JP3151285B2 - 1-hydroxyvitamin D derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 1-hydroxyvitamin D derivative. The compound of the present invention is useful as an agent for preventing and treating osteoporosis, a therapeutic agent for skin ulcer, and an antitumor agent.

[0002]

2. Description of the Related Art Activated vitamin D having a hydroxyl group at position 1
Is widely used for the treatment of osteoporosis, and has recently been found to have the ability to induce differentiation, and has been tried for the treatment of psoriasis and its application as an anticancer agent.

[0003] On the other hand, vitamin A acid is a substance that is biosynthesized from vitamin A in a living body and is considered to be an intermediate active substance when the effect of vitamin A is developed in a living body. That is, it has been clarified that functions of vitamin A, such as growth promotion, protein metabolism, and stabilization of epithelial cell tissue, are performed via this vitamin A acid. Then, all trans-vitamin A acid, 1
3-cis vitamin A acid, 9-cis vitamin A acid and the like are known.

[0004] Focusing on the fact that the above-mentioned physiologically active vitamin A acid has a carboxylic acid group, it has been considered to form an ester with a physiologically active alcohol compound to create a more useful substance. For example, vitamin A
Esters of acid and α-tocopherol (vitamin E), that is, α-tocopherol vitamin A acid esters are disclosed in JP-A-48-469 and JP-A-54-92967. However, esters of vitamin A acid and vitamin D are not known.

[0005]

SUMMARY OF THE INVENTION The present invention relates to osteoporosis,
An object of the present invention is to provide a 1-hydroxyvitamin D derivative having an excellent preventive or therapeutic effect on skin ulcers and tumors.

[0006]

According to the present invention, there is provided a compound of the formula (I)

Embedded image [Wherein, A represents an acyl group derived from vitamin A acid, X represents a hydroxyl group, and R represents the formula (II)

Embedded image Wherein R ₁ and R ₂ each represent a hydrogen atom or together form a carbon-carbon double bond, R ₃ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a hydroxyl group, R
₄ represents a hydrogen atom or a hydroxyl group).
And a 1-hydroxyvitamin D derivative represented by the formula:

In the above formula, A is an acyl group derived from vitamin A acid, and the formula (III) derived from all-trans-vitamin A acid

Embedded image Formula (IV) derived from an acyl group having the formula or 13-cis-vitamin A acid

Embedded image Represents an acyl group having the formula:

X represents a hydroxyl group.

R ₁ and R ₂ each represent a hydrogen atom or together form a carbon-carbon double bond.

R ₃ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a hydroxyl group. The alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, and n.
-Butyl, isobutyl and the like.

R ₄ represents a hydrogen atom or a hydroxyl group.

In the above formula (I), X may be bonded to the α- or β-position of the asymmetric carbon atom to which it is bonded. When R ₃ represents a C ₁ -C ₄ alkyl group or a hydroxyl group, the R-position of the asymmetric carbon atom to which it is bonded or the S-position
-Position. When R ₁ and R ₂ together form a carbon-carbon double bond, they indicate a trans-form or a cis-form.

The 1-hydroxyvitamin D derivative (I) of the present invention protects the hydroxyl group present in 3β-acetoxy-1-hydroxyvitamin D (V) by compound (VI) as shown in the following reaction formula. The compound (VI) is deacetylated to give a compound (VII), the compound (VII) is esterified with vitamin A acid to give a compound (VIII), and the hydroxyl-protecting group is removed from the compound (VIII). Manufactured by releasing.

[0014]

Embedded image

In the above formula, A, X and R have the meanings described above, X 'represents a protected hydroxyl group, and R' is a compound of the formula (IX)

Embedded image (In the above formula, R ₁ and R ₂ have the meaning described above,
R ₃ 'is hydrogen atom, C ₁ -C ₄ represents an alkyl group or a protected hydroxyl group, R _4' represents a represents a hydrogen atom or a protected hydroxyl group).

The hydroxyl-protecting group is preferably a group that can be chemically distinguished from the acetyl group at the 3-position, does not decompose the vitamin A and vitamin D skeletons, and can be easily removed. Examples include a t-butyldimethylsilyl group and a triethylsilyl group.

The compound of formula (V) is described in DeLuca, J .; Or
g. Chem., 45 , 3253 (1980).

Compound (VI) can be obtained by protecting a free hydroxyl group present in compound (V) according to a conventional method. For example, it can be obtained by reacting compound (V) with t-butyldimethylsilyl chloride or triethylsilyl chloride in an inert organic solvent such as dimethylformamide in the presence of a weak base such as imidazole.

Compound (VII) can be obtained by selectively removing the acetyl group at the 3-position of compound (VI) according to a conventional method. For example, it can be obtained by treating compound (VII) with an alkali such as sodium hydroxide or potassium hydroxide in a lower alcohol such as methanol or ethanol.

The compound (VIII) can be prepared by a conventional method.
It is obtained by reacting I) with vitamin A acid or a reactive derivative thereof. For example, the compound (VII) is reacted with a vitamin A acid in an inert organic solvent such as isopropyl ether or tetrahydrofuran in the presence of a dehydration catalyst such as dicyclohexylcarbodiimide (DCC) or trifluoroacetic anhydride, or It is obtained by reacting compound (VII) with a reactive derivative of vitamin A such as an acid halide or acid anhydride. In order to maintain the steric structure of the double bond of vitamin A acid and to prevent isomerization and cyclization, it is desirable to carry out the reaction under mild conditions as much as possible. desirable.

Compound (I) can be obtained by removing the hydroxyl-protecting group present in compound (VIII) by a conventional method. For example, it can be obtained by treating compound (VIII) with a weak base such as tetrabutylammonium fluoride in an inert organic solvent such as tetrahydrofuran.

In each of the above reactions, the reaction product is purified according to a conventional method. For example, purifying the desired product by distilling off the solvent from the reaction mixture or extracting with a suitable organic solvent and then distilling off the solvent from the extract, and recrystallizing or chromatographing the residue. Can be. Compound (VIII) obtained by acylating compound (VII) with vitamin A acid can be obtained without purification.
It is desirable to provide for the next deprotection step.

Specific examples of the compound having the formula (I) of the present invention and the compounds having the formulas (V) to (VIII), which are raw materials for synthesizing the same, are shown in Tables 1 to 5 below. The compound numbers in the table are referred to in the examples.

In Tables 1 to 5, "double bond" represents R ₁
And R ₂ together form a trans double bond.

In Tables 3 to 5, Z represents a t-butyldimethylsilyl group, and Z 'represents a triethylsilyl group.

[0026]

[Table 1]

[0027]

[Table 2]

[0028]

[Table 3]

[0029]

[Table 4]

[0030]

[Table 5]

The 1-hydroxyvitamin D derivative (I) of the present invention is formulated and administered in the same manner as conventionally known active vitamin D. That is, the compound of the present invention is a suitable carrier, excipient, diluent, for example, calcium carbonate, starch,
It is mixed with sucrose, lactose, talc, magnesium stearate, etc. to form powders, tablets, capsules, granules, injections, suppositories, ointments and the like for oral administration or parenterally to humans or animals Is administered. The dose may vary depending on the patient's condition, age, weight, etc.
An appropriate amount is 0.1 to 100 μg per day for an adult.

[0032]

Industrial Applicability The 1-hydroxyvitamin D derivative (I) of the present invention has an excellent effect for preventing and treating osteoporosis, and also has an excellent therapeutic effect on skin ulcers and tumors.

[0033]

The present invention will be described more specifically with reference to production examples of the compounds of the present invention.

[0034] Example 1 1.alpha.-hydroxy cholecalciferol mosquito Rushifu E rolls vitamin A acid (all-trans form) ester (Compound I-1) prepared in (1) 3.beta .- acetoxy-1 alpha-t-butyldimethylsilyloxy vitamin D ₃ (compound Preparation of VI-1) Compound V-1 (600 mg) was added to dimethylformamide (5
ml), and t-butyldimethylsilyl chloride (300 mg) and imidazole (300 mg) were added. After holding at 40 ° C. for 1 hour, it was extracted with ether, washed with brine and the ether was distilled off. The residue was chromatographed on silica gel (hexane / ethyl acetate = 9).
5/5) to give the title compound VI-1 (620 mg)
(Oil). ¹ H-NMR (CDCl ₃ ): δ 2.03 (3H, s, COCH ₃ ), 4.36 (1H, m,
H-1), 4.93 (1H, s, 19-Z), 5.21 (1H, m, H-3), 5.27 (1
H, s, 19-E), 6.05, 6.32 (2H, ABq, J = 12.0Hz, H-6, H-
7).

(2) Production of 1α-t-butyldimethylsilyloxyvitamin D ₃ (compound VII-1) Compound VI-1 (500 mg) was dissolved in ethanol (5 ml), and further a 10% KOH ethanol solution (5. 0 ml) and stirred at room temperature for 30 minutes. Extract with ethyl acetate,
After washing with brine, the solvent was distilled off. The residue was chromatographed on silica gel (hexane / ethyl acetate = 9).
/ 1) to give the title compound VII-1 (410 mg)
(Oil). ¹ H-NMR (CDCl ₃ ): δ 4.24 (1 H, m, H-3), 4.40 (1 H, m, H-
1), 4.93 (1H, s, 19-Z), 5.30 (1H, s, 19-E), 6.04, 6.3
5 (2H, ABq, J = 12.1Hz, H-6, H-7).

(3) 1α-hydroxycholecalciferol vitamin A acid (all-trans) ester (compound I
Preparation of -1) To a mixture of all-trans-vitamin A acid (300 mg) and isopropyl ether (3 ml) was added dropwise trifluoroacetic anhydride (0.18 ml) and stirred for 30 minutes.
Then, a tetrahydrofuran solution (5 ml) of the compound VII-1 (400 mg) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Aqueous ammonia (0.5 ml) was added, extracted with ether, washed with brine, the ether phase was concentrated, and the residue was chromatographed on silica gel (hexane / ethyl acetate = 9).
(5/5) to give compound VIII-1 (490 mg). Then Compound VIII-1 a (490 mg) was dissolved in tetrahydrofuran (5 ml), and tetrabutylammonium fluoride (Bu ₄ NF) of 1M solution of (3 ml) was added. After stirring at room temperature for 3 hours, it was extracted with ethyl acetate, washed with brine and the ethyl acetate was distilled off.
The residue was purified by silica gel chromatography (hexane / ethyl acetate = 9/1) to give the title compound I-1.
(340 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.55 (3H, s), 0.87 (3H, s), 0.89 (3
H, s), 0.93 (3H, d), 1.03 (6H, s), 1.71 (3H, s), 2.01
(3H, s), 2.35 (3H, s), 4.43 (1H, m), 5.00 (1H, s), 5.2
8 (1H, m), 5.34 (1H, s), 5.74 (1H, s), 6.00-6.36 (6H,
m), 7.01 (1H, m).

Example 2 Preparation of 1β-hydroxycholecalciferol vitamin A acid (all-trans) ester (compound I-2) Compound V-2 was prepared in the same manner as in Examples 1 (1) and (2).
To give compound VII-2 via compound VI-2. Compound VII-2 (300 mg) was treated in the same manner as in Example 1 (3) to obtain compound I-2 (220 mg). ¹ H-NMR (CDCl ₃ ): δ 0.55 (3H, s), 0.87 (3H, s), 0.89 (3H, s)
H, s), 0.93 (3H, d), 1.03 (6H, s), 1.71 (3H, s), 2.01
(3H, s), 2.35 (3H, s), 4.20 (1H, m), 5.00 (1H, s), 5.0
4 (1H, m), 5.36 (1H, s), 5.74 (1H, s), 6.00−6.36 (6H,
m), 7.01 (1H, m).

Example 3 Preparation of 1α-hydroxyergocalciferol vitamin A acid (all-trans) ester (compound I-3) (1) 3β-acetoxy-1α-t-butyldimethylsilyloxyvitamin D ₂ (compound VI) Preparation of -3) Compound V-3 (400 mg) was treated in the same manner as in Example 1 (1) to give the title compound VI-3 (410 mg) (oil). ¹ H-NMR (CDCl ₃ ): δ 2.03 (3H, s, COCH ₃ ), 4.37 (1H, m,
H-1), 4.93 (1H, s, 19-Z), 5.21 (3H, m, H-3, H-22, H-2
3), 5.29 (1H, s, 19-E), 6.06, 6.31 (2H, ABq, J = 12.1H
z, H-6, H-7).

(2) Preparation of 1α-t-butyldimethylsilyloxyvitamin D ₂ (Compound VII-3) Compound VI-3 (300 mg) was treated in the same manner as in Example 1 (2) to give the title compound VII-3. (250 mg) (oil). ¹ H-NMR (CDCl ₃ ): δ 4.26 (1H, m, H-3), 4.40 (1H, m, H-
1), 4.94 (1H, s, 19-Z), 5.23 (2H, m, H-22, H-23), 5.2
9 (1H, s, 19-E), 6.06, 6.37 (2H, ABq, J = 12.1Hz, H-6,
H-7).

(3) 1α-hydroxyergocalciferol vitamin A (all-trans) ester (compound I
Preparation of -3) Trifluoroacetic anhydride (0.13 ml) was added to a mixture of all-trans-vitamin A acid (200 mg) and isopropyl ether (2 ml), and the mixture was stirred at room temperature for 15 minutes. A solution of compound VII-3 (280 mg) in tetrahydrofuran (5 ml) was added dropwise, and the mixture was left overnight at 5 ° C. Aqueous ammonia (0.4 ml) was added, stirred for 30 minutes and extracted with ether. After washing with brine, the ether was removed and the residue was chromatographed on silica gel (hexane / ethyl acetate = 9/1) to give compound VIII-3 (31
0 mg). This compound VIII-3 with (310 mg) was dissolved in tetrahydrofuran (4ml), Bu ₄ NF 1M solution (2 ml) added and stirred at room temperature for 4 hours. After extraction with ethyl acetate and washing with brine, the ethyl acetate was distilled off. The residue was purified by silica gel chromatography to give the title compound 1-3 (220 mg). ¹ H-NMR (CDCl ₃ ): δ 0.55 (3H, s), 0.82 (3H, d), 0.84 (3
H, d), 0.92 (3H, d), 1.01 (3H, d), 1.03 (6H, s), 1.71
(3H, s), 2.00 (3H, s), 2.35 (3H, s), 4.44 (1H, m), 5.0
1 (1H, s), 5.22 (2H, m), 5.28 (1H, m), 5.34 (1H, s),
5.76 (1H, s), 6.01-6.35 (6H, m), 7.00 (1H, m).

Example 4 Preparation of 1β-hydroxyergocalciferol vitamin A acid (all-trans) ester (compound I-4) Compound V-4 was prepared in the same manner as in Examples 1 (1) and (2).
To give compound VII-4 via compound VI-4. Compound VII-4 (200 mg) was treated in the same manner as in Example 3 (3) to give the title compound I-4 (150 mg). ¹ H-NMR (CDCl ₃ ): δ 0.55 (3H, s), 0.82 (3H, d), 0.84 (3
H, d), 0.92 (3H, d), 1.01 (3H, d), 1.03 (6H, s), 1.71
(3H, s), 2.01 (3H, s), 2.35 (3H, s), 4.20 (1H, m), 5.0
1 (1H, s), 5.04 (1H, m), 5.22 (2H, m), 5.37 (1H, s),
5.74 (1H, s), 6.00-6.36 (6H, m), 7.01 (1H, m).

Example 5 Preparation of 1α, 25-dihydroxycholecalciferol Vitamin A acid (all-trans) ester (compound I-5) Compound V-5 was prepared in the same manner as in Examples 1 (1) and (2).
To give compound VII-5 via compound VI-5. However, triethylsilyl chloride was used instead of t-butyldimethylsilyl chloride in Example 1 (1).

To a mixture of all trans vitamin A acid (200 mg) and isopropyl ether (3 ml) was added dropwise trifluoroacetic anhydride (0.1 ml) and stirred for 30 minutes. Next, a solution of compound VII-5 (270 mg) in tetrahydrofuran (5 ml) was added, and the mixture was stirred at room temperature for 2 hours. Aqueous ammonia (0.5 ml) was added, extracted with ether, washed with brine and evaporated. The residue was chromatographed on silica gel (hexane / ethyl acetate =
95/5) to give Compound VIII-5 (330 mg). Compound VIII-5 (330 mg) was dissolved in tetrahydrofuran (5 ml), a 1 M solution of Bu ₄ NF (3 ml) was added, and the mixture was stirred at 50 ° C for 1 hour. After extraction with ethyl acetate and washing with brine, the solvent was distilled off. Silica gel chromatography of the residue (hexane / ethyl acetate = 4/1)
Then, compound I-5 (190 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.54 (3H, s), 0.94 (3H, d), 1.03 (6
H, s), 1.21 (6H, s), 1.71 (3H, s), 2.01 (3H, s), 2.35
(3H, s), 4.42 (1H, m), 5.00 (1H, s), 5.27 (1H, m), 5.3
5 (1H, s), 5.74 (1H, s), 6.00-6.37 (6H, m), 7.01 (1H,
m).

Example 6 Production of 1β, 25-dihydroxycholecalciferol vitamin A acid (all-trans) ester (compound I-6) In the same manner as in Example 5, compound V-6 was converted to compound VI-6. The compound VII-6 was obtained by the reaction, and the compound VII-6 (20
0 mg) was treated in the same manner as in Example 5 to give compound I-6 (90
mg). ¹ H-NMR (CDCl ₃ ): δ 0.53 (3H, s), 0.94 (3H, d), 1.03 (6
H, s), 1.20 (6H, s), 1.71 (3H, s), 2.01 (3H, s), 2.35
(3H, s), 4.20 (1H, m), 5.00 (1H, s), 5.04 (1H, m), 5.3
6 (1H, s), 5.74 (1H, s), 6.00-6.36 (6H, m), 7.01 (1H, s)
m).

Example 7 Preparation of 1α, 25-dihydroxyergocalciferol vitamin A acid (all-trans) ester (compound I-7) In the same manner as in Example 5, compound V-7 was converted to compound VI-7. To give a compound VII-7.
0 mg) was treated in the same manner as in Example 5 to give compound I-7 (29
0 mg). ¹ H-NMR (CDCl ₃ ): δ 0.54 (3H, s), 0.93 (3H, d), 1.00 (3
H, d), 1.03 (6H, s), 1.16 (3H, s), 1.17 (3H, s), 1.71
(3H, s), 2.01 (3H, s), 2.35 (3H, s), 4.42 (1H, m), 5.0
0 (1H, s), 5.22 (2H, m), 5.27 (1H, m), 5.35 (1H, s),
5.74 (1H, s), 6.00-6.36 (6H, m), 7.02 (1H, m).

Example 8 Preparation of 1β, 25-dihydroxyergocalciferol vitamin A acid (all-trans) ester (compound I-8) In the same manner as in Example 5, compound V-8 was converted to compound VI-8. To obtain a compound VII-8.
0 mg) was treated in the same manner as in Example 5 to give compound I-8 (12
0 mg). ¹ H-NMR (CDCl ₃ ): δ 0.53 (3H, s), 0.94 (3H, d), 1.01 (3
H, d), 1.02 (6H, s), 1.15 (3H, s), 1.17 (3H, s), 1.70
(3H, s), 2.01 (3H, s), 2.34 (3H, s), 4.19 (1H, m), 5.0
1 (1H, s), 5.04 (1H, m), 5.23 (2H, m), 5.36 (1H, s),
5.75 (1H, s), 6.00-6.36 (6H, m), 7.00 (1H, m).

Example 9 Preparation of 1α, 24R-dihydroxycholecalciferol vitamin A acid (all-trans) ester (compound I-9) In the same manner as in Example 5, compound V-9 was converted to compound VI-9. To obtain a compound VII-9, and the compound VII-9 (14
0 mg) was treated in the same manner as in Example 5 to give compound I-9 (10 mg).
0 mg). ¹ H-NMR (CDCl ₃ ): δ 0.56 (3H, s), 0.96 (3H, d), 1.03 (6
H, s), 1.17 (6H, d), 1.70 (3H, s), 2.01 (3H, s), 2.36
(3H, s), 3.22 (1H, m), 4.40 (1H, m), 4.97 (1H, s), 5.2
7 (1H, m), 5.33 (1H, s), 5.74 (1H, s), 6.00−6.38 (6H,
m), 7.01 (1H, m).

Example 10 1α, 24S, 25-Trihydroxycholecalciferol Vitamin A acid (all-trans) ester (compound I-
Preparation of 10) Compound V-10 to compound VI-1 in the same manner as in Example 5.
0 to give compound VII-10.
0 (80 mg) was treated in the same manner as in Example 5 to give compound I-1.
0 (35 mg) was obtained. ¹ H-NMR (CD ₃ OD-CDCl ₃ ): δ 0.57 (3H, s), 0.97 (3H, d),
1.03 (6H, s), 1.21 (6H, d), 1.70 (3H, s), 2.01 (3H, s),
2.37 (3H, s), 3.25 (1H, m), 4.41 (1H, m), 4.97 (1H,
s), 5.26 (1H, m), 5.33 (1H, s), 5.74 (1H, s), 6.01-
6.39 (6H, m), 7.01 (1H, m).

Example 11 Preparation of 1α-hydroxycholecalciferol vitamin A acid (13-cis type) ester (compound I-11) 13-cis-vitamin A acid (100 mg) was used in place of all-trans-vitamin A acid. Compound VII-1 (10
0 mg) was treated in the same manner as in Example 1 (3) to give the title compound I.
-11 (95 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.54 (3H, s), 0.86 (3H, s), 0.87 (3
H, s), 0.92 (3H, d), 1.03 (6H, s), 1.71 (3H, s), 2.03
(3H, s), 2.17 (3H, s), 4.43 (1H, m), 5.00 (1H, m), 5.3
0 (1H, m), 5.35 (1H, m), 5.95 (1H, s), 6.01-6.32 (5H,
m), 7.04 (1H, d), 7.85 (1H, d).

Example 12 Preparation of 1β-hydroxycholecalciferol vitamin A acid (13-cis type) ester (compound I-12) 13-cis-vitamin A acid (60 mg) was all-trans-
Used in place of vitamin A acid, compound VII-2 (50m
g) was treated in the same manner as in Example 1 (3) to give the title compound I-
12 (30 mg) were obtained. ¹ H-NMR (CDCl ₃ ): δ 0.54 (3H, s), 0.86 (3H, s), 0.87 (3
H, s), 0.92 (3H, d), 1.03 (6H, s), 1.71 (3H, s), 2.03
(3H, s), 2.17 (3H, s), 4.20 (1H, m), 5.01 (1H, m), 5.0
5 (1H, m), 5.35 (1H, m), 5.95 (1H, s), 6.01-6.33 (5H,
m), 7.04 (1H, d), 7.86 (1H, d).

Example 13 Preparation of 1α-hydroxyergocalciferol vitamin A acid (13-cis type) ester (compound I-13) 13-cis-vitamin A acid (50 mg) was all-trans-
Used in place of Vitamin A acid, compound VII-3 (60 m
g) was treated as in Example 3 (3) to give the title compound I-
13 (30 mg) were obtained. ¹ H-NMR (CDCl ₃ ): δ 0.55 (3H, s), 0.82 (3H, d), 0.84 (3
H, d), 0.92 (3H, d), 1.01 (3H, d), 1.03 (3H, s), 1.71
(3H, s), 2.03 (3H, s), 2.17 (3H, s), 4.44 (1H, m), 5.0
1 (1H, m), 5.28 (1H, m), 5.34 (1H, m), 5.20 (2H, m),
5.95 (1H, s), 6.00-6.35 (5H, m), 7.04 (1H, d), 7.84 (1
H, d).

Example 14 Preparation of 1β-hydroxyergocalciferol Vitamin A acid (13-cis type) ester (Compound I-14) 13-cis-Vitamin A acid (50 mg) was all-trans-
Compound VII-4 (60 m) was used in place of vitamin A acid.
g) was treated as in Example 3 (3) to give the title compound I-
14 (25 mg) were obtained. ¹ H-NMR (CDCl ₃ ): δ 0.55 (3H, s), 0.82 (3H, d), 0.84 (3
H, d), 0.92 (3H, d), 1.01 (3H, d), 1.03 (6H, s), 1.71
(3H, s), 2.03 (3H, s), 2.17 (3H, s), 4.21 (1H, m), 5.0
0 (1H, m), 5.04 (1H, m), 5.22 (2H, m), 5.36 (1H, m),
5.95 (1H, s), 6.01-6.35 (5H, m), 7.05 (1H, d), 7.87 (1
H, d).

Example 15 Preparation of 1α, 25-dihydroxycholecalciferol Vitamin A acid (13-cis type) ester (Compound I-15) 13-cis-Vitamin A acid (50 mg) was all-trans-
Compound VII-5 (60m) was used in place of vitamin A acid.
g) was treated as in Example 5 to give the title compound I-15.
(40 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.54 (3H, s), 0.94 (3H, d), 1.03 (6
H, s), 1.21 (6H, s), 1.71 (3H, s), 2.01 (3H, s), 2.35
(3H, s), 4.42 (1H, m), 5.00 (1H, s), 5.27 (1H, m), 5.3
5 (1H, s), 5.94 (1H, s), 6.01-6.35 (5H, m), 7.05 (1H, s)
d), 7.86 (1H, d).

Example 16 Preparation of 1β, 25-dihydroxycholecalciferol vitamin A acid (13-cis type) ester (compound I-16) 13-cis-vitamin A acid (50 mg) was all-trans-
Compound VII-6 (60 m) was used in place of vitamin A acid.
g) was treated as in Example 5 to give the title compound I-16.
(25 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.53 (3H, s), 0.94 (3H, d), 1.03 (6
H, s), 1.20 (6H, s), 1.71 (3H, s), 2.01 (3H, s), 2.35
(3H, s), 4.21 (1H, m), 5.00 (1H, s), 5.04 (1H, m), 5.3
6 (1H, s), 5.95 (1H, s), 6.01-6.34 (5H, m), 7.04 (1H, s)
d), 7.87 (1H, d).

Example 17 1α, 25-Dihydroxyergocalciferol Vitamin A acid (13-cis type) ester (Compound I-17)
Preparation of 13-cis-vitamin A acid (50 mg) with all-trans-
Compound VII-7 (60m) was used in place of vitamin A acid.
g) was treated as in Example 5 to give the title compound I-17.
(45 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.54 (3H, s), 0.93 (3H, d), 1.00 (3
H, d), 1.03 (6H, s), 1.16 (3H, s), 1.17 (3H, s), 1.71
(3H, s), 2.01 (3H, s), 2.35 (3H, s), 4.42 (1H, m), 5.0
0 (1H, s), 5.23 (2H, m), 5.27 (1H, m), 5.35 (1H, s),
5.95 (1H, s), 6.01-6.34 (5H, m), 7.05 (1H, d), 7.86 (1
H, d).

Example 18 1β, 25-Dihydroxyergocalciferol Vitamin A acid (13-cis type) ester (Compound I-18)
Preparation of 13-cis-vitamin A acid (50 mg) with all-trans-
Compound VII-8 (60 m) was used in place of vitamin A acid.
g) was treated as in Example 5 to give the title compound I-18.
(30 mg) was obtained. ¹ H-NMR (CDCl ₃ ): δ 0.53 (3H, s), 0.94 (3H, d), 1.00 (3
H, d), 1.02 (6H, s), 1.16 (3H, s), 1.17 (3H, s), 1.70
(3H, s), 2.01 (3H, s), 2.34 (3H, s), 4.19 (1H, m), 5.0
1 (1H, s), 5.04 (1H, m), 5.23 (2H, m), 5.36 (1H, s),
5.95 (1H, s), 6.00-6.34 (5H, m), 7.04 (1H, d), 7.87
(1H, d).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 43/00 101 A61P 43/00 101

Claims (2)

(57) [Claims] 1. A compound of the formula (I) [In the formula, A represents an acyl group derived from a vitamin A acid, X represents a hydroxyl group, and R represents a compound of the formula (II). Wherein R ₁ and R ₂ each represent a hydrogen atom or together form a carbon-carbon double bond, R ₃ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a hydroxyl group, R
₄ represents a hydrogen atom or a hydroxyl group).
A 1-hydroxyvitamin D derivative represented by the formula: 2. Formula (V) [In the formula, X represents a hydroxyl group, and R represents a compound of the formula (II). Wherein R ₁ and R ₂ each represent a hydrogen atom or together form a carbon-carbon double bond, R ₃ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a hydroxyl group, R
₄ represents a hydrogen atom or a hydroxyl group).
Protecting the hydroxyl group in 3β-acetoxy-1-hydroxyvitamin D represented by the following formula (VI): [In the formula, X ′ represents a protected hydroxyl group, and R ′ is a group represented by the formula (I
X) (In the above formula, R ₁ and R ₂ have the meaning described above,
R ₃ ′ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a protected hydroxyl group, and R ₄ ′ represents a hydrogen atom or a protected hydroxyl group). (VI) is subjected to a deacetylation reaction to give a compound of formula (VII) (Wherein X ′ and R ′ have the above-mentioned meanings), and this compound (VII) is esterified with vitamin A acid to give a compound of formula (VIII) (Wherein A represents an acyl group derived from a vitamin A acid, and X ′ and R ′ have the above-mentioned meanings), a compound (VIII) esterified with a vitamin A acid, Formula (I) comprising removing a protecting group for a hydroxyl group from (VIII). (Wherein, A, X and R have the above-mentioned meanings).