JPH10182597A - Isomerized vitamin d derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an isomerized vitamin D derivative capable of separating a main effect and a side effect and enlarging a safety zone as a medicine by reversing configuration of hydroxide at 1-position or 3-position, or allowing the 3-position not to bond with hydroxy group. SOLUTION: This isomerized vitamin D derivative is a compound of the formula [R<1> is H or OH; R<2> is a 4-10C organic group (with the proviso that 4-methyl-pentyl and 4-hydroxy-4-methyl-pentyl are omitted); when R<1> is OH, the configuration of the 1-position and the 3-position are (1S,3S), (1R,3R) or (1R,3S)], etc., e.g. (5Z,7E)-26,26,26,27,27,27-hexafluoro-9,10-secocholest-5,7,10(19)- trien-1α,3α,23S,25-tetraol. The objective compound is obtained by protecting all OH in a natural vitamin D derivative of (1S,3R) configuration with t- butyldimethylsilyl group, selectively deprotecting the protecting group at the 3-position with a weak acid, performing oxidation and reduction reactions of the product and thereafter lastly deprotecting the product to provide the objective compound having (1S,3S) configuration at the 1- and 3-positions.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel isomerized vitamin D derivative useful as a medicine. In particular, the present invention relates to an osteogenesis promoter, a bone resorption inhibitor, or osteoporosis, rickets, osteomalacia, psoriasis, cancer (breast cancer, colorectal cancer, etc.), hypoparathyroidism, hyperparathyroidism, chronic The present invention relates to a novel isomerized vitamin D derivative useful as a therapeutic agent for renal failure, atopic dermatitis, cutaneous keratosis and the like.

[0002]

BACKGROUND OF THE INVENTION Various vitamin D ₃ compound is a pharmaceutical, specifically, for example, osteogenesis promoting agents, bone resorption inhibitors, or osteoporosis, rickets, osteomalacia, psoriasis, cancer (breast, colon, etc.) ,
It is known to be useful as a therapeutic agent for hypoparathyroidism, hyperparathyroidism, chronic renal failure, atopic dermatitis, cutaneous keratosis, etc. ("All of vitamin D")
Published by Kodansha, Etsuro Ogata, edited by Tatsuo Suda, 1993). However, conventionally known vitamin Ds have a strong effect as the above-mentioned therapeutic agent and are useful as medicines. For example, 1α, 25-dihydroxy-vitamin D ₃ has a very strong side effect, It is known that the safety margin is narrow. So, in recent years, and the development of vitamin D derivatives for the purpose of separation of the main action and side effects has attracted great interest (THE BONE 1995.3 9 (1) , p.53).
Among them, search and development of vitamin D derivatives having various functional groups on side chains have been carried out.
The 1α, 25-dihydroxy-vitamin D ₃ derivative hexafluoro at the 27-position has been reported as a compound having excellent vitamin D-like activity and low toxicity (for example, see US Pat. No. 4,248,791; Japanese Patent Publication No. 58-501176; 63-24949), but there is a demand for the development of a vitamin D derivative having a wider safety margin as a medicament. J. Org. Chem., 58, 1895 (1993) et al. Describe that isomers of 1α-hydroxy-vitamin D ₃ and 1α, 25-dihydroxy-vitamin D _{3 at} the 1- and 3-positions are receptors for vitamin D. to have been described to have affinity, Biochem Biophys.Res Commun, 65, 24 in the (1975) or the like, l [alpha], 25-dihydroxy -... of vitamin D ₃ 3-
It is described that the deoxy form has an affinity for the vitamin D receptor. However, no known side effects of these compounds are known.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel vitamin D derivative used as a medicament which has a wide range of safety as a medicament by separating main effects and side effects.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a vitamin D derivative in which the steric position of the hydroxyl group at the 1- or 3-position or a derivative having no hydroxyl group at the 3-position has a main effect. The present invention has been completed by finding that it is a vitamin D derivative which has a wide range of safety as a drug with isolated side effects.

That is, the present invention relates to (A). General formula (1)

Embedded image [Wherein, R ¹ represents a hydrogen atom or a hydroxyl group, and R ² represents an organic group having 4 to 10 carbon atoms (excluding 4-methyl-pentyl and 4-hydroxy-4-methyl-pentyl). . However, when R ¹ is a hydroxyl group, the 1- and 3-position stereoscopy are (1S, 3S), (1R,
3R) or (1R, 3S). A vitamin D derivative or a pharmaceutically acceptable salt thereof,

(B). General formula (2)

Embedded image [Wherein, R ¹ and R ² are as defined above. A vitamin D derivative or a pharmaceutically acceptable salt thereof,
(C). The vitamin D derivative or a pharmaceutically acceptable salt thereof according to (A) or (B), wherein R ¹ is a hydroxyl group;

(D). The vitamin D derivative according to any one of (A) to (C), wherein R ² is any of the following groups;

Embedded image (E). R ² is 4-hydroxy-4-trifluoromethyl-5,5,5-trifluoropentyl or 2,4
-Dihydroxy-4-trifluoromethyl-5,5,5
The vitamin D derivative according to any one of (A) to (C), which is trifluoropentyl, and (F). The present invention relates to a medicine containing the vitamin D derivative according to any one of (A) to (E) or a pharmaceutically acceptable salt thereof.

[0008] The organic group having 4 to 10 carbon atoms is, for example, a linear or branched saturated hydrocarbon group having 4 to 10 carbon atoms, and oxygen is contained in the chain of the hydrocarbon group. May contain an atom, a sulfur atom, a double bond, a 3- to 6-membered hydrocarbon ring, and the like, and may also have a hydroxyl group, an oxo group,
Examples include groups that may be substituted with a halogen atom or the like. Preferred organic groups having 4 to 10 carbon atoms include:
An organic group having 4 to 10 carbon atoms in which any carbon at the 3- to 5-position is substituted with a hydroxyl group to form a quaternary carbon is exemplified. Specific examples include the following groups.

Embedded image

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The stereo at position 20 may be in either the R or S configuration.

When the vitamin D derivative represented by the general formula (1) is a basic or acidic compound, it can be a pharmaceutically acceptable salt. Specific examples of the pharmaceutically acceptable salts include acid addition salts to which acids such as hydrochloric acid, sulfuric acid, citric acid, fumaric acid and benzenesulfonic acid are added, or base addition salts such as sodium salts and calcium salts. . The present invention also includes solvates such as hydrates.

The vitamin D derivative represented by the general formula (1) can be produced by various methods. Specifically, for example, the stereo at the 1-position and the 3-position is (1) by the following method.
A vitamin D derivative which is (S, 3S), (1R, 3R) or (1R, 3S), and a vitamin D derivative having no hydroxyl group at the 3-position can be produced.

Method 1: The 1- and 3-position stereoscopy are (1S,
Method for producing vitamin D derivative which is 3S)

Embedded image Wherein R ² is as defined above. R ³ represents an organic group defined in R ² protected with a protecting group as required. R ⁴ represents a protecting group for a hydroxyl group. ]

The compound (1) is protected by protecting all the hydroxyl groups of the natural vitamin D derivative (3) in which the 1- and 3-positions are (1S, 3R) and, if necessary, other functional groups with a protecting group. 4). As the protecting group for the hydroxyl group used herein, any protecting group that can easily and selectively remove the 3-position at the subsequent step of removing the protecting group for the 3-position hydroxyl group may be used. A bulky silyl group such as a silyl group and a triethylsilyl group is preferably used. The protection by these protecting groups is carried out by a commonly used method ("Protective Groups in Organic Synthesis" TWG)
reene, PM Wuts John. Wiley and sons 1991). The selective deprotection reaction of the protecting group at the 3-position of compound (4) can be carried out under ordinary conditions for deprotecting the protecting group. For example, when a t-butyldimethylsilyl group is used, the reaction can be carried out by reacting a weak acid such as p-toluenesulfonic acid in a solvent such as alcohol using a catalytic amount. The oxidation reaction of compound (5) can be carried out using various oxidizing agents. As the oxidizing agent, for example, Dess-Martin reagent, active manganese dioxide, swan oxidation reaction reagent and the like are suitably used (Experimental Chemistry Lecture Vol. 23, pp. 1-31 and 299-345). Compound (6)
In the reduction reaction, various reducing agents can be used. For example, sodium borohydride, lithium aluminum hydride, tetramethylammonium triacetoxyborohydride and the like are preferably used (Experimental Chemistry Course, Vol. 26)
159-266). By subjecting the compound (7) to a deprotection reaction, a vitamin D derivative (8) in which the stereo at the 1- and 3-positions is (1S, 3S) can be obtained.

Method 2: The stereo at the 1-position and 3-position is (1R,
Method for producing vitamin D derivative which is 3R)

Embedded image Wherein R ² and R ³ are as defined above. ]

The natural vitamin D derivative (3) is protected with another protecting group if necessary, and further oxidized at the 1-position hydroxyl group, whereby the oxidation reaction and the isomerization reaction proceed, and the compound ( 9) can be obtained. As the oxidizing agent, various oxidizing agents can be used. For example, Dess-Martin reagent, activated manganese dioxide, swan oxidation reaction reagent and the like are preferably used. The isomerization reaction follows this oxidation reaction,
It proceeds quickly at room temperature without using heat, light, etc., and gives compound (9) in good yield. Various reduction agents can be used for the reduction reaction of compound (9). Specifically, sodium borohydride, lithium aluminum hydride, tetramethylammonium triacetoxyborohydride and the like are suitably used. Compound (10) is thermally isomerized in an organic solvent to give a vitamin D derivative (11) in which the 1- and 3-positions are (1R, 3R).
Can be obtained. As the organic solvent, various solvents can be used, and any inert solvent that can dissolve the compound (10) may be used, and for example, acetone, benzene, toluene, hexane, methanol, acetonitrile, and the like are suitably used. The reaction can be carried out by heating at 20 to 120 ° C, preferably 50 to 100 ° C, for about 2 to 10 hours (Japanese Patent Publication No. 7-64804).

Method 3: The stereo at the 1-position and 3-position is (1R,
Method for producing vitamin D derivative which is 3S)

Embedded image Wherein R ² and R ³ are as defined above. Compound (14) can be obtained from compound (8) obtained by method 1 in the same manner as in method 2.

Method 4: Vitamin D induction without a hydroxyl group at the 3-position
Conductor manufacturing method

Embedded image [Wherein, R ² , R ³ and R ⁴ are as defined above. The vitamin D derivative (16) having no hydroxyl group at the 3-position can be obtained by reducing the hydroxyl group at the 3-position of the compound (15) and removing the protecting group. As the compound (15), the compound (5) obtained by the method 1 and the like can be used. The reduction of the hydroxyl group can be carried out by a usual method, and as a reducing agent, for example, tributyltin hydride or the like can be used (Experimental Chemistry Course Vol. 26
191-195).

Method 5: Bi by palladium coupling
Method for producing Tamine D derivative

Embedded image Wherein R ² and R ³ are as defined above. R ⁵ represents a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group. R ⁶ and R ⁷ independently represent a hydroxyl-protecting group. The stereo at the 1- and 3-positions is (1S, 3S), (1R, 3
R) or (1R, 3S) a vitamin D derivative (1
9) is a transhydrindan derivative (17) in the same manner as in the method described in J. Am. Chem. Soc., 114, 9836 (1992).
And an eneyne compound (18) having a corresponding steric structure by a coupling reaction using a palladium catalyst. The transhydrindan derivative (17) and the enyne compound (18) are disclosed in
The compound can be synthesized in the same manner as described in -12502. By subjecting the vitamin D derivative (19) to a deprotection reaction in the same manner as in Method 1, the 1- and 3-position stereoscopy is (1S, 3S), (1R, 3R) or (1R, 3S)
Vitamin D derivative (20) can be obtained.

As the protector for the hydroxyl group in R ⁶ and R ⁷ , any protector can be used as long as it can be used under the reaction conditions (for example, “Protective Groups in Orga”).
nicSynthesis "TW Greene, PM Wuts John. Wiley
and sons 1991, pp. 10-142) can be used, for example, protecting groups which can be easily removed by acid or alkali hydrolysis. Specifically, substituted silyl groups such as trimethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, t-butyldiphenylsilyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, Examples include substituted methyl groups such as methoxyethoxymethyl and tetrahydropyranyl, alkanoyl groups such as monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, acetyl, propionyl, butyryl, isobutyryl, and pivaloyl, and aroyl groups such as benzoyl. Preferable are a substituted silyl group and a substituted alkyl group. Particularly preferred are triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methoxymethyl, tetrahydropyranyl, benzyloxymethyl, methoxyethoxymethyl and the like. Can be mentioned. The obtained vitamin D derivative is
If necessary, purification can be carried out by means such as high performance liquid chromatography and recrystallization. In addition, a pharmaceutically acceptable salt can be obtained by an ordinary technique.

The vitamin D derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof may be orally or parenterally (intramuscular or intravenous injection, rectal administration in the form of a suppository, topical use) Agent, etc.). For example, when administered orally, commonly used dosage forms, such as tablets, capsules, syrups,
It can be in the form of a suspension or the like. In addition, the above-mentioned suitable dosage form can be prepared by using a conventional acceptable carrier, excipient, binder,
It can be produced by blending a vitamin D derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof with a stabilizer or the like. When used as an injection, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. The dose and frequency of administration vary depending on symptoms, age, weight, dosage form, etc.
Generally from 0.002 to about 100 μg, preferably 0.01, per day.
-20 μg, more preferably 0.02-10 μg, can be administered once or in several divided doses.

[0021]

EXAMPLES Next, the present invention will be described more specifically with reference to examples and reference examples, but the present invention is of course not limited by these. The following abbreviations are used in the examples. TBS = t-butyldimethylsilyl Ac = acetyl TMS = trimethylsilyl Example 1 (5Z, 7E) -26,26,26,27,27,27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1α, 3α, 23S, 25-
Synthesis of tetraol (1-7)

Embedded image

Step 1 (5Z, 7E) -23S, 25-diacetoxy-1α,
3β-bis (t-butyldimethylsilyloxy) -2
6,26,26,27,27,27-hexafluoro-
9,10-Secocolesta-5,7,10 (19) -Tri
Synthesis of ene (1-2) 1.10 g of compound (1-1) (JP-A-7-126246)
And 35 mg of dimethylaminopyridine in 10 g of pyridinium
And 3.0 g of acetic anhydride was added thereto.
Stir for 12 hours. Water is added to the reaction solution, and extracted with ethyl acetate.
Issued. The organic layer was washed with 2N hydrochloric acid, 5% aqueous sodium bicarbonate, and saturated saline.
Wash sequentially and dry over magnesium sulfate, then evaporate the solvent
The residue is subjected to silica gel column chromatography (migration
Phase, hexane: ethyl acetate = 50: 1)
1.14 g (94%) of the compound were obtained.¹ H-NMR (CDCl_Three) Δ: 0.05-0.07 (1
2H, m), 0.55 (3H, s), 0.85-0.8
9 (18H, m), 1.00 (3H, d, J = 5.0H
z), 2.00 (3H, s), 2.18 (3H, s),
4.18 (1H, m), 4.38 (1H, m), 4.8
6 (1H, s), 5.18 (1H, m), 5.19 (1
H, s), 6.02 (1H, d, J = 11.2 Hz),
6.22 (1H, d, J = 11.2Hz)

Step 2 (5Z, 7E) -23S, 25-diacetoxy-1α-
t-butyldimethylsilyloxy-26,26,26,
27,27,27-hexafluoro-9,10-secoco
Lester-5,7,10 (19) -triene-3β-oh
1.14 g of the compound (1-2) of toluene (1-3) was dissolved in 5 ml of methanol, and 10 ml of a methanol solution of p-toluenesulfonic acid (2.2 mmol / l) was added thereto.
Stirred for hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (mobile phase, hexane: ethyl acetate = 5: 1). , 362 mg of the title compound (35
%). ¹ H-NMR (CDCl ₃ ) δ: 0.07-0.09 (6
H, m), 0.85-0.91 (12H, m), 2.0
0 (3H, s), 2.18 (3H, s), 4.21 (1
H, m), 4.37 (1H, m), 4.91 (1H,
s), 5.15 (1H, m), 5.26 (1H, s),
6.02 (1H, d, J = 11.2 Hz), 6.31
(1H, d, J = 11.2Hz)

Step 3 (5Z, 7E) -23S, 25-diacetoxy-1α-
t-butyldimethylsilyloxy-26,26,26,
27,27,27-hexafluoro-9,10-secoco
Lester-5,7,10 (19) -trien-3-one
362 mg of the synthetic compound (1-3 ) of (1-4) was dissolved in 50 g of dichloromethane, 480 mg of Dess-Martin reagent was added in two portions, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline,
After drying over magnesium sulfate, the solvent was distilled off and the residue was subjected to silica gel column chromatography (mobile phase, hexane:
Purification with ethyl acetate = 5: 1) gave 347 mg of the title compound.
(96%). ¹ H-NMR (CDCl ₃ ) δ: 0.06-0.08 (6
H, m), 0.54 (3H, s), 0.83-0.86
(9H, m), 1.00 (3H, d, J = 5.3H
z), 2.00 (3H, s), 2.17 (3H, s),
2.59-2.88 (4H, m), 3.16 (1H,
d, J = 17.0 Hz), 3.27 (1H, d, J = 1)
7.0 Hz), 4.43 (1H, m), 5.12 (1
H, m), 5.15 (1H, s), 5.43 (1H,
s), 6.02 (1H, d, J = 11.2 Hz), 6.0.
32 (1H, d, J = 11.2Hz)

Step 4(5Z, 7E) -23S, 25-diacetoxy-1α-
t-butyldimethylsilyloxy-26,26,26,
27,27,27-hexafluoro-9,10-secoco
Lester-5,7,10 (19) -triene-3α-O
Synthesis of (1-5)  Dissolve 347 mg of compound (1-4) in 10 ml of methanol.
And at 180 ° C, 180 mg of sodium borohydride
The mixture was stirred for 1 hour. Add 1N hydrochloric acid to the reaction mixture and dilute with water.
And extracted with ethyl acetate. Saturate the organic layer with saturated aqueous sodium bicarbonate
Wash with sodium chloride solution sequentially, dry with magnesium sulfate,
The solvent is distilled off and the residue is subjected to silica gel column chromatography.
-(Mobile phase, hexane: ethyl acetate = 5: 1)
This gave 233 mg (67%) of the title compound.¹ H-NMR (CDCl_Three) Δ: 0.07-0.09 (6
H, s), 0.51 (3H, s), 0.86 (9H,
s), 1.97 (3H, s), 2.14 (3H, s),
3.97 (1H, m), 4.32 (1H, m), 4.8
9 (1H, s), 5.16 (2H, m), 6.00 (1
H, d, J = 10.9 Hz), 6.38 (1H, d, J =
10.9Hz)

Step 5 (5Z, 7E) -23S, 25-diacetoxy-26,
26, 26, 27, 27, 27-hexafluoro-9,
10-secocholesta-5,7,10 (19) -triene
233 mg of synthetic compound (1-5) of -1α, 3α-diol (1-6) was dissolved in 5 ml of methanol, and 0.02 ml of methanesulfonic acid was added.
Stirred for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off.
mg was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.54 (1 H, s),
0.99 (1H, s), 1.98 (3H, s), 2.0
2 (3H, s), 4.00 (1H, m), 4.25 (1
H, m), 4.96 (1H, s), 5.13 (1H,
m), 5.28 (1H, s), 6.00 (1H, d, J
= 11.2 Hz), 6.39 (1H, d, J = 11.2H)
z)

Step 6 (5Z, 7E) -26, 26, 26, 27, 27, 27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1α, 3α, 23S, 25-
247 mg of a synthetic compound (1-6) of tetraol (1-7) was dissolved in 30 ml of a 10% potassium hydroxide in methanol solution, and the mixture was stirred at room temperature for 1 day. The reaction solution is concentrated, the residue is dissolved in ethyl acetate, and the organic layer is washed with saturated saline, dried over magnesium sulfate, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (mobile phase, hexane: ethyl acetate = 1: 1)
129 mg (75%) of the title compound were obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.56 (3H, s),
0.96 (3H, d, J = 5.3 Hz), 2.42 (1
H, dd, J = 5.3, 13.4 Hz), 2.55 (1
H, d, J = 11.2 Hz), 2.84 (1H, d, J)
= 10.9 Hz), 4.05 (1H, m), 4.29
(2H, m), 4.98 (1H, s), 5.28 (1
H, s), 6.01 (1H, d, J = 11.2 Hz),
6.41 (1H, d, J = 11.2Hz)

Example 2 (5Z, 7E) -26,26,26,27,27,27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1α, 3α, 25-trio
Synthesis of (2-6)

Embedded image

Step 1 (5Z, 7E) -1α, 3β, 25-tris (t-butyl
Dimethylsilyloxy) -26,26,26,27,
27,27-hexafluoro-9,10-secocholesta
Synthesis of -5,7,10 (19) -triene (2-2) Compound (2-1) (JP-B-3-48903) 10.0 m
g and N, N-dimethyl-4-aminopyridine 22 mg
Dissolve in 0.5 ml of dichloromethane and add t-butyl
Tilsilyl trifluoromethanesulfonate 41mg
In addition, the mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. Reaction mixing
20 mg of N, N-dimethyl-4-aminopyridine
Nt-butyldimethylsilyl-N-methyltrifluoro
Add 30 mg of loacetamide and add 3 more under nitrogen atmosphere.
Stirred at room temperature for hours. Water was added to the reaction mixture, and ethyl acetate was added.
And dried over magnesium sulfate.
The silica gel column chromatography (mobile phase, f
Xane) and 14.0 mg (86%) of the title compound.
I got¹ H-NMR (CDCl_Three) Δ: 0.06 (12H,
s), 0.17 (6H, s), 0.53 (3H, s),
0.88 (18H, s), 0.90 (9H, s), 0.
94 (3H, d, J = 6.3 Hz), 2.22 (1H,
dd, J = 13.5, 7.3 Hz), 2.45 (1H,
m), 2.83 (1H, m), 4.19 (1H, m),
4.38 (1H, m), 4.87 (1H, s), 5.1
8 (1H, s), 6.01 (1H, d, J = 10.9H
z), 6.23 (1H, d, J = 10.9Hz)

Step 2 (5Z, 7E) -1α, 25-bis (t-butyl dimethyl)
Lucylyloxy) -26,26,26,27,27,2
7-hexafluoro-9,10-secocholesta-5,
7,10 (19) -trien-3β-ol (2-3)
Compound of (2-2) 42.0 mg was dissolved in ethanol 2 ml, and stirred at room temperature for 6 hours under a nitrogen atmosphere was added a p- toluenesulfonic acid monohydrate 1.3 mg. Water was added to the reaction mixture, extracted with ethyl acetate, dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (mobile phase, hexane: ethyl acetate = 50: 1).
-10: 1) and 16.1 mg (44) of the title compound.
%). ¹ H-NMR (CDCl ₃ ) δ: 0.08 (6H, s),
0.17 (6H, s), 0.54 (3H, s), 0.9
0 (9H, s), 0.91 (9H, s), 0.94 (3
H, d, J = 6.3 Hz), 2.28 (1H, dd, J)
= 13.4, 6.4 Hz), 2.57 (1H, m),
2.82 (1H, m), 4.22 (1H, m), 4.3
7 (1H, m), 4.92 (1H, s), 5.26 (1
H, s), 6.02 (1H, d, J = 11.5 Hz),
6.32 (1H, d, J = 11.2Hz)

Step 3 (5Z, 7E) -1α, 25-bis (t-butyl dimethyl)
Lucylyloxy) -26,26,26,27,27,2
7-hexafluoro-9,10-secocholesta-5,
7,10 (19) -trien-3-one (2-4)
Forming compound (2-3) 6.4 mg was dissolved in dichloromethane 1 ml, and stirred at room temperature for 4 hours under a nitrogen atmosphere was added Dess Martin reagent 9.4 mg. An aqueous sodium thiosulfate solution and aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate.
After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (mobile phase, hexane: ethyl acetate = 10: 1) to obtain 4.7 mg of the title compound.
(73%). ¹ H-NMR (CDCl ₃ ) δ: 0.08 (6H, s),
0.17 (6H, s), 0.53 (3H, s), 0.8
6 (9H, s), 0.91 (9H, s), 0.94 (3
H, d, J = 6.6 Hz), 2.58 (1H, dd, J)
= 15.8, 5.8 Hz), 2.67 (1H, dd, J)
= 15.0, 4.1 Hz), 2.81 (1H, m),
3.18 (1H, d, J = 16.8 Hz), 3.28
(1H, d, J = 16.8 Hz), 4.44 (1H,
m), 5.17 (1H, s), 5.42 (1H, s),
6.04 (1H, d, J = 11.2 Hz), 6.32
(1H, d, J = 11.2Hz)

Step 4 (5Z, 7E) -1α, 25-bis (t-butyl dimethyl)
Lucylyloxy) -26,26,26,27,27,2
7-hexafluoro-9,10-secocholesta-5,
7,10 (19) -trien-3α-ol (2-5)
Compound of (2-4) 4.7 mg was dissolved in methanol 0.3 ml, and stirred at 4 hours -10 ° C. under nitrogen was added sodium borohydride 2.4 mg. The reaction mixture was mixed with 1% hydrochloric acid, extracted with ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, evaporated, and the residue was distilled on silica gel column chromatography (mobile phase, hexane: ethyl acetate = 4: 1). ) To give the title compound 3.4
mg (72%). ¹ H-NMR (CDCl ₃ ) δ: 0.09 (3H, s),
0.11 (3H, s), 0.17 (6H, s), 0.5
1 (3H, s), 0.87 (9H, s), 0.90 (9
H, s), 0.94 (3H, d, J = 6.6 Hz),
2.51 (2H, m), 2.86 (1H, m), 4.0
4 (1H, m), 4.38 (1H, m), 4.92 (1
H, s), 5.17 (1H, s), 6.03 (1H,
d, J = 10.9 Hz), 6.44 (1H, d, J = 1)
0.9Hz)

Step 5 (5Z, 7E) -26, 26, 26, 27, 27, 27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1α, 3α, 25-trio
Dissolve 3.4 mg of the compound (2-5) of the compound (2-6) in 0.3 ml of tetrahydrofuran (THF), add 0.6 ml of a THF solution (1M) of tetrabutylammonium fluoride, and add a solution under a nitrogen atmosphere. For 3.5 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to preparative thin-layer silica gel chromatography (mobile phase, hexane: ethyl acetate = 1:
1) Purification by high performance liquid chromatography (Zorbax (registered trademark) BP SIL, mobile phase, hexane: dichloromethane: methanol = 50: 50: 3) to obtain 1.8 mg (72%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.55 (3H, s),
0.95 (3H, d, J = 6.4 Hz), 2.44 (1
H, dd, J = 13.4, 5.5 Hz), 2.56 (1
H, m), 2.85 (1H, m), 4.05 (1H,
m), 4.30 (1H, m), 5.00 (1H, s),
5.30 (1H, s), 6.02 (1H, d, J = 1
1.3Hz), 6.44 (1H, d, J = 11.3H)
z) UV (ethanol) nm λ _max 262, λ _min 22
8 MS (m / z) 524 (M ⁺ ), 506 (M ⁺ -H
₂ O), 488 (M ⁺ -2H ₂ O)

Example 3 (5Z, 7E) -26,26,26,27,27,27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1β, 3β, 23S, 25-
Synthesis of tetraol (3-4)

Embedded image

Compound (3-1) (JP-B-7-6480)
4) 30 mg was dissolved in 0.20 ml of dichloromethane, and a suspension of Dess-Martin reagent (28.2 mg) in dichloromethane / acetonitrile (1/2, 0.45 ml) was added at room temperature. After 25 minutes, a saturated aqueous sodium thiosulfate solution, 5% aqueous sodium hydrogen carbonate and ethyl acetate were added, and the mixture was separated. The aqueous layer was extracted three times with ethyl acetate, and the organic layer was washed with saturated saline. After drying over magnesium sulfate, the solvent was distilled off. The obtained compound (3-2) was directly dissolved in methanol (0.50 ml) without purification, and cooled to -15 to -5 ° C. Sodium borohydride (28.7 mg) was added, and one hour later, saturated saline, ethyl acetate, and sodium chloride were added, and the mixture was separated. The aqueous layer was extracted four times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by preparative thin-layer silica gel chromatography (mobile phase, ethyl acetate) to obtain Compound (3-3) as a mixture of stereoisomers (16.5 mg). The obtained mixture of stereoisomers (16.5 mg) was added to acetone (4.0%).
ml) and heated at 80-85 ° C for 6 hours. The solvent is distilled off, and the residue is subjected to high performance liquid chromatography (Zor
Bax BP SIL, mobile phase, hexane: dichloromethane: methanol = 50: 50: 3) to give 2.3 mg (8%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.58 (3H, S),
0.85-0.91 (1H, m), 0.98 (3H,
d, J = 5.7 Hz), 1.17-2.20 (18H,
m), 2.29-2.35 (1H, m), 2.43-
2.63 (2H, m), 2.74-2.90 (2H,
m), 4.08-4.17 (1H, m), 4.31-
4.44 (2H, m), 5.00 (1H, d, J = 2.
0 Hz), 5.29 (1H, S), 6.06 (1H,
d, J = 11.2 Hz), 6.31 (1H, S), 6.
44 (1H, d, J = 11.2 Hz) UV (ethanol) nm λ _max 263, λ _min 22
8

Example 4 (5Z, 7E) -26,26,26,27,27,27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1β, 3α, 23S, 25-
Synthesis of tetraol (4-12)

Embedded image

Embedded image

Step 1 (S) -1-cyano-2-hydroxy-5- (trimethy
Synthetic Compound of Lucylyl) -4-pentyne (4-2) (4-1: Chem. Eur. J., 2 (5), 545 (1996))
To a solution of 0.779 g of dimethyl sulfoxide (16 ml) was added potassium cyanide (0.19 g). After 1 hour, the temperature was raised to 40 ° C. and the mixture was heated for 4 hours. The mixture was poured on ice, and ethyl acetate was added to separate the layers. Further, the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with a saturated saline solution. After drying over magnesium sulfate, the solvent was distilled off. The crude product was purified by silica gel column chromatography (mobile phase, ethyl acetate: hexane = 1: 3) to give the title compound 427.
mg (98%). ¹ H-NMR (CDCl ₃ ) δ: 0.17 (9H, s),
2.40 (1H, d, J = 5.7 Hz), 2.59 (2
H, d, J = 5.9 Hz), 2.68 (2H, d, J =
5.5 Hz), 4.06-4.16 (1H, m)

Step 2 (S) -2- (t-butyldimethylsilyloxy) -1
-Cyano-5- (trimethylsilyl) -4-pentyne
Compound of (4-3) (4-2) 0.427 g of dichloromethane (35
ml) solution at 0-5 ° C with 2,6-lutidine (1.05
ml) and t-butyldimethylsilyl trifluoromethanesulfonate (0.98 ml) were added. After 30 minutes, the temperature was raised to room temperature, and the mixture was further stirred for 30 minutes. Add saturated aqueous sodium bicarbonate,
Further, ethyl acetate and hexane were added to carry out liquid separation. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off to obtain a crude product (1.5 g). Purification by silica gel column chromatography (mobile phase, ethyl acetate: hexane = 1: 4) gave 702 mg (100%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 0.10 (3H, s),
0.12 (3H, s), 0.15 (9H, s), 0.9
0 (9H, s), 2.44 (1H, dd, J = 7.3,
16.8 Hz), 2.52 (1H, dd, J = 5.1,
16.8 Hz), 2.57 (1H, dd, J = 6.4,
16.5 Hz), 2.68 (1H, dd, J = 4.4,
16.5 Hz), 4.07 (1H, dddd, J = 4.
4,5.1,6.4,7.3 Hz)

Step 3 (3R, 5S) -and (3S, 5S) -5- (t-bu
Tyldimethylsilyloxy) -3-hydroxy-8-
(Trimethylsilyl) -oct-1-en-7-yne
0.74 g of a synthetic compound (4-3) of (4-5) THF (5.7 ml)
A solution of diisobutylaluminum hydride in toluene (1.01M, 3.05 ml) was added to the solution at -70 ° C. After 30 minutes, the temperature was raised to room temperature. One hour later, 1N hydrochloric acid was added and the mixture was stirred for 10 minutes. Ethyl acetate was added to carry out liquid separation. The aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off to obtain 623 mg of the aldehyde (4-4). The obtained aldehyde compound was dissolved in THF (5.7 ml),
With a solution of vinylmagnesium bromide in THF (0.9
9M, 2.9 ml) was added. After 15 minutes, the temperature was raised to 0 ° C., and the mixture was further stirred for 30 minutes. Water and ethyl acetate were added to carry out liquid separation. The aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off to obtain a crude product. Purification by silica gel column chromatography (mobile phase, ethyl acetate: hexane = 1: 3), 349 mg (50%) of compound (4-4) as a raw material
%) To give 133 mg (17%) of the title compound.

Step 4 (3R, 5S) -and (3S, 5S) -5- (t-bu
Tyldimethylsiloxy) -3-hydroxy-octa-1
133 mg of methanol (0.80 m ) of a synthetic compound (4-5) of -en-7- yne (4-6)
l) Potassium carbonate (13.0 mg) was added to the solution. After stirring at room temperature for 1 hour, the solvent was distilled off. Water and ethyl acetate were added to carry out liquid separation. The aqueous layer was extracted three times with ethyl acetate.
The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off to obtain a crude product. Silica gel column chromatography (mobile phase, ethyl acetate: hexane =
1: 3), and the starting compound (4-5) 107
mg (80%) along with 24.0 mg (23
%).

Step 5 (3R, 5S) -and (3S, 5S) -3,5-di
(T-butyldimethylsiloxy) -oct-1-ene-
Synthesis of 7- yne (4-7) Compound (4-6) 40.2 mg of dichloromethane (2.
0 ml) solution, 2,6-lutidine (142 ml) and t-butyldimethylsilyl trifluoromethanesulfonate (133 ml) were added at 0-5 ° C. After 10 minutes, saturated aqueous sodium hydrogen carbonate was added, and ethyl acetate was further added to carry out liquid separation. The aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off to obtain a crude product (200 mg). Purification by silica gel column chromatography (mobile phase, ethyl acetate: hexane = 1: 5) gave 90.1 mg of the title compound as a mixture with disiloxane.

Step 6 (1R, 3aR, 4R, 7aR) -and (1R, 3a
R, 4S, 7aR) -2,3,3a, 5,6,7-hex
Sahydro-1-[(1R, 3S) -3,5-diacetoxy
Ci-1-methyl-6,6,6-trifluoro-5- (g
Trifluoromethyl) hexyl] -7a-methyl-1H-
Synthetic compound (1-2) of inden-4-ol (4-8) 0.914 g of methanol (5 ml)
Ozone was blown into a mixed solution of hexane and dichloromethane (5 ml) at -60 ° C to -75 ° C. One hour later, it was confirmed that the light blue color of ozone had developed, and oxygen was blown to drive off ozone. After 30 minutes, sodium borohydride (38
0 mg) was added and the temperature was raised to room temperature. After the solvent was concentrated, water and ethyl acetate were added to the residue, and the mixture was separated. The aqueous layer was extracted three times with ethyl acetate. Wash the organic layer with saturated saline,
After drying over magnesium sulfate, the solvent was distilled off and the crude product (0.
917 g). Purification by silica gel column chromatography (mobile phase, ethyl acetate: hexane = 1: 3) gave 486.8 mg (93%) of the title compound as a mixture with the one lacking the acetyl group at the 5-position.

Step 7(1R, 3aR, 7aR) -2, 3, 3a, 5, 6, 7
-Hexahydro-1-[(1R, 3S) -3,5-dia
Sethoxy-1-methyl-6,6,6-trifluoro-5
-(Trifluoromethyl) -hexyl] -7a-methyl
Synthesis of -1H-inden-4-one (4-9) Compound (4-8): 517 mg of dichloromethane (4.5)
ml) solution of Dess-Martin reagent (1.34 g)
Dichloromethane (9.0 ml) / acetonitrile (18 ml)
The suspension was added. After 1 hour, saturated aqueous sodium thiosulfate
The solution was added. Further, add hexane and ethyl acetate and separate
Liquid. The aqueous layer was extracted twice with ethyl acetate. Organic
The layer was washed with saturated saline and dried over magnesium sulfate.
Was. The solvent was distilled off to obtain a crude product. Silica gel column
Chromatography (mobile phase, silica gel, ethyl acetate
Hexane = 1: 3). Aceti by-product
The compound from which the hydroxyl group was removed was further treated with acetic anhydride (4.9 m
l), dimethylaminopyridine (55 mg), pyridine
(16 ml) was added and stirred for 3 hours. Add water and 1N
Hydrochloric acid and ethyl acetate were added to carry out liquid separation. Ethyl acetate from aqueous layer
Extraction three times. Wash the organic layer with saturated saline,
After drying over magnesium sulfate, the solvent was distilled off and the crude product (0.
917 g). Silica gel column chromatography
-(Mobile phase, ethyl acetate: hexane = 1: 3)
This gave 416 mg (81%) of the title compound. ¹ H-NMR (CDCl_Three) Δ: 0.66 (3H, S),
1.03 (3H, d, J = 5.5 Hz), 1.19−
2.35, 2.43 (1H, dd, J = 7.3, 11.
7 Hz), 2.59 (1H, d, J = 16.1 Hz),
2.83 (1H, dd, J = 9.5, 15.9 Hz),
5.11-5.20 (1H, m)

Step 8(1R, 3aR, 4E, 7aR) -4-bromomethylene
-2,3,3a, 5,6,7-hexahydro-1-
[(1R, 3S) -3,5-diacetoxy-1-methyl
-6,6,6-trifluoro-5- (trifluoromethyl
-Hexyl] -7a-methyl-1H-indene (4
Synthesis of -10)  1,1,1,3,3,3-hexamethyldisilazane (1
10 ml) in toluene (1.85 ml).
In a hexane solution of n-butyllithium (1.47 M,
0.265 ml) was added. 50 minutes later, bromomethyl
Liphenylphosmium bromide (227 mg) was added.
Then, the temperature was raised to 0 ° C. as it was. After 15 minutes, again at -70 ° C
And cooled to 63.7 mg of compound (4-9) in toluene.
(0.60 ml) solution was added. The temperature was raised to 0 ° C. Fifteen
Minutes later, add water and hexane and ethyl acetate.
Separated. The aqueous layer was extracted three times with ethyl acetate. Yes
The organic layer is washed with a saturated saline solution and dried with magnesium sulfate,
The solvent was distilled off to obtain a crude product. Silica gel column chromatography
Chromatography (mobile phase, ethyl acetate: hexane = 1:
Purification in 5) gave 27 mg (37%) of the title compound.¹ H-NMR (CDCl_Three) Δ: 0.58 (3H, S),
1.01 (3H, d, J = 5.7 Hz), 1.15
2.22 (14H, m), 2.09 (3H, S), 2.
19 (3H, S), 2.58 (1H, d, J = 16.5)
Hz), 2.79-2.92 (2H, m), 5.10-
5.20 (1H, m), 5.65 (1H, S)

Step 9 (1β, 3α, 5Z, 7E, 23S) -and (1α,
3α, 5Z, 7E, 23S) -23,25-diacetoxy
C-26,26,26,27,27,27-Hexaful
Oro-9,10-Secocolesta-5,7,10 (19)
Synthesis of triene-1,3-diol (4-11) 5.5 mg of tris- (dibenzylideneacetone) dipalladium (0) chloroform complex and 12.9 mg of triphenylphosphine in triethylamine (0.40 ml)
And toluene (0.40 ml). 18.2 mg of compound (4-7) and compound (4-10) 2 were added to this solution.
A solution of 1.6 mg of toluene (0.80 ml) was added, and 7
Heated at 5-80 ° C. Thirty minutes later, 4.5 mg of tris- (dibenzylideneacetone) dipalladium (0) chloroform complex was added. After 1 hour, compound (4-7) 3.
6 mg was added. After another hour, the solvent was distilled off. The residue was purified by preparative thin-layer silica gel chromatography (mobile phase, ethyl acetate: hexane = 1: 5) to obtain 15.6 mg (48%) of the title compound.

Step 10 (5Z, 7E) -26, 26, 26, 27, 27, 27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1β, 3α, 23S, 25-
Synthesis of tetraol (4-12) To a solution of 18.9 mg of compound (4-11) in acetonitrile (2.0 ml) was added 46% hydrofluoric acid (10 drops). After 30 minutes, saturated aqueous sodium bicarbonate was added. Further, ethyl acetate was added to carry out liquid separation. The aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off to obtain a crude product. A 10% potassium hydroxide in methanol solution (3.
3 ml) was added. After 2 hours, the solvent was distilled off. The residue was purified by preparative thin-layer silica gel chromatography (mobile phase, ethyl acetate) to give the title compound as a mixture of stereoisomers (6.5 mg, 55%). The stereoisomers were separated by high performance liquid chromatography (Zorbax BPSIL, mobile phase, hexane: dichloromethane: methanol = 50: 50: 3) to obtain 0.7 mg of the title compound together with 2.5 mg of compound (1-7). ¹ H-NMR (CDCl ₃ ) δ: 0.57 (3H, S),
0.82-0.91 (1H, m), 0.98 (3H,
d, J = 5.5 Hz), 1.15 to 2.08 (19H,
m), 2.12 (1H, d, J = 15.2 Hz), 2.
26-2.33 (1H, m), 2.59-2.65 (1
H, m), 2.80-2.87 (1H, m), 4.16
-4.27 (1H, m), 4.31-4.48 (2H,
m), 5.00 (1H, S), 5.32 (1H, S),
6.02 (1H, d, J = 10.8 Hz), 6.30
(1H, S), 6.39 (1H, d, J = 11.2H
z) UV (ethanol) nm λ _max 265, λ _min 22
7

Example 5 (5Z, 7E) -26,26,26,27,27,27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1β, 3β, 25-trio
Synthesis of (5-3)

Embedded image

Step 1 (6Z) -26,26,26,27,27,27-hex
Safluoro-9,10-secocholesta-5 (10),
6,8-triene-3β, 25-diol-1-one
5.0 mg of the compound (2-1) synthesized in (5-1) was dissolved in 2.5 ml of acetonitrile, 10 mg of Dess-Martin reagent was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. An aqueous sodium thiosulfate solution and aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to preparative thin-layer silica gel chromatography (mobile phase, hexane: ethyl acetate = 2). : 1) to give 3.3 mg (66%) of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.72 (3H, s),
0.97 (3H, d, J = 6.6 Hz), 1.79 (3
H, s), 2.40-2.60 (2H, m), 2.72.
-2.86 (2H, m), 2.96 (1H, m), 3.
17-3.29 (2H, m), 4.23 (1H, m),
5.49 (1H, m), 6.03 (1H, d, J = 1
1.9 Hz), 6.14 (1H, d, J = 11.8H)
z)

Step 2 (6Z) -26,26,26,27,27,27-hex
Safluoro-9,10-secocholesta-5 (10),
6,8-triene-1β, 3β, 25-triol (5
3.3 mg of the synthesized compound (5-1) of -2) was dissolved in 0.5 ml of methanol, and 11.2 mg of sodium borohydride was added thereto, followed by stirring at 0 ° C for 1.5 hours under a nitrogen atmosphere. The reaction mixture was added with 1N aqueous hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, evaporated, and the residue was purified by preparative thin-layer silica gel chromatography (mobile phase, hexane: ethyl acetate = 1: 1). Purification, 2.2m of the title compound as a colorless oil
g (67%). ¹ H-NMR (CDCl ₃ ) δ: 0.71 (3H, s),
0.97 (3H, d, J = 6.6 Hz), 1.81 (3
H, s), 2.64 (1H, m), 2.92 (1H,
m), 4.02 (1H, m), 4.24 (1H, m),
5.56 (1H, m), 5.79 (1H, d, J = 1
2.2Hz), 5.96 (1H, d, J = 12.2H)
z)

Step 3(5Z, 7E) -26,26,26,27,27,27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1β, 3β, 25-trio
Synthesis of (5-3) Dissolve 2.2 mg of compound (5-2) in 1 ml of acetone
Then, it was heated at 80 ° C. for 6 hours in a sealed tube. Solvent is distilled off and residue
Is separated by thin-layer silica gel chromatography (mobile phase,
Hexane: ethyl acetate = 1: 1), high-performance liquid chromatography
Raffy (Zorbax BP SIL, Mobile phase, Heki
Sun: dichloromethane: methanol = 50: 50: 3)
1.8 mg (90%) of the title compound as a colorless oil
I got ¹H-NMR (CDCl_Three) Δ: 0.55 (3
H, s), 0.95 (3H, d, J = 6.7 Hz),
2.48 (1H, dd, J = 13.6, 4.4 Hz),
2.56 (1H, m), 2.85 (1H, dd, J = 1
1.6, 3.3 Hz), 4.10 (1H, m), 4.3
5 (1H, m), 5.01 (1H, m), 5.29 (1
H, m), 6.06 (1H, d, J = 11.3 Hz),
6.45 (1H, d, J = 11.3 Hz) UV (ethanol) nm λ_max 264, λ_min 22
8 MS (m / z) 524 (M⁺), 506 (M⁺-H
_TwoO), 489 (M⁺-2H_TwoO + 1)

Example 6 (5Z, 7E) -26,26,26,27,27,27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1β, 3α, 25-trio
Synthesis of (6-3)

Embedded image

Step 1 (6Z) -26,26,26,27,27,27-hex
Safluoro-9,10-secocholesta-5 (10),
6,8-triene-3α, 25-diol-1-one
Synthesis of (6-1) 6.5 mg of compound (2-6) was added to 5 ml of acetonitrile.
And added 13 mg of Dess-Martin reagent, and
The mixture was stirred at room temperature for 5 hours. Na thiosulfate was added to the reaction mixture.
An aqueous thorium solution and aqueous sodium bicarbonate solution were added, and the mixture was extracted with ethyl acetate.
After drying over magnesium phosphate, distill off the solvent and remove the residue
Layer silica gel chromatography (mobile phase, hexane:
Purify with ethyl acetate = 2: 1) to give the title compound as a colorless oil
3.9 mg (60%) were obtained.¹ H-NMR (CDCl_Three) Δ: 0.73 (3H, s),
0.97 (3H, d, J = 6.6 Hz), 1.79 (3
H, s), 2.45-2.60 (2H, m), 2.72.
-2.86 (2H, m), 4.18 (1H, m), 5.
48 (1H, m), 6.03 (1H, d, J = 11.9)
Hz), 6.14 (1H, d, J = 11.9 Hz)

Step 2 (6Z) -26,26,26,27,27,27-hex
Safluoro-9,10-secocholesta-5 (10),
6,8-triene-1β, 3α, 25-triol (6
3.9 mg of the synthetic compound (6-1) of -2) was dissolved in 5 ml of acetonitrile, 3 drops of acetic acid and 30 mg of tetramethylammonium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Further, every hour, 20 mg of tetramethylammonium triacetoxyborohydride was added and stirred. After reacting for a total of 7 hours, aqueous sodium bicarbonate was added to the reaction mixture, extracted with ethyl acetate, dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to preparative thin-layer silica gel chromatography (mobile phase, hexane: ethyl acetate = 1: 1)
0.8 mg (20%) of the title compound as a colorless oil
I got ¹ H-NMR (CDCl ₃ ) δ: 0.71 (3H, s),
0.97 (3H, d, J = 6.4 Hz), 1.77 (3
H, s), 2.51 (1H, dd, J = 15.9, 4.
6Hz), 2.83 (1H, m), 4.05 (1H,
m), 4.20 (1H, m), 5.50 (1H, m),
5.79 (1H, d, J = 12.2 Hz), 5.92
(1H, d, J = 12.2 Hz)

Step 3 (5Z, 7E) -26, 26, 26, 27, 27, 27
-Hexafluoro-9,10-secocholesta-5,7,
10 (19) -triene-1β, 3α, 25-trio
Compound le (6-3) to (6-2) 0.8 mg was dissolved in acetone 2 ml, it was heated for 6 hours at 80 ° C. in a sealed tube. The solvent is distilled off and the residue is separated by preparative thin-layer silica gel chromatography (mobile phase,
Hexane: ethyl acetate = 1: 1), high performance liquid chromatography (first Zorbax BP SIL, mobile phase, hexane: dichloromethane: methanol = 50: 5)
0: 3; 2nd time CHIRALCEL® O
D, mobile phase, hexane: ethanol = 20: 1) to give 0.4 mg (50%) of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.55 (3H, s),
0.94 (3H, d, J = 6.7 Hz), 2.30 (1
H, dd, J = 13.3, 7.5 Hz), 2.62 (1
H, dd, J = 13.4, 4.0 Hz), 2.83 (1
H, dd, J = 11.8, 4.2 Hz), 4.20 (1
H, m), 4.42 (1H, m), 5.01 (1H,
m), 5.32 (1H, m), 6.01 (1H, d, J
= 11.3 Hz), 6.39 (1H, d, J = 11.3)
Hz) UV (ethanol) nm λ _max 262, λ _min 22
7 MS (m / z) 524 (M ⁺ ), 506 (M ⁺ -H
₂ O), 488 (M ⁺ -2H ₂ O)

Example 7 Binding Test to Vitamin D Receptor 1 Using a duodenum extract of a chicken embryo containing α, 25-dihydroxy-vitamin D ₃ receptor (VDR),
Competition experiments with tritium-labeled 1α, 25-dihydroxy-vitamin D ₃ (1,25 (OH) ₂ D ₃ )
The binding ability of the vitamin D ₃ derivative obtained in the example to VDR was evaluated. Method: Chicken embryo duodenum extract was buffered (0.25 M sucrose, 50 mM Tris, 25 mM KCl, 5 mM MgC
l ₂ , 1mM EDTA, 12mM thioglycerol: pH 7.4)
This was a DR solution. 200 μl VDR solution (0.08 mg protein)
To the solution was added 1 nM [ ³ H] -1,25 (OH) ₂ D ₃ (177 Ci / mmol).
μl was added and incubated at 4 ° C. for 24 hours in the presence or absence of various concentrations of the test substance. Activated carbon suspension 950
μl was added and centrifuged, and the radioactivity of [ ³ H] -1,25 (OH) ₂ D ₃ bound to VDR in the supernatant was measured with a liquid scintillation counter.

Results: The binding ability to the vitamin D receptor was compared by the addition concentration (IC ₅₀ ) of the test substance at which the binding of [ ³ H] -1,25 (OH) ₂ D ₃ was inhibited by 50%. Table 1 shows the binding ability of the compound (1-7).

[Table 1] Table 1 Compound IC₅₀(Fmol / tube) ―――――――――――――――――――――――――― 1,25 (OH)_TwoD_Three 38.1  Compound (3-1) 62.7  Compound (1-7) 113.8

Table 2 shows the binding abilities of compound (2-6), compound (5-3) and compound (6-3).

[Table 2] Table 2 Compound IC₅₀(Fmol / tube) ―――――――――――――――――――――――――― 1,25 (OH)_TwoD_Three 30.1.  Compound (2-1) 66.8  Compound (2-6) 92.8 Compound (5-3) 286.5  Compound (6-3) 455.4

Example 8 Inhibition of cell proliferation (epidermis of rat skin by application of TPA)
Effect on Cell Hyperproliferation) TPA (12-Ot) was applied to the back skin of male Wistar rats (6 weeks old)
etradecanoylphorbol-13-acetate) is hyperproliferative epidermal cells by coating, the effects of vitamin D ₃ derivative obtained (1-7) in Example 1 was evaluated histologically number epidermal cells to this. TPA administration method: After shaving the back of the rat with a clipper, 100 μl of a 0.5 mg / ml TPA acetone solution was applied in a circle having a diameter of 2 cm. Test substance administration method: Immediately after application of 100 μl of TPA acetone solution, 40 mg of vitamin D ₃ derivative (1-7) or vaseline ointment of 1,25 (OH) ₂ D ₃ (10, 50, 250 μg / g) was applied to the same site. did. In addition, as an untreated group, a group in which 40 mg of placebo (vaseline ointment) was applied to the same site immediately after applying 100 μl of acetone instead of applying 100 μl of the TPA acetone solution was set. Group 1: Acetone 100 μl + placebo (Vaseline ointment) 40 mg
[Non-treated group] Group 2: TPA acetone 100 µl + placebo (Vaseline ointment) 40 mg [TPA-treated control] Group 3: TPA acetone 100 µl + compound (1-7) 10 µg /
g ointment 40 mg group 4: TPA acetone 100 μl + compound (1-7) 50 μg /
g ointment 40 mg group 5: TPA acetone 100 µl + compound (1-7) 250 µg
/ g ointment 40 mg Group 6: TPA acetone 100 µl + 1,25 (OH) ₂ D ₃ 10
[mu] g / g ointment 40mg group 7: TPA acetone _{100μl + 1,25 (OH) 2 D} 3 50
μg / g ointment 40 mg Group 8: TPA acetone 100 μl + 1,25 (OH) ₂ D ₃ 25
0μg / g ointment 40mg

Tissue section preparation method: Two days after application, the skin at the application site was collected, fixed with 4% formaldehyde buffer, embedded in paraffin, and a section was prepared at a thickness of 3 mm. This was stained with hematoxylin and eosin (HE staining) to obtain a sample. Method for measuring the number of epidermal cells One tissue section (five sections in each group) was prepared from one individual, and three sites were randomly selected from one section. Under a microscope, the length of the basement membrane in the visual field and the number of epidermal cells below the spinous layer were measured, and the number of cells per 1 mm of the basement membrane was calculated. Results: The results are shown in Table 1. The TPA application significantly increased the number of epidermal cells. In contrast, vitamin D
₃ Derivatives (1-7) showed significant inhibitory effects at 50 and 250 μg / g ointment, respectively. Since administration of 1,25 (OH) ₂ D ₃ required an ointment at a concentration of 250 μg / g to show a significant inhibitory effect, the vitamin D ₃ derivative (1-7)
Is considered to be slightly stronger than 1,25 (OH) ₂ D ₃ .

[0060]

[Table 3] Table 3 Group Epidermal cell count (cells / mm), mean ± SD (n = 5) ―――――――――――――――――――――――――― ――――――― Group 1 132.08 ± 7.92 ** Group 2 211.20 ± 21.21 Group 3 202.71 ± 20.93 Group 4 167.11 ± 9.44 ** Group 5 171 .08 ± 15.43 ** Group 6 192.37 ± 8.70 Group 7 187.25 ± 12.26 Group 8 176.47 ± 12.89 ** (**: p <0.01 vs. Group 2)

[0061]

Industrial Applicability According to the present invention, it is possible to provide a novel vitamin D derivative having a wide safety margin as a medicine by separating main effects and side effects.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/59 ADS A61K 31/59 ADS ADU ADU // C07M 7:00

Claims (6)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ represents a hydrogen atom or a hydroxyl group, and R ² represents an organic group having 4 to 10 carbon atoms (excluding 4-methyl-pentyl and 4-hydroxy-4-methyl-pentyl). . However, when R ¹ is a hydroxyl group, the 1- and 3-position stereoscopy are (1S, 3S), (1R,
3R) or (1R, 3S). Or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula (2) [Wherein, R ¹ and R ² have the same meaning as in claim 1]. Or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1, wherein R ¹ is a hydroxyl group.
Or a pharmaceutically acceptable salt thereof. 4. The vitamin D derivative according to claim 1, wherein R ² is any one of the following groups. Embedded image 5. The method according to claim 5, wherein R ² is 4-hydroxy-4-trifluoromethyl-5,5,5-trifluoropentyl or 2,4-dihydroxy-4-trifluoromethyl-
The vitamin D derivative according to any one of claims 1 to 3, which is 5,5,5-trifluoropentyl. 6. A medicament comprising the vitamin D derivative according to claim 1 or a pharmaceutically acceptable salt thereof.