for 3 days at a temperature of 37°C in an atmosphere consisting of 5% CO2and 95% air. To each well add [3H]thymidine (with 7.4 kBq/well) and the plates further incubated for 1 day. After removal of medium to each well treated with 0.05% trypsin/0.53 mm EDTA for purification of cells. Included in cell number [3H]thymidine was determined by liquid scintillation counter (1450 MicroBeta, Wallac). Table 46 presents the results obtained. The growth inhibition of keratinocytes expressed in the table as a relative value for each connection in comparison with active vitamin D3: Relative inhibition = (IR50(mol/l) of active vitamin D3)/(IR50(mol/l) test connection).

The connection 6 is 1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 17 (4). Compound 7 is 1,3-dihydroxy-20(S)-(1-isopropyl-2-methylpropanesulfonate)-9,10-scoprega-5,7,10(19),16-Ter the 10-scoprega-5,7,10(19),16-tetraen, obtained in example 18 (2). The connection 9 is 1,3-dihydroxy-20(S)-(1-ethyl-1-methylpropionamidine)-9,10-scoprega-5,7,10(19)-triene obtained in example 23 (4). The connection 10 is 1,3-dihydroxy-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 19 (2). The connection 11 is 1,3-dihydroxy-20(S)-{2-(1-ethyl-1-methylpropanesulphonic)ethoxy}-9,10-scoprega-5,7,10(19),16-tetraen obtained in example 20 (3). The connection 12 is {(1,3-dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide, obtained in example 22 (2).

Industrial applicability

Derivatives of vitamin D of the present invention not only have excellent physiological activities, but also deliver reduced hypercalcemic effect compared to the normal derivative of vitamin D. Therefore, derivatives of vitamin D of the present invention is effective in the treatment of diseases, which allow for only a limited introduction of the normal derivatives of vitamin D to avoid hypercalcemia and other problems.

1. Derivative of vitamin D formulas (1)

where X represents an oxygen atom or a sulfur atom;

R4represents a hydrogen atom;

R5represents a hydrogen atom or hydroxyl group, or R4and R5together form a double bond between the 16 - and 17-positions;

R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched alkyl group which may be substituted by one or more fluorine atoms or a cyclic alkyl group), or-NR9R10(where R9and R10 each represents a hydrogen atom, a straight or branched alkyl group which may be substituted by one or more fluorine atoms or a cyclic alkyl group, or a cyclic alkyl group which may be substituted by one or more fluorine atoms, or R9and R10may form a ring together with the nitrogen atom, if R4and R5together form a double bond between the 16 - and 17-positions);

R6is-OR11(where R11represents a hydrogen atom or a protective group);

R7present yet an oxygen atom or a sulfur atom, m represents a number from 1 to 3, R1and R2each represents a hydrogen atom or1-C4alkyl group, R4represents a hydrogen atom, R5represents a hydrogen atom or hydroxyl group, or R4and R5together form a double bond between the 16 - and 17-positions, R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched C1-C15alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C10alkyl group), or-NR9R10(where R9and R10each represents a hydrogen atom, a straight or branched C1-C15alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C10alkyl group, or a cyclic3-C15alkyl group which may be substituted by one or more fluorine atoms, or R9and R10form a 3-10-membered ring, s), R6represents a hydroxyl group, and R7represents a hydrogen atom.

3. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R4and R5at the same time represent a hydrogen atom, or R4represents a hydrogen atom, and R5represents a hydroxyl group, or R4and R5together form a double bond between the 16 - and 17-positions, R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched C1-C10alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C8alkyl group), or-NR9R10(where R9and R10each represents a hydrogen atom, a straight or branched C1-C10alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C9and R10form a 3-10-membered ring together with the nitrogen atom, if R4and R5together form a double bond between the 16 - and 17-positions), R6represents a hydroxyl group, and R7represents a hydrogen atom.

4. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched C1-C8alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C8alkyl group), or-NR9R10(where R9and R10each represents a hydrogen atom, a straight or branched C1-C8alkyl group which may be substituted onicescu3-C8alkyl group which may be substituted by one or more fluorine atoms, or R9and R10form a 3-8-membered ring together with the nitrogen atom, if R4and R5together form a double bond between the 16 - and 17-positions), R6represents a hydroxyl group, and R7represents a hydrogen atom.

5. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R3is-YR8(where Y represents an oxygen atom or a sulfur atom, R8represents a hydrogen atom, a straight or branched C1-C8alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C6alkyl group), R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

UB POS="POST">1and R2each represents a hydrogen atom or methyl group, R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R3is-NR9R10(where R9and R10 each represents a hydrogen atom, a straight or branched C1-C8alkyl group which may be substituted by one or more fluorine atoms or cyclic WITH3-C6alkyl group, or a cyclic3-C8alkyl group which may be substituted by one or more fluorine atoms, or R9and R10form a 3-6-membered ring together with the nitrogen atom, if R4and R5together form a double bond between the 16 - and 17-positions), R6represents a hydroxyl group, and R7represents a hydrogen atom.

7. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

8. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom or a sulfur atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R3is-SR8(where R8is branched C3-C8alkyl group), R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

9. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom or a sulfur atom, m represents 1, R1and R2each represents a hydrogen atom or methyl group, R3is-NR9R10(where R9represents a hydrogen atom or p or branched C1-C8alkyl group which may be substituted by one or more fluorine atoms), R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

10. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or methyl group, R3is-OR8(where R8is branched C6-C8alkyl group), R4and R5each represents a hydrogen atom, or R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

11. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom, m represents a number from 1 to 2, R1and R2each represents a hydrogen atom or a methyl group, provided that one of R18(where R8is branched C6-C8alkyl group), R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

12. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom, m represents 1, R1and R2each represents a hydrogen atom or a methyl group, provided that one of R1and R2must represent a methyl group,R3is-NR9R10(where R9represents a hydrogen atom or methyl group, R10is a straight or branched C1-C4alkyl group which may be substituted by one or more fluorine atoms), R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

13. Derivative of vitamin D on p. 1, where in formula (1), X represents an oxygen atom, m represents 1, R1and R2>must represent a methyl group,R3is-NR9R10(where R9represents a hydrogen atom, R10is sawn group which may be substituted by one or more fluorine atoms), R4and R5together form a double bond between the 16 - and 17-positions, R6represents a hydroxyl group, and R7represents a hydrogen atom.

14. 1,3-Dihydroxy-20(S)-(1-ethyl-1-methylpropanesulphonic-methoxy)-9,10-scoprega-5,7,10(19),16-tetraen.

15. 1,3-Dihydroxy-20(S)-(1-isopropyl-2-methylpropoxy-carbonyloxy)-9,10-scoprega-5,7,10(19),16-tetraen.

16. 1,3-Dihydroxy-20(S)-(1,1-dimethylphenylcarbamate)-9,10-scoprega-5,7,10(19),16-tetraen.

17. 1,3-Dihydroxy-20(S)-(1,1-dimethylphenylcarbinol-methoxy)-9,10-scoprega-5,7,10(19),16-tetraen.

18. 1,3-Dihydroxy-20(S)-{2-(1-ethyl-1-methylpropoxy-carbonyl)ethoxy}-9,10-scoprega-5,7,10(19),16-tetraen.

19. {(1,3-Dihydroxy-9,10-scoprega-5,7,10(19),16-tetraen-20(S)-yl)oxy}-N-(2,2,3,3,3-pentafluoropropyl)ndimethylacetamide.

20. 1,3-Dihydroxy-20(S)-(1-ethyl-1-methylpropanesulphonic-methoxy)-9,10-scoprega-5,7,10(19)-triene.

21. Pharmaceutical composica, contains a derivative of vitamin D according to any one of paragraphs.1-20.

22. Therapeutic agent for the treatment of skin diseases, which contains as active ingredient a derivative of vitamin D according to any one of paragraphs.1-20.

23. Therapeutic agent for the treatment of skin diseases on p. 22, where the skin disease is psoriasis.

24. The method of treatment of skin diseases, including stage injection to a patient in need of such effect, a therapeutically effective amount of a derivative of vitamin D under item 1.

25. The method according to p. 24, where the skin disease is psoriasis.

Priority points and features:

15.06.2000 on PP.1-4, 6, 8-12, 14-25 - for all values of X, m, R1-R7, Y, R8-R10, R11;

15.06.2000 on PP. 5, 7 for all values of X, m, R1-R7, Y, R8-R10, R11except for m=2;

17.11.2000 under item 5, when m=2, and p. 13;

08.12.2000 under item 7, when m=2.



 

Same patents:

The invention relates to new derivatives of vitamin D General formula I

< / BR>
where Y1- OH, C1-12alkanoyloxy or optionally substituted benzoyloxy, Y2- H, C1-12alkanoyl or optionally substituted benzoline group, R1and R2together ekzoticheskaya methylene group, R3and R4independently - H, C1-4alkyl, Q - C1-3alkylen, possibly substituted inoris HE in the group, which, in turn, can be etherification, R5and R6at the same time C1-4alkyl, or R5and R6together with carbon atom C-25 form cyclopropyl group, Z is a 5-6-membered aromatic Carbo - or heterocycle, such as phenyl, oxazole, thiazole, furan, thiophene, pyrrole, isoxazol, pyrazole, triazole, pyridine, pyrimidine, possibly substituted C1-12alkylen

The invention relates to novel vitamin D analogues of the formula (I), where X is hydrogen, hydroxy or protected hydroxy; R1and R2is hydrogen, methyl or ethyl; Q3-C6hydrocarbide where hydrocarbide means biradical obtained after removal of two hydrogen atoms from a straight or branched, saturated or unsaturated hydrocarbon, in which any one of CH2group can be optionally replaced by an oxygen atom or carbonyl group such that the carbon atom (C-22), directly associated with the C-20 was a hybridized carbon atom is sp2or sp3i.e

The invention relates to novel vitamin D analogues of formula I, where X Is H or HE, R1and R2- CH3or2H5or together with the carbon atom bearing the group X, can form WITH3-C5carbocycle, Q is a single bond or C1-C8-hydrocarbide, in which one of the groups-CH2- not associated with a group, optionally substituted by an IT group or replaced by an oxygen atom, Y is a single bond or C1-C8-hydrocarbide, or other derivative

The invention relates to vitamin D analogues of General formula I, where X is hydroxy; R1and R2- the same or different, H, CH3WITH2H5or cyclopropyl; Q is methylene, ethylene, tri -, or tetramethylene, optionally substituted hydroxy-group or group-or SIG3where R3Is h, methyl or ethyl; Y is a single bond or C1-C2- hydroxycarbonyl

The invention relates to new derivatives of vitamin D3formula (I), where Q is methylene, ethylene, tri -, or tetramethylene, -CH=CH-, -CH=CH-CH=CH-; Y is a single bond, - CH(OH), -O-(C6H4)-(meta) or-S-(C6H4)-(meta); R1and R2the same or different, is methyl, ethyl, or R1and R2together with the carbon atom marked with an asterisk in formula I bearing a group Z may form WITH3-C6carbocyclization ring; Z is hydrogen or hydroxy, provided that when Y is CH(OH)-, R1and R2- mately, Z is hydroxy, the configuration at C-20 cannot be R

The invention relates to vitamin D analogues of the formula I in which Q represents a C1-C8hydrocarbononly biradical; R represents a C1-C6hydrocarbide; expression hydrocarbide (hydrocarbide) denotes the radical (biradical) obtained after removal of the 1 (2) atom(s) of hydrogen from an unbranched, branched or cyclic, saturated or unsaturated hydrocarbon, or in which two groups of R, taken together with the carbon atom carrying the hydroxyl group can form WITH3-C8carbocyclic ring

The invention relates to a synthetic derivative of vitamin D General formula I, where Q is CH2- or-CC - and-C1-C6alkylene; R1-H, C1-C4alkyl group YR1where Y -,- SO-, C1-C4alkyl, Z is H or a hydroxyl

The invention relates to vitamin D analogues of General formula I, where X IS HE; R1and R2the same or different, - C1-C3alkyl, benzyl or YR4where R4is phenyl, Q - (CH2)nn=1-4

The invention relates to new derivatives of vitamin D General formula I

< / BR>
where Y1- OH, C1-12alkanoyloxy or optionally substituted benzoyloxy, Y2- H, C1-12alkanoyl or optionally substituted benzoline group, R1and R2together ekzoticheskaya methylene group, R3and R4independently - H, C1-4alkyl, Q - C1-3alkylen, possibly substituted inoris HE in the group, which, in turn, can be etherification, R5and R6at the same time C1-4alkyl, or R5and R6together with carbon atom C-25 form cyclopropyl group, Z is a 5-6-membered aromatic Carbo - or heterocycle, such as phenyl, oxazole, thiazole, furan, thiophene, pyrrole, isoxazol, pyrazole, triazole, pyridine, pyrimidine, possibly substituted C1-12alkylen
The invention relates to medicine

The invention relates to new derivatives of vitamin D3formula (I), where Q is methylene, ethylene, tri -, or tetramethylene, -CH=CH-, -CH=CH-CH=CH-; Y is a single bond, - CH(OH), -O-(C6H4)-(meta) or-S-(C6H4)-(meta); R1and R2the same or different, is methyl, ethyl, or R1and R2together with the carbon atom marked with an asterisk in formula I bearing a group Z may form WITH3-C6carbocyclization ring; Z is hydrogen or hydroxy, provided that when Y is CH(OH)-, R1and R2- mately, Z is hydroxy, the configuration at C-20 cannot be R

The invention relates to a synthetic derivative of vitamin D General formula I, where Q is CH2- or-CC - and-C1-C6alkylene; R1-H, C1-C4alkyl group YR1where Y -,- SO-, C1-C4alkyl, Z is H or a hydroxyl

The invention relates to vitamin D analogues of formula I, where R represents a group

< / BR>
where q is 0,1; n is from 2 to 4; m is 0; Y1and Y2independently represent hydrogen, halogen atom; R1and R2independently represent hydrogen, lower alkyl, optionally substituted by halogen atoms or sidegroups; X represents hydrogen or a hydroxy-group, with the available hydroxy-group can be protected, also describes a pharmaceutical composition having inhibitory activity against proliferation of cancer cells on the basis of the compounds I
The invention relates to medicine, namely, rheumatology, and for the treatment of osteoporosis in patients with rheumatoid arthritis on a background of glucocorticoid therapy

FIELD: veterinary science.

SUBSTANCE: about 20-25 d before calving one should introduce intramuscularly 0.5%-sodium selenite solution for cows at the dosage of 10 ml. Twice before and twice after calving at 10-d-long interval - tetravit at the dosage of 10 ml at the content of 50000 IU vitamin A, 25000 IU vitamin D, 20 mg vitamin E and 5 mg vitamin F per 1 ml. Succinic acid should be introduced 20-25 d both before and after calving at the dosage of 1.0 g. The method provides efficient correction of the main values of homeostasis in cows after calving.

EFFECT: higher efficiency of normalization.

2 ex, 4 tbl

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to production of a curative-prophylactic agent used in treatment of diseases associated with deficiency of calcium in human body. Invention proposes a group of inventions combined with the unit inventive idea and providing achievement of the unit technical result. Invention relates to a composition used in prophylaxis and treatment of diseases caused by calcium deficiency and this composition comprises amaranthus milled dried leaves, vitamin D, calcium salts and phosphorus compounds of mineral or organic origin. Also, invention relates to a composition used for prophylaxis and treatment of diseases caused by calcium deficiency, and comprising amaranthus milled dried leaves, vitamin D, calcium salts, phosphorus compounds of mineral or organic origin, dried Jerusalem artichoke or bilberry fruits. Intake of the proposed composition allows obtaining the required blood calcium concentration in its ionized form.

EFFECT: valuable medicinal properties of composition.

6 cl, 120 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to producing a curative-prophylactic agent used in diseases associated with calcium deficiency in human body. Invention proposes a composition used in prophylaxis and treatment of diseases caused by calcium deficiency and comprising amaranthus dry leaves, vitamin D and phosphorus compounds of mineral or organic origin, wt.-%. Also, invention proposes a composition used in prophylaxis and treatment of diseases caused by calcium deficiency comprising amaranthus milled dry leaves, vitamin D, phosphorus compounds of mineral or organic origin, dry Jerusalem artichoke or bilberry fruits. Digestion of this composition allows providing the required concentration of blood calcium in its ionized form.

EFFECT: valuable medicinal properties of composition.

5 cl, 84 ex

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