JPH07330714A - 22-thiavitamin d3 derivative - Google Patents

Abstract

PURPOSE:To obtain a new 22-thiavitamin D3 derivative having strong suppressive activity against keratinocyte growth. CONSTITUTION:This is a compound of formula I (R<1> is a 1-10C alkyl optionally substituted with >=1 OH; R2 and R3 are each H or OH), e.g. 20(S)-(3-e thyl-3- hydroxypentylthio)-1alpha,3beta,16alpha-trihydroxy-9,--10-secopregna-5 ,7,10(19)-triene. Among the compounds of formula I, a compound having a steric configuration of formula II and a group of formula III [R4 and R5 are each H or OH, where the both of them can not be OH at the same time; (m)=1-4; (n)=0-2] as it R1 is preferable. Compounds of formula IV (R25 is R1; R26 and R27 are each H or a protecting group; R28 is H or OH) including compounds of formula I are obtained by subjecting a compound of formula V to light radiation and thermal isomerization. Examples of a useful intermediate for producing the compound of formula I include compounds of formula Vl and formula VII (R6, R7, R15, R16, R19 and R20 are each H or a protecting group; R8 and R21 each are a 1-10C alkyl optionally substituted; A1 and A3 are each CHOH or CO).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel vitamin D ₃ derivative. More specifically, it relates to a vitamin D ₃ derivative in which the 22nd position is substituted with a sulfur atom, and a method for producing the same.
It also relates to an intermediate useful for producing this compound and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Active vitamin D ₃ is known to have many physiological activities such as a differentiation inducing action and an immunoregulatory action in addition to a calcium metabolism regulating action.

[0003]

In recent years, physiological activities of vitamin Ds have been successively revealed. Vitamin Ds,
For example, 1α, 25-dihydroxyvitamin D ₃ is known to exhibit various physiological activities such as calcium metabolism regulating action, tumor cell growth inhibiting action, differentiation inducing action, and immunoregulatory action. However, 1α, 25-
Dihydroxyvitamin D ₃ has a drawback that it causes hypercalcemia by long-term and continuous administration, and is not suitable for use as, for example, an antitumor agent or an antirheumatic agent. Therefore, many vitamin D derivatives have recently been synthesized for the purpose of separating the actions of these vitamin Ds, and their physiological activities have been investigated.

One of them is Vitamin D ₃ 22.
Japanese Patent Application Laid-Open No. 61-
267550, 1α, 3β-dihydroxy-20 (S)-(3-hydroxy-3-methylbutyloxy-9,10-secopregna-5,7,10.
(19) -There is a triene. The present inventors have found that vitamin D
As a result of investigating the derivative, it was found that vitamin D in which the 22-position is substituted with a sulfur atom has a strong keratinocyte growth inhibitory action.

[0005]

The present invention relates to a 22-thiavitamin D derivative represented by the following general formula (I).

[Chemical 20] (In the formula, R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, R ₂ represents a hydrogen atom or a hydroxyl group, and R ₃ represents a hydrogen atom or a hydroxyl group.) General In the compound represented by the formula (I), R ₃ is preferably a hydroxyl group. Further, R ₁ is preferably an alkyl group having 1 to 10 carbon atoms, which is substituted with one or more hydroxyl groups, and particularly, the general formula (III)

[Chemical 21] (In the formula, R ₄ and R ₅ are the same or different and represent a hydrogen atom or a hydroxyl group. However, they are not simultaneously a hydroxyl group.
m is preferably an integer of 1 to 4 and n is an integer of 0 to 2). Here, it is particularly preferable that R ₄ and R ₅ are hydrogen atoms. The configuration of the general formula (I) is not particularly limited, but the general formula (I
I)

[Chemical formula 22] (Wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂ represents a hydrogen atom or a hydroxyl group) are particularly preferable. Further, the present invention is 22-position process for the preparation of vitamin D ₃ derivatives substituted by sulfur atoms. That is, the general formula (XV)

[Chemical formula 23] (In the formula, R ₂₅ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂₆ , R
₂₇ are the same or different and each represents a hydrogen atom or a protective group, and R ₂₈ represents a hydrogen atom or a hydroxyl group), and a compound represented by the general formula (XVI)

[Chemical formula 24] (In the formula, R ₂₅ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂₆ , R
₂₇ are the same or different and each independently represent a hydrogen atom or a protective group, and R ₂₈ represents a hydrogen atom or a hydroxyl group).

The present invention also relates to a synthetic intermediate useful for producing the compound represented by the general formula (I) and a method for producing the same. Typical examples of synthetic intermediates include, for example, general formula (VI)

[Chemical 25] (In the formula, R ₆ and R ₇ are the same or different and each represents a hydrogen atom or a protective group, and R ₈ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent). XI)

[Chemical formula 26] (In formula, R <_15> , R < ₁₆ > is the same or different and shows a hydrogen atom or a protective group, A < ₁ > is -CHOH- or -C.
O-) and the general formula (XIII)

[Chemical 27] (In the formula, R ₁₉ and R _{20 each} represent a hydrogen atom or a protecting group, and R ₂₁ represents a carbon atom having 1 to 1 which may have a substituent.
Represents an alkyl group of 0, A ₃ is —CHOH— or —C
And a compound represented by the general formula (X) is particularly preferable.

[Chemical 28] (In the formula, R ₁₂ and R ₁₃ are the same or different and each represents a hydrogen atom or a protective group, and R ₁₄ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent), the general formula ( XII)

[Chemical 29] (In the formula, R ₁₇ and R ₁₈ represent a hydrogen atom or a protective group, and A ₂ represents —CHOH— or —CO—) and the general formula (XIV).

[Chemical 30] (In the formula, R ₂₂ and R ₂₃ represent a hydrogen atom or a protective group, and R ₂₄ represents a carbon atom having 1 to 1 which may have a substituent.
0 represents an alkyl group, A ₄ is —CHOH— or —C
And a compound represented by O-). Here, examples of R ₈ , R ₁₁ , R ₁₄ , R ₂₁ , and R ₂₄ include 1 to 10 carbon atoms substituted with one or more hydroxyl groups.
And an alkyl group of formula (II
I)

[Chemical 31] (In the formula, R ₄ and R ₅ are the same or different and represent a hydrogen atom or a hydroxyl group. However, they are not simultaneously a hydroxyl group.
m is preferably an integer of 1 to 4 and n is an integer of 0 to 2). Here, it is particularly preferable that R ₄ and R ₅ are hydrogen atoms. In the present invention, the alkyl group in the alkyl group having 1 to 10 carbon atoms which may be substituted with a hydroxyl group represents a linear or branched alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, i In addition to -propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decanyl group and the like can be mentioned. Preferably, 3-methylbutyl group, 3-ethylpentyl group, 4-
Methylpentyl group, 3- (n-propyl) hexyl group,
4-ethylhexyl group, 5-methylhexyl group, 6-methylheptyl group, 5-ethylheptyl group, 4- (n-propyl) heptyl group and the like, and more preferably,
Examples thereof include a 3-methylbutyl group, a 3-ethylpentyl group and a 4-methylpentyl group.

Further, in the alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, examples of the number of substituted hydroxyl groups are, for example, 0, 1, 2,
3, etc. are mentioned, preferably 1 or 2, and more preferably 1. Examples of the alkyl group having 1 to 10 carbon atoms, which is substituted with one or more hydroxyl groups, include 3-
Hydroxy-3-methylbutyl group, 2-hydroxy-3
-Methylbutyl group, 4-hydroxy-3-methylbutyl group, 2,3-dihydroxy-3-methylbutyl group, 2,
4-dihydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl group, 3-hydroxy-3-
Ethyl pentyl group, 2-hydroxy-3-ethyl pentyl group, 4-hydroxy-3-ethyl pentyl group, 2,3
-Dihydroxy-3-ethylpentyl group, 2,4-dihydroxy-3-ethylpentyl group, 3,4-dihydroxy-3-ethylpentyl group, 4-hydroxy-4-methylpentyl group, 3-hydroxy-4-methyl Pentyl group, 5-hydroxy-4-methylpentyl group, 3,4-
Dihydroxy-4-methylpentyl group, 3,5-dihydroxy-4-methylpentyl group, 4,5-dihydroxy-4-methylpentyl group, 3-hydroxy-3- (n-
Propyl) hexyl group, 4-hydroxy-3- (n-propyl) hexyl group, 2-hydroxy-3- (n-propyl) hexyl group, 2,3-dihydroxy-3- (n-
Propyl) hexyl group, 3,4-dihydroxy-3-
(N-Propyl) hexyl group, 2,4-dihydroxy-
3- (n-propyl) hexyl group, 3-hydroxy-4
-Ethylhexyl group, 4-hydroxy-4-ethylhexyl group, 5-hydroxy-4-ethylhexyl group, 3,
4-dihydroxy-4-ethylhexyl group, 3,5-dihydroxy-4-ethylhexyl group, 4,5-dihydroxy-4-ethylhexyl group, 4-hydroxy-5-methylhexyl group, 5-hydroxy-5-methylhexyl group , 6-hydroxy-5-methylhexyl group, 4,5-
Dihydroxy-5-methylhexyl group, 4,6-dihydroxy-5-methylhexyl group, 5,6-dihydroxy-5-methylhexyl group, 5-hydroxy-6-methylheptyl group, 6-hydroxy-6-methylheptyl group Base,
7-hydroxy-6-methylheptyl group, 5,6-dihydroxy-6-methylheptyl group, 5,7-dihydroxy-6-methylheptyl group, 6,7-dihydroxy-6
-Methylheptyl group, 4-hydroxy-5-ethylheptyl group, 5-hydroxy-5-ethylheptyl group, 6-
Hydroxy-5-ethylheptyl group, 4,5-dihydroxy-5-ethylheptyl group, 4,6-dihydroxy-
5-ethylheptyl group, 5,6-dihydroxy-5-ethylheptyl group, 3-hydroxy-4- (n-propyl) heptyl group, 4-hydroxy-4- (n-propyl) heptyl group, 5-hydroxy- 4- (n-propyl) heptyl group, 3,4-dihydroxy-4- (n-propyl) heptyl group, 3,5-dihydroxy-4- (n
-Propyl) heptyl group, 4,5-dihydroxy-4-
(N-propyl) heptyl group and the like, and preferably 3-hydroxy-3-methylbutyl group, 2,3-dihydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl group, 3-hydroxy-3. -Ethylpentyl group, 2,3-dihydroxy-3-ethylpentyl group, 3,4-dihydroxy-3-ethylpentyl group, 4
-Hydroxy-4-methylpentyl group, 3,4-dihydroxy-4-methylpentyl group, 4,5-dihydroxy-4-methylpentyl group and the like, and more preferably 3-hydroxy-3-methylbutyl group, 3-hydroxy-3-ethylpentyl group, 4-hydroxy-4-
Examples include a methylpentyl group.

Examples of the protective group include an acyl group, a substituted silyl group and a substituted alkyl group, and an acyl group and a substituted silyl group are preferable. The acyl group includes a hydrogen atom, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent. Optionally lower alkyloxy group, an optionally substituted aryloxy group or a carbonyl group substituted by an optionally substituted aralkyloxy group, and the like, preferably a formyl group , A lower alkylcarbonyl group, a phenylcarbonyl group which may have a substituent, a lower alkyloxycarbonyl group, a phenylalkyloxycarbonyl group which may have a substituent and the like, more preferably a formyl group, Acetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group, ethoxycarbonyl group, t
-Butoxycarbonyl group, benzyloxycarbonyl group and the like are shown. The substituted silyl group refers to a silyl group substituted with one or more lower alkyl groups which may have a substituent, aryl groups which may have a substituent, etc., and are preferably trisubstituted. Indicates a silyl group. Preferred examples of the substituted silyl group include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldiphenylsilyl group, t-butyldimethylsilyl group and the like. The substituted alkyl group refers to an alkyl group substituted with one or more substituents, and preferable examples of the substituent here include an aryl group which may have a substituent and a substituent which has a substituent. And an alkyloxy group which may have a substituent such as an alkyloxy group is particularly preferable. Examples of the alkyloxy group which may have a substituent such as an alkyloxy group include a tetrahydropyran-2-yl group in addition to the methoxymethyl group and the 2-methoxyethoxymethyl group. The protecting group for R ₆ , R ₇ , R ₁₂ , and R ₁₃ is preferably a stable group under acidic conditions, more preferably an acyl group, and particularly preferably an acetyl group. R ₉ , R ₁₀ , R ₁₅ , R ₁₆ , R
The protecting group for ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₂ , and R ₂₃ is preferably a substituted silyl group, more preferably a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, and t. -Butyldiphenylsilyl group and the like, and particularly preferable one is t-butyldimethylsilyl group.

The term "reducing conditions" means that a reducing agent is present in the reaction system. Examples of the reducing agent used here include borane and trialkylsilane, and preferably trialkylsilane. More preferred is triethylsilane. The basic condition means that a base is present in the reaction system, and the base used here may be any one capable of forming a thioalcoholate, and examples thereof include potassium hydroxide, sodium hydroxide and tetraborate. Examples thereof include sodium acid salt, and preferably sodium tetraborate.

As the substituent, for example, a halogen atom,
Examples thereof include a cyano group, a nitro group, a hydroxyl group, an alkoxy group, an amino group, a mercapto group and an acyloxy group. R
Particularly preferred examples of the substituents in ₈ , R ₁₁ , R ₁₄ , R ₂₁ and R ₂₄ include a hydroxyl group, an alkoxy group, an acyloxy group and the like, and a most preferred group is a hydroxyl group.

The compound of the present invention has a strong keratinocyte growth inhibitory action. The configuration at the 20-position and the configuration at the hydroxyl group of the compound of the present invention may be R, S or α, β. The 1-position is preferably substituted with a hydroxyl group, and the hydroxyl group is more preferably α-coordinated.

The compounds of the present invention are all novel compounds and are synthesized, for example, as follows. The thiol used as a starting material for the synthesis of the side chain beyond the 22nd position is described in Tokuhyo 5-50561.
Method or reaction route 1 described in JP-A-3

[Chemical 32] (Wherein, X represents a halogen atom, j represents an integer from 0 to 2, and k represents an integer from 2 to 5). That is, it can be obtained by using a halogenated ester as a raw material, reacting it with a metal salt of thiocarboxylic acid such as potassium thioacetate, and reacting with a Grignard reagent. It is also possible to obtain the compound by reducing or hydrolyzing the resulting compound under alkaline conditions by performing the reaction after the above reaction.

Of the compounds represented by the general formula (I), R
Those having ₂ hydrogen atoms are synthesized, for example, as follows. (Reaction path 2)

[Chemical 33] (In the formula, R ₂₉ represents an optionally substituted alkyl group having 1 to 10 carbon atoms)

The compound (6) used as a starting material can be prepared, for example, according to the method of Murayama et al. (Bioorg. Med. C).
hem. Lett. 2, 1289 (1992)). After deprotecting the hydroxyl-protecting group of the compound (6), the compound (8) is obtained by protecting again with an acyl group, preferably an acetyl group. By subjecting this compound (8) to a reductive thioalkylation reaction, a compound (9) is obtained. Reductive thioalkylation is, for example,
Boron trifluoride ether complex or boron trifluoride monohydrate, and a method of reacting triethylsilane, a method using a trifluoroacetic acid-borane pyridine complex, etc. are carried out, preferably boron trifluoride ether complex and It is carried out by a method of using triethylsilane. As the solvent used in this reaction, for example, a halogen-based solvent, an ether-based solvent, an aromatic hydrocarbon-based solvent and the like are used, preferably a halogen-based solvent, more preferably dichloromethane and the like. The reaction temperature varies depending on the kind of the compound used, the reagent, etc., but the temperature at which the 5,7-diene moiety does not isomerize is preferably from -30 ° C to room temperature, more preferably around 0 ° C, and the reaction time is the amount of the reagent and the compound used It is 1 to 12 hours, preferably 3 to 10 hours, and more preferably 5 to 7 hours.

Next, the obtained compound (9) is deprotected by a conventional method, diastereomers are separated if necessary, and then light irradiation and a thermal isomerization reaction are carried out by a conventional method to give compound (12). can get. If diastereomers are difficult to separate in this step, they can be separated by converting the protective groups for the hydroxyl groups at the 1-position, the 3-position, or both to appropriate protective groups, if necessary.

Of the compounds represented by the general formula (I), R
_{When 2} is a hydroxyl group, it is synthesized, for example, as follows. (Reaction path 3)

[Chemical 34] The compound (13) as a starting material is, for example, Muray.
ama et al. (Chem. Pharm. Bull. 3).
4, 4410 (1986)). First, an oxygen functional group is introduced at the 16-position of compound (13). Examples of the method of introducing an oxygen functional group include a method of reacting 2- (phenylsulfonyl) -3-phenyloxaziridine in the presence of a base and a method of introducing a halogen at the 16-position and then converting it into a hydroxyl group. However, a method of reacting 2- (phenylsulfonyl) -3-phenyloxaziridine in the presence of a base is preferable. Examples of the base used here include metal alkoxides, metal amides, metal hydrides, etc., preferably metal alkoxides, and more preferably potassium-t-butoxide.

A Wittig type reaction is carried out on the obtained compound (14) to obtain a mixture of E and Z of the compound (15), and then an oxidation reaction is carried out to obtain the compound (16). it can. This reaction is chromate,
It can be carried out by a usual oxidation reaction using dimethyl sulfoxide or the like, but an oxidation reaction by dimethyl sulfoxide or the like is preferable. In this step, the compound (1
When the mixture of E and Z in 5) is oxidized with manganese dioxide, E
The reaction proceeds only in the body to obtain the E-form compound (16). Here, the unreacted Z-form compound (15) is Swern.
Oxidation or the like can lead to the Z-form compound (16). (Reaction path 4)

[Chemical 35]

The E form of compound (15) can also be synthesized as follows. (Reaction path 5)

[Chemical 36] The compound (17) as a starting material is, for example, Murayama.
Et al. (Chem. Pharm. Bull. 34, 4).
410 (1986)). Compound (1
The 5,7-diene moiety of 7) is replaced with, for example, 4-phenyl-
After protection with a protecting group such as 1,2,4-triazoline-3,5-dione, oxidization with an oxidizing agent such as selenium dioxide, chromic acid, manganese (III) acetate, preferably selenium dioxide, followed by deprotection The E form of compound (15) is obtained.

The compound (20) is obtained by adding 1,4 of various thiols to the compound (16) obtained by the above method. For this reaction, a usual method of 1,4-addition reaction to α, β-unsaturated ketone can be applied. Examples thereof include a method of performing the reaction under basic conditions, preferably a method of using sodium hydroxide and sodium tetraborate, and more preferably a method of using sodium tetraborate. The solvent used here varies depending on the reagent used and the like, but when sodium tetraborate is used, an ether solvent, an alcohol solvent or the like is used alone or mixed with water, and preferably an ether solvent Examples thereof include a mixed solvent of water, and more preferable examples include a mixed solvent of tetrahydrofuran and water.

The reaction temperature varies depending on the reagents used and the like, but it is -20 to 60 ° C., preferably 0 to 40 ° C., more preferably 15 to 25 ° C., and the reaction time varies depending on the reagents and the amount of compounds used, but it is 3 to 24 hours. It is preferably 9 to 15 hours, more preferably 12 to 15 hours.

The obtained compound (20) can be converted to the compound (23) by reduction, deprotection, light irradiation and thermal isomerization by a conventional method. (Reaction path 6)

[Chemical 37] (In the formula, R ₃₀ represents an optionally substituted alkyl group having 1 to 10 carbon atoms)

[0022]

The present invention will be described in more detail with reference to the following examples.

[0023]

Example 1 4-Ethyl-4-hydroxy-1-hexanethiol Acetone (30 ml) in 4-bromobutyric acid ethyl ester (1.5 ml, 10.5 mmol) and potassium thioacetate (1.8 g, 15. (8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, filtered, and the solid was washed with acetone. The filtrate was concentrated and then purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to obtain 4-acetylthiobutyric acid ethyl ester (2.03 g). Next, ethylmagnesium bromide (1.04M tetrahydrofuran solution, 31.
3 ml, 32.6 mmol) was added, the mixture was cooled to 0 ° C., a solution of the compound 886 mg obtained above in dry tetrahydrofuran (4 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the reaction, quench with saturated ammonium chloride aqueous solution, 10%
-The solution was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (221 mg, 2 step 29).
%) Was obtained.

[0024]

Example 2 5-hydroxy-5-methyl-1-hexanethiol Dry tetrahydrofuran (80 m
l) Methylmagnesium bromide (0.99 M tetrahydrolaran solution, 70 ml, 69.3 mmol) was added, cooled to 0 ° C., and ethyl 5-bromovalerate (3.66 ml, 23.1 mmol) in dry tetrahydrofuran (10 ml) was added. ) The solution was added dropwise, stirred at room temperature for 1.5 hours, then quenched with saturated aqueous ammonium chloride solution,
The mixture was poured into water, extracted with ethyl acetate, the extract was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude 6-bromo-2-methyl-2-hexanol (5.2
8 g) was obtained. This was dissolved in acetone (80 ml), potassium thioacetate (3.96 g, 34.7 mmol) was added, the mixture was stirred at room temperature for 1.5 hr, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 6-
Acetylthio-2-methyl-2-hexanol (3.7
5 g) is obtained. Obtained 6-acetylthio-2-methyl-
2-Hexanol in tetrahydrofuran (130 ml)
Lithium aluminum hydride (2.24 g, 59.0 mmol) was added little by little at 0 ° C.
After stirring this suspension at room temperature for 1.5 hours, excess lithium aluminum hydride was treated with ethyl acetate, and the reaction solution was acidified with 4N-hydrochloric acid. This was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (2.95 g, 3ste).
p 85%).

[0025]

Example 3 6-Hydroxy-6-methyl-1-heptanethiol By the same procedure as in Example 2, the title compound was synthesized from ethyl 6-bromocaproate.

[0026]

Example 4 3-Hydroxy-3-n-propyl-1-
Hexanethiol By the same procedure as in Example 2, the title compound was synthesized from ethyl 3-bromopropionate and n-propylmagnesium bromide.

[0027]

Example 5 1α, 3β-Dihydroxy-20-oxopregna-5,7-diene Under an argon atmosphere, 1α, 3β-bis (t-butyldimethylsilyloxy) -20-oxopregna-5,7-
Diene (4.10 g, 7.33 mmol) was dissolved in dry tetrahydrofuran (80 ml), tetra-n-butylammonium fluoride (1M tetrahydrofwan solution, 74 ml, 74.0 mmol) was added, and the mixture was heated under reflux for 16 hours and then water. And extract with ethyl acetate, 10%-
The organic layer was washed with hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in that order, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane: ethanol 15: 1) to obtain the title compound (1.68 g, 69%) as a white solid.

[0028]

Example 6 1α, 3β-diacetoxy-20-oxopregna-5,7-diene The compound obtained in Example 5 (1.68 g, 5.08 mm)
ol) was dissolved in pyridine (60 ml), and acetic anhydride (3
0 ml) and 4-dimethylaminopyridine (DMAP,
60 mg) was added, and the mixture was stirred at room temperature for 4 days. After the reaction, the mixture was poured into water, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate 3: 1) gave the title compound as a white solid (1.65g, 78%). 281,292.

[0029]

Example 7 1α, 3β-diacetoxy-20- (3-
Hydroxy-3-methylbutylthio) pregna-5,7
-Diene (mixture of R-isomer and S-isomer at the 20th position) The compound obtained in Example 6 (100
mg, 0.241 mmol) and 3-methyl-3-hydroxy-1-butanethiol (34.7 mg, 0.28)
A solution of 9 mmol) in dry dichloromethane (0.5 ml) was cooled to 0 ° C. and boron trifluoride ether complex (35.
5 μl, 0.289 mmol) was added and stirred for 3 minutes, then triethylsilane (57.8 μl, 0.362 mmol)
Was added and the mixture was stirred at 0 ° C. for 5.5 hours. After the reaction, the mixture was poured into water, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was subjected to preparative thin-layer chromatography (2 pieces, dichloromethane: ethanol 2
Purification (0: 1, developed once) gave a colorless oily mixture of the title compound (55.7 mg, 45%). At this time, the raw material (43.3 mg, 35%) was also recovered.

[0030]

Example 8 1α, 3β-diacetoxy-20 (S)-
(4-Ethyl-4-hydroxyhexylthio) pregna-5,7-diene and 1α, 3β-diacetoxy-20
(R)-(4-Ethyl-4-hydroxyhexylthio)
Pregna-5,7-diene The compound obtained in Example 6 (150 mg, 0.361 m
mol), the compound obtained in Example 1 (73.0 mg,
0.450 mmol), boron trifluoride ether complex (55.3 μl, 0.450 mmol), dry dichloromethane (1 ml), triethylsilane (201 μl,
The same procedure as in Example 7 was performed using 1.26 mmol), and then preparative thin layer chromatography (4 sheets, dichloromethane:
Purification with ethyl acetate 9: 1, developed once), colorless oily mixture of the title compound (38.8 mg, 19%) and recovery 9
(89.4 mg) was obtained. The resulting mixture was further purified by preparative thin layer chromatography (4 sheets, dichloromethane: ethyl acetate 25: 1, developed 5 times) to give the 20S form (8.6 mg, 4%) and 20R form of the title compound. (2
1.1 mg, 10%) was obtained (all are colorless oils).

[0031]

Example 9 1α, 3β-diacetoxy-20- (4-
Hydroxy-4-methylpentylthio) pregna-5
7-Diene (mixture of R isomer and S isomer at the 20th position) Compound obtained in Example 6 (200 mg, 0.482 m
mol), 4-hydroxy-4-methylpentanethiol (77.6 mg, 0.578 mmol), boron trifluoride ether complex (71.0 μl, 0.578 mmo).
1), dry dichloromethane (1 ml), and triethylsilane (115 μl, 0.723 mmol) were used, and the same procedure as in Example 7 was performed, followed by preparative thin layer chromatography (4
Of the title compound as a colorless oil (93.3 mg, 3).
6%) and starting material (133 mg) were obtained.

[0032]

Example 10 1α, 3β-diacetoxy-20 (S)
-(3-Ethyl-3-hydroxypentylthio) pregna-5,7-diene and 1α, 3β-diacetoxy-20
(R)-(3-Ethyl-3-hydroxypentylthio)
Pregna-5,7-diene The compound obtained in Example 6 (180 mg, 0.434 m
mol), 3-ethyl-3-hydroxypentylthiol (85.7 mg, 0.578 mmol), boron trifluoride ether complex (71.0 μl, 0.578 mmo).
1), dry dichloromethane (1 ml), and triethylsilane (115 μl, 0.723 mmol) were used, and the same procedure as in Example 7 was performed, followed by preparative thin layer chromatography (4
Of the title compound (dichloromethane: ethyl acetate 9: 1, developed once) to obtain a colorless oily mixture of the title compound and raw material recovery (50.1 mg). The obtained mixture was further purified by preparative thin layer chromatography (4 sheets, dichloromethane: ethyl acetate 30: 1, developed 5 times) to give 20S form (12.5 mg, 5%) and 20R form of the title compound. (28.2 mg, 12%) was obtained (all are colorless oils)

[0033]

Example 11 1α, 3β-diacetoxy-20 (S)
-(5-Hydroxy-5-methylhexylthio) pregna-5,7-diene and 1α, 3β-diacetoxy-20
(R)-(5-hydroxy-5-methylhexylthio)
Pregna-5,7-diene The compound obtained in Example 6 (200 mg, 0.482 m
mol), the compound obtained in Example 2 (85.7 mg,
0.578 mmol), boron trifluoride ether complex (71.0 μl, 0.578 mmol), dry dichloromethane (1 ml), triethylsilane (115 μl,
0.723 mmol) and after the same operation as in Example 7,
The product was purified by preparative thin layer chromatography (4 sheets, dichloromethane: ethyl acetate 10: 1, developed 3 times), and the S-form (10.6 mg, 4%) and R-form (37.8) of the title compound were purified.
mg, 14%) (all are colorless oils).

[0034]

Example 12 1α, 3β-diacetoxy-20 (S)
-(6-Hydroxy-6-methylheptylthio) pregna-5,7-diene and 1α, 3β-diacetoxy-20
(R)-(6-hydroxy-6-methylheptylthio)
Pregna-5,7-diene The compound obtained in Example 6 (200 mg, 0.482 m
mol), the compound obtained in Example 3 (93.8 mg,
0.578 mmol), boron trifluoride ether complex (71.0 μl, 0.578 mmol), dry dichloromethane (1 ml), triethylsilane (115 μl,
0.723 mmol) and after the same operation as in Example 7,
It was purified by preparative thin layer chromatography (4 sheets, dichloromethane: ethyl acetate 7: 1, developed once) to obtain a colorless oily mixture of the title compound and thiol as a raw material, and raw material recovery (109 mg). The resulting mixture was purified by preparative thin layer chromatography (4 sheets, developed with dichloromethane: ethyl acetate 12: 1, 5 times) to give a mixture of the 20S isomer of the title compound and the starting thiol (33.9 m).
g) and 20R form of the title compound (26.4 mg, 10
%) (All are colorless oils). For the former, the following reaction was carried out while keeping the mixture.

[0035]

Example 13 1α, 3β-diacetoxy-20 (S)
-(3-Hydroxy-3-n-propylhexylthio)
Pregna-5,7-diene and 1α, 3β-diacetoxy-20 (R)-(3-hydroxy-3-n-propylhexylthio) pregna-5,7-diene The compound obtained in Example 6 (200 mg, 0.482m
mol), the compound obtained in Example 4 (102 mg,
0.578 mmol), boron trifluoride ether complex (71.0 μl, 0.578 mmol), dry dichloromethane (1 ml), triethylsilane (115 μl,
0.723 mmol) and after the same operation as in Example 7,
Purification by preparative thin layer chromatography (4 sheets, hexane: ethyl acetate: ethanol 4: 1: 0.1, developed once) gave a mixture of the title compounds as colorless oil (134 mg, 48).
%) And raw material recovery (48.1 mg). The resulting mixture was further purified by preparative thin layer chromatography (4 sheets, dichloromethane: ethyl acetate 30: 1, developed 4 times) to give 20S form of the title compound (23.6 mg, 9
%) And a 20R compound (78.2 mg, 28%) were obtained (all are colorless oils).

[0036]

Example 14 1α, Hydroxy-3β- (t-butyldimethylsilyloxy) -20 (S)-(4-hydroxy-4-methylpentylthio) pregna-5,7-diene and 1α, hydroxy-3β- (T-Butyldimethylsilyloxy) -20 (R)-(4-hydroxy-4-methylpentylthio) pregna-5,7-diene Compound obtained in Example 9 under argon atmosphere (mixture)
(93.3 mg, 0.175 mmol) was dissolved in dry tetrahydrofuran (4 ml), lithium aluminum hydride (13.3 mg, 0.350 mmol) was added little by little, and after stirring at room temperature for 30 minutes, 10% -sodium hydroxide aqueous solution was added. Quenched with, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was subjected to preparative thin-layer chromatography (two pieces, dichloromethane: ethanol 17: 3, 1,
(Development twice) to obtain 40.1 mg of a colorless solid. This was treated with dimethylformamide (2.6
ml), t-butyldimethylsilyl chloride (72.5 mg, 0.481 mmol) and imidazole (65.5 mg, 0.962 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the mixture was poured into water, extracted with hexane: ethyl acetate 3: 1, washed with brine and dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (2 sheets, hexane: ethyl acetate 5: 1, developed 6 times) to give 20% of the title compound.
S form (12.9 mg, 13%) and 20R form (23.7)
mg, 24%) (each is a colorless oil).

[0037]

Example 15 1α, 3β-Dihydroxy-20 (S)
-(3-Hydroxy-3-methylbutylthio) pregna-5,7-diene and 1α, 3β-dihydroxy-20
(R)-(3-Hydroxy-3-methylbutylthio) pregna-5,7-diene Under argon atmosphere, the compound (mixture) obtained in Example 7 (55.0 mg, 0.106 mmol) was dried with tetrahydrofuran ( 2 ml) dissolved and lithium aluminum hydride (8.0 mg, 0.212 mmo)
l) was added little by little and then stirred at room temperature for 30 minutes. Quench the reaction with 10% aqueous sodium hydroxide,
The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was subjected to preparative thin layer chromatography (1 sheet, dichloromethane:
The product was purified with ethanol 17: 1 (developed 8 times) to obtain 20S form (10.1 mg, 22%) and 20R form (19.3 mg, 42%) of the title compound (all colorless oils).

[0038]

Example 16 1α, 3β-dihydroxy-20 (S)
-(4-Ethyl-4-hydroxyhexylthio) pregna-5,7-diene 20S form obtained in Example 8 (8.6 mg, 15.3μ)
mol), dry tetrahydrofuran (1.5 ml), lithium aluminum hydride (1.7 mg, 46.
(0 μmol), the reaction was carried out in the same manner as in Example 15, and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 8: 1, developed once) to give the title compound as a white solid ( 5.7 mg, 78%) was obtained.

[0039]

Example 17 1α, 3β-Dihydroxy-20 (R)
-(4-Ethyl-4-hydroxyhexylthio) pregna-5,7-diene 20R form (21.1 mg, 37.6) obtained in Example 8
μmol), dry tetrahydrofuran (2 ml), lithium aluminum hydride (4.3 mg, 0.11)
3 mmol) and the reaction was carried out in the same manner as in Example 15 and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 8: 1, developed once) to give the title compound as a white solid ( 16.0 mg, 89%)
Got

[0040]

Example 18 1α, 3β-dihydroxy-20 (S)
-(4-Hydroxy-4-methylpentylthio) pregna-5,7-diene Under argon atmosphere, 20S isomer (1 obtained in Example 14)
2.9 mg, 22.9 μmol) was dissolved in dry tetrahydrofuran (1.5 ml), and tetra-n-butylammonium fluoride (1M tetrahydrofuran solution,
1 ml) was added, and the mixture was gently heated to reflux for 16 hours. After completion of the reaction, the mixture was poured into water, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 9: 1, developed once) to obtain the colorless oily title compound (7.7 mg, 75%).

[0041]

Example 19 1α, 3β-Dihydroxy-20 (R)
-(4-Hydroxy-4-methylpentylthio) pregna-5,7-diene The 20R compound (23.7 mg, 42.
1 μmol), dry tetrahydrofuran (1.5 m
Using 1) and tetra-n-butylammonium fluoride (1M tetrahydrofuran solution, 1 ml), the title compound (10.0 mg, 53%) was obtained as a colorless oil by the same procedure as in Example 18.

[0042]

Example 20 1α, 3β-Dihydroxy-20 (S)
-(3-Ethyl-3-hydroxypentylthio) pregna-5,7-diene The 20S isomer obtained in Example 10 (12.5 mg, 22.
9 μmo1), dry tetrahydrofuran (1 ml), lithium aluminum hydride (2.6 mg, 68.
(7 μmol) and the reaction was carried out in the same manner as in the synthesis of Example 15, followed by preparative thin layer chromatography (1
Of the title compound as a colorless oil (8.2 mg, 77).
%) Was obtained.

[0043]

Example 21 1α, 3β-Dihydroxy-20 (R)
-(3-Ethyl-3-hydroxypentylthio) pregna-5,7-diene The 20R compound (28.2 mg, 51.
6 μmol), dry tetrahydrofuran (2 ml), lithium aluminum hydride (5.9 mg, 0.1
55 mmol) and the reaction was carried out in the same manner as in Example 15, followed by preparative thin layer chromatography (1 sheet,
Purified by dichloromethane: ethanol 9: 1, developed once, colorless oily title compound (8.2 mg, 77%)
Got

[0044]

Example 22 1α, 3β-Dihydroxy-20 (S)
-(5-Hydroxy-5-methylhexylthio) pregna-5,7-diene The 20S form (10.6 mg, 19.
4 μmol), dry tetrahydrofuran (1 ml), lithium aluminum hydride (2.5 mg, 65.
(8 μmol), the reaction was carried out in the same manner as in Example 15, and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 7: 1, developed once) to give the title compound (white solid) (6.1 mg, 68%) was obtained.

[0045]

Example 23 1α, 3β-Dihydroxy-20 (R)
-(5-Hydroxy-5-methylhexylthio) pregna-5,7-diene The 20R form (36.5 mg, 69.
1 μmol), dry tetrahydrofuran (2 ml), lithium aluminum hydride (7.9 mg, 0.2
(07 mmol) was used and the reaction was carried out in the same manner as in Example 15, followed by preparative thin layer chromatography (1 sheet,
Purify with dichloromethane: ethanol 7: 1, developed once to give the title compound as a colorless oil (25.0 mg, 78).
%) Was obtained.

[0046]

Example 24 1α, 3β-dihydroxy-20 (S)
-(6-Hydroxy-6-methylheptylthio) pregna-5,7-diene A mixture of the 20S form obtained in Example 12 and the starting thiol (33.9 mg, dry tetrahydrofuran (1 m
l), lithium aluminum hydride (20.0m
(g, 0.527 mmol), the reaction was carried out in the same manner as in Example 15, and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 7: 1, developed once) to give a colorless oil. Of the title compound (5.8 m
g) was obtained.

[0047]

Example 25 1α, 3β-Dihydroxy-20 (R)
-(6-Hydroxy-6-methylheptylthio) pregna-5,7-diene The 20R form (26.4 mg, 47.
1 μmol), dry tetrahydrofuran (2 ml), lithium aluminum hydride (5.4 mg, 0.1
41 mmol), the reaction was carried out in the same manner as in the synthesis of Example 15, and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 7: 1, developed once) to give a colorless oily product. Compound (15.0m
g, 67%).

[0048]

Example 26 1α, 3β-Dihydroxy-20 (S)
-(3-Hydroxy-3-n-propylhexylthio)
Pregna-5,7-diene 20S form obtained in Example 13 (35.9 mg, 62.
4 μmol), dry tetrahydrofuran (3 ml), lithium aluminum hydride (7.1 mg, 0.1
87 mmol) and the reaction was carried out in the same manner as in Example 15, followed by preparative thin layer chromatography (1 sheet,
Purify by dichloromethane: ethanol 6: 1, developed once, and obtain the title compound as a colorless oil (21.4 mg, 70).
%) Was obtained.

[0049]

Example 27 1α, 3β-Dihydroxy-20 (R)
-(3-Hydroxy-3-n-propylhexylthio)
Pregna-5,7-diene 20R form (126 mg, 0.22) obtained in Example 13
0 mmol), dry tetrahydrofuran (10 ml),
Lithium aluminum hydride (25mg, 0.6
60 mmol) and the reaction was carried out in the same manner as in Example 15, followed by preparative thin layer chromatography (2 sheets,
Purify by dichloromethane: ethanol 6: 1, developed once, and obtain the title compound as a white solid (74.4 mg, 69).
%) Was obtained.

[0050]

Example 28 1α, 3β-Dihydroxy-20 (S)
-(3-Hydroxy-3-methylbutylthio) -9,1
0-secopregna-5,7,10 (19) -triene The 20S form obtained in Example 15 (10.1 mg, 23.
2 μmol) in ethanol (200 ml),
While bubbling argon at 0 ° C., light was irradiated for 2 minutes by a light passing through a 400 W high pressure mercury lamp Vycor filter, and then gently heated under reflux for 2 hours. Remove the solvent and purify by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 3 times),
The title compound (1.7 mg, 17%) was obtained as a colorless oil.

[0051]

Example 29 1 μ, 3β-dihydroxy-20 (R)
-(3-Hydroxy-3-methylbutylthio) -9,1
0-secopregna-5,7,10 (19) -triene 20R form obtained in Example 15 (19.3 mg, 44.
4 μmol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 3.75 minutes), followed by purification by preparative thin layer chromatography (1 sheet dichloromethane: ethanol 10: 1, developed 3 times), Colorless oily title compound (1.6 m
g, 8%) was obtained.

[0052]

Example 30 1α, 3β-Dihydroxy-20 (S)
-(4-Ethyl-4-hydroxyhexylthio) -9,
10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 16 (5.1 mg, 10.7 µ)
mol) was used in the same manner as in Example 28 (light irradiation for 1.5 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 9: 1, developed twice). , The title compound as a colorless oil (1.1 m
g, 22%).

[0053]

Example 31 1α, 3β-Dihydroxy-20 (R)
-(4-Ethyl-4-hydroxyhexylthio) -9,
10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 17 (16.0 mg, 33.6).
μmol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 2.5 minutes), and then preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 9: 1, developed 3 times → further hexane: Ethyl acetate: ethanol 5: 5:
The product was purified by 0.3 times development to give the title compound (2.2 mg, 14%) as a colorless oil.

[0054]

Example 32 1α, 3β-dihydroxy-20 (S)
-(4-hydroxy-4-methylpentylthio) -9,
10-Secopregna-5,7,10 (19) -triene Compound obtained in Example 18 (7.7 mg, 17.2 μ)
mol) was used in the same manner as in Example 28 (light irradiation for 1.75 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 9: 1, developed 3 times). , The title compound as a colorless oil (2.0 m
g, 26%).

[0055]

Example 33 1α, 3β-dihydroxy-20 (R)
-(4-hydroxy-4-methylpentylthio) -9,
10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 19 (10.0 mg, 22.3).
μmol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 1.25 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 9: 1, developed 3 times). , Colorless oily title compound (1.9 m
g, 19%).

[0056]

Example 34 1α, 3β-dihydroxy-20 (S)
-(3-Ethyl-3-hydroxypentylthio) -9,
10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 20 (8.2 mg, 17.7 μ).
mol) was used in the same manner as in the synthesis of Example 28 (light irradiation for 1.5 minutes), followed by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 9: 1, developed 3 times). Purified and colorless oily title compound (1.7 m
g, 21%).

[0057]

Example 35 1α, 3β-Dihydroxy-20 (R)
-(3-Ethyl-3-hydroxypentylthio) -9,
10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 21 (20.9 mg, 45.2).
μmol) and the reaction was carried out in the same manner as in the synthesis of Example 28 (light irradiation for 3.25 minutes), and then preparative thin layer chromatography (one piece, dichloromethane: ethanol 9: 1,
The product was purified 3 times → further developed with hexane: ethyl acetate: ethanol 5: 5: 0.3, 4 times) to give the title compound (2.3 mg, 11%) as a colorless oil.

[0058]

Example 36 1α, 3β-Dihydroxy-20 (S)
-(5-hydroxy-5-methylhexylthio) -9,
10-Secopregna-5,7,10 (19) -triene Compound obtained in Example 22 (6.1 mg, 13.2 μ)
mol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 1.75 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 12: 1, developed 3 times). , The title compound as a colorless oil (1.2 m
g, 20%).

[0059]

Example 37 1α, 3β-dihydroxy-20 (R)
-(5-hydroxy-5-methylhexylthio) -9,
10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 23 (25.0 mg, 54.0).
μmol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 3.5 minutes), and then preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 12: 1, developed 4 times → further hexane: Ethyl acetate: ethanol 5: 5:
0.1, developed three times) to obtain the title compound (2.3 mg, 9%) as a colorless oil.

[0060]

Example 38 1α, 3β-Dihydroxy-20 (S)
-(6-hydroxy-6-methylheptylthio) -9,
10-Secopregna-5,7,10 (19) -triene Compound obtained in Example 24 (5.8 mg, 12.2 μ)
mol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 1.75 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 12: 1, developed 4 times). , The title compound as a colorless oil (0.99
mg, 17%).

[0061]

Example 39 1α, 3β-dihydroxy-20 (R)
-(6-hydroxy-6-methylheptylthio) -9,
10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 25 (15.0 mg, 31.5
μmol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 2.5 minutes), and then preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 12: 1, developed 3 times → further hexane: Ethyl acetate: ethanol 5: 5:
0.1, 4 times development) to obtain the title compound (2.0 mg, 13%) as a colorless oil.

[0062]

Example 40 1α, 3β-Dihydroxy-20 (S)
-(3-Hydroxy-3-n-propylhexylthio)
-9,10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 26 (20.2 mg, 41.2).
μmol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 3.5 minutes), and then preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 3 times → further hexane: Ethyl acetate: ethanol 6: 4:
The product was purified by 0.5 times and developed 3 times) to give the title compound (1.8 mg, 9%) as a colorless oil.

[0063]

Example 41 1α, 3β-Dihydroxy-20 (R)
-(3-Hydroxy-3-n-propylhexylthio)
-9,10-Secopregna-5,7,10 (19) -triene The compound obtained in Example 27 (41.3 mg, 84.2).
μmol) and the reaction was carried out in the same manner as in Example 28 (light irradiation for 4.75 minutes), and then preparative thin layer chromatography (2 sheets, dichloromethane: ethanol 10: 1, developed 3 times → 1 more sheet). , Hexane: ethyl acetate: ethanol 6: 4: 0.5, developed three times) to obtain the title compound (4.6 mg, 11%) as a colorless oil.

[0064]

Example 42 1α, 3β-bis (t-butyldimethylsilyloxy) -16α-hydroxy-17-oxoandrosta-5,7-diene Under an argon atmosphere, potassium t-butoxide (4.1
A solution of 3 g, 36.8 mmol) in dry tetrahydrofuran (500 ml) was cooled to -78 ° C, and 1α,
3β-bis (t-butyldimethylsilyloxy) -17
-Oxoandrosta-5,7-diene (13.0 g,
24.5 mmol) of tetrahydrofuran (40 ml)
The solution was added dropwise and after stirring at that temperature for 1 hour, 2- (phenylsulfonyl) -3-phenyloxaziridine (9.62) was added.
g, 36.8 mmol) of tetrahydrofuran (40 m
l) The solution was added dropwise and further stirred at -78 ° C for 1.5 hours. Quench this with saturated aqueous ammonium chloride,
It was poured into water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, the precipitated solid was filtered, the filtrate was concentrated again, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform 7: 1: 2) to give the title compound as a white solid. (3.10 g, 23%) was obtained.

[0065]

Example 43 1α, 3β-bis (t-butyldimethylsilyloxy) -16α-hydroxypregna-5
7,17 (E) -triene and 1α, 3β-bis (t-butyldimethylsilyloxy) -16α-hydroxypregna-5,7,17 (Z) -triene Dry tetrahydrofuran (50 m
1) potassium t-butoxide (1.29 g, 11.
4 mmol) and ethyltriphenylphosphonium bromide (4.28 g, 11.4 mmol) were added, and the temperature was 60 ° C.
After stirring for 1.5 hours at room temperature, the temperature was returned to room temperature, a solution of the compound (2.10 g, 3.84 mmol) obtained in Example 42 in tetrahydrofuran (20 ml) was added, and the mixture was stirred at 60 ° C. for 1 hour again. This was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 7: 1) to obtain the title compound E form (375 mg, 18%), Z form (351 mg, 16%) and a mixture of the two (14
2 mg, 6%) was obtained.

[0066]

Example 44 1α, 3β-bis (t-butyldimethylsilyloxy) -16-oxopregna-5,7,17
(E) -triene Trichloromethyl chloroformate (11
8 μl, 0.68 mmol) of dry dichloromethane (3
ml) solution was cooled to −78 ° C., dimethylsulfoxide (186 μl, 2.61 mmol) was added, and the mixture was stirred for 5 minutes, and then E form (350) of the compound obtained in Example 43
mg, 0.63 mmol) of dry dichloromethane (2 m
l) The solution was added dropwise. After stirring at −78 ° C. for 15 minutes, triethylamine (435 μl, 3.10 mmol) was added, and the mixture was stirred at −78 ° C. for 15 minutes and at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into water, extracted with dichloromethane, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate 5
(0: 3) and the title compound (147m
g, 42%).

[0067]

Example 45 1α, 3β-Bis (t-butyldimethylsilyloxy) -16-oxopregna-5,7,17
(Z) -Triene Z-form of the compound obtained in Example 43 (347 mg, 0.
62 mmol) in dry dichloromethane (2 ml),
Trichloromethyl chloroformate (118 μl, 0.68 m
mol) in dry dichloromethane (3 ml), dimethyl sulfoxide (186 μl, 2.61 mmol), and triethylamine (435 μl, 3.10 mmo).
Using l) and following the same procedure as in Example 44 gave the title compound (111 mg, 32%) as a pale yellow solid.

[0068]

EXAMPLE 46 1α, 3β-Bis (t-butyldimethylsilyloxy) -16-oxopregna-5,7,17
(E) -Triene A mixture of the E-form and the Z-form of the compound obtained in Example 43 (mixture of about 1: 1, 1.76 g, 3.15 mmol) was dissolved in chloroform (150 ml), and manganese dioxide (70 g) was added. ) Was added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated and then purified by silica gel column chromatography (hexane: ethyl acetate: chloroform 84: 6: 1) to give the title compound (879 mg, 50%) as a white solid and the Z-form of the starting material. (Recovery, 5
60 mg, 32%) was obtained.

[0069]

EXAMPLE 47 1α, 3β-Bis (t-butyldimethylsilyloxy) -16-oxopregna-5,7,17
(Z) -Triene Z-rest (533 mg, 0.95 m recovered in Example 46.
mol) in dry dichloromethane (1.5 ml), bis (trichloromethyl) carbonate (312 mg,
1.05 mmol) in dry dichloromethane (3 ml), dimethyl sulfoxide (284 μl, 4.00 mm
ol), and triethylamine (666 μl, 4.7
8 mmol) and the reaction was carried out in the same manner as in Example 44, followed by purification by silica gel column chromatography (hexane: ethyl acetate 14: 1) to obtain the title compound (333 mg, 63%) as a pale yellow solid.

[0070]

Example 48 1α, 3β-Bis (t-butyldimethylsilyloxy) pregna-5,7,17 (E) -triene 4-phenyl-1,2,4-triazoline-3,5
-Dione adduct 1α, 3β-bis (t-butyldimethylsilyloxy)
Pregna-5,7,17 (E) -triene (1.00
g, 1.84 mmol) of dichloromethane (90 ml)
4-phenyl-1,2,4-triazoline-3, in solution
A solution of 5-dione (330 mg, 1.88 mmol) in dichloromethane (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, the solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate 150: 1) to give a pale yellow solid. The title compound (1.02 g, 77%) was obtained.

[0071]

Example 49 1α, 3β-Bis (t-butyldimethylsilyloxy) -16α-hydroxypregna-5
4-phenyl-1,2,4 of 7,17 (E) -triene
-Triazoline-3,5-dione adduct The compound obtained in Example 48 (931 mg, 1.3 mm)
Ol) was dissolved in dichloromethane (40 ml), selenium dioxide (5.1 mg, 45.5 μmol) and t-butyl hydroperoxide (70%, 422 mg, 4.6).
8 mmol) was added and the mixture was stirred at room temperature for 27 hours. The reaction solution was diluted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate 20: 1) to obtain a pale yellow solid title compound (885 mg, 92%).

[0072]

Example 50 1α, 3β-Bis (t-butyldimethylsilyloxy) -16α-hydroxypregna-5
7,17 (E) -triene The compound obtained in Example 49 (80.0 mg, 109μ)
(mol) was dissolved in 1,3-dimethyl-2-imidazolidinone (6 ml), and the mixture was heated with stirring at 140 ° C. for 16 hours. This was poured into water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to preparative thin layer chromatography (1
The product was purified by a single step, hexane: ethyl acetate 4: 1, developed once to obtain the title compound (39.2 mg, 64%).

[0073]

Example 51 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (S)-(3-hydroxy-3-
Methylbutylthio) -16-oxopregna-5,7-
Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (R)-(3-hydroxy-3-methylbutylthio) -16-oxopregna-5,7-diene Compound obtained in Example 44 (140 mg, 251 μm
ol) in tetrahydrofuran (4 ml),
1M-Sodium tetraborate (4 ml) and 3-hydroxy-3-methylbutanethiol (121 μl) were added, and the mixture was stirred at room temperature for 12 hours, water was added, the mixture was extracted with chloroform, washed with saturated brine and dried over anhydrous magnesium sulfate. did. After distilling off the solvent under reduced pressure, preparative thin layer chromatography (3
Of the title compound as a white solid (115.mg, 6)
8%), and colorless oily R-form (52.0 mg, 31%)
Got

[0074]

Example 52 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (S)-(3-hydroxy-3-
Methylbutylthio) -16-oxopregna-5,7-
Diene and 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (R)-(3-hydroxy-3-methylbutylthio) -16-oxopregna-5,7-diene An example similar to Example 51 Compound obtained in 45 (8
0.0 mg, 144 μmol), 0.1 M-sodium tetraborate (2.3 ml), 3-hydroxy-3-methylbutanethiol (80 μl), tetrahydrofuran (2.3 ml) were reacted in the same manner, and the reaction was carried out. Preparative thin layer chromatography (2 sheets, hexane: ethyl acetate 3:
S-form (1) of the title compound
3.6 mg, 14%), R form (62.5 mg, 64%)
Got

[0075]

Example 53 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (S)-(4-ethyl-4-hydroxyhexylthio) -16-oxopregna-5,7
-Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (R)-(4-ethyl-4-hydroxyhexylthio) -16-oxopregna-5,7-diene Obtained in Example 44. Compound (110 mg, 197 μm
ol, 0.1 M-sodium tetraborate (3 ml), 4-
Ethyl-4-hydroxyhexanethiol (100μ
Example 5 using l) and tetrahydrofuran (3 ml)
After carrying out the reaction by the same operation as in 1, the preparative thin layer chromatography (2 sheets, dichloromethane: ethyl acetate: ethanol 15: 1: 0.1, developed twice, further 2 sheets,
Purification by hexane: ethyl acetate 4: 1, developed 5 times) to give S-form (64.2 mg, 45%) N- and R-forms (8.1 mg, 6%) of the title compound. In addition, Example 45
The compound obtained in (90.0 mg, 162 μmol),
0.1 M-sodium tetraborate (2.5 ml), 4-ethyl-4-hydroxyhexanethiol (90 μl),
Example 51 using tetrahydrofuran (2.5 ml)
After the reaction was performed by the same procedure as in (1), the product was purified by preparative thin-layer chromatography (2 sheets, dichloromethane: ethyl acetate: ethanol 15: 1: 0.1, developed twice) to give the S-form (trace) of the title compound. ), And R form (49.9)
mg, 45%).

[0076]

Example 54 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (S)-(4-hydroxy-4-)
Methylpentylthio) -16-oxopregna-5,7
-Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (R)-(4-hydroxy-4-methylpentylthio) -16-oxopregna-5,7-diene Obtained in Example 44. Compound (100 mg, 180 μm
ol), 0.1 M sodium tetraborate (3 ml), 4
-Hydroxy-4-methyl-1-pentanethiol (1
00 μl) and tetrahydrofuran (3 ml) were used to carry out the reaction in the same manner as in Example 51, and then preparative thin layer chromatography (2 sheets, hexane: ethyl acetate 3: 2).
Purified by developing once or three times to obtain S-form (8
5.8 mg, 69%) and R-form (19.7 mg, 1)
6%) was obtained. In addition, the compound (8
Example 51 using 0.0 mg, 144 μmol), 0.1 M sodium tetraborate (2.3 ml), 4-hydroxy-4-methyl-1-pentanethiol (100 μl), and tetrahydrofuran (2.3 ml). After performing the reaction by the same operation, the product was purified by preparative thin-layer chromatography (2 sheets, hexane: ethyl acetate 3: 1, developed 3 times), and the S form (trace) of the title compound and R were obtained.
The body (91.7 mg, 92%) was obtained.

[0077]

Example 55 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (S)-(3-ethyl-3-hydroxypentylthio) -16-oxopregna-5,7
-Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (R)-(3-ethyl-3-hydroxypentylthio) -16-oxopregna-5,7-diene Obtained in Example 44. Compound (152 mg, 273 μm
ol), 0.1 M sodium tetraborate (4.2 m
l), 3-ethyl-3-hydroxy-1-pentanethiol (140 μl), tetrahydrofuran (4.2 m)
l) was used and the reaction was carried out in the same manner as in Example 51, and then preparative thin layer chromatography (2 sheets, hexane:
Ethyl acetate 3: 1, developed 3 times → 2 more, dichloromethane: ethyl acetate: ethanol 15: 1: 0.1, 2
The product was purified by the following process and the S form of the title compound (100 m
g, 52%) and R form (17.7 mg, 9%) were obtained. In addition, the compound obtained in Example 45 (42.1 m
g, 75.6 μmol), 0.1 M sodium tetraborate (1.2 ml), 3-ethyl-3-hydroxy-1-
Using pentanethiol (40 μl) and tetrahydrofuran (1.2 ml), the reaction was carried out in the same manner as in Example 51, and then preparative thin layer chromatography (1 sheet,
Purified with hexane: ethyl acetate 4: 1, 3 times), and the S form (trace) and R form (3
(4.3 mg, 64%) was obtained.

[0078]

Example 56 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (S)-(3-hydroxy-3-
Methylbutylthio) -16β-hydroxypregna
5,7-Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (S)-(3-hydroxy-3
-Methylbutylthio) -16α-hydroxypregna-
5,7-Diene 20S isomer of the compound obtained in Example 51 (113 mg,
167 μmol) to tetrahydrofuran (3.5 ml)
Dissolved in lithium aluminum hydride (10.
1 mg, 266 μmol) was added little by little, and the mixture was stirred at room temperature for 30 minutes, quenched with 10% aqueous sodium hydroxide solution, added water, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. did. The solvent was distilled off under reduced pressure and the resulting residue was subjected to preparative thin-layer chromatography (2 sheets, hexane: ethyl acetate 1: 1, developed twice).
The white solid, the β-form of the title compound (73.4
mg, 65%) and colorless oily α-form (22.0 mg, 1
9%) was obtained.

[0079]

Example 57 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (R)-(3-hydroxy-3-
Methylbutylthio) -16β-hydroxypregna
5,7-Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (R)-(3-hydroxy-3
-Methylbutylthio) -16α-hydroxypregna-
5,7-Diene 20R form (51.7 m) of the compound obtained in Example 51
g, 76.3 μmol), tetrahydrofuran (1.5
ml), lithium aluminum hydride (4.6m
g, 122 μmol), the reaction was carried out in the same manner as in Example 56, and then purified by preparative thin layer chromatography (1 sheet, hexane: ethyl acetate 1: 1, developed twice),
Β-form of the title compound as a colorless oil (13.2 mg, 25%)
And a colorless oily α-form (10.1 mg, 19%) were obtained.

[0080]

Example 58 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (S)-(4-ethyl-4-hydroxyhexylthio) -16β-hydroxypregna
5,7-Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (S)-(4-ethyl-4-hydroxyhexylthio) -16α-hydroxypregna-5,7-diene Example 20S form of the compound obtained in 53 (61.0 m
g, 84.8 μmol), tetrahydrofuran (2.4
ml), lithium aluminum hydride (5.2 m
g, 136 μmol), a reaction was performed in the same manner as in Example 56, and then purified by preparative thin layer chromatography (1 sheet, hexane: ethyl acetate 3: 1, developed 3 times),
Β-form of the title compound as a colorless oil (40.4 mg, 66%)
And a colorless oily α-form (121 mg, 20%) were obtained.

[0081]

Example 59 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (R)-(4-ethyl-4-hydroxyhexylthio) -16β-hydroxypregna
5,7-Diene 20R form (49.9 m) of the compound obtained in Example 53
g, 69.4 μmol), tetrahydrofuran (2.0
ml, lithium aluminum hydride (4.2m
g, 111 μmol), the reaction was performed in the same manner as in Example 56, and then purified by preparative thin layer chromatography (2 sheets, hexane: ethyl acetate 3: 1, developed 3 times),
The title compound (36.7 mg, 73%) was obtained as a colorless oil.

[0082]

Example 60 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (S)-(4-hydroxy-4-)
Methylpentylthio) -16β-hydroxypregna
5,7-Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (S)-(4-hydroxy-4
-Methylpentylthio) -16α-hydroxypregna-5,7-diene 20S form (85.0 m) of the compound obtained in Example 54
g, 123 μmol), tetrahydrofuran (2.5 m
l), lithium aluminum hydride (7.5m
g, 197 μmol) and the reaction was carried out in the same manner as in Example 56, followed by preparative thin layer chromatography (1 sheet, hexane: ethyl acetate 1: 1, developed 3 times → 1 sheet, dichloromethane: ethanol 30: Purified by developing once or five times, and is a colorless oily β-form of the title compound (58.3 mg, 68).
%) And a colorless oily α-form (9.7 mg, 11%) were obtained.

[0083]

Example 61 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (R)-(4-hydroxy-4-)
Methylpentylthio) -16β-hydroxypregna
5,7-Diene 20R form (91.1 m) of the compound obtained in Example 54
g, 132 μmol), tetrahydrofuran (2.5 m
l), lithium aluminum hydride (8.0m
g, 211 μmol) and a reaction similar to the synthesis of Example 56, followed by preparative thin layer chromatography (2
Sheet, dichloromethane: ethanol 20: 1, developed 5 times)
And the colorless oily title compound (57.0 mg,
62%) was obtained.

[0084]

EXAMPLE 62 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (S)-(3-ethyl-3-hydroxypentylthio) -16β-hydroxypregna
5,7-Diene and 1α, 3β-bis (t-butyldimethylsilyloxy) -20 (S)-(3-ethyl-3-hydroxypentylthio) -16α-hydroxypregna-5,7-diene Example 55S compound 20S (98.8m
g, 140 μmol), tetrahydrofuran (50 m
l), lithium aluminum hydride (8.5m
g, 224 μmol), followed by a reaction similar to the synthesis of Example 56, followed by preparative thin layer chromatography (2
Of the title compound as a colorless oil (42.6 mg, 4)
3%) and a colorless oily α-form (12.2 mg, 12%) were obtained.

[0085]

Example 63 1α, 3β-Bis (t-butyldimethylsilyloxy) -20 (R)-(3-ethyl-3-hydroxypentylthio) -16β-hydroxypregna
5,7-Diene 20R form (33.3 m) of the compound obtained in Example 55
g, 47.2 mol), tetrahydrofuran (1.1 m
l), lithium aluminum hydride (2.9m
g, 75.2 μmol), followed by a reaction similar to the synthesis of Example 56, followed by purification by preparative thin layer chromatography (1 sheet, hexane: ethyl acetate 3: 1, developed 3 times), Colorless oily title compound (18.2 mg, 55
%) Was obtained.

[0086]

Example 64 20 (S)-(3-Hydroxy-3-methylbutylthio) -1α, 3β, 16β-trihydroxypregna-5,7-diene The compound obtained in Example 56 under an argon atmosphere. Of 16
The β-form (70.1 mg, 103 μmol) was dissolved in dry tetrahydrofuran (1.1 ml), tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.1 ml) was added, and the mixture was gently heated under reflux for 16 hours. Pour this in water and extract with ethyl acetate.
% -Hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 5: 1, developed once) to give the title compound as a colorless oil (41.1 m
g, 89%).

[0087]

Example 65 20 (S)-(3-Hydroxy-3-methylbutylthio) -1α, 3β, 16α-trihydroxypregna-5,7-diene The 16α form of the compound obtained in Example 56 ( 22.0m
g, 32.4 μmol), dry tetrahydrofuran (1.1 ml), tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.1 ml)
And after carrying out the reaction in the same manner as in Example 64,
Purification by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 5: 1, developed once) gave the title compound (11.5 mg, 79%) as a colorless oil.

[0088]

Example 66 20 (R)-(3-Hydroxy-3-methylbutylthio) -1α, 3β, 16β-trihydroxypregna-5,7-diene The 16β form of the compound obtained in Example 57 ( 55.1m
g, 81.1 μmol) dry tetrahydrofuran (1.
0 ml) and tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml) were used to carry out the reaction in the same manner as in Example 64, and then the preparative thin layer chromatography (1 sheet, dichloromethane). : Ethanol 5: 1, developed once to give the title compound (31.9 mg, 88%) as a colorless oil.

[0089]

Example 67 20 (R)-(3-Hydroxy-3-methylbutylthio) -1α, 3β, 16α-trihydroxypregna-5,7-diene The 16α form of the compound obtained in Example 57 (15) .8m
g, 23.3 μmol), dry tetrahydrofuran (1.0 ml), tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 0.8 ml)
And after carrying out the reaction in the same manner as in Example 64,
Purification by preparative thin-layer chromatography (1 sheet, dichloromethane: ethanol 5: 1, developed once) gave the title compound (8.6 mg, 82 :) as a colorless oil.

[0090]

Example 68 20 (S)-(4-Ethyl-4-hydroxyhexylthio) -1α, 3β, 16β-trihydroxypregna-5,7-diene The 16β form of the compound obtained in Example 58 ( 36.5m
g, 50.6 μmol), dry tetrahydrofuran (1.
0 ml) and tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml), the reaction was performed in the same manner as in Example 64, and then preparative thin layer chromatography (1 sheet, dichloromethane: Purification by ethanol 16: 3 (developed once) gave the title compound (21.3 mg, 86%) as a colorless oil.

[0091]

Example 69 20 (S)-(4-Ethyl-4-hydroxyhexylthio) -1α, 3β, 16α-trihydroxypregna-5,7-diene The 16α form of the compound obtained in Example 58 ( 12.0m
g, 16.6 μmol), dry tetrahydrofuran (1.0 ml), tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml)
And after carrying out the reaction in the same manner as in Example 64,
Purification by preparative thin-layer chromatography (1 sheet, dichloromethane: ethanol 16: 3, developed once) gave the title compound (6.3 mg, 77%) as a colorless oil.

[0092]

Example 70 20 (R)-(4-Ethyl-4-hydroxyhexylthio) -1α, 3β, 16β-trihydroxypregna-5,7-diene The compound obtained in Example 59 (34.0 mg) , 47.1
mol), dry tetrahydrofuran (1.0 ml) and tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml), and Example 64.
After carrying out the reaction by the same procedure as described above, preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 16:
Purified by 3 times and 1 time), and the title compound (1
2.1 mg, 52%) was obtained.

[0093]

Example 71 20 (S)-(4-Hydroxy-4-methylpentylthio) -1α, 3β, 16β-trihydroxypregna-5,7-diene The 16β form of the compound obtained in Example 60 ( 58.3m
g, 84.1 μmol), dry tetrahydrofuran (1.0 ml), tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml)
And after carrying out the reaction in the same manner as in Example 64,
Purification by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 5: 1, developed once) gave the title compound (22.9 mg, 59%) as a colorless oil.

[0094]

Example 72 20 (S)-(4-Hydroxy-4-methylpentylthio) -1α, 3β, 16α-trihydroxypregna-5,7-diene The 16α form of the compound obtained in Example 60 ( 9.7 mg,
14.0 μmol), dry tetrahydrofuran (1.0
ml) and tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml), the reaction was carried out in the same manner as in Example 64, and then preparative thin layer chromatography (1 sheet, dichloromethane: Purification by ethanol (5: 1, developed once) gave the title compound (4.6 mg, 71%) as a colorless oil.

[0095]

Example 73 20 (R)-(4-Hydroxy-4-methylpentylthio) -1α, 3β, 16β-trihydroxypregna-5,7-diene The compound obtained in Example 61 (57.0 mg). , 82.2
μmol), dry tetrahydrofuran (1.0 ml),
Example 6 using tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml)
After carrying out the reaction by the same operation as in 4, the preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 5:
The product was purified by once and developed once to obtain the title compound (30.4 mg, 80%) as a colorless oil.

[0096]

Example 74 20 (S)-(3-Ethyl-3-hydroxypentylthio) -1α, 3β, 16β-trihydroxypregna-5,7-diene The 16β form of the compound obtained in Example 62 ( 42.6m
g, 60.2 μmol), dry tetrahydrofuran (1.0 ml), tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.2 ml)
And after carrying out the reaction in the same manner as in Example 64,
Purification by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 5: 1, developed once) gave the title compound (23.9 mg, 83%) as a colorless oil.

[0097]

Example 75 20 (S)-(3-Ethyl-3-hydroxypentylthio) -1α, 3β, 16α-trihydroxypregna-5,7-diene The 16α form of the compound obtained in Example 62 ( 12.2m
g, 17.2 μmol), dry tetrahydrofuran (1.0 ml), tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml)
And after carrying out the reaction in the same manner as in Example 64,
Purification by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 5: 1, developed once) gave the title compound (6.3 mg, 77%) as a colorless oil.

[0098]

Example 76 20 (R)-(3-Ethyl-3-hydroxypentylthio) -1α, 3β, 16α-trihydroxypregna-5,7-diene The compound obtained in Example 63 (18.0 mg) , 25.5
μmol), dry tetrahydrofuran (1.0 ml),
Example 6 using tetra-n-butylammonium fluoride (1M-tetrahydrofuran solution, 1.0 ml)
After carrying out the reaction by the same operation as in 4, the preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 5:
The product was purified by once and developed once to give the title compound (8.5 mg, 70%) as a colorless oil.

[0099]

Example 77 20 (S)-(3-Hydroxy-3-methylbutylthio) -1α, 3β, 16β-trihydroxy-9,10-secopregna-5,7,10 (19)-
Triene Compound obtained in Example 64 (40.2 mg, 89.2)
μmol) dissolved in ethanol (200 ml),
While bubbling with argon, light was irradiated for 2.5 minutes by a 400 W high pressure mercury lamp Vycor filter transmitted light, and then gently heated under reflux for 2 hours. The solvent was distilled off, and the residue was purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 5: 1, developed 3 times) to obtain the title compound as a colorless oil (4.6 mg, 11%).

[0100]

Example 78 20 (S)-(3-Hydroxy-3-methylbutylthio) -1α, 3β, 16α-trihydroxy-9,10-secopregner 5,7,10 (19)-
Triene Compound obtained in Example 65 (11.5 mg, 25.5
μmol) and the reaction was carried out in the same manner as in Example 77 (light irradiation for 2.5 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 6: 1, developed 5 times). , Colorless oily title compound (0.7 m
g, 6%) was obtained.

[0101]

Example 79 20 (R)-(3-Hydroxy-3-methylbutylthio) -1α, 3β, 16β-trihydroxy-9,10-secopregna-5,7,10 (19)-
Triene Compound obtained in Example 66 (31.9 mg, 70.8
μmol) in the same manner as in Example 77 (light irradiation for 2.5 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 6: 1, developed twice). , The title compound as a colorless oil (3.5 m
g, 11%).

[0102]

Example 80 20 (R)-(3-Hydroxy-3-methylbutylthio) -1α, 3β, 16α-trihydroxy-9,10-secopregna-5,7,10 (19-triene In Example 67) Obtained compound (8.6 mg, 19.1 μ)
mol) and the reaction was carried out in the same manner as in Example 77 (light irradiation for 2.0 minutes), followed by purification by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 6: 1, developed 5 times). , The title compound as a colorless oil (1.3 m
g, 15%).

[0103]

Example 81 20 (S)-(4-Ethyl-4-hydroxyhexylthio) -1α, 3β, 16α-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 68 (21.3 mg, 43.2)
μmol) and the reaction was carried out in the same manner as in Example 77 (light irradiation for 2.5 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethantan: ethanol 10: 1, developed 3 times). The colorless oily title compound (3.9 m
g, 18%).

[0104]

Example 82 20 (S)-(4-Ethyl-4-hydroxyhexylthio) -1α, 3β, 16α-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 69 (6.3 mg, 12.7 μ)
mol) was used in the same manner as in Example 77 (light irradiation for 1.75 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 5 times). , The title compound as a colorless oil (1.3 m
g, 21%).

[0105]

Example 83 20 (R)-(4-Ethyl-4-hydroxyhexylthio) -1α, 3β, 16α-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 70 (12.1 mg, 24.6)
μmol) in the same manner as in Example 77 (light irradiation 1.75 minutes), and then purified by preparative thin-layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 3 times). , The title compound as a colorless oil (1.5 m
g, 12%).

[0106]

Example 84 20 (S)-(4-Hydroxy-4-methylpentylthio) -1α, 3β, 16β-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 71 (22.9 mg, 49.2)
μmol) and the reaction was carried out in the same manner as in Example 77 (light irradiation for 2.5 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 7 times). , The title compound as a colorless oil (2.4 m
g, 10%) was obtained.

[0107]

Example 85 20 (S)-(4-Hydroxy-4-methylpentylthio) -1α, 3β, 16α-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 72 (5.9 mg, 12.7 μ)
mol) was used in the same manner as in Example 77 (light irradiation for 1.25 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 5 times). , The title compound as a colorless oil (0.5 m
g, 8%) was obtained.

[0108]

Example 86 20 (R)-(4-hydroxy-4-methylpentylthio) -1α, 3β, 16β-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 73 (18.3 mg, 39.4)
μmol) and the same reaction as in Example 77 (light irradiation: 2.25 minutes), followed by purification by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 5 times), and colorless Oily title compound (1.5 m
g, 8%) was obtained.

[0109]

Example 87 20 (S)-(3-Ethyl-3-hydroxypentylthio) -1α, 3β, 16β-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 74 (23.9 mg, 49.9)
μmol) in the same manner as in Example 77 (light irradiation for 2.5 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 6 times). , The title compound as a colorless oil (4.3 m
g, 18%).

[0110]

Example 88 20 (S)-(3-Ethyl-3-hydroxypentylthio) -1α, 3β, 16α-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 75 (6.3 mg, 13.2μ
mol) was used in the same manner as in Example 77 (light irradiation for 1.5 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: methanol 10: 1, developed 8 times). , Colorless oily title compound (1.0 m
g, 18%).

[0111]

Example 89 20 (R)-(3-Ethyl-3-hydroxypentylthio) -1α, 3β, 16β-trihydroxy-9,10-secopregna-5,7,10 (19)
-Triene Compound obtained in Example 76 (8.5 mg, 17.8 μ)
mol) was used and the reaction was carried out in the same manner as in Example 77 (light irradiation for 1.75 minutes), and then purified by preparative thin layer chromatography (1 sheet, dichloromethane: ethanol 10: 1, developed 8 times). , The title compound as a colorless oil (1.1 m
g, 13%) was obtained.

[0112]

[Test Example 1] Growth inhibition experiment of human keratinocytes 1) Human keratinocytes were plated at a density of 2.4 × 10 ^{3 / well (} 0.32 cm ² ) on a 96-well plate plated with X2 treated J2 cells. After plating, add each concentration of drug and add K
GM / DMEM (1: 1) medium for 3 days at 37 ° C, 5% C
The culture was performed with O ₂ and 95% air. 2) [ ³ H] thymidine was added to a final concentration of 1 μCi / ml, and the cells were further cultured for 3 days. 3) After washing twice with PBS, the cells were peeled off with 0.25% trypsin, and beta plates (pharmacia) were used.
The amount of [ ³ H] thymidine incorporated into DNA was measured using a product manufactured by KK The incorporation amount of [ ³ H] thymidine when no drug was added was defined as 100%, and the ratio of the incorporation amount at each drug concentration is shown in the figure. 1α, 25-
The results of dihydroxyvitamin D ₃ and the compound obtained in Example 88 are shown in FIGS. 1 and 2, respectively.

[0113]

[Test Example 2] 1) Human keratinocytes were plated on a 96-well plate at a cell number of 2.2 × 10 ^{3 / well (} 0.32 cm ² ), and then each concentration of a drug was added to the KG.
M / DMEM (1: 1) medium for 1 day at 37 ℃, 5% CO
_The culture was performed at 2,95% air. 2) [ ³ H] thymidine was added to a final concentration of 1 μCi / ml, and the cells were further cultured for 3 days. 3) After washing twice with PBS, the cells were peeled off with 0.25% trypsin, and beta plates (pharmacia) were used.
The amount of [ ³ H] thymidine incorporated into DNA was measured with the use of the same company), and the amount of [ ³ H] thymidine incorporated when the agent was not added was defined as 100%. Is shown in the figure. The results of 1α, 25-dihydroxyvitamin D ₃ , the compound obtained in Example 33 and the compound obtained in Example 35 are shown in FIGS. 3, 4 and 5, respectively. In the graphs of FIGS. 1 to 5, * indicates a significant difference at a risk rate of 5%, ** at 1% and *** at 0.1%. As is clear from FIGS. 1 to 5, the compound of the present invention has a strong human keratinocyte growth inhibitory activity.

[0114]

INDUSTRIAL APPLICABILITY The vitamin D derivative of the present invention in which the 22-position is substituted with a sulfur atom has a strong keratinocyte growth inhibitory action.

[Brief description of drawings]

FIG. 1 shows the growth inhibitory effect of human keratinocytes at various concentrations of 1α, 25-dihydroxyvitamin D ₃ .

FIG. 2 shows human keratinocyte growth inhibitory effects at various concentrations of the compound of Example 88.

FIG. 3 shows the human keratinocyte proliferation inhibitory effect of 1α, 25-dihydroxyvitamin D ₃ at various levels.

FIG. 4 shows the growth inhibitory effect of human keratinocytes at various concentrations of the compound of Example 33.

FIG. 5 shows human keratinocyte growth inhibitory effects at various concentrations of the compound of Example 35.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display area C07J 31/00 7433-4C 51/00 7433-4C 75/00 7433-4C

Claims (36)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ₁ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, R ₂ represents a hydrogen atom or a hydroxyl group, and R ₃ represents a hydrogen atom or a hydroxyl group.) The compound represented by. 2. The compound according to claim 1, wherein R ₃ is a hydroxyl group. 3. The compound according to claim 2, wherein R ₁ is an alkyl group having 1 to 10 carbon atoms, which is substituted with one or more hydroxyl groups. 4. A compound represented by the general formula (II): (Wherein R ₁ represents an alkyl group having 1 to 10 carbon atoms, which may be substituted with one or more hydroxyl groups, and R ₂ represents a hydrogen atom or a hydroxyl group). The described compound. 5. The compound according to claim 4, wherein R ₁ is an alkyl group having 1 to 10 carbon atoms substituted with one or more hydroxyl groups. 6. R ₁ is represented by the general formula (III): (In the formula, R ₄ and R ₅ are the same or different and represent a hydrogen atom or a hydroxyl group. However, they are not simultaneously a hydroxyl group.
6. The compound according to claim 5, wherein m is an integer of 1 to 4 and n is an integer of 0 to 2.). 7. The compound according to claim 1, wherein R ₂ is a hydrogen atom. 8. The compound according to claim 6, wherein R ₂ is a hydrogen atom. 9. The compound according to claim 1, wherein R ₂ is a hydroxyl group. 10. The compound according to claim 2, wherein R ₂ is a hydroxyl group. 11. The compound according to claim 3, wherein R ₂ is a hydroxyl group. 12. The compound according to claim 4, wherein R ₂ is a hydroxyl group. 13. The compound according to claim 5, wherein R ₂ is a hydroxyl group. 14. The compound according to claim 6, wherein R ₂ is a hydroxyl group. 15. The compound according to claim 6, wherein the 20-position is R-coordinate. 16. The compound according to claim 9, wherein the 20-position is R-coordinate. 17. The compound according to claim 14, wherein the 20-position is R-coordinate. 18. The compound according to claim 6, wherein the 20-position is S-coordinate. 19. The compound according to claim 9, wherein the 20-position is S-coordinate. 20. The compound according to claim 14, wherein the 20-position is S-coordinate. 21. The compound according to claim 14, wherein R ₄ and R ₅ are hydrogen atoms. 22. A compound represented by the general formula (IV): (Wherein R ₆ and R ₇ are the same or different and each represents a hydrogen atom or a protecting group), and a compound represented by the general formula (V): (Wherein R ₈ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent), and is reacted with the compound represented by the general formula (VI): (Wherein R ₆ , R ₇ and R ₈ have the same meanings as described above). 23. A compound represented by the general formula (VII): (Wherein R ₉ and R ₁₀ are the same or different and each represents a hydrogen atom or a protecting group), the compound represented by the general formula (VIII): (Wherein R ₁₁ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent), and is reacted with the compound represented by the general formula (IX): (Wherein R ₉ , R ₁₀ and R ₁₁ have the same meanings as described above). 24. General formula (VI): (In the formula, R ₆ and R ₇ are the same or different and each represents a hydrogen atom or a protective group, and R ₈ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent). Compound. 25. The compound according to claim 24, wherein the protecting group is an acyl group or a substituted silyl group, and R ₈ is an alkyl group having 1 to 10 carbon atoms substituted with one or more hydroxyl groups. . 26. R ₈ is a compound represented by the general formula (III): (In the formula, R ₄ and R ₅ are the same or different and represent a hydrogen atom or a hydroxyl group. However, they are not simultaneously a hydroxyl group.
m is an integer of 1 to 4, and n is an integer of 0 to 2).
The described compound. 27. A compound represented by the general formula (X): (In the formula, R ₁₂ and R ₁₃ are the same or different and each represents a hydrogen atom or a protecting group, and R ₁₄ represents an optionally substituted alkyl group having 1 to 10 carbon atoms). 25. The compound according to claim 24, wherein 28. The compound according to claim 27, wherein the protecting group is an acyl group or a substituted silyl group, and R ₁₄ is an alkyl group having 1 to 10 carbon atoms substituted with one or more hydroxyl groups. . 29. A compound represented by the general formula (XI): (In formula, R < ₁₅ >, R < ₁₆ > is the same or different and shows a hydrogen atom or a protective group, A < ₁ > is -CHOH- or -CO.
-Indicated). 30. The compound according to claim 29, wherein the protecting group is a substituted silyl group. 31. A compound represented by the general formula (XII): (In formula, R <_17> , R < ₁₈ > is the same or different and shows a hydrogen atom or a protective group, A < ₂ > is -CHOH- or -CO.
The compound of claim 29, which is represented by 32. A compound represented by the general formula (XIII): (In the formula, R ₁₉ and R ₂₀ are the same or different and each represents a hydrogen atom or a protecting group, R ₂₁ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, and A ₃ represents —CH
A compound represented by OH- or -CO-). 33. The protecting group is a substituted silyl group, R ₂₁
33. The compound according to claim 32, wherein is an alkyl group having 1 to 10 carbon atoms, which is substituted with one or more hydroxyl groups. 34. R ₂₁ is of the general formula (III): (In the formula, R ₄ and R ₅ are the same or different and represent a hydrogen atom or a hydroxyl group. However, they are not simultaneously a hydroxyl group.
34. m is an integer of 1 to 4, and n is an integer of 0 to 2).
The described compound. 35. A compound represented by the general formula (XIV): (In the formula, R ₂₂ and R ₂₃ are the same or different and represent a hydrogen atom or a protecting group, R ₂₄ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent, and A ₄ represents —CH
33. The compound according to claim 32, which is represented by OH- or -CO-. 36. A compound represented by the general formula (XV): (In the formula, R ₂₅ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂₆ , R
₂₇ are the same or different and each represents a hydrogen atom or a protective group, and R ₂₈ represents a hydrogen atom or a hydroxyl group), and the compound represented by the general formula (XVI) is subjected to light irradiation and thermal isomerization reaction. ) [Chemical 19] (In the formula, R ₂₅ represents an alkyl group having 1 to 10 carbon atoms which may be substituted with one or more hydroxyl groups, and R ₂₆ , R
₂₇ are the same or different and each independently represent a hydrogen atom or a protective group, and R ₂₈ represents a hydrogen atom or a hydroxyl group).