JPH0539261A - Active type vitamin d derivative - Google Patents

Abstract

PURPOSE:To obtain a new active type vitamin D derivative useful as an agent for osteoporosis, an agent for skin ulcer and an antitumor agent. CONSTITUTION:An active type vitamin D derivative shown by formula I or formula II (R is group shown by formula III or formula IV) such as 1alpha- hydroxycholecalciferol vitamin A acid (whole trans type ester. These compounds are obtained by protecting hydroxyl group at the 3-position of a compound shown by formula V obtained from vitamin D3 and vitamin D2 by four processes, then hydrolyzing acetoxy group at the 1-position to give a compound shown by formula VI (X is protecting group), then subjecting this compound to ester condensation with whole trans-vitamin A acid (whole trans-retinoic acid shown by formula VII or 13-cis-vitamin A acid (13-cis-retinoic acid) shown by formula VIII, and finally eliminating protecting group of hydroxyl group at the 3-position.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an active vitamin D derivative useful as an osteoporosis agent, a skin ulcer agent and an antitumor agent.

[0002]

2. Description of the Related Art Active vitamin D having a hydroxyl group at the 1α position has been widely used for the treatment of osteoporosis, and recently, it was discovered that it has the ability to induce differentiation.
Application as an anti-cancer agent has also been attempted.

On the other hand, vitamin A acid is a substance which is biosynthesized from vitamin A alcohol in the living body and is considered to be an intermediate activator in the expression of the vitamin A action in the living body. That is, it has been elucidated that the functions of vitamin A such as growth promotion, protein metabolism, and stabilization of epithelial cell tissues are performed via this vitamin A acid. The presence of all-trans vitamin A acid, 13-cis vitamin A acid, 9-cis vitamin A acid and the like is known in this vitamin A acid due to the unsaturated bond of the side chain.

Vitamin A having the above physiological activity
To produce a useful substance by esterifying an acid with an alcohol having the same physiological activity by focusing on its function as an acid, for example, an ester of vitamin A acid and α-tocopherol, that is, α-tocopherol vitamin A acid. The esters are known from JP-A-48-469 and JP-A-54-92967. However, an ester of vitamin A acid and active vitamin D is not known.

[0005]

The object of the present invention is to provide a novel active vitamin D derivative having an excellent pharmacological action.

[0006]

DISCLOSURE OF THE INVENTION As a result of intensive studies by the present inventors, the following formulas (I) and (II)

[Chemical 3]

Or the following formulas (III) and (IV)

[Chemical 4] It was found that the active vitamin D derivative represented by, that is, an ester compound of active vitamin D and vitamin A acid exhibits an excellent pharmacological effect.

The active vitamin D derivative of the present invention can be easily produced by the method described below.

Formulas (V) and (VI) obtained from vitamin D ₃ and vitamin D _{2 in} four steps

[Chemical 5] Compound represented by (DeLuca, J. Org. Chem., 45 , 3
253 (see 1980)), protecting the hydroxyl group at the 3-position to give formulas (VII) and (VIII)

[0010]

[Chemical 6] (In the formula, X is a protecting group).
As this protective group, a protective group that can be chemically distinguished from the acetoxy group at the 1-position, such as tetrahydropyranyl, t-butyldimethylsilyl, and methoxymethyl group, is used. It is preferable to protect the vitamin A and vitamin D skeletons with a protecting group that does not decompose and is easily removable, for example, a t-butyldimethylsilyl group. When the t-butyldimethylsilyl group is introduced as a protecting group, it is easily carried out by a conventional means of reacting the compound (V) or (VI) with t-butyldimethylsilyl chloride in dimethylformamide in the presence of imidazole.

Next, the acetoxy group at the 1-position of the compounds (VII) and (VIII) is hydrolyzed to give formulas (IX) and (X).

[Chemical 7] (In the formula, X is a protecting group).
The hydrolysis is carried out in the customary manner, i.e. with sodium hydroxide or potassium hydroxide in methanol or ethanol.

Next, the compounds (IX) and (X) are represented by the following structural formulas:

[Chemical 8] All-trans-vitamin A acid (all-trans-retinoic acid) represented by or the following structural formula

[0013]

[Chemical 9] Is ester-condensed with 13-cis-vitamin A acid (13-cis-retinoic acid) represented by the formula (XI) and (XI
I)

[0014]

[Chemical 10] (In the formula, X is a protecting group)

Or formulas (XIII) and (XIV)

[Chemical 11] (In the formula, X is a protecting group). The ester condensation is carried out using a known technique, for example, a method of directly condensing in the presence of a dehydration catalyst such as dicyclohexylcarbodiimide (DCC) or trifluoroacetic anhydride, or a method of converting vitamin A acid into an acid halide and then condensing it. Etc. are used. In order to maintain the double bond steric structure of vitamin A acid and prevent isomerization and cyclization reactions, it is desirable to carry out the reaction under mild conditions as possible. In that respect, trifluoroacetic anhydride should be used. The esterification reaction of is preferred.

Finally, the compounds (XI), (XII), (XII
The active vitamin D derivative compounds (I), (II), (III) and (IV) of the present invention described above can be obtained by removing the protecting group for the hydroxyl group at the 3-position of (I) and (XIV). When the protecting group is a t-butyldimethylsilyl group, it can be easily eliminated by using tetrabutylammonium fluoride.

The method of the present invention is illustrated by the reaction using specific reaction reagents, as shown in the following reaction scheme.

[0018]

[Chemical formula 12]

[0019]

[Chemical 13]

[0020]

EXAMPLES The present invention will now be described in more detail by way of examples, which should not be construed as limiting the invention.

Example 1 1α-acetoxy-3β-t-butyldimethylsilyloxyvitamin D ₃ (VII) Compound (V) (700 mg) was added to dimethylformamide (5
ml) and t-butyldimethylsilyl chloride (350 mg) and imidazole (350 mg) were added.
After keeping 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 = 95 /
Purification according to 5) gave 520 mg of the title compound (VII) (oil). ¹ H-NMR (CDCl ₃ ): δ 2.03
_{(3H, s, COCH 3)} , 4.23 (1H, m, H-
3), 4.93 (1H, s, 19-Z), 5.41 (1
H, m, H-1), 5.27 (1H, s, 19-E),
6.05, 6.32 (2H, ABq, J = 12.0Hz,
H-6, H-7).

Example 2 1α-acetoxy-3β-t-butyldimethylsilyloxyvitamin D ₂ (VIII) Compound (VI) (500 mg) was treated in the same manner as in Example 1 to obtain 430 mg of the title compound (VIII). (Oil). ¹ H-
NMR (CDCl ₃ ): δ 2.03 (3H, s, COC
H ₃ ), 4.24 (1H, m, H-3), 4.93 (1
H, s, 19-Z), 5.21 (2H, m, H-22,
H-23), 5.29 (1H, s, 19-E), 5.36.
(1H, m, H-1), 6.06, 6.31 (2H, AB
q, J = 12.1 Hz, H-6, H-7).

Example 3 3β-t-butyldimethylsilyloxy-1α-hydroxyvitamin D ₃ (IX) Compound (VII) (500 mg) was dissolved in ethanol (5 ml), and 10% KOH ethanol solution (0.5 ml) was added. )
Was added and stirred for 30 minutes at room temperature. After extraction with ethyl acetate and washing with brine, the solvent was evaporated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 9/1) to give 330 mg of the title compound (IX).
Obtained (oil). ¹ H-NMR (CDCl ₃ ): δ 4.2
2 (1H, m, H-3), 4.41 (1H, m, H-
1), 4.93 (1H, s, 19-Z), 5.30 (1
H, s, 19-E), 6.04, 6.35 (2H, AB
q, J = 12.1 Hz, H-6, H-7).

Example 4 3β-t-Butyldimethylsilyloxy-1α-hydroxyvitamin D ₂ (X) Compound (VIII) (300 mg) was treated in the same manner as in Example 3 to obtain 210 mg of the title compound (X). (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), 5.29 (1H, s, 19-E), 6.06,
6.37 (2H, ABq, J = 12.1Hz, H-6, H
-7).

Example 5 1α-Hydroxycholecalciferol vitamin A acid (all-trans type) ester (I) To a mixture of all-trans-vitamin A acid (300 mg) and isopropyl ether (3 ml), trifluoroacetic anhydride (0) was added. .18 ml) was added dropwise and stirred for 30 minutes. Then, a tetrahydrofuran solution (5 ml) of compound (IX) (300 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 purified by silica gel chromatography (hexane / ethyl acetate = 95/5) to give the compound (XI ) Was obtained. Compound (XI) (310 mg) was then dissolved in tetrahydrofuran (5 ml) and a 1M solution of tetrabutylammonium fluoride (3 ml) was added. 3 at room temperature
After stirring for hours, it was extracted with ethyl acetate, washed with brine and the ethyl acetate was evaporated. Silica gel chromatography of the residue (hexane / ethyl acetate = 9/1)
The title compound (I) (210 mg) was obtained as an oil. ¹ H-NMR (CDCl ₃ ): δ 0.55 (3H,
s), 0.87 (3H, s), 0.89 (3H, s),
0.93 (3H, d, J = 6Hz), 1.03 (6H,
s), 1.71 (3H, s), 2.01 (3H, s),
2.35 (3H, s), 4.19 (1H, m), 5.00
(1H, s), 5.34 (1H, s), 5.53 (1H, s
m), 5.74 (1H, s), 6.00-6.36 (6
H, m), 7.01 (1H, dd, J ₁ = 15 Hz, J ₂
= 11 Hz).

Example 6 1α-Hydroxyergocalciferol vitamin A
(All-trans) ester (II) To a mixture of all-trans-vitamin A acid (150 mg) and isopropyl ether (2 ml) was added trifluoroacetic anhydride (0.13 ml), and the mixture was stirred at room temperature for 15 minutes.
A tetrahydrofuran solution (5 ml) of the compound (X) (200 mg) was added dropwise, and the mixture was left at 5 ° C overnight. Aqueous ammonia (0.4 ml) was added, stirred for 30 minutes and extracted with ether. After washing with brine, the ether was distilled off, and the residue was subjected to silica gel chromatography (hexane / ethyl acetate = 9/1) to give compound (XII) 21
0 mg was obtained. This compound (XII) (210 mg) was dissolved in tetrahydrofuran (4 ml), a 1M solution of Bu ₄ NF (1.5 ml) was added, and the mixture was stirred at room temperature for 4 hours. After extraction with ethyl acetate and washing with brine, ethyl acetate was evaporated. The residue was purified by silica gel chromatography to obtain 130 mg of the title compound (II). ¹ H
_{-NMR (CDCl 3): δ 0.55} (3H, s), 0.
82 (3H, d, J = 6 Hz), 0.84 (3H, d,
J = 6 Hz), 0.92 (3H, d, J = 6 Hz), 1.
01 (3H, d, J = 6Hz), 1.03 (6H,
s), 1.71 (3H, s), 2.00 (3H, s),
2.35 (3H, s), 4.20 (1H, m), 5.01
(1H, s), 5.22 (2H, m), 5.34 (1H,
s), 5.54 (1H, m), 5.76 (1H, s),
6.01-6.35 (6H, m), 7.00 (1H, d
d, J ₁ = 15 Hz, J ₂ = 11 Hz).

Example 7 1α-Hydroxycholecalciferol Vitamin A acid (13-cis type) ester (III) 13α-cis-vitamin A acid (100 mg) was used in place of all-trans-vitamin A acid. Treatment in the same manner as in Example 5 gave 120 mg of the title compound (III). ¹ H-NMR
(CDCl ₃ ): δ 0.54 (3H, s), 0.86 (3
H, s), 0.87 (3H, s), 0.92 (3H, d,
J = 6 Hz), 1.03 (6H, s), 1.71 (3H,
s), 2.03 (3H, s), 2.17 (3H, s),
4.20 (1H, m), 5.00 (1H, m), 5.35
(1H, m), 5.56 (1H, m), 5.95 (1H,
s), 6.01-6.32 (5H, m), 7.04 (1
H, dd, J ₁ = 15 Hz, J ₂ = 11 Hz), 7.85
(1H, d, J = 15Hz).

Example 8 1α-Hydroxyergocalciferol vitamin A acid (13-cis type) ester (IV) 13-cis-vitamin A acid (50 mg)
By the same procedure as in Example 6 except that vitamin A acid was used, 38 mg of the title compound (IV) was obtained. ¹ H-NMR (C
DCl ₃ ): δ 0.55 (3H, s), 0.82 (3H,
d, J = 6Hz), 0.84 (3H, d, J = 6H
z), 0.92 (3H, d, J = 6Hz), 1.01 (3
H, d, J = 6 Hz), 1.03 (3H, s), 1.71
(3H, s), 2.03 (3H, s), 2.17 (3H,
s), 4.21 (1H, m), 5.01 (1H, m),
5.28 (1H, m), 5.34 (1H, m), 5.20
(2H, m), 5.59 (1H, m), 5.95 (1H,
s), 6.00-6.35 (5H, m), 7.04 (1
H, dd, J ₁ = 15 Hz, J ₂ = 11 Hz), 7.84
(1H, d, J = 15Hz).

[0029]

The active vitamin D derivative of the present invention exhibits an excellent pharmacological action as an osteoporosis agent, a skin ulcer agent and an antitumor agent, and is useful as a medicine.

When the compound of the present invention is used as a medicine,
It can be administered in the form of powder, tablets, capsules, granules, injections, suppositories, ointments and the like by mixing with a suitable carrier, excipient, diluent and the like. The dose may vary depending on the patient's symptoms, age, body weight, etc., but normally, for example, 0.2 to 20 μg per day for an adult is suitable.

Claims (1)

[Claims] 1. The following formulas (I) and (II): Or the following formulas (III) and (IV) An active vitamin D derivative represented by: