JP2850628B2 - Fluorinated vitamin D analogs - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel fluorine derivative of vitamin D. More specifically, the present invention provides a novel vitamin which has an excellent pharmacological action, that is, an enhanced cell differentiation-inducing action without showing hypercalcemia due to calcium metabolism, and is expected to be used as a drug such as an anticancer drug. D relates to a fluorine derivative.

[0002]

Is the Background of the Invention in vivo metabolite of vitamin D _3,
It is known that 1α, 25-dihydroxyvitamin D ₃ , which is known as active vitamin D ₃ , has an activity of promoting calcium absorption from the intestine and is effective as a therapeutic agent for bone lesions and the like. In addition, recently activated vitamin D and its analogs have a differentiation-inducing effect of returning cancerous cells to normal cells.
(Hirofumi Tanaka et al .: Biochemistry 55, 1323, 1983)
Have been found, and among these, the action of actually inhibiting the progression of cancer (KW Colton et al., Lancet . Jan. 28 , 188)
P. 1989). However, active vitamin D ₃ has a strong action on calcium metabolism, and this action is an undesirable side effect when vitamin D is used as an anticancer drug.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have improved the cell differentiation-inducing effect of returning cancerous cells to normal cells without showing hypercalcemia due to effects on calcium metabolism. Research was conducted for the purpose of creating a vitamin D analog in which the calcium metabolism action and the cell differentiation induction action were separated, and the present invention was completed.

[0004]

The novel vitamin D analog provided by the present invention has the general formula (I):

Embedded image (Wherein R ¹ represents a hydrogen atom or a hydroxyl-protecting group). Examples of the hydroxyl-protecting group include acetal-based protecting groups such as methoxymethyl, ethoxyethyl, methoxyethoxymethyl, and tetrahydropyranyl; silyl ether-based protecting groups such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and acetyl. And the like.

[0005] As a typical specific example of the compound represented by the general formula (I), a compound represented by the formula:

Embedded image (Compound A) represented by the formula:
α, 3-bis (t-butyldimethylsilyl) ether, 1
α, 3-bis (trimethylsilyl) ether, 1α, 3-bis (methoxymethyl) ether and the like, but are not limited thereto.

There are various methods for producing the compound (I) of the present invention, and one of the best examples is shown below. That is, the general formula (II):

Embedded image And a ketone represented by the general formula (III):

Embedded image (Wherein, R ¹ represents a protecting group for a hydroxyl group) by subjecting it to a coupling reaction with an anion derived from a phosphine oxide represented by the following formula, and deprotecting as necessary. As the base used to derive the anion of the phosphine oxide, an alkyl lithium such as n-butyl lithium is preferable.

[0007] The coupling reaction is carried out at -100 ° C to 50 ° C.
C., preferably at -80.degree. C. to 20.degree. C., under an inert atmosphere such as argon. The reaction solvent is ether,
An ether solvent such as tetrahydrofuran is preferable, and the reaction time is 10 minutes to 24 hours, preferably 30 minutes to 2 hours. The resulting product can be purified on a silica gel column. The product is optionally deprotected, which can be done in a known manner.

[0008] The target compound of the present invention is obtained as described above, and the compound (II) as a raw material is synthesized by the following route.

Embedded image (In the above formula, R ² is a protecting group for a hydroxyl group.)

That is, the aldehyde compound (1) is treated with a methyllithium ether solution, and the resulting compound (2) is oxidized to obtain a compound (3). Next, the compound (3) is treated with lithium diisopropylamide (LDA) and N-phenyltrifluoromethanesulfonimide, and the obtained compound (4) is treated with vinyltributyltin in the presence of a palladium catalyst to give the compound (5). obtain. Hexafluoroisobutene is added to compound (5), and the resulting compound (6) is subjected to a deprotection reaction by a conventional method to obtain compound (7). Further, the desired compound (II) can be obtained by oxidizing the compound (7). Hereinafter, the compound of the present invention will be specifically described with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0010]

EXAMPLES Example 1 1) 1α, 3-bis (t-butyldimethylsilyl) ether of compound (A) by the Wittig reaction of compound (II) and compound (III) wherein R ¹ is t-butyldimethylsilyl The compound (II) wherein R ¹ is t-butyldimethylsilyl
I) A solution of (589 mg) in anhydrous THF (5 ml) was added at -78 ° C.
-BuLi (2.5 M, 422 μl) was added dropwise and stirred for 5 minutes. To this solution was added a solution of compound (II) (50 mg) in anhydrous THF (2 ml), and the mixture was warmed to room temperature and stirred for 10 minutes. The reaction solution was poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was separated by column chromatography to obtain 26 mg of the title compound. ¹ H-NMR (CDC
l ₃ ) δ: 0.01 (s, 6H), 0.07 (s, 6H), 0.47 (s, 3
H), 0.82 (d, J = 8.6 Hz, 3H), 0.83 (s, 18
H), 4.18 (m, 1H), 4.37 (m, 1H), 4.86 (d, J =
2.6 Hz, 1 H), 5.17 (d, J = 2.6 Hz, 1 H), 6.0
0 (d, J = 11.2 Hz, 1 H), 6.23 (d, J = 11.2 H
z, 1H).

2) Preparation of Compound (A) by Deprotection Reaction The silyl compound (25 mg) obtained in Example 1-1) was mixed with 1 g of an ion exchange resin (50 W- × 4) in methanol (10 m
l) Added to the suspension and stirred at room temperature for 24 hours. After filtration, the solvent was distilled off, and the residue was purified by column chromatography to obtain 13.8 mg of the desired compound (A). 191.2-193.9 ° C (ether / hexane) α ²⁰ _D = + 87.7 °

[0012] Reference Example 1 R ² compounds wherein R ² is benzyl from compound is benzyl (1) (2) of the manufacturing methyllithium ether solution (1.4M, 11.5 ml)
Compound (1) wherein R ² is benzyl at −78 ° C.
(1.04 g) in anhydrous THF (5 ml) was added and stirred for 5 minutes. After rising to room temperature, the reaction solution was poured into a saturated ammonium chloride solution and extracted with ether. After washing the ether layer with water and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by column chromatography to obtain 1.02 g of a compound (2) in which R ² was benzyl. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (d, J = 6.2 Hz, 3
H), 0.97 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H),
3.72 (m, 1H), 3.96 (m, 1H), 4.36 (d, J = 1
(2.8 Hz, 1 H), 4.62 (d, J = 12.8 Hz, 1 H), 7.
2-7.4 (m, 5H). IR (neat) 3385,2935,1
453,1100cm ^-1

Reference Example 2 Preparation of Compound (3) wherein R ² is benzyl by oxidation of Compound (2) obtained in Reference Example 1 A dichloromethane solution containing oxalyl chloride (551 μl)
(33 ml) was added dropwise a solution of DMSO (596 μl) in dichloromethane (2.2 ml) at −78 ° C. and stirred for 10 minutes. Next, the alcohol (2) (1 g) obtained in Reference Example 1
Was added dropwise over 5 minutes.
Stir at 8 ° C for 15 minutes and at -45 ° C for 1 hour. Triethylamine (3.3 ml) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 20 minutes. A saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel chromatography, compounds wherein R ² is benzyl (3) was obtained 0.8 g. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (s, 3H), 1.10 (d,
J = 6.8 Hz, 3H), 2.11 (s, 3H), 3.73 (m, 1
H), 4.36 (d, J = 6.1 Hz, 1H), 4.62 (d, J = 6.
IR (neat) 2934, 2875, 1710 cm ^-1 (1 Hz, 1 H), 7.2-7.4 (m, 5 H)

Reference Example 3 Preparation of Compound (4) wherein R ² is benzyl from Compound (3) obtained in Reference Example 2 A solution of LDA (7.71 mmol) in THF (30 ml) was added at −78 ° C.
Then, a THF solution of the compound (3) (1.6 g) obtained in Reference Example 2 was added, and the mixture was stirred for 1 hour. Next, N-phenyltrifluoromethanesulfonimide (2.2 g) was added, and the mixture was stirred at room temperature overnight. The saturated ammonium chloride solution was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography to obtain 1.52 g of a compound (7) in which R ² was benzyl.

Reference Example 4 Preparation of Compound (5) wherein R ² is benzyl from Compound (4) obtained in Reference Example 3 Compound (4) (1.3 g) obtained in Reference Example 3, vinyltributyl Tin (1.1 ml), tetrakis (triphenylphosphine) palladium (140 mg), lithium chloride (400 m
A mixture of g) and THF (10 ml) was heated at reflux for 17 hours. Next, the reaction solution was washed with aqueous ammonia, the solvent was distilled off, and the residue was purified by column chromatography to obtain 399 mg of a compound (5) in which R ² was benzyl. ¹ H-NMR (CDCl ₃ ) δ: 1.03 (s, 3H), 1.08 (d,
J = 6.8 Hz, 3 H), 3.73 (m, 1 H), 4.36 (d, J =
12.3 Hz, 1 H), 4.62 (d, J = 12.3 Hz, 1 H),
4.90 (brs, 1H), 5.00 (brs, 1H), 5.00 (d, J =
6.9 Hz, 1 H), 5.34 (d, J = 17.3 Hz, 1 H), 6.
32 (dd, J = 17.3, 6.9 Hz, 1 H), 7.2-7.4 (m,
5H) .IR (neat) 2933, 1590, 1453 cm ^-1

Reference Example 5 R ² by the addition reaction of the compound (5) obtained in Reference Example 4
Production of Compound (6) wherein is benzyl A mixture of compound (5) (400 mg) obtained in Reference Example 4, hydroquinone (4 mg) and hexafluoroisobutene (1 ml) was reacted at 150 ° C. for 72 hours in a stainless steel reaction tube. did.
After the completion of the reaction, the mixture was purified by column chromatography to obtain 356 mg of a compound (6) in which R ² was benzyl. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (s, 3H), 1.19 (d,
J = 7.0 Hz, 3H), 2.85 (brs, 1H), 4.37 (d, J
= 14.2 Hz, 1 H), 4.63 (d, J = 14.2 Hz, 1 H),
5.31 (brs, 1H), 7.2-7.4 (m, 5H).

Reference Example 6 Preparation of compound (7) by deprotection of compound (6) obtained in Reference Example 5 Compound (6) (300 mg) obtained in Reference Example and 5% P
A suspension of dC (30 mg) in methanol (20 ml) was stirred under a hydrogen atmosphere (room temperature, normal pressure) for 12 hours. After filtration and concentration, the residue was purified by column chromatography to obtain 156 mg of compound (7). ¹ H-NMR (CDCl ₃ ) δ: 0.95 (s, 3H), 1.00 (d,
J = 6.8 Hz, 3 H), 4.08 (brs, 1 H), 5.32 (m, 1
H).

Reference Example 7 Preparation of Compound (II) by Oxidation of Compound (7) Obtained in Reference Example 6 A solution of compound (7) (68 mg) obtained in Reference Example 6 in dichloromethane (5 ml) was subjected to PCC (200 mg). ) Dichloromethane
(20 ml) was added dropwise to the suspension and stirred at room temperature for 2 hours. This was extracted with ether, and the ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain 46 mg of the desired compound (II). ¹ H-NMR (CDCl ₃ ) δ: 0.66 (s, 3H), 1.06 (d,
J = 6.8 Hz, 3 H), 5.40 (m, 1 H) .IR (neat) 296
0,2875,1715cm ^-1

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 401/00 A61K 31/59 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula: (Wherein, R ¹ represents a hydrogen atom or a hydroxyl-protecting group). 2. The method according to claim 1, wherein the hydroxyl group is methoxymethyl, ethoxyethyl, methoxyethoxymethyl, tetrahydropyranyl,
The compound according to claim 1, wherein the compound is selected from trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and acetyl.