JPH1135553A - Activated vitamin d derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound manifesting excellent bone quantity-improving activities, differentiation-inducing activities and cell growth- inhibiting activities without causing hypercalcemia. SOLUTION: The objective compound is an activated vitamin D derivative of formula I (R1 and R2 are each H or OH with the proviso that R1 and R2 are not simultaneously OH; R3 and R4 are each H, OH or methyl with the proviso that R3 and R4 are not simultaneously OH or simultaneously methyl; R5 is H or OH). The compound of formula I is obtained by subjecting 5,7-dienic body of formula II, which is a precursor of the activated vitamin D derivative, to ultraviolet irradiation, and carrying out thermal isomerization of the product. The compound has a use of a medicine as a bone quantity improver, a differentiation inducer and an immunosuppressive agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel active vitamin D derivative having excellent bone mass improving action, differentiation inducing action and immunosuppressive action, a method for producing the same, and the active vitamin D derivative as an active ingredient. Related to medicine.

[0002]

2. Description of the Related Art Active vitamin D ₃ and its derivatives are:
It is known to have a differentiation-inducing action, a cell growth-suppressing action, and the like in addition to a bone mass improving action, and is being actively studied (Endocrine Reviews, 16, 200 (1995)). However, it is known that these compounds cause hypercalcemia as a side effect due to a blood calcium elevating action which is an intrinsic action of vitamin D.

[0003]

Therefore, separation of the above-mentioned actions possessed by these active forms of vitamin D ₃ and its derivatives, ie, without causing hypercalcemia,
It is required to find an active vitamin D derivative having excellent bone mass improvement / differentiation induction / cell proliferation inhibitory effects.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to elucidate the above-mentioned problems. As a result, the compound of the following general formula (I) has a strong effect of increasing blood calcium although it has a weak effect of increasing blood calcium. The present inventors have found that they have a bone mass improving effect, a differentiation inducing effect, a cell growth suppressing effect and an immunosuppressive effect, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (I)

Embedded image (In the formula, R ₁ and R ₂ represent a hydrogen atom or a hydroxyl group, but both do not simultaneously represent a hydroxyl group, and R ₃ and R ₄ represent a hydrogen atom, a hydroxyl group, or a methyl group, but both represent a hydroxyl group at the same time. Or R ₅ does not represent a methyl group and R ₅ represents a hydrogen atom or a hydroxyl group).

The present invention relates to a compound represented by the general formula (II):

Embedded image (In the formula, R ₁ and R ₂ represent a hydrogen atom or a hydroxyl group, but both do not simultaneously represent a hydroxyl group, and R ₃ and R ₄ represent a hydrogen atom, a hydroxyl group, or a methyl group, but both represent a hydroxyl group at the same time. Or a methyl group, and R ₅ represents a hydrogen atom or a hydroxyl group). The active vitamin D derivative precursor represented by the formula (I) is subjected to ultraviolet irradiation, and then thermally isomerized. I)

Embedded image (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the meanings described above).

Further, the present invention relates to a compound of the formula (I)

Embedded image (In the formula, R ₁ and R ₂ represent a hydrogen atom or a hydroxyl group, but both do not simultaneously represent a hydroxyl group, and R ₃ and R ₄ represent a hydrogen atom, a hydroxyl group, or a methyl group, but both represent a hydroxyl group at the same time. Or a methyl group, and R ₅ represents a hydrogen atom or a hydroxyl group).

[0008] More specifically, the present invention relates to a bone mass improving agent containing the above-mentioned novel active vitamin D derivative as an active ingredient. Furthermore, the present invention also relates to a differentiation inducer containing the above-mentioned novel active vitamin D derivative as an active ingredient. Furthermore, the present invention also relates to an immunosuppressant containing the above-mentioned novel active vitamin D derivative as an active ingredient.

The active vitamin D derivative compound of the present invention is a novel compound which has not been described in the literature. The precursor of this vitamin D derivative compound is a steroid compound having a hydroxyl group at 1α-position and a precursor steroid compound. Prepared by coupling with a sulfone derivative forming the side chain of the compound and, if necessary, by introducing a hydroxyl group into the side chain, subjecting the precursor steroid compound to ultraviolet irradiation and then thermal isomerization It is obtained. The thus-obtained active vitamin D derivative compound of the general formula (I) may have an R-configuration, an S-configuration, or a mixture thereof at positions 23, 24 and 25.

Next, the active vitamin D derivative compound of the general formula (I) of the present invention is coupled with a steroid derivative having a hydroxyl group at the 1α-position and a sulfone derivative forming a side chain of the precursor steroid compound. And, if necessary, introduction of a hydroxyl group into a side chain, a method of subjecting this precursor steroid compound to ultraviolet irradiation and then thermal isomerization is included in each general formula (I). The active vitamin D derivative compound will be described in detail with reference to the following reaction schemes 1 to 5.

First, (25R) -1α, 3β, 25,26-
Tetrahydroxyvitamin D ₄ (Ia) can be produced by the method shown in Reaction Scheme 1. That is, a phenylsulfone derivative (III) (Bull. Chem. So
c. Jpn., 63, 2233 (1990)), epoxidation of the compound (IV) obtained by dehydration and then acetonide of the diol (V) obtained by hydrolysis to obtain the (R) form (VI) The (R) -form (VI) was separated from the mixture of the acetonide of the (S) -form (VII), and the resulting diol was protected by a trimethylsilyl group to give a phenylsulfone derivative (VIII). This phenyl sulfone derivative (VIII) and a 22-iodine form (X) of a steroid (Bull.
Chem. Soc. Jpn., 62, 2599 (1989)) in the presence of a base, reduce the resulting 23-phenylsulfone derivative, and further remove the protecting group to obtain the 5,7-diene compound (XI ). The 5,7-diene compound (XI) is irradiated with ultraviolet light to cut the bond between the carbon atom at the 9-position and the carbon atom at the 10-position of the steroid skeleton, and then thermally isomerized to give (25R)-. 1α, 3β, 25,26-Tetrahydroxyvitamin D ₄ (Ia) is obtained.

[0012]

Embedded image The corresponding 25-position epimer, (25S) -1α, 3
β, 25,26-tetrahydroxyvitamin D ₄ (I-
b)

Embedded image Is the (S) -form acetonide (VI) instead of the (R) -form acetonide (VI)
It can be produced by carrying out a similar reaction using I).

The above (25R) -1α, 3β, 25,26
2 corresponding to tetrahydroxyvitamin D ₄ (Ia)
4-position epimer (Ic)

Embedded image Can be produced by performing the same reaction using the enantiomer in place of the phenylsulfone derivative (III) in the above reaction scheme.

Further, (23S) -1α, 3β, 23,25-
Tetrahydroxyvitamin D ₄ (Id) can be produced by the method shown in Reaction Scheme 2. That is, (XII) obtained by protecting the hydroxyl group of the phenylsulfonic acid derivative (III) and the 22-iodo-form (X) of the steroid are coupled, and oxygen is blown in the presence of a base to obtain 23 -Deprotection of the protecting group of the oxo form (XIII), reduction and formation of the two 5,7
-The diene forms (XIV) and (XV) are separated and the former 5,7-
The diene compound (XIV) is subjected to ultraviolet irradiation and then thermally isomerized to obtain (23S) -1α, 3β, 23,25-tetrahydroxyvitamin D ₄ (Id).

[0015]

Embedded image The corresponding 23-position epimer, (23R) -1α, 3
β, 23,25-tetrahydroxyvitamin D ₄ (I-
e)

Embedded image Can be produced by performing the same reaction using the latter diene compound (XV) in place of (XIV) in the above Reaction Scheme 2.

The above (23S) -1α, 3β, 23,25
-24-position epimer (If) corresponding to tetrahydroxyvitamin D ₄ (Id)

Embedded image Can be produced by performing the same reaction using the enantiomer in place of the phenylsulfone derivative (XII) in the above reaction scheme.

Further, (24R) -1α, 3β, 24,25-
Tetrahydroxyvitamin D ₄ (Ig) can be produced by the method shown in Reaction Scheme 3. That is, a phenylsulfonic acid derivative (XVII) (J. Org. Che
m., 58, 1496 (1993)) and 4-phenyl-1,2,4 of (X).
-Triazoline-3,5-dione (PTAD) adduct (X
VI) and reduced (XVII)
The hydroxyl group at the 28-position of I) is dehydrated in 3 steps (tosylation, iodination, dehydrohalogenation) to obtain 24 (2) of (XIX).
8) The (XX) obtained by successively epoxidizing the olefin, reducing, deprotecting the protecting group, and resolving is subjected to ultraviolet irradiation, and then thermally isomerized to give (24R) -1α, 3.
β, 24,25-tetrahydroxyvitamin D ₄ (I-
g) is obtained.

[0018]

Embedded image Corresponding 24-position epimer (Ih)

Embedded image Can be produced in the same manner using a 5,7-diene compound (XXI). Compound (XIX) obtained as an intermediate compound in this Reaction Scheme 3 can also be produced by treating (XXIII) derived from a phenylsulfone derivative (XXII) in four steps with (XVI) as shown in Reaction Scheme 4. Can be done.

[0019]

Embedded image In addition, compound (XX) and compound (XXI) obtained as an intermediate compound in the above-mentioned reaction scheme 3 are obtained by the reaction scheme 5
Can also be derived from the 24-oxo derivative (XXIV).

[0020]

Embedded image

The thus-obtained compound of the present invention is used for pharmaceutical use, specifically for use as a bone mass improving agent, a differentiation inducer, or an immunosuppressant. These compounds can be administered orally or parenterally, but usually from 0.01 μg to 1000 μg for adults.
g, preferably from 0.1 μg to 100 μg. The compound of the present invention can be formulated into various dosage forms, for example, tablets, granules, powders, liquids such as injections, and the like.

[0022]

Next, examples of the present invention will be described. These examples are for describing the present invention in more detail.
The present invention is not limited by these. Example 1 (2R), (3R) -dimethyl-4-phenylsulfonyl-
1,2-butanediol ditrimethylsilyl ether (V
III) Compound (III) (10.0 g) was dissolved in ether (300 ml), and methanesulfonyl chloride (10.0 g) was dissolved in ether.
Added at ° C. After triethylamine (100 ml) was added dropwise at the same temperature, the mixture was stirred at room temperature overnight. 10% hydrochloric acid,
After washing with brine, drying and concentrating the product (IV)
(8.2 g) was dissolved in chloroform (150 ml).
-Chloroperbenzoic acid (m-CPBA) (8.0 g) was added and reacted for 2 hours. After washing with 5% potassium carbonate and brine, the mixture was concentrated. The concentrate is added to tetrahydrofuran (TH
F) (100 ml) and dissolved in 0.5N H ₂ SO ₄ (60 m
l) was added and stirred overnight at room temperature. Extracted with ethyl acetate and washed with saturated NaHCO ₃ , brine. The concentrate was dissolved in acetone (100 ml), p-toluenesulfonic acid (p-TsOH) (100 mg) was added, and the mixture was stirred for 30 minutes. Extracted with ethyl acetate, washed with brine and concentrated.
The concentrate was purified by silica gel chromatography to obtain 3.7 g of compound (VI) and 3.3 g of compound (VII). Compound (VIII) (3.7 g) was dissolved in 90% ethanol (30 ml), pyridinium-p-toluenesulfonate (PPTS) (700 mg) was added, and the mixture was heated under reflux for 30 minutes. Extracted with ethyl acetate, washed with brine and concentrated. The concentrate is treated with dimethylformamide (DM
F) (15 ml), Me ₃ SiCl (3.0 g) and imidazole (3.0 g) were added, and the mixture was heated and stirred at 50 ° C. for 1 hour. Extracted with ethyl acetate, washed with brine, concentrated, and the concentrate was purified by silica gel chromatography,
3.5 g of the title compound (VIII) was obtained. ^{1 H-NMR: 1.13 (3H} , d), 1.22 (3H, s), 2.18 (1H, m), 3.3
8 (2H, m), 4.11 (2H, m), 7.60-7.95 (5H, m)

Example 2 (24S), (25R) -1α, 3β, 25,26-Tetrahydroxyergota-5,7-diene (XI) Compound (VIII) (3.5 g) was added to tetrahydrofuran (T
HF) (30 ml) and cooled to -40 ° C. 1.
6M n-BuLi (6 ml) and 1,3-dimethyl-2
-Imidazolidinone (DMI) (1 ml) was added and stirred for 30 minutes. The 22-iodine form (X) of the steroid (3.5)
g) in THF (15 ml) at the same temperature.
For 2 hours and at room temperature for 1 hour. Saturated aqueous NH ₄ Cl was added, extracted with ethyl acetate, washed with brine and concentrated. The concentrate was dissolved in methanol (30 ml) and Na ₂ H
PO ₄ (500 mg) and 5% Na-Hg (15 g) were added, and the mixture was stirred overnight at room temperature. Mercury was separated, the reaction solution was extracted with ethyl acetate, washed with brine, and concentrated. The concentrate was dissolved in methanol (20 ml), p-TsOH (50 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Extracted with chloroform, washed with brine and concentrated. The concentrate was purified by silica gel chromatography to give the title compound (XI) in 2.0.
g was obtained. ¹ H-NMR: 0.81 (3H, s), 0.94 (3H, s), 1.00 (6H, m), 1.
28 (3H, s), 3.78 (1H, m), 4.05 (1H, m), 5.31 (1H, m),
5.49 (1H, m)

Example 3 (25R) -1α, 3β, 25,26-Tetrahydroxyvitamin D ₄ (Ia) 5,7-diene (XI) (200 mg) was added to THF (500 m 2).
l) and irradiated with a high-pressure mercury lamp (450 W) for 10 minutes. The reaction solution was concentrated, and ethanol (10 ml) was added to the concentrate.
Was added and heated under reflux for 1 hour. The ethanol was concentrated, and the concentrate was purified by high performance liquid chromatography (HPLC) to obtain 24 mg of the title compound (Ia). ¹ H-NMR: 0.57 (3H, s), 1.00 (3H, d), 1.03 (3H, d), 1.2
0 (3H, s), 4.24 (1H, m), 4.42 (1H, m), 5.00, 5.33 (1 each
H, m), 6.01, 6.38 (1H, m each)

Example 4 (23S) -1α, 3β, 23,25-Tetrahydroxyvitamin D ₄ (Id) Compound (XII) (3.0 g) was dissolved in THF (30 ml) and cooled to -40 ° C. did. 1.6M n-BuLi (6m
l) and DMI (1 ml) were added. Compound (X) (1.5
g) in THF (15 ml) at the same temperature.
For 2 hours and at room temperature for 2 hours. Saturated NH ₄ Cl was added, extracted with ethyl acetate, washed with brine, dried and concentrated. The concentrate (2.5 g) was dissolved in THF (25 ml) and cooled to -20 ° C. Diisopropylamine (8m
l) 1.6 M n-BuLi (30 ml) and hexamethylphosphoric triamide (HMPA) (25 ml) were added. Oxygen was passed at the same temperature for one hour. Saturated Na ₂ SO ₃ (20 ml)
And extracted with ethyl acetate. After washing with brine, the solvent was concentrated. The concentrate was purified by silica gel chromatography to obtain 650 mg of 23-oxo form (XIII). This (XIII) (650 mg) was dissolved in THF (10 ml).
iALH ₄ (200 mg) was added. Stir at room temperature for 1 hour and add a small amount of water. MgSO ₄ was added and filtered.
The filtrate was concentrated, the concentrate was dissolved in 90% ethanol (10 ml), p-TsOH (25 mg) was added, and the mixture was heated at 80 ° C for 1 hour. After extraction with chloroform and washing with brine,
Concentrated. The concentrate was purified by silica gel chromatography, and 150 mg of the 5,7-diene compound (XIV) was added to another 5,7-diene compound (XIV).
145 mg of a diene compound (XV) was obtained. ¹ H-NMR (XIV): 0.69 (3H, s), 0.85 (3H, d), 0.87 (3H,
s), 0.95 (3H, d), 1.09, 1.12 (3H, s), 3.64 (1H, m),
3.92 (1H, m), 5.31 (1H, m), 5.59 (1H, m) ((XV) also showed the same NMR spectrum). 5,7-diene (XIV)
(100 mg) was dissolved in THF (300 ml) and irradiated with a high-pressure mercury lamp (450 W) for 5 minutes. The THF was concentrated, ethanol (5 ml) was added, and the mixture was heated under reflux for 1 hour. The ethanol was concentrated and the concentrate was purified by HPLC to give the title compound (I
-D) was obtained in an amount of 18 mg. ¹ H-NMR: 0.55 (3H, s), 0.91 (3H, s), 0.96 (3H, d), 1.1
6, 1.18 (3H, s), 4.22 (1H, m), 4.44 (1H, m), 5.00 (1
H, m), 5.34 (1H, m), 6.02, 6.39 (2H, ABq)

Example 5 (24R) -1α, 3β, 24,25-Tetrahydroxyvitamin D ₄ (Ig) Compound (XVII) (10.0 g) was dissolved in THF (50 ml) and the solution was dissolved at -40 ^° C. Cool. 1.6M n-BuLi
(20 ml) and DMI (3 ml). After stirring at the same temperature for 1 hour, steroid derivative (XVI) (10.0 g)
Was added. After stirring at 0 ° for 2 hours and at room temperature for 1 hour, saturated NH ₄ Cl was added and extracted with ethyl acetate. After washing with brine, it was dried and concentrated. The concentrate (19 g) was dissolved in methanol (200 ml), Na ₂ HPO ₄ (5 g) and 5% Na-Hg (40 g) were added, and the mixture was stirred overnight at room temperature. After mercury was separated, methanol was concentrated and extracted with ethyl acetate. After washing with brine, it was concentrated. The concentrate was dissolved in pyridine (50 ml), p-toluenesulfonyl chloride (6 g) was added, and the mixture was stirred overnight. Extracted with ethyl acetate, washed with saturated NaHCO ₃ and brine, dried and concentrated. The concentrate (14 g) was dissolved in acetone (60 ml) and NaI (15 g) was added. After heating under reflux for 5 hours, the mixture was extracted with chloroform. After washing with 5% Na ₂ SO ₃ and brine, the mixture was concentrated. Concentrate (12 g) was added to benzene (50 m
l) and 1,8-diazabicyclo [5.5.0] -7
-Undecene (DBU) (10 ml) was added and the mixture was heated under reflux for 2 hours. After washing with brine, it was concentrated. The concentrate was purified by silica gel chromatography to obtain compound (XIX). This compound (XIX) (9.5 g) was dissolved in chloroform (100 ml), and m-CPBA (5.0 g) was added. After stirring overnight at room temperature, it was washed with 5% K ₂ CO ₃ and brine. After drying, the mixture was concentrated, and the concentrate (9.5 g) was treated with T
It was dissolved in HF (100 ml), LiAlH ₄ (3 g) was added, and the mixture was heated under reflux for 1 hour. After adding a small amount of water, MgS
O ₄ was added and filtered. The filtrate is concentrated and the concentrate (6.5)
g) was dissolved in 90% ethanol (100 ml) and p-T
sOH (200 mg) was added, and the mixture was stirred at 50 ° C. for 3 hours.
Extracted with chloroform, washed with brine and concentrated.
The concentrate is purified by silica gel chromatography,
1.6 g of the 7-diene compound (XX) and 1.4 g of another 5,7-diene compound (XXI) were obtained. ^{1 H-NMR (XX):} 0.83 (3H, s), 0.95 (6H, m), 1.12 (3H, s),
1.22, 1.27 (each 3H, s), 3.66 (1H, m), 4.08 (1H, m), 5.
32, 5.52 (each 1H, m) ((XXI) also showed similar NMR spectra). 5,7-diene (XX) (200 mg) was added to TH
F (500 ml) and 10 with a high-pressure mercury lamp (450 W)
Irradiated for minutes. The THF was concentrated and ethanol (10 ml)
Was added and heated under reflux for 1 hour. The ethanol was concentrated and the concentrate was purified by HPLC to give 24 mg of the title compound (Ig).
Obtained. ¹ H-NMR: 0.55 (3H, s), 0.91 (6H, d), 1.21, 1.24 (3H,
s), 4.24 (1H, m), 4.45 (1H, m), 5.00 (1H, m), 5.33 (1
H, m), 6.03, 6.38 (1H, m each)

Example 6 1,25 (OH) _{2 of} compounds (Ia), (Id) and (Ig)
Discussed RRA method shown below affinity for D ₃ receptor (VDR). Chicken small intestine 1,25 (OH)
The ₂ D ₃ receptors 25mg dissolved in 50mM phosphate buffer pH 7.4 100 ml containing 0.3 M KCl, the 500μ
adding ^{[3 H] -1,25 (OH)} 2 D 3, 10000dpm and vitamin D derivatives of various concentrations l at 4 ° C., and incubated for 24 hours. After that, 0.25% dextran-corted c
The reaction was stopped by adding 200 μl of harcol, and the radioactivity of 500 μl of the supernatant obtained by centrifugation was measured. Comparison of affinity for VDR was performed at 50% B / BO. The results obtained are shown in Table 1 below.

[0028]

[Table 1]

Example 7 Differentiation-Inducing Activity of Compounds (Ia), (Id) and (Ig) NBT reducing ability was measured as an indicator of differentiation induction of human myeloid leukemia cells (HL-60). . Human myeloid leukemia cells (HL-60) were RPMI-164 containing 10% FBS.
The solution was adjusted to 2 × 10 ⁵ cells / ml on a 0 × medium (manufactured by Gibco BRL), and various concentrations of vitamin derivatives were added.
Cultured for days. The cells were collected by centrifugation, the supernatant was removed, and then 0.2% nitrobrutetrazolium (NBT)
(Sigma) and 200 ng / ml phorbol 12-myristate 13-acetate (TPA) (Sigma) were added and incubated at 37 ° C. for 20 minutes. The number of cells in which NBT was reduced and stained blue was measured, and the ratio to the total number of cells was calculated. The results obtained are shown in Table 2 below.

[0030]

[Table 2] Next, preparation examples of the medicament of the present invention are shown.

Formulation Example 1 Preparation of Tablets Active Vitamin D Derivative (Ia) 1 mg Lactose Suitable amount Crystalline Cellulose 50 g Cyclodextrin 20 g Magnesium Stearate 2.5 g Total 250 g And Using a rotary tableting machine, this is a tablet of 250 mg per tablet 1000
Tablets were prepared.

Formulation Example 2 Preparation of Injection Active Vitamin D Derivative (Id) 1 mg Polysorbate 200 ml Propylene glycol 800 ml Sodium chloride 20 g Sodium hydroxide Appropriate amount Injection water Appropriate amount did. The obtained solution was dispensed into ampoules by aseptic operation in 3 ml portions, and the ampules were sealed.

Formulation Example 3 Preparation of Capsules Containing Granules Active Vitamin D Derivative (If) 0.5 mg Lactose Appropriate Quantity Crystalline Cellulose 50 g Cyclodextrin 20 g Magnesium Stearate 1 g Total 100 g Active Vitamin D Derivative in the Ingredients Above (If) was dissolved in a small amount of ethanol, the whole was uniformly mixed, and the mixture was granulated to prepare granules. This was filled with 0.5 g per capsule to prepare 200 capsules.

[0034]

According to the present invention, a novel active vitamin D derivative is provided. As can be seen from Examples 6 and 7, this vitamin D derivative exhibited a strong differentiation-inducing action despite a weak calcium-increasing action, indicating that the separation of the actions was achieved.

Claims (6)

[Claims] 1. A compound of the general formula (I) (In the formula, R ₁ and R ₂ represent a hydrogen atom or a hydroxyl group, but both do not simultaneously represent a hydroxyl group, and R ₃ and R ₄ represent a hydrogen atom, a hydroxyl group, or a methyl group, but both represent a hydroxyl group at the same time. Or a methyl group, and R ₅ represents a hydrogen atom or a hydroxyl group). 2. A compound of the general formula (II) (In the formula, R ₁ and R ₂ represent a hydrogen atom or a hydroxyl group, but both do not simultaneously represent a hydroxyl group, and R ₃ and R ₄ represent a hydrogen atom, a hydroxyl group, or a methyl group, but both represent a hydroxyl group at the same time. Or a methyl group, and R ₅ represents a hydrogen atom or a hydroxyl group). The active vitamin D derivative precursor represented by the formula (I) is subjected to ultraviolet irradiation, and then thermally isomerized. I) (Wherein, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the above-mentioned meanings). 3. A compound of the general formula (I) (In the formula, R ₁ and R ₂ represent a hydrogen atom or a hydroxyl group, but both do not simultaneously represent a hydroxyl group, and R ₃ and R ₄ represent a hydrogen atom, a hydroxyl group, or a methyl group, but both represent a hydroxyl group at the same time. Or a methyl group, and R ₅ represents a hydrogen atom or a hydroxyl group). 4. The medicament according to claim 3, which is a bone mass improving agent. 5. The medicament according to claim 3, which is a differentiation inducer. 6. The medicament according to claim 3, which is an immunosuppressant.