9,10-secopregnane derivative and pharmaceutical agents

FIELD: chemistry.

SUBSTANCE: invention describes a novel useful vitamin D3 derivative, which has excellent vitamin D3 activity, and has relatively low action on system calcium metabolism compared to other traditional vitamin D3 derivatives. The invention includes a 9,10-secopregnane derivative of general formula [1] and a pharmaceutical composition containing said derivative as an active ingredient. [Formula 1]

.

In general formula [1], the next part of the structure between position 16 and position 17 denotes a single bond or a double bond. Y denotes a single bond, alkylene, alkenylene or phenylene; R1 and R2 are identical or different and each denotes hydrogen, alkyl or cycloalkyl; or R1 and R2, taken together with an adjacent carbon atom, form a cycloalkyl; R3 denotes hydrogen or methyl; Z denotes hydrogen, hydroxy or -NR11R12, where R11 and R12 assume values given in the claim.

EFFECT: obtaining a useful D3 derivative.

14 cl, 73 ex, 8 tbl

 

The SCOPE of the INVENTION

The present invention relates to 9,10-securegateway derivative (derivative of vitamin D3and pharmaceutical compositions containing it as active ingredient.

The LEVEL of TECHNOLOGY

Psoriasis, actiony syndrome, keratosis of the palms and soles, the pustular eruption of the palms and soles, as well as hair zoster are dyskeratosis in a broad sense, showing various characteristic skin symptoms such as erythema, weeping, hypertrophy, keratinization and cornification. This disease is refractory chronic disease and causes significant limitations comfort of the everyday life of patients. In accordance with its pathological root cause of the disease, as suggested, based on the disturbance growth and differentiation as cells of inflammation, and skin cells.

Psoriasis, which is a common disease with diskeratoz, is not a fatal disease, but is poorly known and is accompanied by prejudice with respect to its appearance, as well as mental suffering. Therefore, in most cases, the quality of life (QOL) is significantly disrupted.

Most therapeutic methods were applied to the aforementioned keratosis, such as psoriasis. However, there is no radical treatment, prevodilac the symptomatic therapy and care over a longer period of time. As the main method of treatment is widely accepted external applications from adrenocorticosteroids agents to achieve excellent therapeutic effect. However, there are also serious side effects and the induction of skin atrophy and the rebound effect of skin manifestations, which, in particular, are seen as the problem.

In recent years, widely used by the local application of derivatives of vitamin D3with the skeleton 9,10-scopigno. Compared with steroids that are suitable for local application agent has fewer side effects and has the effect of prolonging survival period (see, for example, non-Patent Reference 1). Assume that a derivative of vitamin D3effective for keratosis, including psoriasis, due to the overwhelming influence on the growth of epidermal cells (see, for example, non-Patent References 2 and 3)stimulate the differentiation of epidermal cells (see, for example, non-Patent References 4 and 6), the overwhelming effect on the production of cytokines and suppressing effects on the activation of T cells (see, for example, non-Patent Reference 7), etc.

As regards derivative of vitamin D3with the skeleton 9,10-scopigno, for example, various known derivatives, such as (1S,3R,20S)-20-(3-hydroxy-3-methylbutoxy)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol (between Narodnoe generic name: Maximality) (method of synthesis and pharmacological action referred to, for example, non-Patent References 8-10), compounds mentioned in the Patent Reference 2 or non-Patent Reference 11, etc.

On the other hand, it is well known that 1α,25(OH)2D3, which is the active form of vitamin D increases the level of calcium concentration in the serum level of parathyroid hormone in serum by which calcium homeostasis are maintained and controlled. The most alarming side effects of derivatives of vitamin D3that clinically detected currently: dry mouth, discomfort, lethargy, anorexia, vomiting, abdominal pain and muscle weakness as a result of increasing concentrations of serum calcium (hypercalcemia). Accordingly there is a need for periodic measurement of the concentration of calcium in the blood not only in the case when the introduction is done for patients suffering from hypercalcemia, but also patients who do not suffer from this disease. There is also a limitation of the dose (see, for example, non-Patent References 12 and 13).

Therefore, there is urgent need for a derivative of vitamin D3that compared with traditional derivatives of vitamin D3has a relatively small impact on systemic calcium metabolism and is able to specifically weaken diskeratoz epidermal cells is to a as a therapeutic agent when keratosis, such as psoriasis.

Patent Reference 1: EP-A 0184112

Patent Reference 2: Japanese Patent 2908566

Patent Reference 3: US 6296997

Patent Reference 4: US 5612325

Patent Reference 5: US Application 2004-0019023

Patent Reference 6: JP-A-Hei-10-231284

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Description of the INVENTION

TASKS THAT STAND BEFORE the INVENTION of

The main object of the invention is the introduction of a new and useful derivative of vitamin D3that is an excellent activity of vitamin D3and that compared to the normal derivative of vitamin D3has a relatively small impact on systemic calcium metabolism.

TOOLS TO SOLVE PROBLEMS

Conducted various intensive studies and found that the new 9,10-seroprevalence derived, which will be mentioned below, or its pharmaceutically acceptable salt, reaches decisions of the task.

The invention may include 9,10-seroprevalence derivative represented by the following General formula [1] (hereafter referred to as the connection according to the invention), or its pharmaceutically acceptable salt. Characteristic of the compounds according to the invention from the point of view of its structure is that carbonyloxy directly linked to the carbon atom at the 20-position and not in between alkylenes chain.

[Formula 1]

In General formula [1]

the next part of the structure between the 16-position and a 17 position means a simple bond or double bond:

[Formula 2]

Y represents (1) tapping the link, (2) alkylene having from 1 to 5 carbon atoms, and optionally substituted from 1 to 3 substituents selected from the group of halogen, hydroxy and oxo, (3) albaniles having from 2 to 5 carbon atoms, or (4) phenylene;

R1and R2are the same or different, each represents (1) hydrogen, (2) alkyl, having from 1 to 6 carbon atoms, and optionally substituted from 1 to 3 halogen atoms, or (3) cycloalkyl having from 3 to 8 carbon atoms; or R1and R2taken together with the adjacent carbon atom, forms cycloalkyl having from 3 to 8 carbon atoms;

R3represents hydrogen or methyl;

Z represents hydrogen, hydroxy, or-NR11R12; R11represents hydrogen or alkyl having from 1 to 6 carbon atoms; R12represents (1) an alkyl having from 1 to 6 carbon atoms, and optionally substituted by hydroxy or (2) alkylsulfonyl having from 1 to 6 carbon atoms;

Raand Rbboth represent hydrogen atoms, or Raand Rbtaken together form methylene;

Rcand Rdare the same or different, each represents hydrogen or methyl, or Rcand Rdtaken together form methylene.

However, compounds, where (1) Raand Rbtaken together form a methylene, (2) Rcand Rdrepresent hydrogen atoms, and (3) partial structure between the 16-position and the 17-position is a simple link, excluded.

The invention also includes a pharmaceutical composition comprising the compound according to the invention or its pharmaceutically acceptable salt as an active ingredient or therapeutic agent for treatment of dyskeratosis, including psoriasis, which contains a compound of the invention or its pharmaceutically acceptable salt as an active ingredient.

Of the compounds according to the invention, for example, preferred are the following compounds (1) through (35):

(1) (1S,3R,20S)-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol,

(2) (1R,3R,20S)-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(3) (1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(4) (1R,3R,20S)-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,

(5) (1R,3R,20S)-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(6) (1R,3R,20S)-2-methylene-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(7) (1R,3R,20S)-2-methylene-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,

(8) (1R,3R,20S)-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(9) (1R,3R,20S)-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(10)(1R,3R,20S)-19-nor-2-methylene-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(11) (1S,3R,20S)-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol,

(12) (1R,2α,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(13) (1R,2β,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(14) (1R,3R,20S)-2-methyl-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(15) (1R,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,

(16) (1R,3R,20S)-19-nor-2-methyl-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(17) (1R,3R,20S)-19-nor-2-methylene-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(18) (1R,3R,20S)-19-nor-2-methylene-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(19) (1R,3R,20S)-2-methylene-19-nor-20-(5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(20) (1R,2α,3R,20S)-2-methyl-19-nor-20-(5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(21) (1R,2β,3R,20S)-2-methyl-19-nor-20-(5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(22) (1R,2α,3R,20S)-2-methyl-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(23) (1R,2β,3R,20S)-2-methyl-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,

(24) (1R,2α,3R,20S)-19-nor-2-methyl-20-(4-what hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(25) (1R,2β,3R,20S)-19-nor-2-methyl-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(26) (1R,2α,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,

(27) (1R,2β,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,

(28) (1R,2α,3R,20S)-2-methyl-19-nor-20-[4-ethyl-4-hydroxyhexanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol,

(29) (1R,2β,3R,20S)-2-methyl-19-nor-20-[4-ethyl-4-hydroxyhexanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol,

(30) (1R,3R,20S)-19-nor-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(31) (1R,3R,20S)-19-nor-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol,

(32) (1S,3R,20S)-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol,

(33) (1S,3R,20S)-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol,

(34) (1R,3R,20S)-19-nor-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol,

(35) (1R,3R,20S)-19-nor-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol.

The invention also includes the following connection with (1) through (5) or its pharmaceutically acceptable salt, pharmaceutical composition containing the following compound (1) through (5), or its pharmaceutically acceptable salt as an active ing is edient, or therapeutic agent for treatment of dyskeratosis, including psoriasis, which contains the following connection with (1) through (5) or its pharmaceutically acceptable salt as an active ingredient.

(1) (1S,3R,20S)-20-(5-hydroxy-5-ethylheptanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol,

(2) (1S,3R,20S)-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol,

(3) (1S,3R,20S)-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol,

(4) (1S,3R,20S)-20-(6,6,6-Cryptor-5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol,

(5) (1S,3R,20S)-20-(5,5,5-Cryptor-4-hydroxy-4-methyl-3-oxopentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol.

The invention is described in detail below.

The term "halogen" in the invention includes, for example, fluorine, chlorine, bromine, iodine.

The term "alkylene" in the invention is a linear or branched chain, having from 1 to 5 carbon atoms, including, for example, methylene, ethylene, trimethylene, mutilation, tetramethylene, metallisation, ethylethylene, pentamethylene, methyltyramine, ethyltryptamine. Particularly preferred is a linear alkylene having from 1 to 3 carbon atoms. Alkylen in the invention may be substituted by 1 to 3 substituents selected from the group consisting of halogen, hydroxy and oxo.

The term "albaniles" in the invention before the hat is a linear or branched chain, having from 2 to 5 carbon atoms. For example, it includes ethenylene, propylen, butylene, penttinen. Particularly preferred is a linear albaniles having from 2 to 4 carbon atoms.

The term "phenylene" in the invention includes, for example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene.

The term "alkyl" in the invention is a linear or branched chain, having from 1 to 6 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl. Particularly preferred are methyl and ethyl. Alkyl in the invention may be substituted by 1 to 3 halogen atoms.

The term "cycloalkyl" in the invention has a value of, for example, mono-to tricyclic alkyl having from 3 to 8 carbon atoms, in particular including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecane, substituted (1-substituted, 2-substituted, and so forth), 2-bicyclo[3.1.1]heptyl and 2-bicyclo[2.2.1]heptyl. In particular, it is preferable monocrotaline alkyl having from 4 to 6 carbon atoms.

If not specifically defined, the protective group for hydroxy" in the invention can be any hydroxyamino group used in the reaction, including, for example, 1) trialkylsilyl, such as triethylsilyl, tributers the sludge, tert-butyldimethylsilyl, and so on; 2) (2-trimethylsilyl)ethoxymethyl, 3) arylmethyl, such as benzyl, 4-methoxyphenethyl, and so on; 4) acyl, such as acetyl, and so forth; and 5) 2-tetrahydropyranyl.

The BEST OPTION of carrying out the INVENTION

The connection according to the invention can be obtained from known compounds or readily synthesized intermediate compounds, for example, in accordance with the method mentioned below. When the connection according to the invention, in the case when the original product has a Deputy who can influence the course of the reaction, as a rule, the original product pre protects a suitable protecting group in accordance with the known method and then carry out the reaction. The protective group can be removed after the reaction in accordance with the known method.

[Formula 3]

[In the formula, Y, Z, R1, R2, R3, Ra, Rb, Rcand Rdhave the same values as above. Y1represents (1) a simple link, (2) alkylene having from 1 to 5 carbon atoms, and optionally substituted from 1 to 3 substituents selected from the group consisting of halogen, protected hydroxy-group and oxo, (3) albaniles having from 1 to 5 carbon atoms, or (4) phenylene. R5and R6each represents a protective group for GI is Roxie. Z1, Z2and Z3are the same or different, each represents halogen, nitro or cyano. Z4represents (1) hydrogen, (2) a protected hydroxy-group or (3)-NR13R14. R13represents hydrogen or alkyl having from 1 to 6 carbon atoms; R14represents (1) an alkyl having from 1 to 6 carbon atoms, and optionally substituted by protected hydroxy-group or (2) alkylsulfonyl having from 1 to 6 carbon atoms.]

This reaction is a condensation of the compound (alcohol) General formula [2] and compounds (carboxylic acid) of the General formula [3] with a subsequent removal of the protection, and so it can be carried out in accordance with the method per se as the condensation and removal of the protection. For example, the higher the alcohol interacts with the above carboxylic acid, followed by removal of the protection, which thus leads to the production of compounds according to the invention.

The first phase (condensation)

The specified stage is designed for condensation of alcohol [2] and carboxylic acids [3] at the reaction temperature in the range from -20 to 100ºC in the presence or absence of a base (e.g. organic bases such as triethylamine, N,N-aminobutiramida-N-ethylamine, N,N-diethylaniline, pyridine, 4-dimethylaminopyridine and 1,8-diazabicyclo[5,4 .0]undec-7-ene), ISOE is isua condensing agent (for example, 1,1'-oxalylamino, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethylthiophosphate, diphenylphosphoryl and iodide 2-chloro-1-methylpyridine). Applicable, if not specifically defined, any solvent not participating in the reaction, including, for example, ethers such as tetrahydrofuran, diethyl ether and so on; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and the like; NITRILES, such as acetonitrile, propionitrile, and the like; hydrocarbons such as benzene, toluene, and so forth; kalogeropoulou, such as chloroform, dichloromethane, and so forth; or mixed solvents. In this stage can be entered additive (for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide, and so on).

The reaction time varies depending on the type of initial products and agents of the condensation, the reaction temperature and other conditions, but in General it is appropriate in the range of from 30 minutes to 24 hours. The number of the above carboxylic acids [3] and an appropriate condensing agent is preferably in the range from 1 to 3 molar units regarding alcohol [2].

Instead of the above carboxylic acids [3] for use in this stage also apply it reaktsionnosposobnykh derived. Reaktsionnosposobnykh derived this includes that, as PR is usually used afrobrazil condensation, for example, acid halides (e.g. acid chlorides and bromohydrin acid), mixed acid anhydrides, imidazolides, active amides, and so on. When using the reactive derivative in the reaction above the condensing agent can be excluded.

For example, when using a mixed acid anhydride as reaktsionnosposobnykh carboxylic acid derivative [3], using pyridine solvent, such as pyridine, 4-methylpyridine or similar, or the same base and solvent, as described above, and the condensation can be carried out at the reaction temperature in the range from -20 to 100ºC. As an additive can be introduced, for example, 4-dimethylaminopyridine. The reaction time varies depending on the type of the mixed anhydride of the acid and the reaction temperature, but in General it is appropriate in the range of from 30 minutes to 24 hours. At the stage of using the mixed anhydride of the acid mixed acid anhydride is preferably a mixed anhydride of the acid of the following General formula [3A] (for example, referring to non-Patent Reference 14).

[Formula 4]

[In the formula Y1, R1, R2, Z1, Z2, Z3and Z4have the same the values, as specified above.]

R5and R6not specifically defined and may be any hydroxyamino group used in the reaction. For example, they include the above-mentioned protective group.

The original compound of General formula [2] can be obtained in accordance with the known method (for example, referring to Patent Reference 5 and non-Patent References 15 through 17) or similar method or in accordance with the method described in the Examples below.

The original connection with the General formula [3] can be obtained, for example, in accordance with the same manner as in the above non-Patent Reference 18 to 22, or in accordance with a method similar to the method described in Patent Reference 4, or non-Patent References from 26 to 41.

The second stage (unprotect)

The specified stage is the removal of the protection of the hydroxy-group, and may be implemented as such, in accordance with a customary method. Specifically, since the variation is dependent on the type of the protective group using tert-butyldimethylsilyl as a protective group, it can be removed in accordance with the method mentioned below.

For removing protection from compounds of General formula [4] can be used by the agent to remove the protection (for example, tetrabutylammonium fluoride, hydrogen fluoride, fluoride in Gorod-pyridine, acetic acid and triperoxonane acid) and removing the protection can be carried out at the reaction temperature in the range from -20 to 100ºC. Can be used, if not specifically defined, any solvent not participating in the reaction, including, for example, ethers such as tetrahydrofuran, diethyl ether, and so on; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and the like; NITRILES, such as acetonitrile, propionitrile, and the like; hydrocarbons such as benzene, toluene, and so forth; kalogeropoulou, such as chloroform, dichloromethane, and so forth; or mixed solvents. The reaction time varies depending on the type of the original product and the agent remove the protection, but in General it is appropriate in the range of from 30 minutes to 24 hours. The number of agent unprotect is preferably from 1 to 100 molar units relative to the compounds of General formula [4].

The connection according to the invention includes compounds that have an asymmetric carbon atom, and the invention includes not only its optically active compounds, but also its racemic compounds. To obtain such optically active compounds applicable is the usual method of separation using a chiral column; however, they may also be obtained via asymmetric synthesis of the original soy is inane [2] (for example, they can be obtained in accordance with a technique similar to the technique of asymmetric obtain, presented in non-Patent References 15 and 16).

When the connection according to the invention includes geometric isomers or tautomers, not just any one of them isomer, but also their mixtures are included in the scope of the compounds according to the invention.

The connection according to the invention can be used as pharmaceutical agents directly as it is in the form of a free base, but can be used after translation in pharmaceutically acceptable salt according to a known manner. Salt include salts with inorganic acid such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, and so forth; or salts with organic acid such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluensulfonate acid, benzolsulfonat acid, methanesulfonate acid, and so forth.

For example, hydrochloride compounds according to the invention can be obtained by dissolving the compounds according to the invention in an alcohol solution, etiracetam solution or ether solution of hydrogen chloride.

The connection according to the invention is useful as pharmaceutical agents as shown in Test Examples below, and in particular is useful as a therapeutic agent for the treatment of dyskeratosis, including psoriasis.

When the connection according to the invention is administered as pharmaceutical agents, the connection according to the invention can be introduced mammals, including humans, either directly as such or in the form of a pharmaceutical composition containing pharmaceutically acceptable and non-toxic inert carrier in an amount of, for example, from 0.0001 to 99.5%, preferably from 0.001 to 90%.

The carrier may be at least one of solid, semi-solid or liquid diluents, fillers and other auxiliary means for compositing. The pharmaceutical composition is preferably administered in a single dose. Route of administration for the pharmaceutical compositions according to the invention is not specifically defined; however, it cannot be said that the composition is administered in the form of a formulation suitable for used as a way of introduction. Preferred is the local administration (transdermal introduction, and so on).

The dose of therapeutic agent for the treatment of dyskeratosis, including psoriasis, preferably determined taking into account the characteristics and extent of disease, conditions of the patient, such as age, body weight and other such conditions and method of administration. In total dose, as a rule, is from 0.01 to 1000 mg/person/day, preferably from 0.1 to 500 mg/person/day as the effective amount of the compounds according to the invention for adult patients.

It is possible that the dose may be lower than mentioned above, or, on the contrary, it may be necessary to provide a greater dose than the above. The dose can be divided into 2-5 servings that can be entered at different times during the day.

EXAMPLES

The invention is described in more detail with reference to the following Referential Examples, Examples, Test Examples and Examples of Compositions, which, however, the invention should not be limited.

Reference Example 1:

3-(tert-butyldimethylsilyloxy)-3-matlakala acid

Stage 1:

4-Dimethylaminopyridine (0,78 g) is added to anhydrous chlorothalidone to a solution of 3-hydroxy-3-methylmalonic acid (3,76 g) and benzyl alcohol (4,13 g) and stirred under ice cooling. To the resulting reaction mass is added N,N'-dicyclohexylcarbodiimide (9,9 g), then bath with ice is removed and the reaction mass is stirred over night at room temperature. Planted insoluble substance is removed by filtration and the mother liquor is concentrated, which gives the residual oil (13 g). It is cleaned by chromatography on a column of silica gel, which gives benzyl-3-hydroxy-3-ethyl butyrate (7, g) in the form of oil pale yellow color.

1H-NMR (CDCl3) δ: of 1.28 (6H, s)to 2.55 (2H, s), 5,16 (2H, s), of 7.36 (5H, s).

Stage 2:

2,6-Lutidine (3.6 g) is added to anhydrous chlorothalidone solution of benzyl-3-hydroxy-3-methylbutyrate (3.5 g)obtained in stage 1, and stirred under ice cooling. Gradually to the resulting reaction mass is added dropwise tert-butyldimethylchlorosilane (3,9 ml) and stirred for one hour while cooling with ice and then for 2 hours at room temperature. The reaction liquid was diluted with ethyl acetate, then washed with water, saturated aqueous ammonium chloride and saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate and concentrated. 4.5 g of the residue purified via chromatography on a column of silica gel, which gives benzyl-3-(tert-butyldimethylsilyloxy)-3-methylbutyrate (2,62 g) as a colourless oil.

1H-NMR (CDCl3) δ: x 0.07 (6H, s)of 0.82 (9H, s)of 1.36 (6H, s), 2,52 (2H, s), 5,09 (2H, s), to 7.35 (5H, s).

Stage 3:

Benzyl-3-(tert-butyldimethylsilyloxy)-3-methylbutyrate (2.37 g), obtained in stage 2, dissolved in ethyl acetate (30 ml) and to the resulting reaction mass is added 10% palladium on coal (0,47 g) hydrogenation with H2at atmospheric pressure. After 40 minutes stirring is stopped and the catalyst was removed by filtration. Uterine fluid mpariwa the t under reduced pressure, that gives named the title compound (1.70 g) as a colourless oil.

1H-NMR (CDCl3) δ: 0,18 (6H, s)to 0.89 (9H, s)of 1.40 (6H, s), of 2.51 (2H, s).

Reference Example 2:

(1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol

Through tertrahydrofuran ring solution (500 ml) of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-pregna-5,7-Dien-20-ol (155 mg) (method thereof, for example, described in non-Patent Reference 23) bubbled argon while cooling with ice for 10 minutes. Then in the reaction bath is placed mercury vapor lamp, high pressure power 500-watt, while the cooling layer circulates with a solution of filtrate Nickel sulfate copper sulfate (this is disclosed, for example, non-Patent Reference 24) and the irradiation is carried out for 5 minutes under ice cooling. Additionally, the reaction liquid is then irradiated for 2.5 minutes and then transferred into the flask brown and heated at boiling temperature under reflux for 3 hours. The solvent is evaporated under reduced pressure and the residue purified via chromatography on a column of silica gel and preparative thin-layer chromatography, giving named the title compound (30 mg) as a colourless oil.

1H-NMR (CDCl3) δ: is 0.06 (12H, s)of 0.54 (3H, s)to 0.88 (18H, s)of 1.23 (3H, d), a 2.45 (1H, DD), 2,84 (1H, DD), 3,71 (2H, m), 4,19 (1H, m), to 4.38 (H, DD), a 4.86 (1H, d), is 5.18 (1H, s), 6,03 (1H, d), 6,23 (1H, d).

Example 1:

(1S,3R,20S)-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

2,4,6-Trichlorobenzoyl (13 μl) are added to tertrahydrofuran ring solution (0.5 ml) of 4-triethylsilyl-4-methylpentanoic acid (20 mg)obtained in accordance with the method described in non-Patent Reference 25, and triethylamine (11,2 ml) and then stirred at room temperature for 30 minutes. After separation of the crystalline product by filtration, the tetrahydrofuran evaporated and the residue is dried under reduced pressure. Add anhydrous benzene solution (0.5 ml) of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol (30 mg)obtained according to Reference Example 2 and 4-dimethylaminopyridine (30 mg) to the residue in the gas atmosphere of argon and then stirred at room temperature for 30 minutes. The reaction liquid was diluted with ethyl acetate, then washed with saturated aqueous sodium hydrogen carbonate and saturated brine in order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives (1S,3R,20S)-20-(4-triethylsilyl-4-methylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-t the yen (27 mg) as a colourless oil.

1H-NMR (CDCl3) δ: is 0.06 (12H, s)of 0.54 (3H, s), or 0.57 (6H, q), of 0.87 (18H, s)to 0.94 (9H, t), of 1.20 (6H, s), a 2.36 (2H, t)2,84 (1H, d), 4,19 (1H, m), 4,37 (1H, DD), is 4.85 (1H, d), 4,94 (1H, m)to 5.17 (1H, d), of 6.02 (1H, d), 6,23 (1H, d).

Stage 2:

The reagent obtained by adding acetic acid (16 μl) to a 1 M solution of fluoride, Tetra(n-butyl)ammonium (0,56 ml)is added to anhydrous tertrahydrofuran ring solution (1 ml) of (1S,3R,20S)-20-(4-triethylsilyl-4-methylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triens (22 mg)obtained in stage 1, in argon atmosphere, and then stirred over night at room temperature. To the reaction liquid add cold water and then subjected to extraction with ethyl acetate. An ethyl acetate layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel and preparative thin-layer chromatography, giving named the title compound (7,1 mg) according to the invention in the form of colorless powder.

1H-NMR (CDCl3) δ: 0,55 (3H, s)of 1.23 (6H, s)of 1.23 (3H, d), of 1.80 (2H, t), 2,39 (2H, t), 2,60 (1H, DD), and 2.83 (1H, m), 4,24 (1H, m), 4,43 (1H, DD), of 4.95 (1H, m), 4,99 (1H, DD), 5,33 (1H, usher.), of 6.02 (1H, d), 6,37 (1H, d).

(+) -FABMS m/z 447 [M+H]+

Example 2:

(1S,3R,20S)-20-(3-hydroxy-3-methylbutanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In choosing the accordance with the method, similar to the method presented in stage 1 in Example 1 but using 3-(tert-butyldimethylsilyloxy)-3-methylmalonyl acid (Reference Example 1) instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-3-methylbutanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

1H-NMR (CDCl3) δ: is 0.06 (12H, s), and 0.08 (6H, s)of 0.53 (3H, s), is 0.84 (9H, s)of 0.87 (18H, s)of 1.23 (3H, d), of 1.40 (3H, s)of 1.36 (3H, s), 2,43 (2H, users), 2,84 (1H, d), 4,18 (1H, m), 4,36 (1H, DD), is 4.85 (1H, d), 4,91 (1H, m), to 5.17 (1H, d), of 6.02 (1H, d), 6,23 (1H, d).

Stage 2:

In accordance with the method similar to the method presented in stage 2 of Example 1, but using (1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-3-methylbutanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in stage 1, instead of (1S,3R,20S)-20-(4-triethylsilyl-4-methylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triens get mentioned in the title compound according to the invention.

1H-NMR (CDCl3) δ: 0,56 (3H, s)of 1.26 (3H, d), of 1.27 (6H, s), 2,32 (1H, DD), 2,44 (2H, s), 2,60 (1H, DD), 2,84 (1H, m), 3,74 (1H, usher.), 4,24 (1H, m), 4,43 (1H, DD), 4,99 (1H, s), free 5.01 (1H, m), 5,33 (1H, s), 6,03 (1H, d), 6,37 (1H, d).

ESIMS m/z 455 [M+Na]+

Example 3:

(1S,3R,20S)-20-(5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented at stage 1 in Example 1 but using 5-triethylsilyl-5-methylhexanoic acid obtained in accordance with the method described in non-Patent Reference 26, instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-(5-triethylsilyl-5-methylhexanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(5-triethylsilyl-5-methylhexanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 483,5 [M+Na]+

Example 4:

(1S,3R,20S)-20-(4,4,4-Cryptor-3-hydroxy-3-methylbutanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using 3-(tert-butyldimethylsilyloxy)-4,4,4-Cryptor-3-methylmalonyl acid instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-4,4,4-Cryptor-3-methylbutanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-4,4,4-Cryptor-3-methylbutanoyl is XI]-1,3-bis(tert- butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 509,3 [M+Na]+

Example 5:

(1S,3R,20S)-20-(3-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using 3-(tert-butyldimethylsilyloxy)-4-methylpentanol acid obtained in accordance with the method described in non-Patent Reference 27, instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 469,4 [M+Na]+

Example 6:

(1S,3R,20S)-20-(4,4,4-tripterocalyx-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

tadia 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 4,4,4-cryptomelane acid instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-(4,4,4-tripterocalyx)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(4,4,4-tripterocalyx)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 479,3 [M+Na]+

Example 7:

(1S,3R,20S)-20-[4,4,4-Cryptor-3-hydroxy-3-(trifluoromethyl)butanoyloxy]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using 3-(tert-butyldimethylsilyloxy)-4,4,4-Cryptor-3-(trifluoromethyl)butyric acid instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-4,4,4-Cryptor-3-(trifluoromethyl)butanoyloxy-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-4,4,4-Cryptor-3-(trifluoromethyl)butanoyloxy-1,3-bis(tert-butyldimethylsilyl is XI )-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(-) -FABMS m/z 539,2 [M-H]-

Example 8:

(1S,3R,20S)-20-[(2E)-4-hydroxy-4-methylpent-2-enolase]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using (2E)-4-triethylsilane-4-methylpent-2-envoy acid obtained in accordance with the method described in non-Patent Reference 28, instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-[(2E)-4-triethylsilyl-4-methylpent-2-enorossi]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[(2E)-4-triethylsilyl-4-methylpent-2-enorossi]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 467,3 [M+Na]+

Example 9:

(1S,3R,20S)-20-(3-cyclopropyl-3-hydroxypropanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the FPIC of the BOM, similar to the method presented in stage 1 in Example 1 but using 3-(tert-butyldimethylsilyloxy)-3-cyclopropylamino acid obtained in accordance with the method described in non-Patent Reference 29, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-3-cyclopropylmethoxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)-3-cyclopropylmethoxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 467,3 [M+Na]+

Example 10:

(1S,3R,20S)-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using (2E)-4-(tert-butyldimethylsilyloxy)-4-ethylhex-2-envoy acid obtained in accordance with the method described in non-Patent Reference 28, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[(2E)-4-(tert-butyldimethylsilyloxy)-4-ethylhex-2-enorossi]-1,3-bis(t is the butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[(2E)-4-(tert-butyldimethylsilyloxy)-4-ethylhex-2-enorossi]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 495,5 [M+Na]+

Example 11:

(1S,3R,20S)-20-(5-hydroxy-5-methylheptanoic)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using 5-triethylsilyl-5-methylheptanoic acid obtained in accordance with the method described in non-Patent Reference 30, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-(5-triethylsilyl-5-methylheptanoic)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(5-triethylsilyl-5-methylheptanoic)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/ 475,3 [M+Na] +

Example 12:

(1S,3R,20S)-20-(3-ethyl-3-hydroxydecanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using 3-ethyl-3-triethylchlorosilane acid obtained in accordance with the method described in non-Patent Reference 31, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-(3-ethyl-3-triethylchlorosilane)-1,3-bis(tert-

butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(3-ethyl-3-triethylchlorosilane)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 483,4 [M+Na]+

Example 13:

(1S,3R,20S)-20-(4-ethyl-4-hydroxyhexanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 4-ethyl-4-triethylchlorosilane acid obtained in accordance with the method described in non-Patent Reference 32, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-(4-ethyl-4-triethylsilyl is oxohexanoate)-1,3-bis(tert-

butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(4-ethyl-4-triethylchlorosilane)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 497,5 [M+Na]+

Example 14:

(1S,3R,20S)-20-[3-(1-hydroxy-1-methylethyl)-benzoyloxy]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using 3-(1-triethylsilyl-1-methylethyl)benzoic acid obtained in accordance with the method described in non-Patent Reference 33, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[3-(1-triethylsilyl-1-methylethyl)benzoyloxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[3-(1-triethylsilyl-1-methylethyl)benzoyloxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

+

Example 15:

(1S,3R,20S)-20-[N-(isopropylphenyl)-3-aminopropanoic]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using N-(isopropylphenyl)-β-alanine obtained in accordance with the method described in Patent Reference 3, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[N-(isopropylphenyl)-3-aminopropoxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[N-(isopropylphenyl)-3-aminopropoxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 532,4 [M+Na]+

Example 16:

(1S,3R,20S)-20-(6-hydroxy-6-methylheptanoic)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 6-triethylsilane-6-methylheptanoic acid obtained in accordance with the method described in non-Patent Reference 35, instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-(6-triethylsilyl the C-6 methylheptanoic)-1,3-bis(tert- butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(6-triethylsilane-6-methylheptanoic)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 497.4 m [M+Na]+

Example 17:

(1S,3R,20S)-20-{4-[2,2,2-Cryptor-1-hydroxy-1-(trifluoromethyl)ethyl]benzoyloxy}-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 4-{2,2,2-Cryptor-1-trifluoromethyl-1-[2-(trimethylsilyl)ethoxyethoxy]ethyl}benzoic acid instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-[4-{2,2,2-Cryptor-1-trifluoromethyl-1-[2-(trimethylsilyl)ethoxyethoxy]ethyl}benzoyloxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[4-{2,2,2-Cryptor-1-trifluoromethyl-1-[2-(trimethylsilyl)ethoxyethoxy]ethyl}benzoyloxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives the device the data in the header of the connection according to the invention.

Example 18:

(1S,3R,20S)-20-(5,5,5-cryptocentrus)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 5,5,5-cryptocentrus acid instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-(5,5,5-cryptocentrus)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(5,5,5-cryptocentrus)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 493,3 [M+Na]+

Example 19:

(1S,3R,20S)-20-[N-(2-hydroxy-2-methylpropyl)-N-methyl-2-aminoacetate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using N-(2-triethylsilyl-2-methylpropyl)-N-methyl-2-aminouksusnoy acid obtained in accordance with the method described in non-Patent Reference 40, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[N-(2-triethylsilyl-2-methylpropyl)-N-methyl-2-aminoacylase]-1,3-bis(tert-butyldimethylsilyloxy)-9,1-scoprega-5Z,7E,10(19)-triene.

Stage 2 :

(1S,3R,20S)-20-[N-(2-triethylsilyl-2-methylpropyl)-N-methyl-2-aminoacylase]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 476,4 [M+1]+

Example 20:

(1S,3R,20S)-20-[3-(1-hydroxycyclopent)propenyloxy]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using 3-(1-triethylchlorosilane)propionic acid obtained in accordance with the method described in non-Patent Reference 36, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[3-(1-triethylchlorosilane)propenyloxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[3-(1-triethylchlorosilane)propenyloxy]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 473,5 [M+1]+

Example 1:

(1S,3R,20S)-20-(3,3-debtor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 4-triethylsilyl-3,3-debtor-4-methylpentanol acid obtained in accordance with the method described in Patent Reference 4, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-(4-triethylsilyl-3,3-debtor-4-methylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(4-triethylsilyl-3,3-debtor-4-methylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 483,4 [M+1]+

Example 22:

(1S,3R,20S)-20-[(3S)-3,4-dihydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using (3S)-3,4-bis(triethylsilyl)-4-methylpentanol acid obtained in accordance with the method described in non-Patent Reference 37, instead of 4-triethylsilyl-4-methylpentanoic acid, produces the t (1S,3R,20S)-20-[((3S)-3,4-bis(triethylsilyl)-4-methylpentanoate]-1,3-bis(tert- butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[(3S)-3,4-bis(triethylsilyl)-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 485,4 [M+Na]+

Example 23:

(1S,3R,20S)-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using (4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-methylpentanol acid obtained in accordance with the method described in non-Patent Reference 41, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in which the example 1, that gives named in the title compound according to the invention.

(+) -ESIMS m/z 523,3 [M+Na]+

Example 24:

(1S,3R, 20R)-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using (1S,3R,20R)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol, obtained in accordance with the method described in non-Patent Reference 16, instead of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol obtain (1S,3R,20R)-20-(4-triethylsilyl-4-methylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20R)-20-(4-triethylsilyl-4-methylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 469,4 [M+Na]+

Example 25:

(1S,3R,20R)-20-(3-hydroxy-3-methylbutanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 2, but using (1S,3R,20R)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-5Z,7E,10(19)-trien-20-ol, received in accordance with the method described in non-Patent Reference 16, instead of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol obtain (1S,3R,20R)-20-(3-t-butyldimethylsilyloxy-3-methylbutanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20R)-20-(3-t-butyldimethylsilyloxy-3-methylbutanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -FABMS m/z 432 [M+1]+

Example 26:

(1S,3R,17β)-17-(4-hydroxy-4-methylpentanoate)-9,10-secondrate-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using (1S,3R,17β)-1,3-bis(tert-butyldimethylsilyloxy)-17-hydroxymethyl-9,10-secondrate-5Z,7E,10(19)-triene obtained in accordance with the method described in non-Patent Reference 17, instead of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol, get (1S,3R,17β)-17-(4-triethylsilyl-4-methylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-secondrate-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,17β)-7-(4-triethylsilyl-4-methylpentanoate)-1,3-bis(tert- butyldimethylsilyloxy)-9,10-secondrate-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 455,3 [M+Na]+

Example 27:

(1S,3R,20S)-20-(4-hydroxy-4-methyl-3-oxo-pentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 4-(tert-butyldimethylsilyloxy)-4-methylpent-2-andnew acid obtained in accordance with the method described in non-Patent Reference 38, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-4-methylpent-2-inolex]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

The reagent obtained by adding acetic acid (14 μl) to a 1 M solution of Tetra-n-butylammonium (0,81 ml)is added to anhydrous tertrahydrofuran ring solution (0.4 ml) of (1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-4-methylpent-2-inolex]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triens (32 mg)obtained in stage 1, in argon atmosphere, and then stirred over night at room temperature. To the reaction liquid EXT is make the water and then the reaction liquid three times subjected to extraction with chloroform. The chloroform layer is then washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives named the title compound (9.5 mg) according to the invention in the form of a powder pale brown color.

(+) -ESIMS m/z 483,3 [M+Na]+

Example 28:

(1S,3R,20S)-20-(4-ethyl-4-hydroxy-3-oxo-hexanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 4-triethylsilyl-4-ethylhex-2-andnew acid obtained in accordance with the method described in non-Patent Reference 38, instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-4-ethylhex-2-inolex]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-4-ethylhex-2-inolex]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 27, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 511,5 [M+Na]+

Example 29:

(1S,3R,20S)-20-[3-(hydroxymethyl)phenylacetic the oxy]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1 but using 3-(tert-butyldimethylsilyloxy)phenylacetic acid obtained in accordance with the method described in non-Patent Reference 42, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)phenylacetylene]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[3-(tert-butyldimethylsilyloxy)phenylacetylene]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 503,3 [M+Na]+

Example 30:

(1S,3R,17β)-17-[(2E)-4-ethyl-4-hydroxydec-2-enolacetate]-9,10-secondrate-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 10, but using (1R,3R,17β)-1,3-bis(tert-butyldimethylsilyloxy)-17-hydroxymethyl-9,10-secondrate-5Z,7E,10(19)-triene obtained in accordance with the method described in non-Patent Reference 17, instead of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-sanoprene-5Z,7Z,10(19)-triene-2-alapalooza (1S,3R,17β)-17-[(2E)-4-(tert- butyldimethylsilyloxy)-4-ethylhex-2-enviroxime]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-secondrate-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,17β)-17-[(2E)-4-(tert-butyldimethylsilyloxy)-4-ethylhex-2-enviroxime]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-secondrate-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 481,4 [M+Na]+

Example 31:

(1S,3R,20S)-20-[(3R)-3,4-dihydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using (3R)-3,4-bis(triethylsilyl)-4-methylpentanol acid obtained in accordance with the method described in non-Patent Reference 37, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[(3R)-3,4-bis(triethylsilyl)-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[(3R)-3,4-bis(triethylsilyl)-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method of the ICA, presented at stage 2 in Example 1, giving named in the title compound according to the invention.

(+) -ESIMS m/z 485,4 [M+Na]+

Example 32:

(1S,3R,20S)-20-[5,5,5-Cryptor-4-hydroxy-4-(trifluoromethyl)pentanoate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 1, but using 4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-(trifluoromethyl)pentane acid obtained in accordance with the method described in non-Patent Reference 41, instead of 4-triethylsilyl-4-methylpentanoic acid get (1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-(trifluoromethyl)pentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-(trifluoromethyl)pentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 577,3 [M+Na]+

Example 33:

(1S,3R,20S)-20-(3-hydroxy-3-n-propylpentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the same way, to provide the address stage 1 in Example 1, but using 3-hydroxy-3-n-propylheptanol acid obtained in accordance with the method described in non-Patent Reference 44, instead of 4-triethylsilyl-4-methylpentanoic acid, receive (1S,3R,20S)-20-(3-hydroxy-3-n-propylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(3-hydroxy-3-n-propylpentanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 511,5 [M+Na]+

Example 34:

(1S,3R,20S)-20-(5-hydroxy-5-ethylheptanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

2,4,6-Trichlorobenzoyl (22 μl) are added to tertrahydrofuran ring solution (0.5 ml) 5-triethylsilyl-5-italytravel acid (40 mg)obtained in accordance with the method described in non-Patent Reference 45, and triethylamine (20 μl) and then stirred at room temperature for 15 hours. After separation of the precipitated crystalline product by filtration, the tetrahydrofuran evaporated and the residue is dried under reduced pressure. To the residue add anhydrous toluene solution (1 ml) of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-with koprivna-5Z,7E,10(19)-trien-2-ol (26 mg) and 4-dimethylaminopyridine (51 mg) in an argon atmosphere, and then stirred at room temperature for 30 minutes. The reaction liquid was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine in order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives (1S,3R,20S)-20-(5-triethylsilyl-5-ethylheptanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene (39 mg) as colorless powder.

Stage 2:

The reagent obtained by adding acetic acid (19 μl) to a 1 M solution of Tetra(n-butyl)unmonitored (0,94 ml)is added to anhydrous tertrahydrofuran ring solution (1 ml) of (1S,3R,20S)-20-(5-triethylsilyl-5-ethylheptanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triens (39 mg)obtained in stage 1, in argon atmosphere, and then stirred over night at room temperature. To the reaction liquid add cold water, and the liquid is then subjected to extraction with ethyl acetate. An ethyl acetate layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel and distribution of thin-layer chromatography, giving named the title compound (7,1 mg) according to the invention in the form of colourless what about the powder.

(+) -ESIMS m/z 511,5 [Mn-Na]+

Example 35:

(1S,3R,20S)-20-[(4R) - or (4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 34, but using 4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-methylpentanol acid obtained in accordance with the method described in non-Patent Reference 41, instead of the 5-triethylsilyl-5-italytravel acid get (1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-[4-(tert-butyldimethylsilyloxy)-5,5,5-Cryptor-4-methylpentanoate]-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 of Example 1 and the resulting product was then purified using HPLC [DAICEL CHIRALPAK AD-RH (a 4.6×150 mm ID), 55% acetonitrile-water, 0.5 ml/min, 40ºC, UV 254 nm]. The solution containing the compound that had loirevalley first, concentrate, that gives named in the title compound according to the invention.

1H-NMR (CDCl3) δ: 0,55 (3H, S), 1,25 (3H, d, J=6.2 Hz), 1,338 (3H, s), of 2.51 (2H, t, J=7,2 Hz), 2,85 (1H, t), 4,24 (1H,t), of 4.44 (1H, t), to 4.98 (1H, t), 4,99 (1H, users), 5,33 (1H, users), 6,03 (1H, d, J=of 11.4 Hz), 6,37 (1H, d, J=of 11.4 Hz).

Example 36:

(1S,3R,20S)-20-[(4S) - or (4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

At the stage of fractionation in high-performance liquid chromatography according to the method specified in Example 35, the solution containing the compound that had loirevalley later, concentrate, and purify that gives named in the title compound according to the invention.1H-NMR (CDCl3) δ: 0,55 (3H, s), 1,25 (3H, d, J=6.2 Hz), 1,333 (3H, s), of 2.51 (2H, t, J=7,2 Hz), 2,85 (1H, t), 4,24 (1H, t), of 4.44 (1H, t), to 4.98 (1H, t), 4,99 (1H, users), 5,33 (1H, users), 6,03 (1H, d, J=of 11.4 Hz), 6,37 (1H, d, J=of 11.4 Hz).

Example 37:

(1S,3R,20S)-20-(6,6,6-Cryptor-5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 34, but using 5-triethylsilyl-6,6,6-Cryptor-5-methylhexanoic acid obtained in accordance with the method described in non-Patent Reference 46, instead of the 5-triethylsilyl-5-italytravel acid get (1S,3R,20S)-20-(5-triethylsilyl-6,6,6-Cryptor-4-methylhexanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

(1S,3R,20S)-20-(5-triethylsilyl-6,6,6-Cryptor-4-methylhexanoate)-1,3-bis(tert-butyldimethylsilyloxy)-9,0-scoprega-5Z,7E,10(19)-triene, obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 537,4 [M+Na]+

Example 38:

(1S,3R,20S)-20-(5,5,5-Cryptor-4-hydroxy-4-methyl-3-oxopentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 34, but using 4-triethylsilyl-5,5,5-Cryptor-4-methylpent-2-andnew acid obtained in accordance with the method described in non-Patent Reference 38, instead of the 5-triethylsilyl-5-italytravel acid get (1S,3R,20S)-20-(4-triethylsilyl-5,5,5-Cryptor-4-methylpent-2-inolex)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triene.

Stage 2:

The reagent obtained by adding acetic acid (44,2 ál) to a 1 M solution of fluoride, Tetra(n-butyl)ammonium (2,6 ml), added to (1S,3R,20S)-20-(4-triethylsilyl-5,5,5-Cryptor-4-methylpent-2-inolex)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-triens (108 mg)obtained in stage 1, in argon atmosphere, and then stirred for 23 hours at room temperature. Then add the reagent obtained by adding acetic acid (22 μl) to a 1 M solution of fluoride, Tetra(n-butyl)ammonium (1.25 ml, and stirred at room temperature for 8.5 hours. After the reaction liquid is cooled in a bath with ice and add water. The reaction liquid three times subjected to extraction with chloroform. The chloroform layer was washed with 1 M aqueous citric acid solution and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives named the title compound (29 mg) according to the invention in the form of white powder.

(+) -ESIMS m/z 537,3 [M+Na]+

Example 39:

(1S,3R,20S)-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 34, but using 4-triethylsilyl-4-methylpentanol acid (the way it is received, for example, described in non-Patent Reference 25), instead of 5-triethylsilyl-5-italytravel acid and using (1S,3R,20S)-1,3-bis(triethylsilyl)-20-hydroxypregn-5,7,16-triene obtained in accordance with the method described in Patent Reference 6, instead of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol obtain (1S,3R,20S)-bis(triethylsilyl)-20-(4-triethylsilyl-4-methylpentanoate)-pregna-5,7,16-triene.

Stage 2:

(1S,3R,20S)-1,3-bis(triethylsilyl is hydroxy)-20-(4-triethylsilyl-4-methylpentanoate)-pregna-5,7,16-triene, obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in Example 34, which gives (1S,3R,20S)-1,3-bis(triethylsilyl)-20-(4-hydroxy-4-methylpentanoate)-pregna-5,7,16-triene.

Stage 3:

(1S,3R,20S)-1,3-bis(triethylsilyl)-20-(4-hydroxy-4-methylpentanoate)-pregna-5,7,16-triene obtained in accordance with the above stage 2, process, following a technique similar to the method presented in Reference 2, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 467,3 [M+Na]+

Example 40:

(1R,3R,20S)-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 34, but using 4-triethylsilyl-4-methylpentanol acid (the way it is received, for example, described in non-Patent Reference 25), instead of 5-triethylsilyl-5-italytravel acid and using (20S)-des-A,B-8β-triethylchlorosilane-3-ol, obtained in accordance with the method described in Patent Reference 47, instead of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol get (20S)-des-A,B-8β-triethylsilane-20-(4-triethylsilyl-4-methylpentanoate)pregnan.

Stage 2:

(20S)-des-A,B-8β-triethylsilane-20-(4-triethylsilyl-4-methyl is ethanolate)pregnan, obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in Example 34, which gives (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregnan-8β-ol.

Stage 3:

In an argon atmosphere dichloromethane (2 ml) are added to (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregnan-8β-Olu (42 mg)obtained in accordance with the above stage 2, and then add 4 methylmorpholine N-oxide (39 mg) and 4-eggstremely molecular sieves (10 mg) and perruthenate Tetra-N-Propylamine (24 mg) and stirred for 25 minutes. The reaction solution is purified using chromatography on a column of silica gel, which gives (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregna-8-he (35 mg) as a colourless oil.

Stage 4:

In the atmosphere of argon triethylamine (89,8 μl) and 4-dimethylaminopyridine (8 mg) is added to a dichloromethane solution (0.3 ml) of (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregna-8-it (100 mg)obtained in accordance with the above stage 3, and then cooled in a bath with ice, to the resulting reaction mass add chlorotriethylsilane (81 μl) and then stirred at room temperature for 20 hours. After cooling with a bath with ice to the resulting reaction mass is added ether and water and the solution three times subjected to extraction with ether. The extract is dried over betwo the major magnesium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives (20S)-des-A,B-20-(4-triethylsilyl-4-methylpentanoate)pregnan-8-he (119 mg) as a colourless oil.

(+) -ESIMS m/z 425,4 [M+1]+447,4 [M+Na]+

Stage 5:

In argon atmosphere, anhydrous tertrahydrofuran ring solution (1.5 ml) oxide {2-[(3'R,5'R)-3',5'-bis(tert-butyldimethylsilyloxy)cyclohexylidene]ethyl}diphenylphosphine (method thereof, for example, described in non-Patent Reference 48) is cooled in a bath with ice, and then added dropwise hexane solution of n-utility (1,58 M, 0.06 ml) and stirred for 30 minutes. Then, after cooling to a temperature-78ºC, add anhydrous tertrahydrofuran ring solution (0.3 ml) of (20S)-des-A,B-20-(4-triethylsilyl-4-methylpentanoate)pregnan-8-it (25 mg)obtained in stage 4, and stirred for 3 hours. After heating up to the temperature 0ºC solution was further stirred for 19.5 hours. Add saturated aqueous solution of ammonium chloride and the resulting reaction mass three times subjected to extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives (1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyl-4-methyl is ethanolate)-9,10-scoprega-5Z,7E-diene (15 mg) as a colourless oil.

Step 6:

(1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyl-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene obtained in accordance with the above stage 5, process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 457,4 [M+Na]+

Example 41:

(1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented on stage 5 in Example 40, but using {2-[(3'R,5'R)-3',5'-bis(tert-butyldimethylsilyloxy)-4'-

methyltrichlorosilane]ethyl}diphenylphosphine oxide (method thereof, for example, described in non-Patent Reference 49), instead of {2-[(3'R,5'R)-3',5'-bis(tert-butyldimethylsilyloxy)cyclohexylidene]ethyl}diphenylphosphine oxide receive (1R,3R,20S)-2-methylene-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyl-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene.

Stage 2:

(1R,3R,20S)-2-methylene-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyl-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in Example 34, which gives the device the data in the header of the connection according to the invention.

(+) -ESIMS m/z 469,5 [M+Na]+

Example 42:

(1R,3R,20S)-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

Pyridine (0,28 ml) and dichloromethane (1 ml) are added to (20S)-des-A,B-8β-triethylchlorosilane-20-Olu (361 mg)obtained in accordance with the method described in Patent Reference 47. After cooling in a bath with ice to the resulting reaction mass is added acetic anhydride (0,22 ml) and then stirred at room temperature for 21 hours. In the future, add pyridine (0,14 ml) and acetic anhydride (0,11 ml) and stirred for 18 hours. The reaction liquid is concentrated under reduced pressure and the residue purified via chromatography on a column of silica gel, which gives (20S)-des-A,B-8β-triethylsilane-20-acetoxyphenyl (336 mg) as a colourless oil.

Stage 2:

Tertrahydrofuran ring solution of Tetra(n-butyl)ammonium (1 M, 9,42 ml) are added to (20S)-des-A,B-8β-triethylsilane-20-acetoxyphenyl (334 mg)obtained in accordance with the above stage 1, with a cooling bath of ice, with stirring at room temperature for 22 hours and then cooled in a bath with ice. There is added water and ether and the resulting reaction mass is subjected to extraction three times with ether. The extract was washed with 1 M aqueous citric acid solution and saturated concrete water is sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives (20S)-des-A,B-20-acetoxyphenyl-8β-ol (230 mg) as a colourless oil.

Stage 3:

In accordance with the method similar to the method presented in stage 3 in Example 40, but using (20S)-des-A,B-20-acetoxyphenyl-8β-ol, obtained in accordance with the above stage 2, instead of (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregnan-8β-ol get (20S)-des-A,B-20-acetoxymethyl-8-he.

Stage 4:

In accordance with the method similar to the method presented on stage 5 in Example 40, but using (20S)-des-A,B-20-acetoxymethyl-8-he received in accordance with the above stage 3, instead of (20S)-des-A,B-20-(4-triethylsilyl-4-methylpentanoate)pregnan-8-get it (1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20-acetoxy-9,10-scoprega-5Z,7E-diene.

Stage 5:

Tetrahydrofuran (1 ml)-methanol (1 ml) solution of (1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20-acetoxy-9,10-scoprega-5Z,7E-diene (120 mg)obtained in accordance with the above stage 4, is cooled in a bath with ice. To the resulting reaction mass is added 10% aqueous potassium hydroxide solution (0.5 ml) and then stirred at room temperature for a period of 14.5 hours. Further DOB is given in 10% aqueous solution of potassium hydroxide (0.25 ml) and stirred for 4.5 hours. Then add a 10% aqueous solution of potassium hydroxide (0.25 ml) and stirred for 20 hours. Tetrahydrofuran and methanol is removed by concentration under reduced pressure. Then to the resulting mass of water is added, and an aqueous solution three times subjected to extraction with ethyl acetate. After washing with a saturated aqueous solution of sodium chloride, the reaction mass is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives (1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E-Dien-20-ol (94 mg) as white powder.

Step 6:

In accordance with the method similar to the method presented in stage 1 in Example 34, but using (2E)-4-triethylsilyl-4-ethylhex-2-envoy acid obtained in accordance with the method described in non-Patent Reference 28, instead of 5-triethylsilyl-5-italytravel acid and using (1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E-Dien-20-ol, obtained in accordance with the above stage 5, instead of (1R,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol obtain (1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20[[(2E)-4-ethyl-4-triethylchlorosilane-2-enorossi]-9,10-scoprega-5Z,7E-diene.

Step 7:

(1R,3R,20S)-19-the EOS-1,3-bis(tert- butyldimethylsilyloxy)-20[[(2E)-4-ethyl-4-triethylchlorosilane-2-enorossi]-9,10-scoprega-5Z,7E-diene obtained in accordance with the above stage 6, process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 483,4 [M+Na]+

Example 43:

(1R,3R,20S)-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented on stage 6 in Example 42, but using 4-triethylsilyl-5,5,5-Cryptor-4-methylpentanol acid obtained in accordance with the method described in non-Patent Reference 41, instead of (2E)-4-triethylsilyl-4-ethylhex-2-ene acid get (1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilane-5,5,5-Cryptor-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene.

Stage 2:

(1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilane-5,5,5-Cryptor-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 511,4 [M+Na]+

Example 44:

(1R,3R,20S)-2-methylene-19-nor-20-(5,5,5-Tr is fluoro-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 4 in Example 42, but using the oxide {2-[(3'R,5'R)-3',5'-bis(tert-butyldimethylsilyloxy)-4'-methyltrichlorosilane]ethyl}diphenylphosphine (method thereof, for example, described in Nepatekau Reference 49), instead of the oxide - {2-[(3'R,5'R)-3',5'-bis(tert-butyldimethylsilyloxy)cyclohexylidene]ethyl}diphenylphosphine get (1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-20-acetoxy-9,10-scoprega-5Z,7E-diene.

Stage 2:

3 M Aqueous sodium hydroxide solution (0.2 ml) is added to tetrahydrofuran (5 ml)-methanol (5 ml) solution of (1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-20-acetoxy-9,10-scoprega-5Z,7E-diene (140 mg)obtained in accordance with the above stage 1, and then stirred at room temperature for 3 hours. In the future, add 3 M aqueous sodium hydroxide solution (0.2 ml), stirred for 4 hours, then heated up to 45ºC and stirred for 13 hours. Tetrahydrofuran and methanol is removed by concentration under reduced pressure, and then to the resulting reaction mass is added water and the aqueous solution twice subjected to extraction with ether. The extract is washed with water and saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate and will centerour under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives (1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E-Dien-20-ol (93 mg) as a colourless oil.

Stage 3:

In accordance with the method similar to the method presented in stage 1 in Example 43, but using (1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E-Dien-20-ol, obtained in accordance with the above stage 2, instead of (1R,3R,20S)-19-nor-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E-Dien-20-ol obtain (1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyl-5,5,5-Cryptor-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene.

Stage 4:

(1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-20-(4-triethylsilyl-5,5,5-Cryptor-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene, process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 501,6 [M+1]+of 523.4 [M+Na]+

Example 45:

(1R,3R,20S)-2-methylene-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 3 in Example 44, but using (2E)-4-triethylsilyl the-4-ethylhex-2-envoy acid, received in accordance with the method described in non-Patent Reference 28, instead of 4-triethylsilyl-5,5,5-Cryptor-4-methylpentanoic acid get (1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-20-[(2E)-4-ethyl-4-triethylchlorosilane-2-enorossi]-9,10-scoprega-5Z,7E-diene.

Stage 2:

(1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-20-[(2E)-4-ethyl-4-triethylchlorosilane-2-enorossi]-9,10-scoprega-5Z,7E-diene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 473,4[M+1]+, 495,6 [M+Na]+

Example 46:

(1R,3R,20S)-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol

Stage 1:

In the atmosphere of argon with cooling in a bath with ice, sodium hydrogen carbonate (1.06 g) and m-chloroperbenzoic acid (65%, 1.04 g) is added to anhydrous dichloromethane solution (50 ml) of (Z)-des-A,B-8β-triethylchlorosilane-17(20)-ene (1.48 g), obtained in accordance with non-Patent Reference 47. After stirring for 30 minutes the solution is purified using chromatography on a column of silica gel, which gives des-A,B-8β-triethylsilane-17α,20α-epoxypropane (858 mg) as a colourless oil.

Stage 2:

In an argon atmosphere with about what ladanian in a bath with ice hexane solution (24,0 ml) 0,92 M diethylaluminium added to an anhydrous toluene solution (14 ml) of 2.0 M lithium diisopropylamide/heptane-tetrahydropapaveroline solution (16.6 ml). After stirring for one hour to the resulting reaction mass is added toluene solution (24 ml) of des-A,B-8β-triethylsilane-17α,20α-epoxypropane (858 mg)obtained in accordance with the above stage 1. After subsequent stirring for 3.5 hours to the resulting reaction mass is added saturated aqueous sodium hydrogen carbonate solution and filtered through Celite. The reaction mass is subjected to extraction with ethyl acetate, the extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, which gives (20S)-des-A,B-8β-triethylchlorosilane-6-EN-20-ol (644 mg) in the form of oil pale yellow color.

Stage 3:

In accordance with the method similar to the method presented in stage 1 in Example 34, but using 4-triethylsilyl-4-methylpentanol acid (for example, its preparation is described in non-Patent Reference 25), instead of 5-triethylsilyl-5-italytravel acid and using (20S)-des-A,B-8β-triethylchlorosilane-16-EN-20-ol, obtained in accordance with the above stage 2, instead of (1S,3R,20S)-1,3-bis(tert-butyldimethylsilyloxy)-9,10-scoprega-5Z,7E,10(19)-trien-20-ol get (20S)-des-A,B-8β-triethylsilane-20-(4-triethylsilyl-4-methylpentanoate)pregn-16-ene.

Stage 4:

(20S)-des-A,B-8β-triethylsilane-20-(4-triethylsilyl is hydroxy-4-methylpentanoate)pregn-16-ene, obtained in accordance with the above stage 3 process, following a technique similar to the method presented in stage 2 in Example 34, which gives (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregn-16-ene-8β-ol.

Stage 5:

In accordance with the method similar to the method presented in stage 3 in Example 40, but using (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregn-16-ene-8β-ol, obtained in accordance with the above stage 4, instead of (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregnan-8β-ol get (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregn-16-ene-8-he.

Step 6:

In accordance with the method similar to the method presented in stage 4 in Example 40, but using (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregn-16-ene-8-he received in accordance with the above stage 5, instead of (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregnan-8-get it (20S)-des-A,B-20-(4-triethylsilyl-4-methylpentanoate)pregn-16-ene-8-he.

Step 7:

In accordance with the method similar to the method presented on stage 5 in Example 40, but using (20S)-des-A,B-20-(4-triethylsilyl-4-methylpentanoate)pregn-16-ene-8-he received in accordance with the above stage 6, instead of (20S)-des-A,B-20-(4-triethylsilyl-4-methylpentanoate)pregnan-8-it and using the oxide {2-[(3'R,5'R)-3',5'-bis(4-triethylchlorosilane]ethyl}diphenylphosphine obtained in accordance with non-Patent Reference 48, instead oxide {2-[(3'R,5'R)-3',5'-bis(tert-butyldimethylsilyloxy)cyclohexylidene]ethyl}diphenylphosphine receive (1R,3R,20S)-19-nor-1,3-bis(triethylsilyl)-20-(4-triethylsilyl-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene.

Step 8:

(1R,3R,20S)-19-nor-1,3-bis(triethylsilyl)-20-(4-triethylsilyl-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene obtained in accordance with the above stage 7, process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 455,4 [M+Na]+

Example 47:

(1R,3R,20S)-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 3 in Example 46, but using 4-triethylsilyl-5,5,5-Cryptor-4-methylpentanol acid obtained in accordance with the method described in non-Patent Reference 41, instead of 4-triethylsilyl-4-methylpentanoic acid, receive (20S)-des-A,B-8p-(triethylsilyl)-20-(4-triethylsilyl-5,5,5-Cryptor-4-methylpentanoate)pregn-16-ene.

Stage 2:

(20S)-des-A,B-8β-(triethylsilyl)-20-(4-triethylsilyl-5,5,5-Cryptor-4-methylpentanoate)pregn-16-ene obtained in accordance with the above stage 1 process, following a technique similar to the method is expressed in stage 2 of Example 34, that gives (20S)-des-A,B-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)pregn-16-ene-8β-ol.

Stage 3:

In accordance with the method similar to the method presented in stage 3 in Example 40, but using (20S)-des-A,B-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)pregn-16-ene-8β-ol, obtained in accordance with the above stage 2, instead of (20S)-des-A,B-20-(4-hydroxy-4-methylpentanoate)pregna-8β-ol get (20S)-des-A,B-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)pregn-16-ene-8-he.

Stage 4:

In accordance with the method similar to the method presented in stage 4 in Example 40, but using (20S)-des-A,B-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)pregn-16-ene-8-he received in accordance with the above stage 3, instead of (20S)-des-A,B-20-(4-hydroxy-4-getlinearvelocity)pregnan-8-it and using chlorotrimethylsilane instead of chlorotriethylsilane get (20S)-des-A,B-20-(5,5,5-Cryptor-4-trimethylsilyloxy-4-methylpentanoate)pregn-16-ene-8-he.

Stage 5:

In accordance with the method similar to the method presented on stage 5 in Example 40, but using (20S)-des-A,B-20-(5,5,5-Cryptor-4-trimethylsilyloxy-4-methylpentanoate)pregn-16-ene-8-he received in accordance with the above stage 4, instead of (20S)-des-A,B-20-(4-triethylsilyl-4-methylpentanoate)pregnan-8-it and using the oxide {2-[(3'R,5'R)-3',5'-bis(triethylsilyl)cyclohexylidene]the Teal}diphenylphosphine, received in accordance with non-Patent Reference 48, instead of the oxide - {2-[(3'R,5'R)-3',5'-bis(tert-butyldimethylsilyloxy)cyclohexylidene]ethyl}diphenylphosphine get (1R,3R,20S)-19-nor-1,3-bis(triethylsilyl)-20-(5,5,5-Cryptor-4-trimethylsilyloxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene.

Step 6:

(1R,3R,20S)-19-nor-1,3-bis(triethylsilyl)-20-(5,5,5-Cryptor-4-trimethylsilyloxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene obtained in accordance with the above stage 5, process, following a technique similar to the method presented in stage 2 of Example 1, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 509,4 [M+Na]+

Example 48:

(1R,3R,20S)-19-nor-2-methylene-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented on the stage 7 in Example 46, but using the oxide 2-[(3'R,5'R)-3',5'-bis(triethylsilyl)-4'-methyltrichlorosilane]ethyl]diphenylphosphine received in accordance with non-Patent Reference 49, instead of the oxide 2-[(3'R,5'R)-3',5'-bis(triethylsilyl)cyclohexylidene]ethyl}diphenylphosphine get (1R,3R,20S)-19-nor-2-methylene-1,3-bis(triethylsilyl)-20-(4-triethylsilyl-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene.

Stage 2:

(1R,3R,20S)-19-nor-2-methylene-1,3-bis(triethylsilyl)-20-(4-triethylsilyl is hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 445,4[M+1]+, 467,4 [M+Na]+

Example 49:

(1S,3R,20S)-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol

Stage 1:

In accordance with the method similar to the method presented on stage 5 in Example 47, but using the oxide [3'S-(1'Z,3β,5α)]-{2-[3',5'-bis(triethylsilyl)-2'-methyltrichlorosilane]ethyl}diphenylphosphine received in accordance with non-Patent Reference 50, instead of the oxide - {2-[(3'R,5'R)-3',5'-bis(triethylsilyl)cyclohexylidene]ethyl}diphenylphosphine get (1S,3R,20S)-1,3-bis(triethylsilyl)-20-[5,5,5-Cryptor-4-(trimethylsilyloxy)-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19),16-tetraen.

Stage 2:

(1S,3R,20S)-1,3-bis(triethylsilyl)-20-[5,5,5-Cryptor-4-(trimethylsilyloxy)-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19),16-tetraenreceived in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 521,4 [M+Na]+

Example 50:

(1R,2α,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

Anhydrous benzene (10 ml) saturated with hydrogen gas, for the eat add chloride, Tris(triphenylphosphine)rhodium (34 mg) and stirred, giving a homogeneous solution. Add anhydrous benzene solution (1 ml) of (1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol (8 mg)obtained in Example 41, stirred for 1.5 hours, then rinsed with argon and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel and then fractionary using high-performance liquid chromatography [YMC-Pack ODS-AM (150×20 mm ID), 50% acetonitrile-water, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley later, concentrate, and purify that gives named the title compound (1.9 mg) according to the invention in the form of colorless powder.

1H-NMR (CDCl3) δ: 0,54 (3H, s)of 1.13 (3H, d, J=7,0 Hz)of 1.23 (6H, s)of 1.23 (3H, d, J=6.2 Hz), 2,39 (2H, t, J=8.0 Hz), 2,60 (1H, DD, J=13,2 Hz, J=4.0 Hz), and 2.79 (1H, DD, J=13,2 Hz, J=5.0 Hz), 3,62 (1H, dt, J=9,2 Hz, J=a 4.4 Hz), of 3.97 (1H, users), of 4.95 (1H, Quint, J=6.2 Hz), of 5.83 (1H, d, J=11.2 Hz), 6,36 (1H, d, 11.2 Hz)

(+) -ESIMS m/z 449,4 [M+1]+, 471,4 [M+Na]+

Example 51:

(1R,2β,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

At the stage of fractionation by high performance liquid chromatography according to the method specified in Example 50, the solution containing the compound that had loirevalley first, then concentrate and purify that gives named the title compound (2.1 mg) according to the invention in the form of colorless powder. 1H-NMR (CDCl3) δ: 0,55 (3H, s)and 1.15 (3H, d, J=and 6.6 Hz), 1,24 (6H, s)of 1.24(3H, d, J=6.2 Hz), 2.40 a (2H, t, J=7,2 Hz), and 2.83 (1H, d, J=10 Hz), is 3.08 (1H, DD, J=to 13.6 Hz, J=4.0 Hz), 3,50 (1H, m), 3,91 (1H, users), 4,96 (1H, Quint, J=6.2 Hz), 5,88 (1H, d, J=the 10.9 Hz), and 6.25 (1H, q, j, 10,9 Hz)

(+) -ESIMS m/z 449,4[M+1]+, 471,4 [M+Na]+

Example 52:

(1R,3R,20S)-2-methyl-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

In accordance with the method similar to production method of connection shown in Example 50, but using (1R,3R,20S)-2-methylene-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol obtained in Example 44, instead of (1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol, get mentioned in the title compound according to the invention.

(+) -ESIMS m/z 525,4 [M+Na]+

Example 53:

(1R,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol

In accordance with the method similar to production method of connection shown in Example 50, but using (1R,3R,20S)-2-methylene-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enorossi]-9,10-scoprega-5Z,7E-diene-1,3-diol obtained in Example 45, instead of (1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol receive specified in the header of the connection and the gain.

EIMS m/z 474 M+

Example 54:

(1R,3R,20S)-19-nor-2-methyl-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol

In accordance with the method similar to production method of connection shown in Example 50, but using (1R,3R,20S)-19-nor-2-methylene-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol obtained in Example 48, instead of (1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol get mentioned in the title compound according to the invention.

(+) -ESIMS 469,4 [M+Na]+

Example 55:

(1R,3R,20S)-19-nor-2-methylene-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol

Stage 1:

In accordance with the method similar to the method presented in stage 1 in Example 48, but using (20S)-des-A,B-20-[5,5,5-Cryptor-4-(trimethylsilyloxy)-4-methylpentanoate]pregn-16-ene-8-he obtained in stage 4 in Example 47, instead of (20S)-des-A,B-20-(4-triethylsilyl-4-methylpentanoate)pregn-16-ene-8-get it (1R,3R,20S)-19-nor-2-methylene-1,3-bis(triethylsilyl)-20-[5,5,5-Cryptor-4-(trimethylsilyloxy)-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene.

Stage 2:

(1R,3R,20S)-19-nor-2-methylene-1,3-bis(triethylsilyl)-20-[5,5,5-Cryptor-4-(trimethylsilyloxy)-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene obtained in stage 1, process, CL is blowing technique, similar to the method presented in stage 2 in Example 34, and then fractionary using HPLC [DAICEL CHIRALPAK AD (20×250 mm ID), 15% isopropanol-hexane, 8 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley first, then concentrate and purify that gives named in the title compound according to the invention.

(+) -ESIMS m/z 521,4 [M+Na]+

1H-NMR (CDCl3) δ: 0,784 (3H, s), 1,333 (3H, s), 1,385(3H, d, J=6,6 Hz), and 2.83 (2H, m), 3,23{1H, users), of 4.49 (2H, m), 5,12 (2H, d, J=4.0 Hz), 5,478 (1H, square, and 6.6 Hz), 5,71 (1H, users), 5,975 (1H,d, J=of 11.0 Hz), 6,344 (1H, d, J=of 11.0 Hz).

Example 56:

(1R,3R,20S)-19-nor-2-methylene-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol

At the stage of fractionation by high performance liquid chromatography according to the method specified in Example 55, the solution containing the compound that had loirevalley later, concentrate, and purify that gives named in the title compound according to the invention.

(+) -ESIMS m/z 521,4 [M+Na]+

1H-NMR (CDCl3) δ: 0,782 (3H, s), 1,335 (3H, s), 1,383 (3H, d, J=6,6 Hz), and 2.83 (2H, m), 4,51 (2H, m), 5,11 (2H,d, J=4.0 Hz), 5,475 (1H, square, and 6.6 Hz), 5,71 (1H, users), 5,976 (1H, d, J=of 11.4 Hz), 6,345 (1H, d, J=of 11.4 Hz).

Example 57:

(1R,3R,20S)-2-methylene-19-nor-20-(5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

In accordance with the same way, presented at stage 3 in Example 44, but using 5-triethylsilyl-5-methylhexanoic acid obtained in accordance with the method described in non-Patent Reference 26, instead of 4-triethylsilyl-5,5,5-Cryptor-4-methylpentanoic acid get (1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-20-(5-triethylsilyl-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene.

Stage 2:

(1R,3R,20S)-19-nor-2-methylene-1,3-bis(tert-butyldimethylsilyloxy)-20-(5-triethylsilyl-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene obtained in accordance with the above stage 1 process, following a technique similar to the method presented in stage 2 in Example 34, which gives named in the title compound according to the invention.

(+) -ESIMS m/z 461,4[M+1]+, 483,4 [M+Na]+, 499,5 [M+K]+

Example 58:

(1R,2α,3R,20S)-2-methyl-19-nor-20-(5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

In accordance with the method similar to production method of connection shown in Example 50, but using (1R,3R,20S)-2-methylene-19-nor-20-(5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol obtained in Example 57, instead of (1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol, concentration and purification of the solution containing the compound that uh what was wirewalls later stage fractionation by high performance liquid chromatography get listed in the title compound according to the invention.

1H-NMR (CDCl3) δ: 0,54 (3H, s)of 1.13 (3H, d, J=6,6 Hz)of 1.23 (3H, d, J=6.2 Hz), of 1.23 (6H, s), 2,28 (2H, t, J=the 7.4 Hz), 2,60 (1H, DD, J=at 13.0, 4.0 Hz), 2,80 (2H, t), 3,63 (1H, m), of 3.97 (1H, users), of 4.95 (1H, Quint, J=6.2 Hz), of 5.83 (1H, d, J=11.2 Hz), 6,36 (1H, d, J=11.2 Hz).

(+) -ESIMS m/z 463,4 [M+1]+, 485,4 [M+Na]+, 501,4 [M+K]+

Example 59:

(1R,2β,3R,20S)-2-methyl-19-nor-20-(5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

Stage 1:

At the stage of fractionation by high performance liquid chromatography according to the method specified in Example 58, the solution containing the compound that had loirevalley first, then concentrate and purify that gives named in the title compound according to the invention.

1H-NMR (CDCl3) δ: 0,55 (3H, s)to 1.14 (3H, d, J=6,6 Hz)of 1.23 (3H, d, J=6.2 Hz), of 1.23 (6H, s)to 2.29 (2H, t, J=the 7.4 Hz), is 2.37 (2H, m), of 2.81 (1H, m), of 3.07 (1H, DD, J=12,6, 4,4 Hz), 3,51 (1H, m), 3,91 (1H, users), 4,96 (1H, Quint, J=6.2 Hz), 5,88 (1H, d, J=11.2 Hz), and 6.25 (1H, d, J=11.2 Hz).

(+) -ESIMS m/z 463,3 [M+1]+, 485,5 [M+Na]+, 501,5 [M+K]+

Example 60:

(1R,2α,3R,20S)-2-methyl-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

(1R,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-5,5,5-Cryptor-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol obtained in Example 52, purified by high performance liquid is Oh chromatography [YMC-Pack ODS-AM (150×20 mm ID), 55% acetonitrile-water, 10 ml/min, UV 254 nm], and the solution containing the compound that had loirevalley later, concentrate, and purify that gives named in the title compound according to the invention.

1H-NMR (CDCl3) δ: 0,54 (3H, s)of 1.13 (3H, d, J=7. 0 Hz)to 1.25 (3H, d, J=6,0 Hz), 1,335 (3H, s), of 2.51 (2H, t, J=7,0 Hz), 2,80 (2H, m), the 3.65 (1H, m), of 3.97 (1H, users), to 4.98 (1H, Quint, J=6,0 Hz), of 5.83 (1H, d, J=11.2 Hz), 6,36 (1H, d, J=11.2 Hz).

Example 61:

(1R,2β,3R,20S)-2-methyl-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol

At the stage of fractionation by high performance liquid chromatography according to the method specified in Example 60, the solution containing the compound that had loirevalley first, then concentrate and purify that gives named in the title compound according to the invention.

1H-NMR (CDCl3) δ: 0,55 (3H, s)and 1.15 (3H, d, J=7,0 Hz), 1,25 (3H, d, J=6,0 Hz), 1,338 (3H, s), of 2.51 (2H, t, J=7,0 Hz), 2,82 (1H, d, J=12.0 Hz), is 3.08 (1H, DD, J=12,0, 4,4 Hz), 3,51 (1H, m), 3,91 (1H, users), to 4.98 (1H, Quint, J=6,0 Hz), 5,88 (1H, d, J=11.2 Hz), and 6.25 (1H, d, J=11.2 Hz).

Example 62:

(1R,2α,3R,20S)-19-nor-2-methyl-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol

(1R,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol obtained in Example 54, purified by high performance liquid chromatography according to the following method, similar to the methods described in Example 50, and the solution containing the compound that had loirevalley later, concentrate, and purify that gives named in the title compound according to the invention.

(+) -ESIMS m/z 469,4 [M+Na]+

1H-NMR (CDCl3) δ: 0,77 (3H, s)to 1.14 (3H, d, J=6,6 Hz)of 1.23 (6H, s)to 1.37 (3H, d, J=6.2 Hz), equal to 1.82 (2H, t, J=8.0 Hz), 2,43 (2H, t, J=8.0 Hz), 2,61 (1H, DD, J=12,6, 4,4 Hz), 2,80 (1H, DD, J=14,0, 4,8 Hz), 3,63 (1H, m), of 3.97 (1H, m), 5,46 (1H, square, J=6.2 Hz), 5,70 (1H, users), 5,91 (1H, d, J=11.2 Hz), 6,36 (1H, d, J=11.2 Hz).

Example 63:

(1R,2β,3R,20S)-19-nor-2-methyl-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol

At the stage of fractionation by high performance liquid chromatography according to the method specified in Example 62, the solution containing the compound that had loirevalley first, then concentrate and purify that gives named in the title compound according to the invention.

(+) -ESIMS m/z 469,4 [M+Na]+

1H-NMR (CDCl3) δ: 0,78 (3H, s)and 1.15 (3H, d, J=6,6 Hz)of 1.23 (6H, s)to 1.37 (3H, d, J=6.2 Hz), equal to 1.82 (2H, t, J=8.0 Hz), 2,44 (2H, t, J=8.0 Hz), and 2.79 (1H, user. d, J=9.6 Hz), to 3.09 (1H, DD, J=12,3, 4.6 Hz), 3,53 (1H, m), 3,91 (1H, users), vs. 5.47 (1H, square, J=and 6.6 Hz), 5,71 (1H, users), 5,96 (1H, d, J=11.2 Hz), and 6.25 (1H, d, J=11.2 Hz).

Example 64:

(1R,2β,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol

(1R,3R,20S)-2-methyl-19-nor-20-[(2E)-ethyl-4-hydroxydec-2- enorossi]-9,10-scoprega-5Z,7E-diene-1,3-diol obtained in Example 53, purified by high performance liquid chromatography [YMC-Pack ODS-AM (150×20 mm ID), 55% acetonitrile-water, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley first, then concentrate and then fractionary using HPLC [CHIRALPAK AD (20×250 mm ID), Hexane-EtOH=80:20, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley first, then concentrate and purify that gives named the title compound (1.8 mg) according to the invention.

(+) -ESIMS m/z 497.4 m [MiNa]+, 475,3 [M+1]+

1H-NMR (CDCl3) δ: 0,56 (3H, s)to 0.88 (6H, t, J=7,2 Hz)and 1.15 (3H, d, J=6,6 Hz)of 1.28 (3H, d, J=7,0 Hz), of 2.38 (2H, m), of 2.81 (1H, user. d, J=of 14.0 Hz), to 3.09 (1H, DD, J=12,4, 4.6 Hz), 3,52 (1H, TD, J=10,1, 4,4 Hz), 3,91 (1H, users), 5,02 (1H, Quint, J=6.2 Hz), 5,88 (1H, d, J=11.2 Hz), 6,00 (1H, d, J=to 15.8 Hz), and 6.25 (1H, d, J=11.2 Hz), 6,85 (1H, d, J=to 15.8 Hz).

Example 65:

(1R,2α,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol

(1R,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enorossi]-9,10-scoprega-5Z,7E-diene-1,3-diol obtained in Example 53, purified by high performance liquid chromatography [YMC-Pack ODS-AM (150×20 mm ID), 55% acetonitrile-water, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley later, concentrate, and then distribute using HPC [CHIRALPAK AD (20×250 mm ID), Hexane-EtOH=80:20, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley first, concentrate, and purify that gives named the title compound (2.2 mg) according to the invention.

(+) -ESIMS m/z 497,5 [M+Na]+, 475,3 [M+1]+

1H-NMR (CDCl3) δ: 0,55 (3H, S)to 0.88 (6H, t, J=7,2 Hz), of 1.13 (3H, d, J=6,6 Hz)of 1.27 (3H, d, J=7,0 Hz), 2,60 (1H, DD, J=13,2, 4,4 Hz), and 2.79 (2H, m), 3,62 (1H, TD, J=at 9.2, 4.8 Hz), 3,95 (1H, users), 5,02 (1H, Quint, J=6.2 Hz), of 5.84 (1H, d, J=11.2 Hz), of 5.99 (1H, d, J=15.2 Hz), 6,36 (1H, d, J=11.2 Hz), 6,85 (1H, d, J=15.2 Hz).

Example 66:

(1R,2β,3R,20S)-2-methyl-19-nor-20-[4-ethyl-4-hydroxyhexanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol

Anhydrous benzene (10 ml) saturated with hydrogen gas, then add chloride (triphenylphosphine)rhodium (39 mg) and then stirred, giving a homogeneous solution. Add anhydrous benzene solution (3 ml) of (1R,3R,20S)-2-methylene-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enorossi]-9,10-scoprega-5Z,7E-diene-1,3-diol (10 mg)obtained in Example 45, stirred for one hour, then rinsed with argon and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel and then fractionary using high-performance liquid chromatography [YMC-Pack ODS-AM (150×20 mm ID), 55% acetonitrile-water, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley first, then concentrate is then fractionary using HPLC [CHIRALPAK AD (20×250 mm ID), Hexane-EtOH=80:20, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley later, concentrate, and purify that gives named the title compound (0.9 mg) according to the invention in the form of colorless powder.

(+) -ESIMS m/z 499,5 [M+Na]+, 477,4 [M+1]+

1H-NMR (CDCl3) δ: 0,55 (3H, s)of 0.87 (6H, t, J=I,2Hz)and 1.15 (3H, d, J=and 6.6 Hz), 1,24 (3H, d, J=7,0 Hz), was 2.34 (2H, t, J=7,0 Hz), 2,82 (1H, user. d, J=of 11.0 Hz), to 3.09 (1H, m), 3,51 (1H, m), 3,92 (1H, users), of 4.95 (1H, Quint, J=6.2 Hz), 5,88 (1H, d, J=11.2 Hz), and 6.25 (1H, d, J=11.2 Hz).

Example 67:

(1R,2α,3R,20S)-2-methyl-19-nor-20-[4-ethyl-4-hydroxyhexanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol

Anhydrous benzene (10 ml) saturated with hydrogen gas, then add the chloride Tris(triphenylphosphine)rhodium (39 mg) and then stirred, giving a homogeneous solution. Add anhydrous benzene solution (3 ml) of (1R,3R,20S)-2-methylene-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enorossi]-9,10-scoprega-5Z,7E-diene-1,3-diol (10 mg)obtained in Example 45, stirred for one hour, then rinsed with argon and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel and then fractionary using high-performance liquid chromatography [YMC-Pack ODS-AM (150×20 mm ID), 55% acetonitrile-water, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley later, concentrate and ZAT is fractionary using HPLC [CHIRALPAK AD (20×250 mm ID), Hexane-EtOH=80:20, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley later, concentrate, and purify that gives named the title compound (1.0 mg) according to the invention in the form of colorless powder.

(+) -ESIMS m/z 499,5 [M+Na]+477,4 [M+1]+

1H-NMR (CDCl3) δ: 0,54 (3H, s)of 0.87 (6H, t, J=7,2 Hz), of 1.13 (3H, d, J=and 6.6 Hz), 1,24 (3H, d, J=7,0 Hz), 2,33 (2H, t, J=7,0 Hz), 2,60 (1H, DD, J=13,2, 4,4 Hz), 2,80 (2H, m), 3,63 (1H, m), of 3.97 (1H, users), of 4.95 (1H, Quint, J=6.2 Hz), of 5.83 (1H, d, J=11.2 Hz), 6,36 (1H, d, J=11.2 Hz).

Example 68:

(1R,3R,20S)-19-nor-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E, 16-triene-1,3-diol

(1R,3R,20S)-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol obtained in Example 47, fractionary using HPLC [DAICEL CHIRALPAK AD (20×250 mm ID), 15% isopropanol-hexane, 8 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley first, then concentrate and purify that gives named in the title compound according to the invention.

(+) -ESIMS m/z 509,4 [M+Na]+

1H-NMR (CDCl3) δ: 0,78 (3H, s), 1,335 (3H, s)to 1.38 (3H, d, J=6.2 Hz), 2,77 (2H, m), of 4.12 (2H, m), vs. 5.47 (1H, square, J=6.2 Hz), 5,71 (1H, users), 5,94 (1H, d, J=11.2 Hz), 6,30 (1H, d, J=11.2 Hz).

Example 69:

(1R,3R,20S)-19-nor-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol

The process of fractionation by high performance liquid chromatography according to the method specified in Example 68, the solution containing the compound that had loirevalley later, concentrate, that gives named in the title compound according to the invention.

1H-NMR (CDCl3) δ: 0,78 (3H, S), 1,338 (3H, s)to 1.38 (3H, d, J=6.2 Hz), 2,77 (2H, m), of 4.12 (2H, m), of 5.48 (1H, square, J=6.2 Hz), 5,71 (1H, users), 5,95 (1H, d, J=11.2 Hz), 6,30 (1H, d, J=11.2 Hz).

Example 70:

(1S,3R,20S)-20-[(4R) - or (4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol

(1S,3R,20S)-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol obtained in Example 49, fractionary using HPLC [CHIRALPAK AD (20×250 mm ID), Hexane-i-D=90:10, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley first, then concentrate and purify that gives specified in the title compound (3 mg) according to the invention in the form of colorless powder.

(+) -ESIMS m/z 521,4 [M+Na]+

1H-NMR (CDCl3) δ: 0,771 (3H, s)of 1.33 (3H, s)to 1.37 (3H, d, J=6.2 Hz), 2,53 (2H, t, J=the 6.8 Hz), 2,82 (1H, m), 3,18 (1H, users), 4,24 (1H, m), 4,42 (1H, m)5,00 (1H, users), 5,33 (1H, users), 5,46 (1H, square, 6.2 Hz), 5,67 (1H, users), 6,10 (1H, d, J=11.2 Hz), 6,36 (1H, d, J=11.2 Hz).

Example 71:

(1S,3R,20S)-20-[(4S) - or (4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol

At the stage of fractionation by high performance liquid HRO is ecografia according to the method specified in Example 70, the solution containing the compound that had loirevalley later, concentrate, that gives named in the title compound according to the invention.

(+) -ESIMS m/z 521,4 [M+Na]+

1H-NMR (CDCl3) δ: 0,773 (3H, s)of 1.34 (3H, s)to 1.37 (3H, d, J=6.2 Hz), to 2.57 (2H, t, J=7,0 Hz), 2,82 (1H, m), 3,19 (1H, users), 4,24 (1H, m), 4,42 (1H, m)5,00 (1H, users), of 5.34 (1H, users), 5,46 (1H, square, 6.2 Hz), of 5.68 (1H, users), 6,10 (1H, d, J=of 11.0 Hz), 6,36 (1H, d, J=of 11.0 Hz).

Example 72:

(1R,3R,20S)-19-nor-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol

(1R,3R,20S)-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol obtained in Example 43, fractionary using HPLC [DAICEL CHIRALPAK AD (20×250 mm ID), 10% ethanol-hexane, 10 ml/min, UV 254 nm]. The solution containing the compound that had loirevalley first, then concentrate that gives named in the title compound according to the invention.

(+) -ESIMS m/z 489,3 [M+1]+511,3 [M+Na]+

1H-NMR (CDCl3) δ: 0,54 (3H, s)of 1.24 (3H, d, J=7,0 Hz)of 1.33 (3H, s)of 2.50 (2H, m), 2,78 (1H, m), 3,30 (1H, users), of 4.05 (2H, m), equal to 4.97 (1H, Quint, 7,0 Hz), 5,86 (1H, d, J=the 11.6 Hz), 6,30 (1H, d, J=the 11.6 Hz).

Example 73:

(1R,3R,20S)-19-nor-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol

At the stage of fractionation by high performance liquid chromatography on meth is dick, specified in Example 72, the solution containing the compound that had loirevalley later, concentrate, that gives named in the title compound according to the invention.

(+) -ESIMS m/z 489,4 [M+1]+, 511,4 [M+Na]+

1H-NMR (CDCl3) δ: 0,55 (3H, s)of 1.24 (3H, d, J=6,6 Hz)of 1.34 (3H, s), of 2.51 (2H, m), 2,78 (1H, m), 4,07 (2H, m), equal to 4.97 (1H, Quint, and 6.6 Hz), of 5.81 (1H, d, J=11,0 Hz), 6,30 (1H, d, J=of 11.0 Hz).

Test example 1:

Research the ability to induce differentiation of the cell lines of acute myeloid leukemia human HL-60

It is known that cell line acute human myeloid leukemia HL-60 differentiated in such neutrophils cells under the action of active vitamin D or similar. Thus, cells after differentiation begin to Express the surface marker, such as CD11 and CD32, and at the same time they release oxygen radicals under the influence of forblog ether or similar substances. This test was used above property. As an indicator of the ability to induce differentiation of cells HL-60 number of oxygen radicals formed under the influence of forblog ether, was measured, and the compounds according to the invention mentioned in the Examples were compared with maximalization on their activity of vitamin D3. When using commercial reagents and kits, if any apply, follow the instructions, nor is supplied.

(Process)

Cells HL-60 (obtained from ATCC) are seeded on 96-well plate at a concentration of 5×103cells/100 μl/well, and test the connection in two-fold dilution from 10-7add in rows two through twelve (maximum concentration in the second row). The first row is used for control. After incubation for 72 hours in wet conditions in the presence of 5% CO2at 37°C using CO2incubator, 10 μl of PBS containing 50 mm WST-I (produced by Takara Bio) and 10 μm phorbol 12,13-dodecanoate (produced by SIGMA), added to each well, then incubated for 4 hours. Absorption (relative wavelength: 655 nm) at 450 nm WST-I formisano dye obtained by conversion of WST-I under the influence of oxygen radicals produced by differentiated cells HL-60, measured on a microplate reader device Benchmark microplate reader (BioRad). Applied software control counter absorption MPM3 (BioRad) and the curve of concentration-absorption; 50% of the maximum effective concentration (hereinafter referred to as "EC50"in each case is determined using logistic regression curve. The result is shown in Table 1.

Table 1
Test ConnectionEC50(nm)
Maximalityof 5.4
Connection Example 11,5
Connection Example 34,5
Connection Example 40,31
Connection Example 50,86
Connection Example 70,38
Connection Example 83,4
Connection Example 100,99
Connection Example 112,2
Connection Example 121,5
Connection Example 130,53
Connection Example 192,4
Connection Example 201,4
Connection Example 274,1
The connection is giving in Example 28 1,7
Connection Example 344,2
Connection Example 350,82
Connection Example 360,41
Connection Example 371,1
Connection Example 382,3
Connection Example 391,4
Connection Example 401,6
Connection Example 410,26
Connection Example 421,3
Connection Example 430,45
Connection Example 440,25
Connection Example 450,31
Connection Example 461,4
Connection Example 470,63
Connection Example 48 0,21
Connection Example 500,043
Connection Example 550,15
Connection Example 560,47
Connection Example 570,53
Connection Example 580,53
Connection Example 600,053
Connection Example 611,2
Connection Example 620,23
Connection Example 650,29
Connection Example 670,15
Connection Example 680,23
Connection Example 690,77
Connection Example 700,13
Connection Example 711,1
Connection Example 72,17
Connection Example 731,3

As shown in Table 1, the compounds according to the invention show similar or even stronger ability to induce differentiation of cells compared with maximalization and obviously, they exhibit pronounced activity of vitamin D3.

Test example 2:

Research actions that increase the concentration of calcium in serum

The connection according to the invention mentioned in example 1, or maximality in ethanol containing 0.3% DMSO, injected repeatedly by percutaneous injection (33 µg/200 µl/kg/day) once daily for 7 days in the back of male SD rats (aged 7 weeks). Ethanol containing 0.3% DMSO, injected control group. 24 hours after the last injection, the blood is collected and measured the concentration of calcium in serum. The result is shown in Table 2.

Table 2
Test connectionCalcium concentration in serum (mg/DL)
Control11,5
Connection Example 111,8
Makikallio the 15,0

As shown in Table 2, maximality increases the concentration of calcium in serum, whereas the compound of the present invention has little effect on the concentration of calcium in serum.

Test example 3:

Research actions that increase the excretion of urine calcium (1)

The connection according to the invention mentioned in the Example 1, 36, 43, 47, 48, 55 or 70 or maximality in ethanol containing 0.5% DMSO, injected repeatedly by percutaneous injection (10 μg/200 μl/kg/day) once daily for 4 days in the back of male SD rats (aged 7 weeks). Ethanol containing 0.5% DMSO, injected control group. Measure the concentration of calcium in the urine, which is collected every 24 hours, and multiply by the number of urine for counting the excretion of calcium in the urine. The result is shown in Table 3. The excretion of calcium in urine is shown in Table 3, indicates the total excretion of calcium from 0 to 24 hours, from 0 to 48 hours, from 0 to 72 hours and from 0 to 96 hours.

Table 3
Test connectionCalcium in the urine within 24 hours (mg)Calcium in the urine within 48 hours (mg)Calcium in the urine within 72 hours (mg)Calcium in the che for 96 hours (mg)
Control1,01,52,02,7
Maximality2,64,58,513,9
Connection Example 10,81,42,3the 3.8
Connection Example 361,01,72,84,5
Connection Example 431,21,93,34,6
Connection Example 471,21,82,73,7
Connection Example 481,11,93,55,2
Connection Example 551,1 2,03,44,8
Connection Example 701,41,92,73,7

As shown in Table 3, the level of calcium in the urine of rats of the group treated with the compound of the invention, significantly lower than that in the group treated maximality.

Test example 4:

Research actions that increase the excretion of urine calcium (2)

The connection according to the invention mentioned in Examples 42, 61 or 66, or maximality in saline containing 0.1% Triton×100/5,6% DMSO (22,4 nmol/kg), administered intravenously to male SD rats (aged 7 weeks). Saline containing 0.1% Triton×100/5,6% DMSO, injected control group. The concentration of calcium in the urine collected within 24 hours after the injection, measure and calculate the excretion of calcium in the urine ([concentration of calcium in the urine] × [the number of urine]) and the proportion of excretion of calcium in the urine compared to the control group ([quantity in the urine with the introduction of the test compound]/[amount of calcium in the urine in the control group]). The result is shown in Table 4.

Table 4
The tested compounds is of Calcium in urine (mg)The proportion of calcium in the urine
(for control)
Control0,5-
Maximality2,3460%
Connection Example 420,8160%
Connection Example 610,6120%
Connection Example 660,5100%

As shown in Table 4, the effect of the compounds according to the invention on the level of calcium in the urine significantly lower in the group treated with the compound according to the invention, compared with the group treated maximality.

Test example 5:

The study of metabolic activity in human liver microsomes

Compounds according to the invention mentioned in the Examples and maximality compared with each other in relation to metabolic activity in human liver microsomes.

Use a pool of human liver microsomes (HHM-0323), produced Tissue Transformation Technologies. 0.25 M potassium phosphate buffer (pH 7,4) (200 μl), 5 μl of a 250 μm solution of each of those who together with compounds in DMSO, 50 ál of NADPH-regenerating system (where 20 mg of P-NADP+, 70 mg of glucose-6-phosphate, 40 units of glucose-6-phosphate dehydrogenase and 20 mg of magnesium chloride dissolved in 1 ml of distilled water) and 220 μl of distilled water is added to microprobing and the mixture is subjected to pre-incubation for 5 minutes at 37°C. the Reaction start by adding 25 μl of human liver microsomes (final protein concentration: 1 mg/ml). The incubation is conducted for 2, 10, 30 or 60 minutes and the reaction stopped by adding 500 μl of acetonitrile. After centrifugation at 13,000 rpm for 5 minutes each of the tested compounds in the supernatant fraction (25 µl) was measured by HPLC method (HPLC) under the following conditions.

As speakers use Inertsil ODS-3 (a 4.6×150 mm; GL Science). As a mobile phase, use A solution (acetonitrile/0.1% aqueous solution of ammonium acetate = 10/90) and solution B (acetonitrile/0.1% aqueous solution of ammonium acetate = 90/10) in a linear gradient specified in Tables 5 through 7. The temperature in the column, the flow velocity and the wavelength of detection was set to 40°C; 1.0 ml/min and UV 250 or 270 nm, respectively.

The compound mentioned in Example 38, was analyzed under the conditions shown in Table 6; the compounds mentioned in Examples 55, 56, 68, 69, 72 and 73, was in the conditions shown in Table 7; and the other with the unity was in terms are given in Table 5.

The compounds described in Examples 40, 43 48, 50, 55, 56, 58, 60, 61, 63 and from 65 to 73, were analyzed in terms of UV 250 nm; and other compounds in the UV 270 nm.

Table 5
Time (minutes)Solution A (%)Solution B (%)
05545
101090
10,015545
16End of test

Table 6
Time (minutes)Solution A (%)Solution B (%)
05545
10 1090
121090
12,015545
18End of test

Table 7
Time (minutes)Solution A (%)Solution B (%)
05050
61090
6,015050
11End of test

According to the results of the above test HPLC calculate the metabolic activity of the tested compounds. The results are shown in Table 8.

Table 8
Test connectionMetabolic activity (pmol/min/mg)
Maximality10
Connection Example 178
Connection Example 322
Connection Example 838
Connection Example 1058
Connection Example 1338
Connection Example 2039
Connection Example 3436
Connection Example 3543
Connection Example 3682
Connection Example 3736
Connection Example 3833
Connection Example 3926
Connection Example 4065
Connection Example 4146
Connection Example 4234
Connection Example 4374
Connection Example 4495
Connection Example 4540
Connection Example 4645
Connection Example 4795
Connection Example 4869
Connection Example 5045
Connection Example 55128
Connection Example 56102
Connection Example 5829
Connection Example 6078
Connection Example 61188
Connection Example 6224
The connection is the Rimera 65 29
Connection Example 66116
Connection Example 6738
Connection Example 68126
Connection Example 6986
Connection Example 7060
Connection Example 7140
Connection Example 72111
Connection Example 7363

As shown in Table 8, it is evident that the compounds according to the invention is quickly metabolized in human liver microsomes than maximality.

Example composition 1:

Ointment (1 g) obtained from 0.25 mg of the compound of Example 1, ointment bases (white petrolatum, triglyceride medium chain fatty acids, lanolin, paraffin or mixed base) and other suitable auxiliary substances by mixing or similar methods in accordance with the traditional method.

Example composition 2:

Ointment (1 g) obtained from 0.25 mg of the compound of Example 2, ointment bases (white petrolatum,triglyceride medium chain fatty acids, lanolin, paraffin or mixed base) and other suitable auxiliary substances by mixing or similar methods in accordance with the traditional method.

INDUSTRIAL APPLICABILITY

As described above, the connection according to the invention is a new and useful derivatives of vitamin D3which has exceptional activity of vitamin D3compared with the normal derivative of vitamin D3has a relatively small impact on systemic calcium metabolism.

1. 9,10-Seroprevalence derivative represented by the following General formula [1] or its pharmaceutically acceptable salt:
[Formula 1]

in General formula [1]
the next part of the structure between the 16-position and a 17 positionmeans of a simple bond or double bond:
Y represents (1) a simple link, (2) alkylene having from 1 to 5 carbon atoms, and optionally substituted from 1 to 3 substituents selected from the group of halogen, hydroxy and oxo, (3) albaniles having from 2 to 5 carbon atoms, or (4) phenylene;
R1and R2are the same or different, each represents (1) hydrogen, (2) alkyl, having from 1 to 6 carbon atoms, and optionally substituted from 1 to 3 halogen atoms, or (3) cycloalkyl having from 3 to 8 carbon atoms; and R 1and R2taken together with the adjacent carbon atom, form cycloalkyl having from 3 to 8 carbon atoms;
R3represents hydrogen or methyl;
Z represents hydrogen, hydroxy, or-NR11R12; R11represents hydrogen or alkyl having from 1 to 6 carbon atoms; R12represents (1) an alkyl having from 1 to 6 carbon atoms, and optionally substituted by hydroxy or (2) alkylsulfonyl having from 1 to 6 carbon atoms;
Raand Rbboth represent hydrogen atoms, or Raand Rbtaken together form methylene;
Rcand Rdare the same or different, each represents hydrogen or methyl, or Rcand Rdtaken together form methylene;
however, compounds, where (1) R1and R2taken together form a methylene, (2) Rcand Rdrepresent hydrogen atoms, and (3) the part of the structure between the 16-position and the 17-position represents a simple bond, is excluded.

2. 9,10-Seroprevalence derivative or its pharmaceutically acceptable salt according to claim 1, where Z represents hydroxy.

3. 9,10-Seroprevalence derivative or its pharmaceutically acceptable salt according to claim 1, where Y represents alkylene having from 1 to 5 carbon atoms, or albaniles having from 2 to 5 carbon atoms.

4. 9,0-Seroprevalence derivative or its pharmaceutically acceptable salt according to claim 1, where R1and R2are the same or different, each represents alkyl having from 1 to 6 carbon atoms, and optionally substituted from 1 to 3 halogen atoms.

5. 9,10-Seroprevalence derivative or its pharmaceutically acceptable salt according to claim 1, where R3represents methyl.

6. 9,10-Seroprevalence derivative or its pharmaceutically acceptable salt according to claim 1, where Z represents hydroxy, Y is ethylene or ethenylene, R1and R2are the same or different, each represents a methyl, trifluoromethyl or ethyl, and R3represents methyl.

7. 9,10-Seroprevalence derivative or its pharmaceutically acceptable salt according to claim 1, which represents the following compounds (1) through (26):
(1) (IS,3R,20S)-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol,
(2) (1R,3R,20S)-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,
(3) (1R,3R,20S)-2-methylene-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,
(4) (1R,3R,20S)-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,
(5) (1R,3R,20S)-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,
(6) (1R,3S,20S)-2-methylene-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,
(7) (1R,3R,20S)-2-m is tilen-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,
(8) (1R,3R,20S)-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,
(9) (1R,3R,20S)-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,
(10) (1R,3R,20S)-19-nor-2-methylene-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,
(11) (1S,3R,20S)-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,10(19),16-tetraen-1,3-diol,
(12) (1R,2α,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,
(13) (1R,2β,3R,20S)-2-methyl-19-nor-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,
(14) (1R,3R,20S)-2-methyl-19-nor-20-(5,5,5-Cryptor-4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E-diene-1,3-diol,
(15) (1R,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,
(16) (1R,3R,20S)-19-nor-2-methyl-20-(4-hydroxy-4-methylpentanoate)-9,10-scoprega-5Z,7E,16-triene-1,3-diol,
(17) (1R,3R,20S)-19-nor-2-methylene-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol,
(18) (1R,3R,20S)-19-nor-2-methylene-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol,
(19) (1R,2β,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,
(20) (1R,2α,3R,20S)-2-methyl-19-nor-20-[(2E)-4-ethyl-4-hydroxydec-2-enolase]-9,10-scoprega-5Z,7E-diene-1,3-diol,
(21) (1R,2β,3R,20S)-2-methyl-19-nor-20-[4-ethyl-4-hydroxyhexanoate]-9,10-SECO is regna-5Z,7E-diene-1,3-diol,
(22) (1R,2α,3R,20S)-2-methyl-19-nor-20-[4-ethyl-4-hydroxyhexanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol,
(23) (1R,3R,20S)-19-10p-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol,
(24) (1R,3R,20S)-19-nor-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,16-triene-1,3-diol,
(25) (1R,3R,20S)-19-nor-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol,
(26) (1R,3R,20S)-19-nor-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E-diene-1,3-diol.

8. Pharmaceutical composition for the induction of cell differentiation, comprising as active ingredient an effective amount 9,10-scopigno derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 7.

9. Therapeutic agent for the treatment of dyskeratosis, which contains as an active ingredient 9,10-seroprevalence derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 7.

10. Therapeutic agent for the treatment of psoriasis, which contains as an active ingredient 9,10-seroprevalence derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 7.

11. 9,10-Seroprevalence derivative or its pharmaceutically acceptable salt, which is represented by the following compounds (1) through (5):
(1) (1S,3R,20S)-20-(5-hydroxy-5-ethylheptanoate)-9,cacapava-5Z,7E,10(19)-triene-1,3-diol,
(2) (1S,3R,20S)-20-[(4R)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-52,7E,10(19)-triene-1,3-diol,
(3) (1S,3R,20S)-20-[(4S)-5,5,5-Cryptor-4-hydroxy-4-methylpentanoate]-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol,
(4) (1S,3R,20S)-20-(6,6,6-Cryptor-5-hydroxy-5-methylhexanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol,
(5) (1S,3R,20S)-20-(5,5,5-Cryptor-4-hydroxy-4-methyl-3-oxopentanoate)-9,10-scoprega-5Z,7E,10(19)-triene-1,3-diol.

12. Pharmaceutical composition for the induction of cell differentiation, comprising as active ingredient an effective amount 9,10-scopigno derivative or its pharmaceutically acceptable salt according to item 11.

13. Therapeutic agent for the treatment of dyskeratosis, which contains as an active ingredient 9,10-seroprevalence derivative or its pharmaceutically acceptable salt according to item 11.

14. Therapeutic agent for the treatment of psoriasis, which contains as an active ingredient 9,10-seroprevalence derivative or its pharmaceutically acceptable salt according to claim 11.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of isomerising vitamin D analogues such as compounds used in synthesis of calcipotriol using a flow-type photoreactor or a photoreactor with continuous flow for preparing said vitamin D analogues. The invention also relates to use of intermediates produced using said method to produce calcipotriol or monohydrate of calcipotrol or its pharmaceutical medicinal forms.

EFFECT: improved properties of compounds.

21 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound representing a new derivative of 3,5-seco-4-cholestane presented in the description, its salts, esters and ester salts as medicinal agents, application, particularly as neuroprotectors; besides there are described pharmaceutical compositions.

EFFECT: production of new derivatives of 3,5-seco-4-cholestane which can find application as neuroprotectors.

15 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: method involves: transformation of 1-(4-hydroxy-3-propylphenyl)propane-1-on under effect of trifluoromethane sulphone anhydrite (Tf2O) in the presence of triethylamine (NEt3) into its derivative 4-propyionyl-2-n-propylphenyl ether of trifluoromethane sulphonic acid, with further concentration by Suzuki reaction type with 2-ethyl-5-metoxyphenylboronic acid in the presence of K2CO3, PdCl2(PPh3)2 or Pd(PPh3)4 in catalytic amount, obtaining 1-(2'-ethyl-5'-metoxy-2-propylbiphenyl-4-yl)propane-1-on; demethylation of 1-(2'-ethyl-5'-metoxy-2-propylbiphenyl-4-yl)propane-1-on by heating in the absence of solvent with pyridine salt excess, obtaining 1-(2'-ethyl-5'-hydroxy-2-propylbiphenyl-4-yl)propane-1-on; transformation of 1-(2'-ethyl-5'-hydroxy-2-propylbiphenyl-4-yl)propane-1-on into 6-ethyl-4'-(1-ethyl-1-hydroxypropyl)-2'-propylbiphenyl-3-ol by reaction with ethylmagnesium bromide or ethyllithium, and condensation of 6-ethyl-4'-(1-ethyl-1-hydroxy-propyl)-2'-propylbiphenyl-3-ol with dimethyl ether of 4-bromomethylphthalic acid, with further recovery reaction by lithium borohydride in situ. Claimed method allows for obtainment of target product with high output. Also invention refers to novel 6-ethyl-4'-(1-ethyl-1-hydroxypropyl)-2'-propylbiphenyl-3-ol compound used as intermediary product in the claimed method.

EFFECT: possible application in medicine.

17 cl, 1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to intermediate compounds used in synthesis of calcipotriol or monohydrate of calcipotriol, to methods of synthesising said intermediate compounds and to methods for stereoselective reduction of the said intermediate compounds.

EFFECT: method increases output of C-24 hydroxy epimers of calciprotriol derivatives.

27 cl, 16 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel methods for synthesis of intermediate compounds which are used in synthesis of calcipotriol.

EFFECT: present invention relates to use of intermediate compounds, obtained using said methods for synthesis of calcipotriol or monohydrate of calcipotriol.

15 cl, 10 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention describes application of derivatives of 10,10-dialkylprostanic acid as effective ophthalmic antihypertensive agents. Animal suffering from ocular hypertension or glaucoma is introduced with therapeutically effective amount of composition of general formula : where dotted line indicates presence or absence of bond, cross-hatch wedge designates α-configuration and solid triangle designates β-configuration; B is simple, double or triple covalent bond; n - 0-6; X - CH2, S or O; Y is any pharmaceutically acceptable salt of group CO2H, or group CO2R, CONR2, CONHCH2CH2OH, CON (CH2CH2OH)2, CH2OR, P(O)(OR)2, CONRSO2R, CONR2 or of formula Ia; R - H, C1-6alkyl or C2-6alkenyl; R2 and R3 represent C1-6normal alkyl which can be same or another, and can be connected with each other so that to form ring including carbon atom to which both of them are connected.

EFFECT: invention provides higher efficiency of composition and method of treatment.

52 cl, 1 ex, 2 tbl, 8 dwg

FIELD: medicine; pharmaceutical.

SUBSTANCE: invention refers to pharmaceutical formulation and therapeutic method including introduction to related patient of composition 2-alkyliden derivative of 19-nor-vitamin D and bisphosphonate. In particular, this invention refers to pharmaceutical formulation and therapeutic methods including introduction to related patient of 2-methylene-19-nor-20(S)-1α,25- dihydroxyvitamin D3 and bisphosphonate selected from tyludronate, alendronate, zoledronate, ibanedronate, risedronate, ethydronate, clodronate or pamydronate. Stated invention allows increasing of therapeutic efficiency of such diseases as senile osteoporosis, postclimacteric osteoporosis, bone fracture, bone graft, osteopeny and male osteoporosis.

EFFECT: increased therapeutic efficiency.

18 cl, 2 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: method implies carbonylation of compound of formula , where each of R12, R13 and R14 stands for eliminated group, in solvent, in the presence of organoaluminium reagent (preferably, dimethylaluminium chloride) and palladium catalyst (preferably, tetrakis(triphenylphosphine)palladium) in carbon oxide atmosphere, to obtain compounds of formula , where R12 and R13 stand for above protective groups, and R15 stands for СН3, С2Н5, С3Н7 or С4Н9.

EFFECT: improved carbonylation method for preparation of intermediates in synthesis of new vitamin D derivatives.

2 cl, 6 ex, 2 tbl

FIELD: organic chemistry, vitamins, medicine.

SUBSTANCE: invention relates to analogues of vitamin D of the general formula (I): wherein R1 and R2 mean halogen atom, (C1-C6)-hydrocarbon radical possibly substituted with 1, 2 -OH groups, 1, 2 fluorine (F) atoms, or R1 and R in common means (C3-C6)-carbocycle, or R1 and R2 in common mean a direct bond, or R1 and R2 in common mean hydrogen atom (H); R3 means H or (C1-C3)-hydrocarbon radical; X means (E)-ethylene, (Z)-ethylene, ethynylene or a bond; Y and Z mean H, -CH3; A means -OH, F or H; B means -CH2- or H2 under condition that compound of the formula (I) doesn't mean 3(S)-hydroxy-9,10-secocholesta-5(Z),7(E),10(19),22(E),24-pentaene. Compounds elicit strong suppression effect on secretion of parathyroid hormone and useful in treatment of secondary hyperparathyroiditis possibly associated with renal insufficiency.

EFFECT: valuable medicinal properties of vitamin D analogues.

19 cl, 2 tbl, 36 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes compounds of the general formula (I): or their salts wherein dotted line means a double bond optionally; L means fragment of group comprising -CH2-CH2-CH2-, -CH2-CH=CH- and CH2-C≡C-; each R2 and R3 means independently alkyl or halogenalkyl; R1 and R4 mean independently hydrogen atom, acyl group or hydroxy-protecting group under condition that at least one radical among R1 and R4 mean acyl group. Also, invention relates to using compounds of the formula (I) or their salts as medicinal agents used in treatment of hyperthyroidism, renal osteodystrophy or osteoporosis.

EFFECT: valuable medicinal properties of compounds.

28 cl, 4 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is pharmaceutical composition for treating psoriasis, which includes, at least, one excipient and active agents counted per total composition weight: clobetasol propionate: 0.05-5%, minoxydyl: 0.05-7% and 11-alfa-hydroxyprogesteron: 0.05-12%. Composition can also include other excipients, vitamins and/or mineral compounds. It is demonstrated: 11-alfa-hydroxyprogesteron reduces grease-secretion on affected region, which increases action of other active agents. Efficiency of composition is manifested 2-4 days after beginning of treatment, it does not change skin colour, side effects are manifested in light degree.

EFFECT: composition retards accelerated growth of skin cells, as well as suppresses development of other abnormal phenomena developing in case of psoriasis vulgaris.

15 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound selected from N-((1S)-1-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}ethyl)-2-(7-nitro-1H-benzimidazol-1-yl)acetamide, 2-(7-nitro-1H-benzimidazol-1-yl)-N-{1-[6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl]ethyl}acetamide, N-[1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamde and N-[(1S)-1-(4-tert-butylphenyl)ethyl]-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide. The invention also relates to use of said compounds in preparing a medicinal agent.

EFFECT: novel compounds which are useful in treating VR1 mediated disorders or acute and chronic algesic disorders are obtained.

6 cl, 5 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular for treatment of psoriasis. Medication for treatment of psoriasis, which contains solution of phospholipids in 70% ethyl alcohol and water solution of sodium deoxyribonucleate, components being taken in specified ratio.

EFFECT: medication is efficient for treatment of psoriasis.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I ; or to its pharmaceutically acceptable salts where n represents 0, 1 or 2; Y1 represents a bond or a group C(O); Y2, represents a bond, the groups C(O) or S(O)2; R1 represents hydrogen, halogen, cyano, C1-2alkyl; R2 represents hydrogen, halogen, cyano, C1-4alkyl, C1-3alkoxy, halogen-substituted-C1-3alkyl, halogen-substituted-C1-3alkoxyl, C6aryl-C0alkyl, tetrazolyl, C3-6cycloalkyl-C0alkyl, C6-7heterocycloalkyl-C0-4alkyl where 1 or 2 carbon atoms in the ring are substituted by the groups selected from -O-, -NH-, -S(O) and -SO2-; and phenoxy groups; where said aryl and heterocycloalkyl groups R2 can be substituted by 1 or 2 radicals independently selected from C1-6alkyl; R3 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group and a group -NR6aR6b where R6a and R6b are independently selected from hydrogen and C1-4alkyl; R4 represents hydrogen, halogen, cyano, C1-3alkoxy or halogen-substituted-C1-2alkyl group; R5 represents hydrogen or C1-3alkyl group; L represents a bivalent radical selected from ; ; ; ; ; ; ; ; ; ; ; ; and ; where asterisks the junctions of Y2 and R2; where any bivalent radical L can be substituted by 1 or 2 radicals independently selected from halogen, hydroxy, cyano, C1-4alkyl, C1-4alkyl carbonylamino, C1-4alkoxy, C1-4alkoxycarbonyl, halogen-substituted - C1-4alkyl, C1-3alkylsulfonyl, C1-3alkylsulfonyl-amino, cyano-substituted - C1-4alkyl and halogen-substituted -C1-4alkoxy radicals. Also, the invention refers to a method of Hedgehog path inhibition in a cell and to a method of undesired cell proliferation inhibition which involves the interaction of the compound of formula I and the cell.

EFFECT: new substituted imidazole derivatives which can be effective in treatment of some types of cancer are prepared.

13 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, which are HSP90 (heat-shock proteins) inhibitors and can be used to prepare a medicinal agent for treating tumorous diseases affected by HSP90 inhibition. In formula I R1 denotes Hal, H, OA or A, R2, R3 each independently denotes -O-(X)s-Q, -NHCO-(X)s-Q, -CONH-(X)s-Q, -NH(CO)NH-(X)s-Q, -NH(CO)O-(X)s-Q, -NHSOr(X)s-Q, NHCOA, Hal, Het or H, where, if R2=H, then R3≠H, or if R3=H, then R2≠H, R4 denotes H, R5 denotes H, Hal, A, OA, (CH2)nCOOH, (CH2)nCOOA, O(CH2)oCONH2, NHCOOA, NHCO(CH2)nNH2, NHCONHA or O(CH2)oHet1, A denotes a straight or branched alkyl containing 1-10 carbon atoms, in which 1-5 hydrogen atoms may be substituted with F, Cl and/or Br, X denotes a straight or branched C1-C10 alkylene which is unsubstituted or substituted once, twice or thrice by A, O A, OH, Hal, CN, COOH, COOA, CONH2, NH2, NHCOA, NHCOOA, Q denotes H, Ar or Het, Ar denotes phenyl which is unsubstituted or substituted once, twice or thrice with A, OA, OH, NO2, Hal, CN, (CH2)nCOOH, (CH2)nCOOA and/or tetrazole, Het denotes a cyclic saturated or aromatic 5-6-member heterocycle containing 1-2 N and/or O atoms, optionally condensed with a benzene ring which may be substituted once, twice or thrice with A, OA, OH and/or =O (carbonyl oxygen), Het1 denotes a monocyclic saturated, unsaturated or aromatic heterocycle containing 1-2 N and/or O atoms, which may be mono- or disubstituted with A, OA, OH, Hal and/or =O (carbonyl oxygen), Hal denotes F, Cl, Br or I, n equals , 1, 2, 3 or 4, o equals 1, 2 or 3, s equals 0, 1 or 2.

EFFECT: high efficiency of using said derivatives.

4 cl, 4 dwg, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to certain N-alkylcarbonylaminoacid esters of formula where R1 independently represents hydrogen or methyl; R2 independently represents alkyl C1-C2 and R3 independently represents alkyl C1-C4, offered in the present invention, as well as to compositions and therapies with using the declared compounds.

EFFECT: preparing new compounds which effect on sensory processes.

27 cl, 7 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry, and deals with medication for local application for treating dermatitis, selected from atopic dermatitis, contact dermatitis, or seborrheic dermatitis, as well as for treatment of psoriases or eczema.

EFFECT: medication has high efficiency in treatment of atopic dermatitis, psoriases or eczema.

3 cl, 3 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely - to dermatology. A method involves administration of a sorption corrective agent presented by Lamifaren gel. Gel is taken by 50-150 g 3 times a day 30 minutes before meals. Low-mineralised nitrogenous siliceous baths of radon concentration 4-6 nCu/l at temperature 37-38°C are taken. Then wet skin of the involved regions is coated with Lamifaren gel 3-6 times a day to complete drying of gel. The therapeutic course is 10-14 baths. After termination of a course of baths, Lamifaren gel is consumed internally and applied externally to complete relief of a skin process.

EFFECT: method reduces a number of allergic reactions due to decreased drug administration and prolongs remission.

3 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to orthopedics, and can be used for treatment of postmenopausal osteoporosis. For this purpose patient is administered one tablet of calcemin during meal in the morning and in the evening. In the evening, before going to bed, two hours after intake of calcemin, administered is bivalos, one sachet, diluted in two hundred milliliters of water.

EFFECT: invention makes it possible to increase treatment efficiency due to mutually potentiating impact of medications, with their application in said regimen, which is manifested in normalisation of indices of bone metabolism markers and increase of mineral density of bone tissue.

2 ex, 4 dwg

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