JP2001089442A - Active vitamin d derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an active vitamin D derivative having excellent bone quantity-increasing effect, differentiation-inducing effect, cell growth inhibitory effect, immunoregulation effect, etc., without causing hypercalcemia, and to obtain medicaments each containing the above derivative as active ingredient. SOLUTION: This active vitamin D derivative is represented by the general formula (I) (R1 and R2 are such that one of them is H and the other being ethyl, propyl or butyl; R3 is H or OH; and the bond between C22 and C23 is a single or double bond). Medicaments each containing the above derivative as active ingredient can also be obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an active vitamin D derivative having excellent bone mass improving action, differentiation inducing action, cell growth inhibitory action and immunomodulating action.

[0002]

2. Description of the Related Art Active vitamin D derivatives having a bone mass improving action, a differentiation inducing action, a cell growth inhibitory action, an immunomodulatory action and the like are known and are being actively studied (En).
docrine Rev., Vol.16, p200-257 (1995)). However, some of these compounds are known to cause hypercalcemia as a side effect due to the blood calcium-increasing action which is an intrinsic action of vitamin D.

[0003]

SUMMARY OF THE INVENTION Therefore, an active vitamin D derivative having excellent bone mass improving action, differentiation inducing action, cell growth inhibitory action, immunoregulatory action, etc. without hypercalcemia is to be found. Is required.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, despite the fact that the compound represented by the following general formula (I) has a low blood calcium elevating action, The present inventors have found that they have high bone mass improving action, differentiation inducing action, cell growth inhibitory action, and immunoregulatory action, 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, _one of R ₁ and R ₂ represents a hydrogen atom, the other represents an ethyl group, a propyl group or a butyl group, R ₃ represents a hydrogen atom or a hydroxyl group, and the bond between C 22 and C 23 is a single bond or a double bond. An active vitamin D derivative represented by the following formula:

The present invention also relates to a compound of the general formula (II)

Embedded image (In the formula, _one of R ₁ and R ₂ represents a hydrogen atom, the other represents an ethyl group, a propyl group or a butyl group, R ₃ represents a hydrogen atom or a hydroxyl group, and the bond between C 22 and C 23 is a single bond or a double bond. An active vitamin D derivative precursor represented by the general formula (I), which is subjected to ultraviolet irradiation and then thermally isomerized.

Embedded image (Wherein the bond between R ₁ , R ₂ , R ₃ and C 22 -C 23 has the meaning described above).

[0007] The present invention further relates to a medicament containing an active vitamin D derivative represented by the above general formula (I) as an active ingredient, especially a bone mass improving drug, a differentiation inducer, a cell growth inhibitor or an immunomodulator. .

The active vitamin D derivative of the present invention is a novel compound, which comprises coupling of a sulfone derivative constituting a side chain with a steroid derivative having a hydroxyl group at the 1α-position, followed by necessary modification of the side chain, Deprotecting group, etc. to obtain an active vitamin D precursor (pro-form) represented by the general formula (II), and irradiating the pro-form with ultraviolet rays, followed by thermal isomerization Can be.

In the general formula (I), the bond between C22 and C23 is a single bond, R ₁ is a hydrogen atom, R ₂ is an ethyl group and R
Active vitamin D derivative of the present invention wherein ₃ is a hydroxyl group: (24S) -24-ethyl-9,10-secocholesta-5,7-diene-1α, 3β, 25-triol (I
a) can be produced by the steps shown in the following reaction scheme 1.

[0010]

Embedded image

In reaction scheme 1, steroid 22
-Iodine 4-phenyl-1,2,4-triazoline-
Compound (III) which is a 3,5-dione (PTAD) adduct
(Bull. Chem. Soc. Jpn., 62, 2599 (1989)), the phenyl sulfone derivative (IVa) can be produced by the method shown in the following reaction scheme 2.

[0012]

Embedded image

As shown in Reaction Scheme 1, the compound (III) and the phenylsulfone derivative (IVa) are condensed in the presence of a base, and the protecting group for the hydroxyl group, the phenylsulfonyl group, and the PTAD group are sequentially eliminated. Conduct 5,7-
Diene (IIa). Then, the compound (Ia) can be obtained by irradiating ultraviolet rays and then performing thermal isomerization.
Also, as shown in Reaction Scheme 2, the corresponding 2
The 4-epimer is derived from the enantiomer (X) of the epoxy alcohol (V) instead of (IVa) (XI
It can be produced by using a).

Further, in the general formula (I), the bond between C22 and C23 is a double bond, R ₁ is a hydrogen atom, R ₂ is an ethyl group and R ₃ is a hydroxyl group. Derivative: (24S) -24-ethyl-9,10-
Secocholesta-5,7,22-triene-1α, 3β, 25
-Triol (Ib) can be produced by the steps shown in the following reaction scheme 3.

[0015]

Embedded image

That is, C-20 aldehyde (XIII) derived from ergosterol (Bull. Chem. Soc. Jp.
n., 62, 3132 (1989)) and phenylsulfone derivatives (IV
After condensing a), the same treatment as in the preparation of (Ia) is carried out to obtain (Ib) (see reaction scheme 3). By using the phenyl sulfone derivative (XIa), the corresponding 24-position epimer can be produced in the same manner.

As described above, in the active vitamin D derivative, in formula (I), one of R ₁ and R ₂ is a hydrogen atom, the other is an ethyl group, a propyl group or a butyl group, and R ₃ is A hydrogen atom or a hydroxyl group,
Compounds in which the C22-C23 bond is a single bond or a double bond. Table 1 below shows specific examples of the present active vitamin D derivative.

[0018]

[Table 1]

The thus obtained active vitamin D derivative of the present invention can be used as a drug, specifically, as a bone mass improving drug, a differentiation inducer, a cell growth inhibitor or an immunomodulator. it can.

More specifically, as a bone mass improving drug for the treatment of osteoporosis, etc., as a differentiation-inducing and cytostatic drug, for the treatment of cancer, etc., as an immunomodulator, for the treatment of cancer, autoimmune diseases, etc. or for organ transplantation. Can be used at the time.

An effect of improving the bone mass of an active vitamin D derivative,
The mechanism of each of the differentiation-inducing action, the cell growth-suppressing action, and the immunomodulatory action is unknown, but there is a positive correlation with the strength of each action.

The active vitamin D derivative of the present invention has a considerably lower affinity for the 1,25-dihydroxyvitamin D ₃ receptor and a very low increase in blood calcium concentration which is a side effect. It is.

These compounds can be administered orally or parenterally, but usually from 0.01 μg to 1000 μg, preferably from 0.1 μg to 1000 μg per day for adults.
It is administered in an amount of 100 μg.

The active vitamin D derivative of the present invention can be formulated into various dosage forms and administered, for example, in the form of tablets, granules, powders, liquids such as injections. Can be.

Examples of the synthesis of the active vitamin D derivative of the present invention, test examples showing the effects of the active vitamin D derivative of the present invention, and preparation examples of the active vitamin D derivative of the present invention will be shown below by way of Examples. This does not limit the present invention.

[0026]

EXAMPLE 1 (S) -2-Ethyl-3-methyl-1,3-butanediol (VIIa) Under a nitrogen stream, an ether solution (40 ml) containing CuI (380 mg) was added at -20 to -25.degree. With 1M EtMgBr TH
F solution (VIa) (60 ml) was added and -10 to -20 ° C.
For 3 hours. Epoxy alcohol (V) (2 g)
THF solution (20 ml) was added at -20 to -25 ° C.
The mixture was stirred at the same temperature for 0 minutes. Aqueous NH ₄ Cl was added, extracted with ethyl acetate, washed with brine, and then concentrated. The residue (1.8 g) was purified by silica gel chromatography (chloroform / ethyl acetate, 4/1 to 1/1) to obtain 1.6 g of compound (VIIa) (pale yellow oil). ¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.3 Hz, 2-CH ₂ C
H ₃ ), 1.19 (3H, s, 3-CH ₃ ), 1.30 (3H, s, 4-CH ₃ ), 1.4
1-1.50 (1H, m, 2-H), 3.75 (2H, m, 1-CH ₂ )

Example 2 (S) -3-Methyl-2-propyl-1,3-butanediol (VIIb) In a nitrogen stream, an ether solution (80 ml) containing CuI (800 mg) was added at -20 to -25 ° C. 2M PrMgBr TH
The F solution (VIb) (40 ml) was added, and the mixture was stirred at -5 to -10 ° C for 4 hours. A solution of epoxy alcohol (V) (3 g) in THF (30 ml) was added at -20 to -25 ° C.
Stirred at the same temperature for minutes. Aqueous NH ₄ Cl was added, extracted with ethyl acetate, washed with brine, and then concentrated. The residue (2.5 g) was purified by silica gel chromatography (chloroform / ethyl acetate, 4/1 to 1/1) to obtain 2.3 g of compound (VIIb) (light yellow oil). ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 6.8 Hz, 2- (CH ₂ ) ₂ C
H ₃ ), 1.19, 1.30 (each 3H, s, 3-CH ₃ , 4-CH ₃ ), 1.58 (1H,
m, 2-H), 3.75 (2H, m, 1-CH ₂ )

Example 3 (S) -2-butyl-3-methyl-1,3-butanediol (VIIc) In a nitrogen stream, an ether solution (20 ml) containing CuI (200 mg) was added at -20 to -25 ° C. 1.6 M n-BuLi hexane solution (13 ml) was added, and the mixture was heated at -10 to -15 ° C for 1 hour.
Stirred for hours. T of epoxy alcohol (V) (1 g)
An HF solution (10 ml) was added at -20 to -25 ° C, and the mixture was stirred at the same temperature for 30 minutes. Aqueous NH ₄ Cl was added, extracted with ethyl acetate, washed with brine, and concentrated. Residue (9
(00 mg) was purified by silica gel chromatography (chloroform / ethyl acetate, 4/1 to 1/1) to obtain 690 mg of compound (VIIc) (pale yellow oil). ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 6.8 Hz, 2- (CH ₂ ) ₃ C
H ₃ ), 1.19, 1.30 (each 3H, s, 3-CH ₃ , 4-CH ₃ ), 1.58 (1H,
m, 2-H), 3.75 (2H, m, 1-CH ₂ )

Example 4 (R) -2-methyl-3-phenylsulfonylmethyl-2
-Pentanol (VIIIa) Diol (VIIa) (10 g) was dissolved in pyridine (100 ml), tosyl chloride (17 g) was added at 0 to 5 ° C, and the mixture was stirred at the same temperature for 3 hours. Aqueous NaHCO ₃ and ethyl acetate were added and washed with brine. The solvent was concentrated, and the residue was purified by silica gel chromatography (hexane / ethyl acetate, 4 / 1-2 / 1) to give compound (VIIa).
(25 g) was obtained. Under a nitrogen stream, t
Thiophenol (12 g) was added to a DMF solution (200 ml) containing -BuOK (12 g). Tosylate (25
g) in DMF (125 ml) was added and stirred at room temperature for 2 hours. Water was added, extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was chloroform (1
80 ml), m-CPBA (28 g) was added, and the mixture was stirred at room temperature for 2 hours. Washed with 10% K ₂ CO ₃ , brine, dried and concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate, 4/1) to obtain 16 g of compound (VIIIa) (light yellow oil). ¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.5 Hz, 5-CH ₃ ),
1.06, 1.33 (each 3H, s, 1-CH ₃ , 2-CH ₃ ), 1.30, 1.62
(Each 1H, m, 4-CH ₂ ), 2.02 (1H, m, 3-H), 2.88-2.95,
3.56-3.60 (each 1H, m, CH ₂ SO ₂ Ph), 7.56-7.95 (5H, m,
C ₆ H ₅ )

Example 5 (R) -2-methyl-3-phenylsulfonylmethyl-2
-Hexanol (VIIIb) Diol (VIIb) (8.1 g) was treated in the same manner as compound (VIIa) in Example 4 to give 13.
2 g were obtained (pale yellow oil). ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.8 Hz, 6-CH ₃ ),
1.03, 1.31 (each _{3H, 1-CH 3, 2} -CH 3), 2.10 (1H, m, 3-
H), 2.89 (2H, m, CH ₂ SO ₂ Ph), 7.57 (2H, m, aromati
c), 7.66 (1H, m, aromatic), 7.94 (2H, m, aromatic)

Example 6 (R) -2-methyl-3-phenylsulfonylmethyl-2
-Heptanol (VIIIc) The diol (VIIc) (3.1 g) was treated in the same manner as the compound (VIIa) in Example 4 to give the compound (VIIIc) 3.9.
g (light yellow oil) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 4.4 Hz, 7-CH ₃ ),
1.03, 1.30 (each _{3H, s, 1-CH 3} , 2-CH 3), 2.04 (1H, m, 3
-H), 2.88 (1H, m, CH ₂ SO ₂ Ph), 2.90 (1H, m, CH ₂ SO ₂ P
h), 7.61 (3H, m, aromatic), 7.94 (2H, m, aromatic)

Example 7 (R) -2-Methyl-3-phenylsulfonylmethylpentane (IXa) An ether solution of the compound (VIIIa) (5.8 g) (200 m
l) methanesulfonyl chloride (6 g) was added to
Triethylamine (50 ml) was added dropwise at 5 ° C. After stirring for 1 hour at the same temperature, extraction with ethyl acetate, 5% K ₂ CO ₃ ,
Washed with brine. The solvent was concentrated and the residue was chromatographed on silica gel (hexane / ethyl acetate, 4 /
Purified in 1). The purified product (5.2 g) was treated with ethyl acetate (1 g).
00 ml), PtO ₂ (500 mg) was added, and the mixture was reacted overnight at room temperature under a stream of H ₂ . The catalyst was filtered and the solvent was concentrated. The residue was purified by silica gel chromatography (hexane / ethyl acetate, 4/1) to obtain 4.8 g of compound (IXa). ¹ H-NMR (CDCl ₃ ) δ: 0.73-0.78 (6H, m, 4-CH ₃ , 5-C
H ₃ ), 0.82 (3H, t, J = 7.4Hz, 1-CH ₃ ), 1.45 (1H, m, 2-
H), 1.78, 1.91 (1H, m, 3-H), 1.45 (2H, ABq, J = 6.4H
z, 4-CH ₂ ), 2.88-2.91, 3.08-3.09 (each 1H, m, CH ₂ SO ₂ P
h), 7.53-7.95 (5H, m, C ₆ H ₅ )

Example 8 (S) -2-Methyl-3-phenylsulfonylmethylpentane (XIIa) Epoxy alcohol (X) (2 g) was treated in the same manner as in Examples 1, 4 and 7 to give compound (XIIa). 1.7 g was obtained.
¹ H-NMR (CDCl ₃ ) δ: 0.74-0.78 (6H, m, 1-CH ₃ , 2-CH ₃ ),
0.81 (3H, t, J = 7.4Hz, 5-CH ₃ ), 1.45 (1H, m, 2-H),
1.78, 1.90 (1H, m, 3-H), 1.46 (2H, ABq, J = 6.4Hz, 4
-CH ₂ ), 2.88-2.91, 3.08-3.10 (1H, m, CH ₂ SO ₂ Ph),
7.53-7.94 (5H, m, C ₆ H ₅ )

Example 9 (R) -2-Methyl-3-phenylsulfonylmethylhexane (IXb) The compound (VIIIb) (5 g) was used as a compound (V) in Example 8.
The same treatment as in IIIa) was carried out to obtain 3.6 g of compound (IXb). ¹ H-NMR (CDCl ₃ ) δ: 0.76, 0.77 (6H, m, 1-CH ₃ , 2-
CH ₃ ), 0.83 (3H, t, J = 7.3Hz, 6-CH ₃ ), 1.25 (2H, m, 5
-CH ₂ ), 1.33 (2H, m, 4-CH ₂ ), 1.80, 1.91 (1H, m, 3-
H), 2.90, 3.09 (1H, m, CH ₂ SO ₂ Ph each), 7.57 (2H, m, a
romatic), 7.65 (1H, m, aromatic), 7.91 (2H, m, aro
matic)

Example 10 (R) -2-Methyl-3-phenylsulfonylmethylheptane (IXc) The compound (VIIIc) (2.2 g) was treated in the same manner as the compound (VIIIa) in Example 8 to give the compound (IXc). 1.8 g)
(Light yellow oil). ¹ H-NMR (CDCl ₃ ) δ: 0.75-0.79
(6H, m, 1-CH ₃ , 2-CH ₃ ), 0.86 (3H, t, J = 7.2Hz, 7-C
H ₃ ), 1.13-1.38 (6H, m, 4-CH ₂ , 5-CH ₂ , 6-CH ₂ ), 1.80-
1.92 (2H, m, 2-H, 3-H), 2.88, 3.06 (1H, m, CH ₂ S each
O ₂ Ph), 7.61 (3H, m, aromatic), 7.91 (2H, m, aromat
I c)

Example 11 (R) -2-methyl-3-phenylsulfonylmethyl-2
-Terahydropyraniloxypentane (IVa) Compound (VIIIa) (2.0 g), DHP (1.0 g), PP
A solution of TS (200 mg) in dichloromethane (20 ml) was stirred at room temperature for 2 hours. Extraction with ethyl acetate, saturated NaHC
O ₃ water was added, and the mixture was washed with brine and concentrated. The residue was purified by silica gel chromatography to obtain 1.9 g of compound (IVa) (colorless oil). ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s, J = 6.3 Hz, 5-CH ₃ ), 1.
13, 1.20 (each _{3H, s, 1-CH 3} , 2-CH 3), 2.00 (1H, m, 3-
H), 2.97 (2H, m, 4-CH ₂ ), 3.41, 3.53 (each 1H, m, CH ₂
(THP)), 4.72 (1H, m, CH (THP)), 7.56 (2H, m, aromat
ic), 7.64 (1H, m, aromatic), 7.93 (2H, m, aromatic)

Example 12 (R) -2-methyl-3-phenylsulfonylmethyl-
2-Tetrahydropyranyloxyhexane (IVb) Compound (VIIIb) (2.0 g) was treated in the same manner as in Example 11 to obtain 1.7 g of compound (IVb). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 6.8 Hz, 6-CH ₃ ),
1.13, 1.21 (each _{3H, 1-CH 3, 2} -CH 3), 2.10 (1H, m, 3-
H), 2.89 (2H, m, CH ₂ SO ₂ Ph), 3.40, 3.57 (1H, m,
CH ₂ (THP)), 4.73 (1H, m, CH (THP)), 7.58 (2H, m, aro
matic), 7.66 (1H, m, aromatic), 7.94 (2H, m, aromat
I c)

Example 13 (R) -2-methyl-3-phenylsulfonylmethyl-2
-Tetrahydropyraniloxyheptane (IVc) Compound (VIIIc) (2.0 g) was treated in the same manner as in Example 11 to obtain 1.5 g of compound (IVc). ¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, t, J = 4.4 Hz, 7-CH ₃ ),
1.03, 1.28 (each _{3H, s, 1-CH 3} , 2-CH 3), 2.06 (1H, m, 3
-H), 2.88 (1H, m, CH ₂ SO ₂ Ph), 2.90 (1H, m, CH ₂ SO ₂ P
h), 3.41, 3.56 (each 1H, m, CH ₂ (THP)), 4.74 (1H, m,
CH (THP)), 7.64 (3H, m, aromatic), 7.95 (2H, m, arom
atic)

Example 14 (S) -2-Methyl-3-phenylsulfonylmethyl-2
-Tetrahydropyraniloxypentane (XIa) Epoxy alcohol (X) (2 g) was treated in the same manner as in Examples 1, 4 and 11, to obtain 2.1 g of compound (XIa). ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s, J = 6.3 Hz, 5-CH ₃ ),
1.13, 1.21 (each _{3H, s, 1-CH 3} , 2-CH 3), 2.01 (1H, m,
3-H), 2.96 (2H, m, 4-CH ₂ ), 3.41, 3.53 (1H, m, CH
₂ (THP)), 4.73 (1H, m, CH (THP)), 7.56 (2H, m, aroma
tic), 7.66 (1H, m, aromatic), 7.93 (2H, m, aromati
c)

Example 15 (S) -2-Methyl-3-phenylsulfonylmethyl-2
-Tetrahydropyraniloxyheptane (XIc) Epoxy alcohol (X) (2.5 g) was treated in the same manner as in Examples 3, 4 and 11 to give 1.9 g of compound (XIc).
Obtained. ¹ H-NMR (CDCl ³ ) δ: 0.95 (3H, t, J = 4.4 Hz, 7-CH ₃ ),
1.03, 1.28 (each _{3H, s, 1-CH 3} , 2-CH 3), 2.03 (1H, m, 3
-H), 2.89 (1H, m, CH ₂ SO ₂ Ph), 2.92 (1H, m, CH ₂ SO ₂ P
h), 3.41, 3.56 (each 1H, m, CH ₂ (THP)), 4.74 (1H, m,
CH (THP)), 7.64 (3H, m, aromatic), 7.95 (2H, m, arom
atic)

Example 16 (24S) -24-ethyl-9.10-secocholesta-5,
7-diene-1α, 3β, 25-triol (Ia) Phenyl sulfone derivative (IVa) (3.5 g) was added to THF
(15 ml) and cooled at -40 ° C. 1.0ML
A DA THF solution (12 ml) was added at the same temperature and stirred for 30 minutes. TH of 22-iodine derivative (III) (4.0 g)
The F solution (20 ml) was added, and the mixture was stirred at -40 ° C for 1 hour and then at room temperature for 1 hour. Saturated aqueous NH ₄ Cl was added, extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was dissolved in THF (15 ml) and methanol (15 ml),
p-TsOH (100 mg) was added, and the mixture was stirred at 40 ° C for 1 hour. To this was added water, extracted with ethyl acetate, saturated NaH
After washing with aqueous CO ₃ and brine, dried and concentrated. The residue was dissolved in methanol (100 ml) and Na ₂ H
PO ₄ (15 g) and 5% Na-Hg (25 g) were added, and the mixture was stirred at room temperature overnight. After removing mercury, the residue was concentrated, extracted with ethyl acetate, washed with brine, dried, and concentrated. LiAl
The residue (6. H) was added to a THF solution (20 ml) containing H ₄ (2 g).
A solution of 5 g) in THF (50 ml) was added and refluxed for 1 hour. After adding a small amount of water, MgSO ₄ was added, filtered, and concentrated. The concentrate was purified by silica gel chromatography to give (24S) -24-ethyl-cholesta-5,7-diene-
1.5 g of 1α, 3β, 25-triol (IIa) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.73 (3H, s, 18-CH ₃ ), 0.90-1.01
(9H, m, 19-CH ₃ , 21-CH ₃ , 29-CH ₃ ), 1.10 (3H, s, 26-C
H ₃ ), 1.16 (3H, s, 27-CH ₃ ), 3.74 (1H, m, 1-H), 4.08
(1H, m, 3-H), 5.36 (1H, m, 6-H), 5.67 (1H, m, 7-
H) This compound (IIa) (500 mg) was added to THF (500 ml).
And irradiated with a high-pressure mercury lamp (450 W) for 15 minutes. The reaction solution was concentrated, ethanol was added to the residue, and the mixture was heated under reflux for 1 hour. The ethanol was concentrated and the residue was purified by HPLC to give 110 mg of compound (Ia). ¹ H-NMR (CDCl ₃ ) δ: 0.58 (3H, s, 18-CH ₃ ), 0.93-1.05
(6H, m, 21-CH 3, 29-CH 3), 1.10 (3H, s, 26-CH 3), 1.1
6 (3H, s, 27-CH ₃ ), 4.11 (1H, m, 3-H), 4.32 (1H, m,
1-H), 4.93 (1H, m, 19-H), 5.30 (1H, m, 19-H), 6.0
1, 6.39 (each 1H, ABq, 6-H, 7-H)

Example 17 (24R) -24-Ethyl-9,10-secocholesta-5,
7-diene-1α, 3β, 25-triol (Ig) Instead of the phenylsulfone derivative (IVa), the compound (XI
a) The procedure of Example 16 was repeated except that (3.5 g) was used, to give 100 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.58 (3H, s, 18-CH ₃ ), 0.89-1.04
(6H, m, 21-CH 3, 29-CH 3), 1.09 (3H, s, 26-CH 3), 1.1
6 (3H, s, 27-CH ₃ ), 4.21 (1H, m, 3-H), 4.32 (1H,
m, 1-H). 4.94 (1H, m, 19-H), 5.30 (1H, m, 19-H),
6.01, 6.40 (1H, ABq, 6-H, 7-H each)

Example 18 (24S) -24-ethyl-9,10-secocholesta-5,
7-diene-1α, 3β-diol (Im) Instead of the phenylsulfone derivative (IVa), the compound (IX)
a) The same procedure as in Example 16 was carried out except using (3 g) to obtain 85 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.58 (3H, s, 18-CH ₃ ), 0.89-1.04
(12H, m, 21-CH ₃ , 26-CH ₃ , 27-CH ₃ , 29-CH ₃ ), 4.11 (1
H, m, 3-H), 4.32 (1H, m, 1-H). 4.94 (1H, m, 19-H),
5.30 (1H, m, 19-H), 6.01, 6.40 (1H, ABq, 6-H,
7-H)

Example 19 (24S) -24-Ethyl-9,10-secocholesta-5,
7,22-triene-1α, 3β, 25-triol (I
b) Phenylsulfone derivative (IVa) (2.5 g) was added to THF
(10 ml) and cooled to -70 ° C. 1ML
A DA THF solution (11.0 ml) was added at the same temperature, and the mixture was stirred for 30 minutes. C22-aldehyde derivative (XIII) (7.0
g) in THF solution (20 ml) was added at -70 ° C for 1 hour
Stirred for hours. Saturated aqueous NH ₄ Cl was added, extracted with ethyl acetate, washed with brine, dried and concentrated. Residue T
Dissolve in HF (25 ml) and methanol (25 ml)
p-TsOH (100 mg) was added, and the mixture was stirred at 40 ° C for 1 hour. Water was added and extracted with ethyl acetate, saturated aqueous NaHCO ₃ ,
After washing with brine, dried and concentrated. The residue was dissolved in methanol (100 ml) and Na ₂ HPO ₄ (20
g) and 5% Na-Hg (40 g) were added and stirred at room temperature overnight. Mercury was removed, the residue was concentrated, extracted with ethyl acetate, washed with brine, and concentrated. LiAlH ₄ (3
g) in a THF solution (30 ml) containing (7.5 g)
Was added and the mixture was refluxed for 1 hour. After adding a small amount of water, MgSO ₄ was added, filtered, and concentrated. The concentrate is purified by silica gel chromatography,
6.5 g of (24S) -24-ethyl-cholesta-5,7,22-triene-1α, 3β, 25-triol (IIb)
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.73 (3H, s, 18-CH ₃ ), 0.90-1.01
(9H, m, 19-CH ₃ , 21-CH ₃ , 29-CH ₃ ), 1.13 (3H, s, 26-
CH ₃ ), 1.17 (3H, s, 27-CH ₃ ), 3.75 (1H, m, 1-H), 4.0
8 (1H, m, 3-H), 5.21 (2H, m, 22-H, 23-H), 5.34 (1
(H, m, 6-H), 5.67 (1H, m, 7-H) Compound (IIb) (500 mg) was dissolved in THF (500 ml) and irradiated with a high-pressure mercury lamp (450 W) for 15 minutes. The reaction solution was concentrated, ethanol was added to the residue, and the mixture was heated under reflux for 1 hour. Then, the ethanol was concentrated, and the residue was purified by HPLC to obtain 95 mg of (Ib). ¹ H-NMR (CDCl ₃ ) δ: 0.60 (3H, s, 18-CH ₃ ), 0.93-1.03
(6H, m, 21-CH ₃ , 29-CH ₃ ), 1.12 (3H, s, 26-CH ₃ ), 1.
16 (3H, s, 27-CH ₃ ), 4.10 (1H, m, 3-H), 4.31 (1H,
m, 1-H), 4.92 (1H, s, 19H), 5.23 (2H, m, 22-H, 23-
H), 5.29 (1H, m, 19-H), 6.02, 6.41 (1H, ABq, 6-
H, 7-H)

Example 20 (24R) -24-Ethyl-9,10-secocoleta-5,
7,22-triene-1α, 3β, 25-triol (I
h) Instead of the phenylsulfone derivative (IVa), the compound (XI)
a) The procedure of Example 19 was repeated except that (2.5 g) was used, to give 100 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.60 (3H, s, 18-CH ₃ ), 0.93-1.03
(6H, m, 21-CH ₃ , 29-CH ₃ ), 1.12 (3H, s, 26-CH ₃ ), 1.
16 (3H, s, 27-CH ₃ ), 4.10 (1H, m, 3-H), 4.31 (1H,
m, 1-H). 4.94 (1H, m, 19-H), 5.22 (2H, m, 22-H, 23
-H), 5.29 (1H, m, 19-H), 6.02, 6.41 (1H, ABq, 6-
H, 7-H)

Example 21 (24R) -24-ethyl-9,10-secocholesta-5,
7,22-triene-1α, 3β-diol (In) Instead of phenylsulfone derivative (IVa), compound (IX)
a) The procedure of Example 19 was repeated except that (2.0 g) was used, to give 80 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.60 (3H, s, 18-CH ₃ ), 0.93-1.02
(12H, m, 21-CH 3, 26-CH 3, 27-CH 3, 29-CH 3), 4.10 (1
H, m, 3-H), 4.31 (1H, m, 1-H). 4.94 (1H, m, 19-H),
5.21 (2H, m, 22-H, 23-H), 5.30 (1H, m, 19-H), 6.0
2, 6.40 (1H, ABq, 6-H, 7-H each)

Example 22 24 (S) -Propyl-9,10-secocholesta-5,7,
22-triene-1α, 3β, 25-triol (Id) Instead of the phenylsulfone derivative (IVa), the compound (IV
b) The procedure was as in Example 19, except using 3.5 g, to give 95 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.58 (3H, s, 18-CH ₃ ), 0.89-1.03
(6H, m, 21-CH 3, 30-CH 3), 1.13 (3H, s, 26-CH 3), 1.1
7 (3H, s, 27-CH ₃ ), 4.12 (1H, m, 3-H), 4.33 (1H, m,
4.98 (1H, m, 19-H), 5.22 (2H, m, 22-H, 23-
H), 5.31 (1H, m, 19-H), 6.11, 6.40 (1H, ABq, 6-H,
7-H)

Example 23 24 (R) -Butyl-9,10-secocholesta-5,7,2
2-triene-1α, 3β, 25-triol (II) Instead of the phenylsulfone derivative (IVa), the compound (XI
c) The procedure of Example 19 was repeated except that (4.0 g) was used, to give 100 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.57 (3H, s, 18-CH ₃ ), 0.89-1.02
(6H, m, 21-CH ₃ , 31-CH ₃ ), 1.10 (3H, s, 26-CH ₃ ), 17
(3H, s, 27-CH ₃ ), 4.11 (1H, m, 3-H), 4.32 (1H, m, 1
-93), 4.93 (1H, m, 19-H), 5.22 (2H, m, 22-H, 23-H),
5.31 (1H, m, 19-H), 6.10, 6.39 (1H, ABq, 6-H,
7-H)

Test Example 1 Affinity of Compounds (Ia) and (Ib) for 1,25-Dihydroxyvitamin D ₃ Receptor (VDR) The affinity for the active vitamin D ₃ receptor of the present invention was examined by the RRA method shown below. did. Chicken small intestine VDR (25 mg) was dissolved in 100 ml of 50 mM phosphate buffer (pH 7.4) containing 0.3 M KCL. [ ³ H] -1,25 (OH) ₂ D ₃
Vitamin D of the invention at 1000 dpm and various concentrations
After adding the derivative and incubating at 4 ° C. for 24 hours, the reaction was stopped by adding 200 μl of 0.25% dextran charcoal, and the supernatant obtained by centrifugation was removed.
μl of radioactivity was measured. The affinity for VDR is
B / BO 50% with the measured value of 1,25 (OH) ₂ D ₃ as 1
Was evaluated by relative affinity. Table 2 shows the results.

[0050]

[Table 2]

Test Example 2 Evaluation test of NBT reducing ability of compounds (Ia) and (Ib) using differentiation induction of human myeloid leukemia cells (HL-60) as an index 2 × 10 ⁵ cells / ml in RPMI-1640 medium containing% FBS)
, And various concentrations of 1.25 (OH) ₂ D ₃
Alternatively, the cells were cultured for 4 days after adding the vitamin D derivative of the present invention. The culture was centrifuged to collect the cells, the supernatant was removed, and then 0.2% NBT, 200 ng / ml TPA (phor
boll 12-myristate 13-acetate) and add 2 at 37 ° C.
Incubated for 0 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 measured.
Was calculated. Table 3 shows the results.

[0052]

[Table 3]

According to Test Examples 1 and 2, the active vitamin D derivative of the present invention had the same differentiation-inducing activity as that of active vitamin D ₃ (1,25 (OH) ₂ D ₃ ) even though it had the same differentiation-inducing activity. , And VDR are as low as about 1/100. Next, preparation examples of the compound of the present invention will be shown.

[0054] The above components were uniformly mixed to obtain a powder for direct hitting. Using a rotary tableting machine, a tablet of 250 mg per tablet 100
0 tablets were prepared.

[0055] The above components were uniformly mixed to make a total volume of 3000 ml. The obtained solution was dispensed into ampoules by aseptic operation in an amount of 3 ml each, and the ampules were sealed.

[0056] The compound (Ia) in the above components was dissolved in a small amount of ethanol, the whole was mixed uniformly, and the mixture was granulated to prepare granules. The capsules were filled with 0.5 g per capsule to prepare 200 capsules.

[0057]

EFFECTS OF THE INVENTION The novel active vitamin D derivative provided by the present invention has a strong effect as described in Test Examples 1 and 2, despite its extremely low blood calcium concentration increasing effect as a side effect. It shows a differentiation-inducing effect, and is expected to have an effect as a drug having an excellent bone mass-improving effect, differentiation-inducing effect, cell growth inhibitory effect, and immunomodulatory effect.

Claims (9)

[Claims] 1. A compound of the general formula (I) (Wherein, _one of R ₁ and R ₂ represents a hydrogen atom, the other represents an ethyl group, a propyl group or a butyl group, R ₃ represents a hydrogen atom or a hydroxyl group, and the bond between C 22 and C 23 is a single bond or An active vitamin D derivative represented by the following formula: 2. The active vitamin D derivative according to claim ₁ , wherein R ₁ is a hydrogen atom, R ₂ is an ethyl group, R ₃ is a hydroxyl group and the bond between C 22 and C 23 is a single bond. 3. The active vitamin D derivative according to claim ₁ , wherein R ₁ is a hydrogen atom, R ₂ is an ethyl group, R ₃ is a hydroxyl group, and the bond between C 22 and C 23 is a double bond. 4. A compound of the general formula (II) (Wherein, _one of R ₁ and R ₂ represents a hydrogen atom, the other represents an ethyl group, a propyl group or a butyl group, R ₃ represents a hydrogen atom or a hydroxyl group, and the bond between C 22 and C 23 is a single bond or An active vitamin D derivative precursor represented by the formula (I), which is subjected to ultraviolet irradiation and then thermally isomerized. (Wherein the bond between R ₁ , R ₂ , R ₃ and C22-C23 has the above-mentioned meaning). 5. A medicament comprising the active vitamin D derivative according to claim 1 as an active ingredient. 6. The medicament according to claim 5, which is a bone mass improving drug. 7. The medicament according to claim 5, which is a differentiation inducer. 8. The medicament according to claim 5, which is a cytostatic. 9. The medicament according to claim 5, which is an immunomodulator.