JP3213092B2 - Vitamin D derivative having substituent at 2β position - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] The present invention relates to the preparation of calcium in a living body.
It has a nodal effect and an effect of inducing differentiation of tumor cells, etc.
For example, based on abnormalities in calcium metabolism such as osteoporosis and osteomalacia
Novel Vitamin Useful as a Therapeutic Drug or Antitumor Agent
D derivatives, specifically substituted or unsubstituted at the 2β-position
Lower alkyl group, lower alkenyl group, lower alkynyl group
With vitamin D₃It relates to derivatives. [0002] 2. Description of the Related Art Conventionally known vitamin D₃The class is 2
5-hydroxyvitamin D₃1,1α, 25-dihydroxy
Shivitamin D₃And natural metabolites such as
1α-Hydroxyvitamin D, a synthetic analog thereof₃,
1α, 24-dihydroxyvitamin D₃, Various fluorine
Vitamin D₃And many other compounds. These vitamins
D₃Among the classes, 1α, 25-dihydroxyvitamin
D₃And 26,27-hexafluoro-1α, 25-dihi
Droxyvitamin D₃Strong calcium metabolism by compounds such as
It has a regulatory effect and is known to be useful for various bone lesions.
Have been. [0003] Vitamin D having a substituent at the 2β-position₃
As derivatives, for example, Japanese Patent Publication No. 3-14303
The described 1α, 25-dihydroxy-2β-fluorobita
Min D₃And 2β described in JP-A-61-267549.
D having a substituted lower alkoxy group at the 1-position₃Know
But substituted or unsubstituted at the 2β position,
A kill group, a lower alkenyl group or a lower alkynyl group
Vitamin D₃No kind is known. [0004] PROBLEM TO BE SOLVED BY THE INVENTION A conventionally known active metabolite
Such as natural vitamin D₃Have established metabolic pathways in the body
When used as medicines, there is a
I will. Also, fluorinated non-natural vitamin D₃Kind
Has the manufacturing complexity of introducing fluorine and
Is expected to be less likely to be metabolized in vivo,
There are concerns about side effects due to easy stay. Substitution at 2β position low
D having a lower alkoxy group₃Are substituted
Is introduced through the ether bond,
May be disconnected. [0005] Means for Solving the Problems The present inventors have made intensive studies.
Of the Grignard reagent, organolithium, etc.
Substitution at the 2β position of vitamin D by the reaction of organometallic compounds
Or an unsubstituted lower alkyl group or lower alkenyl
Group or lower alkynyl group can be introduced through a carbon-carbon bond.
These were found to be easy to produce. This knowledge
The present invention has been made based on the observation. That is, the present invention provides a compound represented by the general formula (I) Embedded image (Where R₁Represents a hydrogen atom and a hydroxyl group. R₂Is linear
Or branched lower alkyl, lower alkenyl, lower
Represents a alkynyl group, such as a hydroxyl group, a halogen atom,
Ano group, lower alkoxy group, amino group, acylamino group
May be substituted. Vitamin D represented by)₃Invitation
A conductor is provided. In the present invention, a lower alkyl group is₁To C
₇Represents a straight or branched carbon chain of
Group, ethyl group, propyl group, n-butyl group, i-butyl
And n-pentyl, n-hexyl and the like. Low grade
An alkenyl group is C₂La C₇Linear or branched,
Represents a carbon chain having one or more double bonds, for example,
Vinyl, allyl, butenyl, pentenyl, etc.
can give. A lower alkynyl group is represented by C₂To C₇Directly
Chain or branched carbon chain having one or more triple bonds
Represents, for example, an ethynyl group, a propynyl group,
And a pentynyl group. These are each
Hydroxyalkyl, haloalkyl, amino
Alkyl group, hydroxyalkenyl group, haloalkenyl
Group, aminoalkenyl group, hydroxyalkynyl group, ha
Has a substituent such as a loalkynyl group or an aminoalkynyl group
Alkyl, alkenyl or alkynyl groups. [0008] The compound of the present invention is a novel compound not described in the literature.
And, for example, the general formula Embedded image (Where R₃Represents a hydrogen atom or a hydroxyl group, and the hydroxyl group is
It may be protected. R₄, R₅, R₆, R₇, Is R
₄And R₅, R₆And R₇Are each forming a double bond
Or R₅And R₆Forms a double bond with R₄And R₇At 4
-Phenyl-1,2,4-triazoline-3,5-dio
And conjugated double bonds such as diethyl maleate
Indicates that it is connected to the geno file. )
Epoxy compound having the general formula Embedded image (Where R₈Is a linear or branched lower
Alkyl, lower alkenyl, and lower alkynyl groups
These include hydroxyl, halogen, cyano, lower
It may be substituted with a lucoxy group or an amino group. Substituent
Of these, a hydroxyl group and an amino group may have a protecting group.
X is a halogen atom such as a chlorine atom, a bromine atom and an iodine atom
Represents ) Or a general formula Embedded image (Where R₈Is a linear or branched lower
Alkyl, lower alkenyl, and lower alkynyl groups
These include hydroxyl, halogen, cyano, lower
It may be substituted with a lucoxy group or an amino group. Substituent
Of these, hydroxyl and amino groups may have a protecting group
No. By reacting the compound of the formula
formula Embedded image (Where R₁₀Is linear or branched lower
Represents alkyl, lower alkenyl, and lower alkynyl groups
These include hydroxyl, halogen, cyano, lower
It may be substituted with a lucoxy group or an amino group. Substituent
Of these, a hydroxyl group and an amino group may have a protecting group.
R₁₁Represents a hydrogen atom or a hydroxyl group, and the hydroxyl group is
It may be. Provitamin D represented by)₃Derivative
And then described in, for example, JP-A-50-84555.
It is manufactured by subjecting to light irradiation reaction and thermal isomerization reaction.
You. For the reaction of the compound of formula 3 with the compound of formula 4
The solvent used is not particularly limited as long as it is inert to the reaction.
Or tetrahydrofuran (THF) or diethyl ether
And the like. The reaction temperature is
Not necessarily constant depending on the type, solvent type, and other conditions
Normally, a value between -80 ° C and 80 ° C is selected. The compound of formula 3 used in the reaction is, for example,
From sterols or 25-hydroxycholesterol
JP-A-50-84555 and JP-A-50-84560
Obtained according to the method described in the report. Chemical formula 4 used for the reaction
Can be substituted using a commercially available Grignard reagent.
Or unsubstituted alkyl halides and alkenyl halas
Id, alkynyl halide and metallic magnesium
It may be made. The compound of formula 5 is a commercially available organolithium reagent.
Even if a drug is used, it can be substituted or unsubstituted
And alkenyl halides, alkynyl halides and metals
It may be prepared from lithium. [0014] The compound of the present invention is useful for
It has a regulatory effect and an effect of inducing differentiation of tumor cells, etc.
For example, abnormalities in calcium metabolism such as osteoporosis and osteomalacia
It is useful as a therapeutic drug or an antitumor agent for the following diseases. [0015] Next, the present invention will be described with reference to Examples and Reference Examples.
As will be explained in more detail, this limits the invention.
Not something. [0016] Embodiment 12β-ethyl-1α, 3β-dihydroxy
-9,10-Secocolesta-5,7,10 (19)-
Lien synthesis method i) 2β-ethyl-1α, 3β-dihydroxy-5,7
-Synthesis of cholestadiene 1α, 2α-epoxy under argon atmosphere
-5α, 8α- (3,5-dioxo-4-phenyl-
1,2,4-triazolidino) -6-cholesten-3β
-Dissolve 100 mg of all in 3 ml of THF and add ethyl
Gnesium bromide in a THF solution (1.01 mol /
l) Add 2 ml and stir at room temperature for 19.5 hours, then 4 hours
Heated to reflux. Pour the reaction into water and extract with ethyl acetate.
Was. The organic layer was washed with aqueous ammonium chloride, followed by brine.
After washing and drying over magnesium sulfate, the solvent was distilled off.
Silica gel flash column chromatography of the residue
And a mixed solvent of n-hexane: ethyl acetate = 3: 2
And eluted with 51.2 mg of the colorless crystalline title compound (yield
69%). [0018]¹H-NMR (CDCl₃) Δ: 0.62
(3H, s), 0.85 (3H, s), 0.88 (3
H, s), 0.94 (3H, d, J = 6.1 Hz),
1.01 (3H, s), 3.80 (1H, m), 4.1
2-4.28 (1H, m), 5.30-5.38 (1
H, m), 5.60-5.70 (1H, m). UVλ_max(EtOH) nm: 293, 282, 27
2,263 (sh). MS m / z: 428 (M⁺), 410, 342 (10
0%). [0019]ii) 2β-ethyl-1α, 3β-dihydride
Roxy-9,10-Secocolesta-5,7,10 (1
9) Synthesis of triene 2β-ethyl-1α, 3β-dihydroxy
32.6 mg of -5,7-cholestadiene in ethanol 3
Dissolve in 50 ml and pour argon gas under ice cooling.
Through a Vycor filter, 400W high-pressure mercury lamp
For 180 seconds. Ethanol is distilled off under reduced pressure.
The residue is dissolved in THF (5 ml) and the mixture is dissolved in a nitrogen atmosphere for 1.5 hours.
The mixture was heated under reflux, and the solvent was distilled off. Silica gel flash
After column chromatography, n-hexane:
The mixture was eluted with a mixed solvent of ethyl acetate = 7: 3. Further fractionation
Thin-layer chromatography (silica gel; n-hexa)
Developed twice with ethyl acetate = 7: 3, methylene chloride: d
(Tanol = 9: 1, developed twice) to give the title compound
0.59 mg was obtained. [0021]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.85 (3H, s), 0.88 (3
H, s), 0.92 (3H, d, J = 5.9 Hz),
0.99 (3H, s), 5.03 (1H, s), 5.3
9 (1H, s), 6.02 (1H, d, J = 11.4H)
z), 6.35 (1H, d, J = 11.4 Hz). UVλ_max(EtOH) 263 nm. λ_min22
9 nm. [0022] Embodiment 22β- (4-hydroxybutyl) -1α,
3β-dihydroxy-9,10-secocholesta-5
Method for synthesizing 7,10 (19) -triene i) 2β- (4-hydroxybutyl) -1α, 3β-di
Synthesis of hydroxy-5,7-cholestadiene Cooling to -20 to -25 ° C under a nitrogen atmosphere
Ethylmagnesium bromide in THF (1.01
mol / l) in 4.3 ml of 4-chloro-1-butanol
Add 400 μl, stir at the same temperature for 15 minutes, and return to room temperature.
Was. 90 mg of magnesium is added to this solution, and a nitrogen atmosphere is added.
The mixture was heated and refluxed for 13.5 hours under an atmosphere. Reaction returned to room temperature
In the mixture, 1α, 2α-epoxy-5α, 8α- (3,
5-dioxo-4-phenyl-1,2,4-triazoly
100 mg of dino) -6-cholesten-3β-ol
Dissolve in 3 ml of HF and add, heat for 1 hour under nitrogen atmosphere
Refluxed. Pour the reaction mixture into aqueous ammonium chloride
And extracted with ethyl acetate. Wash the organic layer with saline,
After drying over magnesium sulfate, the solvent was distilled off. Residue
Kagel flash column chromatography, vinegar
Elution with ethyl acid afforded the title compound, colorless and crystalline, 36.8.
mg (45% yield). [0024]¹H-NMR (CDCl₃) Δ: 0.63
(3H, s), 0.85 (3H, s), 0.89 (3
H, s), 0.95 (3H, d, J = 6.1 Hz),
1.00 (3H, s), 5.30.5.40 (1H,
m), 5.58-5.68 (1H, m). UVλ_max(EtOH) nm: 293, 282, 27
2,263 (sh). MS m / z: 436 (100%, M⁺-2H₂O). [0025]ii) 2β- (4-hydroxybutyl)-
1α, 3β-dihydroxy-9,10, secocholesta
Synthesis of 5,7,10 (19) -triene 2β- (4-hydroxybutyl) -1α,
18 mg of 3β-dihydroxy-5,7-cholestadiene
Was dissolved in 300 ml of THF, and argon gas was passed through under ice cooling.
400W high through Vycor filter
Light irradiation was performed with a high pressure mercury lamp for 25 seconds. Then, under nitrogen atmosphere 1
The mixture was heated under reflux for an hour, and the solvent was distilled off. Silica gel
Mesh chloride was applied to lash column chromatography.
Eluting with ethanol: ethanol = 9: 1 to give the title compound 5.3
mg (29% yield). [0027]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.85 (3H, s), 0.88 (3
H, s), 5.00 (1H, s), 5.38 (1H,
s), 6.01 (1H, d, J = 11.6 Hz), 6.
34 (1H, d, J = 11.6 Hz). UVλ_max(EtOH) 263 nm. λ_min22
8 nm. [0028] Embodiment 31α, 3β-dihydroxy-2β- (6-
(Hydroxyhexyl) -9,10-secocholesta-5
Method for synthesizing 7,10 (19) -triene i) 1α, 3β-dihydroxy-2β- (6-hydroxy
Synthesis of (cyhexyl) -cholesta-5,7-diene Under an argon atmosphere at -45 to -55 ° C,
Ethyl magnesium bromide in getyl ether solution
(3 mol / l) 4.3 ml of THF (5 ml) suspension
1.51 g (11.0 g) of 6-chloro-1-hexanol
mmol) in THF (5 ml) was slowly added dropwise.
After stirring at 15 to -45 ° C for 20 minutes, further at room temperature for 20 minutes
While stirring. 271 mg of magnesium (11.2 mmol
l) was added and the mixture was heated under reflux for 17 hours. After cooling, 1α, 2
α-epoxy-5α, 8α- (3,5-dioxo-4-
Phenyl-1,2,4-triazolidino) -6-choles
Ten-3β-ol 150 mg (261 μmol) T
An HF (4.5 ml) solution was added dropwise over 5 minutes,
Heated to reflux for an hour. The reaction mixture is saturated ammonium chloride
Pour into aqueous solution and filter through Hyflo Super-Cell
After that, extract with ethyl acetate and use a saturated aqueous sodium chloride solution.
And washed. Reduce the solvent after drying with anhydrous magnesium sulfate
The residue obtained by distillation under reduced pressure is subjected to preparative thin-layer chromatography.
Fee (silica gel; ethanol: dichloromethane = 1
2: 100), followed by flash column chromatography.
Raffy (silica gel; ethyl acetate: n-hexane =
6: 1) to give 87 mg of the title compound as a white powder.
(Yield 66%) was obtained. [0030]¹H-NMR (CDCl₃) Δ: 0.62
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.94 (3H, d, J = 6.1 Hz), 0.9
8 (3H, s), 3.41 (2H, t, J = 6.6H)
z), 3.73 (1H, brs), 4.08-4.21
(1H, m), 5.28-5.36 (1H, m), 5.
63 (1H, brd, J = 4.9Hz) IR (neat, cm^-1): 3330 (br), 29
45,2870 UVλ_max(EtOH) nm: 293, 282, 27
1 MS m / z: 500 (M⁺), 43 (100%) Ii)1α, 3β-dihydroxy-2β-
(6-hydroxyhexyl) -9,10-secocholesta
Synthesis of -5,7,10 (19) -triene 1α, 3β-dihydroxy-2β- (6-
(Hydroxyhexyl) -cholesta-5,7-diene 4
7.1 mg (94.1 μmol) of ethanol 200 m
l, and bubbling argon gas under ice-cooling.
Use a 400W high-pressure mercury lamp-Vycor filter
After light irradiation for 3 minutes and 45 seconds, the mixture was heated and refluxed for 2 hours. solvent
Was distilled off under reduced pressure, and the residue obtained was separated by thin-layer chromatography.
Fee (silica gel; ethyl acetate: n-hexane = 5:
Purified in 1) to give 11.1 mg of the title compound as a white powder.
(24% yield). [0033]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.92 (3H, d, J = 6.1 Hz), 3.6
4 (2H, t, J = 6.6 Hz), 4.04 (1H, b
rd, J = 7.8 Hz), 4.15 (1H, brs),
5.01 (1H, s), 5.37 (1H, s), 6.0
3 (1H, d, J = 10.8 Hz), 6.34 (1H,
d, J = 10.8Hz) IR (neat, cm^-1): 3345 (br), 29
20,2855 UVλ_max(EtOH): 263 nm. λ_min2
29 nm MS m / z = 500 (M⁺), 43 (100%) [0034] Embodiment 42β- (6-hydroxyhexyl) -1
α, 3β, 25-Trihydroxy-9,10-secocore
Synthesis method of star-5,7,10 (19) -triene i) 2
β- (6-hydroxyhexyl) -1α, 3β, 25-
Synthesis of trihydroxy-cholesta-5,7-diene Ethyl at -20 ° C or lower under an argon atmosphere
Magnesium bromide (3mol / l) diethyl ether
To a solution of 4.3 ml of THF solution (15 ml) in
1.51 g of chloro-1-hexanol (11.0 mm
ol) in THF (5 ml) was slowly added dropwise.
After stirring for 15 minutes at room temperature, the mixture was further stirred at room temperature for 15 minutes. Mug
271 mg (11.2 mmol) of nesium was added, and 14
Heated to reflux for an hour. After standing to cool, 1α, 2α-epoxy-5
α, 8α- (3,5-dioxo-4-phenyl-1,
2,4-triazolidino) -6-cholesten-3β, 2
100 mg (170 μmol) of 5-diol in THF
(5 ml) The solution was gradually added dropwise, and the mixture was heated under reflux for 2 hours.
The reaction mixture was poured into a saturated aqueous ammonium chloride solution,
After filtration through flo Super-Cell, ethyl acetate
Extract and wash with saturated aqueous sodium chloride. Anhydrous sulfur
After drying over magnesium acid, the solvent is obtained by evaporation under reduced pressure.
The remaining residue is purified by flash column chromatography (silica gel).
Rough purification by Kagel; ethyl acetate: n-hexane = 5: 1)
Followed by preparative thin-layer chromatography (silica gel; eta
Nord: dichloromethane = 13: 100 twice)
Purification gave 41 mg of the title compound as a colorless oil (yield 47
%). [0036]¹H-NMR (CDCl₃) Δ: 0.62
(3H, s), 0.96 (3H, d, J = 6.6H
z), 0.99 (3H, s), 1.21 (6H, s),
3.61 (2H, t, J = 6.3 Hz), 3.75 (1
H, brs), 4.09-4.23 (1H, m), 5.
29-5.37 (1H, m), 5.65 (1H, br)
d, J = 5.1 Hz) IR (neat, cm^-1): 3355 (br), 29
35,2860 UVλ_max(EtOH) nm: 294, 282, 27
2 MS m / z: 516 (M⁺), 43 (100%) Ii)2β- (6-hydroxyhexyl)
-1α, 3β, 25-trihydroxy-9,10-seco
Synthesis of Cholesta-5,7,10 (19) -triene 2β- (6-hydroxyhexyl) -1
α, 3β, 25-Trihydroxy-cholesta-5,7-
Diene 36.8 mg (71.2 μmol) in ethanol
Dissolve in 200ml and bubbling argon gas under ice-cooling
While, 400W high pressure mercury lamp-Vycor filter
After light irradiation for 3 minutes and 10 seconds, heat and reflux for 2.5 hours
Was. The residue obtained by evaporating the solvent under reduced pressure is purified by preparative thin-layer chromatography.
Chromatography (silica gel; ethyl acetate: n-hexa)
= 7: 1) to give the title compound 7.9 as a white powder.
mg (21% yield). [0039]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.94 (3H, d, J = 6.1H
z), 1.22 (6H, s), 3.64 (2H, t, J
= 6.6 Hz), 3.99-4.09 (1H, m),
4.15 (1H, brs), 5.02 (1H, s),
5.37 (1H, s) 6.03 (1H, d, J = 10.
7 Hz), 6.34 (1H, d, J = 10.7 Hz) IR (neat, cm^-1): 3410 (br), 29
70,2865 UVλ_max(EtOH): 262 nm. λ_mim2
28nm MS m / z: 516 (M⁺), 59 (100%) [0040] Embodiment 52β- (4-hydroxybutyl) -1α,
3β, 25-trihydroxy-9,10-secocholesta
Method for synthesizing -5,7,10 (19) -trienei)2β-
(4-hydroxybutyl) -1α, 3β, 25-Trich
Synthesis of droxycholesta-5,7-diene Under an argon atmosphere, at -35 to -45 ° C,
Tylmagnesium bromide (3 mol / l in ether)
Liquid) 4.3 ml (12.9 mmol) of THF (15 m
l) 1.20 g of 4-chloro-1-butanol was added to the suspension.
(11.0 mmol) in THF (5 ml) for 20 minutes
After stirring for 15 minutes at -20 ° C or lower,
For 30 minutes at room temperature. 271 mg of magnesium (1
1.2 mmol) and heated to reflux for 13.5 hours. Cooling
Then, 1α, 2α-epoxy-5α, 8α- (3,5-di
Oxo-4-phenyl-1,2,4-triazolidino)
-6-cholesten-3β, 25-diol 100mg
(170 μmol) in THF (5 ml) for 10 minutes
The mixture was dropped and heated under reflux for 2 hours. Saturate the reaction mixture
Pour into aqueous ammonium solution and add Hyflo Super-
After filtration through Cell, extraction with ethyl acetate was performed.
Washed with an aqueous solution of lithium. Dry over anhydrous magnesium sulfate
After that, the residue obtained by evaporating the solvent under reduced pressure, flash
Column chromatography (silica gel; ethanol:
Ethyl acetate = 1:50) and crude purification followed by preparative thin-layer chromatography.
Tomography (silica gel; ethanol: dichlorometa)
15: 100) to give the title compound as a white powder.
27 mg (33% yield) were obtained. [0042]¹H-NMR (dmso-d₆+ CDCl
₃) Δ: 0.62 (3H, s), 0.95 (3H, d,
J = 6.3 Hz), 0.99 (3H, s), 1.20
(6H, s), 3.46 (2H, t, J = 6.1H)
z), 3.72 (1H, brs), 4.11-4.26.
(1H, m), 5.28-5.35 (1H, m), 5.
57-5.64 (1H, m) IR (neat, cm^-1): 3390 (br), 29
45,2875 UVλ_max(EtOH) nm: 294, 282, 27
2 MS m / z: 488 (M⁺), 59 (100%) Ii)2β- (4-hydroxybutyl)-
1α, 3β, 25-trihydroxy-9,10-secoco
Synthesis of Lester-5,7,10 (19) -triene 2β- (4-hydroxybutyl) -1α,
3β, 25-trihydroxycholesta-5,7-diene
16.7 mg (34.2 μmol) of ethanol 200
solution, and bubbling argon gas under ice-cooling.
Using a 400W high-pressure mercury lamp-Vycor filter
After heating for 2 minutes, reflux for 2 hours. Solvent is distilled under reduced pressure
Chromatography for preparative thin-layer chromatography
(Silica gel; ethanol: dichloromethane = 1: 7)
And then perform preparative thin-layer chromatography (silica gel).
And ethanol: ethyl acetate = 1: 100).
To give 4.0 mg of the title compound as a white powder (yield 24%).
I got [0045]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.94 (3H, d, J = 5.9H
z), 1.22 (6H, s), 3.68 (2H, t, J
= 6.1 Hz), 4.01-4.12 (1H, m),
4.16 (1H, brs), 5.02 (1H, s),
5.37 (1H, s), 6.03 (1H, d, J = 1
1.3 Hz), 6.34 (1H, d, J = 11.3H)
z) IR (neat, cm^-1): 3385 (br), 29
45,2875 UVλ_max(EtOH): 264 nm. λ
_mim229 nm MS m / z: 488 (M⁺), 133 (100%) [0046] Embodiment 62β-methyl-1α, 3β, 25-Trich
Droxy-9,10-Secocolesta-5,7,10 (1
9) Synthesis method of triene i)2β-methyl-1α, 3β, 25-trihydroxy
Synthesis of cholesta-5,7-diene Methyl magnesium bromide (1 mol /
l THF solution) 1α, 2 in 2 ml (2.0 mmol)
α-epoxy-5α, 8α- (3,5-dioxo-4-
Phenyl-1,2,4-triazolidino) -6-choles
Ten-3β, 25-diol 100 mg (170 μmo
l) in THF (3 ml) was added under argon atmosphere
Heat to reflux for 2 hours. After cooling, the reaction mixture is saturated with ammonium chloride.
Hyflo Super-cell
, Extracted with ethyl acetate and saturated aqueous sodium chloride
Washed with solution. After drying over anhydrous magnesium sulfate, the solvent
Was distilled off under reduced pressure, and the residue obtained was separated by preparative thin-layer chromatography.
Chromatography (silica gel; ethyl acetate: n-hexane =
9: 1) After crude purification, preparative thin-layer chromatography
(Silica gel; ethanol: dichloromethane = 12: 1)
00) to give 17 mg of the title compound as a white powder.
(23% yield). [0048]¹H-NMR (CDCl₃) Δ: 0.63
(3H, s), 0.96 (3H, d, J = 6.3H
z), 1.01 (3H, s), 1.11 (3H, d, J
= 7.8 Hz), 1.22 (6H, s), 3.67 (1
H, brs), 4.06-4.25 (1H, m), 5.
33-5.43 (1H, m), 5.66-5.73 (1
H, m) IR (neat, cm^-1): 3380 (br), 29
40,2905 UVλ_max(EtOH) nm = 293, 282, 27
2 MS m / z: 430 (M⁺), 59 (100%) Ii)2β-methyl-1α, 3β, 25-
Trihydroxy-9,10-secocholesta-5,7,1
Synthesis of 0 (19) -triene 2β-methyl-1α, 3β, 25-Trich
17.2 mg of droxycholesta-5,7-diene (3
9.9 μmol) in 200 ml of ethanol,
400W high while bubbling argon gas under cooling
Light irradiation for 2 minutes using a pressure mercury lamp-Vycor filter
Then, heat reflux for 2 hours. The residue obtained by evaporating the solvent under reduced pressure
By preparative thin-layer chromatography (silica gel;
Tyl: n-hexane = 5: 1) to give a white foam.
4.1 mg (yield 24%) of the title compound was obtained. [0051]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.94 (3H.d, J = 6.1H
z), 1.15 (3H, d, J = 6.8 Hz), 1.2
2 (6H, s), 3.95-4.03 (1H, m),
4.04 (1H, brs), 5.02 (1H, s),
5.37 (1H, s), 6.03 (1H, d, J = 1
1.7Hz), 6.35 (1H, d, J = 11.7H)
z) IR (neat, cm^-1): 3375 (br), 29
30,2870 UVλ_max(EtOH) = 264 nm. λ_mim
228 nm MS m / z: 430 (M⁺), 59 (100%) [0052] Embodiment 71α, 3β-dihydroxy-2β-methyl
-9,10-Secocolesta-5,7,10 (19)-
Lien synthesis methodi)1α, 3β-dihydroxy-2β-
Synthesis of methylcholesta-5,7-diene Methyl magnesium bromide (1 mol /
l THF solution) 1α, 2 in 2 ml (2.0 mmol)
α-epoxy-5α, 8α- (3,5-dioxo-4-
Phenyl-1,2,4-triazolidino) -6-choles
100 mg (174 μmol) of Ten-3β-ol
An HF (4 ml) solution was added, and the mixture was added under an argon atmosphere for 2 hours.
Heat reflux. After cooling, the reaction mixture is saturated with aqueous ammonium chloride.
Pour into the solution and filter through HyfloSuper-Cell,
Extract with ethyl acetate and wash with saturated aqueous sodium chloride
did. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.
The residue obtained is separated by preparative thin-layer chromatography.
(Silica gel; ethyl acetate: n-hexane = 3: 1)
After purification, 17 mg of the title compound was obtained as a pale yellow powder (yield 2).
4%). [0054]¹H-NMR (CDCl₃) Δ: 0.62
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.94 (3H, d, J = 6.3 Hz), 100
(3H, s), 1.10 (3H, d, J = 7.9H
z), 3.65 (1H, brs), 4.13-4.26.
(1H, m), 5.32-5.41 (1H, m), 5.
69 (1H, brd, J = 5.6Hz) IR (neat, cm^-1): 3345 (br), 29
45,2870 UVλ_max(EtOH) nm: 293, 282, 27
1 MS m / z: 414 (M⁺, 43 (100%) Ii)1α, 3β-dihydroxy-2β-
Methyl-9,10-secocholesta-5,7,10 (1
9) Synthesis of triene 1α, 3β-dihydroxy-2β-methyl
Cholesta-5,7-diene 13.0 mg (31.4 μm
ol) in 200 ml of ethanol, and
400W high pressure mercury lamp while bubbling gon gas
After irradiation with light for 1 minute and 55 seconds using a Vycor filter,
Heat to reflux for 2 hours. The residue obtained by evaporating the solvent under reduced pressure
Preparative thin-layer chromatography (silica gel; ethyl acetate
And n-hexane = 2: 1) to give a colorless oily target.
3.6 mg (yield 28%) of the title compound was obtained. [0057]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.92 (3H, d, J = 5.9 Hz), 1.1
5 (3H, d, J = 6.8 Hz), 3.95-4.02
(1H, m), 4.03 (1H, brs), 5.02
(1H, s), 5.37 (1H, s), 6.03 (1
H, d, J = 11.7 Hz), 6.35 (1H, d, J)
= 11.7 Hz) IR (neat, cm^-1): 3390 (br), 29
45, 2930, 2870 UVλ_max(EtOH): 262 nm. λ_mim
227 nm MS m / z: 414 (M⁺), 148 (100%) [0058] Embodiment 82β-ethyl-1α, 3β, 25-Trich
Droxy-9,10-Secocolesta-5,7,10 (1
9) Synthesis method of triene i)2β-ethyl-1α, 3β, 25-trihydroxy
Synthesis of cholesta-5,7-diene Under argon atmosphere, add 5 ml of ethyl to THF.
A solution of magnesium bromide in THF (1.04 mol /
l) was added, and then 1α, 2α-epoxy-5 was added.
α, 8α- (3,5-dioxo-4-phenyl-1,
2,4-triazolidino) -6-cholesten-3β, 2
A solution of 100 mg of 5-diol in THF (5 ml) was added.
And refluxed for 2.5 hours. Water is added to the reaction solution, and ethyl acetate is added.
And washed with saturated aqueous sodium chloride solution. Nothing
After drying over magnesium sulfate, the solvent is distilled off under reduced pressure.
The residue obtained is purified by preparative thin-layer chromatography (silica).
Gel; purified by dichloromethane: ethanol = 10: 1)
The title compound was obtained as a colorless oil (22.7 mg, yield 30).
%). [0060]¹H-NMR (CDCl₃) Δ: 0.63
(3H, s), 0.96 (3H, d, J = 6.6H
z), 1.01 (3H, s), 1.05 (3H, t, J
= 7.4 Hz), 1.22 (6H, s), 3.80 (1
H, brs), 4.13-4.27 (1H, m), 5.
30-5.40 (1H, m), 5.68 (1H, br)
d, J = 4.3 Hz) IR (neat, cm^-1): 3400 (br), 2
955,2870 UVλ_max(EtOH) nm: 283, 272 MS m / z: 444 (M⁺), 59 (100%) Ii)2β-ethyl-1α, 3β, 25-
Trihydroxy-9,10-secocholesta-5,7,1
Synthesis of 0 (19) -triene 2β-ethyl-1α, 3β, 25-Trich
Add 22.7 mg of droxycholesta-5,7-diene to eta
Dissolved in 200 ml of ethanol, and cooled with ice under argon gas.
400W high-pressure mercury lamp-Vycorff
Using a filter, irradiate with light for 110 seconds, and heat return for 3 hours
Flow. The solvent is distilled off under reduced pressure, and the residue obtained is
Chromatography (silica gel; dichloromethane: eta)
(20: 1) to give 3.56 m of the title compound.
g (16% yield). [0063]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.94 (3H, d, J = 6.3H
z), 0.99 (3H, t, J = 7.0 Hz), 1.2
2 (6H, s), 4.00-4.10 (1H, m),
4.17 (1H, brs), 5.02 (1H, s),
5.38 (1H, s), 6.04 (1H-d, J = 1
1.0 Hz), 6.34 (1H, d, J = 11.0H)
z) IR (neat, cm^-1): 3410 (br), 29
40,2870 UVλ_max(EtOH): 263 nm. λ_mim
228 nm MS m / z: 444 (M⁺), 133 (100%) [0064] Embodiment 91α, 3β-dihydroxy-2β- (4-
Pentenyl) -9,10-secocholesta-5,7,10
(19) -Synthesis of triene i)1α, 3β-dihydroxy-2β- (4-pentenyl
B) Synthesis of cholesta-5,7-diene In an argon atmosphere, magne
After adding 122 mg of sodium, 5-bromo-1-pentene was added.
Add 595 µl of Ten and a small amount of iodine, and add 2.5 hours at room temperature
While stirring. 1α, 2α-epoxy-
3β-hydroxy-5,7-cholestadiene 100mg
Of THF (2 ml) was added and the mixture was added at 2:00 under an argon atmosphere.
Reflux while heating. Saturated aqueous ammonium chloride solution was added to the reaction mixture.
, Extracted with ethyl acetate, and saturated aqueous sodium chloride
Washed with liquid. After drying over anhydrous magnesium sulfate, remove the solvent
The residue obtained by evaporating under reduced pressure is purified by preparative thin-layer chromatography.
Raffy (silica gel; ethyl acetate: n-hexane =
1: 1) to give the title compound as a colorless oil (67.4m).
g (yield 59%) was obtained. [0066]¹H-NMR (CDCl₃) Δ: 0.62
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.94 (3H, d, J = 6.3 Hz), 1.0
0 (3H, s), 3.76 (1H, brs), 4.07
-4.21 (1H, m), 4.85-5.01 (2H,
m), 5.30-5.40 (1H, m), 5.60-
5.69 (1H, m), 5.70-5.95 (1H,
m) IR (neat, cm^-1): 3480 (br), 29
70,2880 UVλ_max(EtOH) nm: 293, 282, 27
1 MS m / z: 468 (M⁺), 55 (100%) Ii)1α, 3β-dihydroxy-2β-
(4-pentenyl) -9,10-secocholesta-5
Synthesis of 7,10 (19) -triene 1α, 3β-dihydroxy-2β- (4-
Pentenyl) cholesta-5,7-diene 20mg
Dissolved in 200 ml of ethanol, and cooled with ice under argon gas.
400W high-pressure mercury lamp-Vycorff
Using a filter, irradiate with light for 110 seconds, then heat for 2.5 hours
Refluxed. For fractionation of the residue obtained by evaporating the solvent under reduced pressure
Thin layer chromatography (silica gel; ethyl acetate: n
-Hexane = 1: 1) to give the title compound 5.06.
mg (yield 25.3%). [0069]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.92 (3H, d, J = 5.8 Hz), 4.0
4-4.13 (1H, m), 4.15 (1H, br)
s), 4.88-5.08 (3H, m), 5.37 (1
H, s), 5.70-5.94 (1H, m), 6.03.
(1H, d, J = 11.0 Hz), 6.35 (1H,
d, J = 11.0 Hz) IR (neat, cm^-1): 3480, 2950, 2
930,2880 UVλ_max(EtOH): 263 nm. λ_mim
229 nm MS m / z: 468 (M⁺), 147 (100%) [0070] Embodiment 102β- (4-pentenyl) -1α, 3
β, 25-trihydroxy -9,10- Seco Coresta
Synthesis of 5,7,10 (19) -triene i)2β- (4-pentenyl) -1α, 3β, 25-to
Synthesis of Rihydroxycholesta-5,7-diene In an argon atmosphere, magne
After adding 146 mg of sodium, 5-bromo-1-pentene was added.
Add 713 μl of ten and a small amount of iodine, and stir at room temperature for 2 hours.
Stirred. The reaction mixture was added to 3β, 25-dihydroxy
-1α, 2α-epoxy-5,7-cholestadiene 10
A 0 mg THF (5 ml) solution was added, and an argon atmosphere was added.
Heat under reflux for 2 hours. Saturated aqueous ammonium chloride solution
Pour the solution and extract with ethyl acetate, saturated sodium chloride
Washed with aqueous solution. After drying over anhydrous magnesium sulfate, dissolve
The residue obtained by evaporating the medium under reduced pressure is separated by thin-layer chromatography for preparative separation.
Tography (silica gel; dichloromethane: ethanol)
= 20: 1) to give the title compound 3 as a colorless oil.
2.8 mg (28% yield) were obtained. [0072]¹H-NMR (CDCl₃) Δ: 0.62
(3H, s), 0.96 (3H, d, J = 6.3H
z), 1.01 (3H, s), 1.22 (6H, s),
3.76 (1H, brs), 4.17-4.18 (1
H, m), 4.92-5.08 (2H, m), 5.31
−5.39 (1H, m), 5.65−5.72 (1H,
m), 5.74-5.91 (1H, m) IR (neat, cm^-1): 3400 (br), 29
40,2870 UVλ_max(EtOH) nm: 294, 281, 27
1 MS m / z: 485 (M⁺), 55 (100%) Ii)2β- (4-pentenyl) -1α,
3β, 25-trihydroxy-9,10-secocholesta
Synthesis of -5,7,10 (19) -triene 2β- (4-pentenyl) -1α, 3β,
25. Trihydroxycholesta-5,7-diene
8 mg was dissolved in 200 ml of ethanol, and
400W high pressure mercury lamp while bubbling gon gas
After irradiation with light for 150 seconds using a Vycor filter, 3
Heat to reflux for hours. The residue obtained by evaporating the solvent under reduced pressure was separated.
Preparative thin-layer chromatography (silica gel; dichlorome
Purified with tan: ethanol = 20: 1) to give the title compound
8.08 mg (yield 25%) was obtained. [0075]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.94 (3H, d, J = 6.3H
z), 1.22 (6H, s), 4.01-4.10 (1
H, m), 4.16 (1H, brs), 4.91-5.
09 (3H, m), 5.37 (1H, s), 5.75-
5.92 (1H, m), 6.03 (1H, d, J = 1
1.2Hz), 6.34 (1H, d, J = 11.2H)
z) IR (neat, cm^-1): 3400 (br), 29
50,2980 UVλ_max(EtOH): 263 nm. λ_mim
228 nm MS m / z: 485 (M⁺), 133 (100%) [0076] Embodiment 112β-butyl-1α, 3β-dihydroxy
C-9,10-Secocolesta-5,7,10 (19)-
Synthetic method of triene i)2β-butyl-1α, 3β-dihydroxycholesta
Synthesis of -5,7-diene Under an argon atmosphere, T cooled to -70 ° C.
Hexane solution of normal butyl lithium in 5 ml of HF
(1.61 mol / l) Add 808 μl and heat at the same temperature
After stirring briefly, 1α, 2α-epoxy-3β was added to this solution.
-Hydroxy-5,7-cholestadiene 100 mg T
An HF (10 ml) solution was added at -70 <0> C. Then 3
57.5 μl of boron fluoride diethyl ether was added,
Stirred at 70 ° C. for 20 minutes. Stir for 30 minutes under ice-cooling
Was. Pour a saturated aqueous ammonium chloride solution into the reaction mixture,
Extract with ethyl acetate and wash with saturated aqueous sodium chloride
did. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.
The residue obtained is separated by preparative thin-layer chromatography.
(Silica gel; dichloromethane: ethanol = 35:
Purify in 1) to give 14 mg (yield) of the title compound as a colorless oil.
12%). [0078]¹H-NMR (CDCl₃) Δ: 0.62
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.90-0.95 (6H, m), 1.02 (3
H, s), 3.78 (1H, brs), 4.13-4.
27 (1H, m), 5.32-5.40 (1H, m),
5.62-5.71 (1H, m) IR (neat, cm^-1): 3400 (br), 29
50,2930,2870 UVλ_max(EtOH) nm: 294, 282, 27
1 MS m / z: 456 (M⁺), 55 (100%) Ii)2β-butyl, 1α, 3β-dihydrido
Roxy-9,10-Secocolesta-5,7,10 (1
9), Synthesis of triene 2β-butyl-1α, 3β-dihydroxy
14 mg of cholesta-5,7-diene in 200 ethanol
solution, and bubbling argon gas under ice-cooling.
Using a 400W high-pressure mercury lamp-Vycor filter
After light irradiation for 80 seconds, light irradiation for 40 seconds and then for 3 hours
Heated to reflux. The residue obtained by evaporating the solvent under reduced pressure was separated.
Preparative thin-layer chromatography (silica gel; dichlorome
Purified with tan: ethanol = 40: 1) to give the title compound
1.52 mg (11% yield) was obtained. [0081]¹H-NMR (CDCl₃) Δ: 0.55
(3Hs), 0.87 (6H, d, J = 6.6 Hz),
0.91-0.98 (6Hm), 4.01-4.10
(1H, m), 4.17 (1H, brs), 5.02
(1H, s), 5.37 (1H, s), 6.03 (1
H, d, J = 11.5 Hz), 6.34 (1H, d, J)
= 11.5Hz) IR (neat, cm^-1): 3400 (br), 29
60,2930,2870 UVλ_max(EtOH): 263 nm. λ_mim
228 nm MS m / z: 456 (M⁺), 57 (100%) [0082] Embodiment 122β-butyl-1α, 3β, 25-tri
Hydroxy-9,10-secocholesta-5,7,10
(19) -Synthesis of triene i)2β-butyl-1α, 3β, 25-trihydroxy
Synthesis of cholesta-5,7-diene Under an argon atmosphere, T cooled to -70 ° C.
Hexane solution of normal butyl lithium in 5 ml of HF
(1.61 mol / l) 1.94 ml was added, and at the same temperature
After stirring for a while, add 3β, 25-dihydroxy
-1α, 2α-epoxy-5,7-cholestadiene 10
0 mg of THF (5 ml) solution was added at -70 <0> C. Next
Then, 55.2 μl of boron trifluoride diethyl ether
The mixture was stirred at -70 ° C for 30 minutes. 30 minutes under ice-cooling
Stirred. Saturated aqueous ammonium chloride solution was added to the reaction mixture.
Pour and extract with ethyl acetate, saturated aqueous sodium chloride
And washed. Reduce the solvent after drying with anhydrous magnesium sulfate
The residue obtained by distillation under reduced pressure is subjected to preparative thin-layer chromatography.
Fee (silica gel; dichloromethane: ethanol = 1)
0: 1), followed by preparative thin-layer chromatography again
-(Silica gel; ethyl acetate: n-hexane = 1: 1)
9.5 mg (yield) of the title compound as a colorless oil.
8%). [0084]¹H-NMR (CDCl₃) Δ: 0.63
(3H, s), 0.89-0.98 (6H, m), 1.
02 (3H, s), 1.22 (6H, s), 3.78
(1H, brs), 4.11-4.16 (1H, m),
5.32-5.31 (1H, m), 5.65-5.74
(1H, m) IR (neat, cm^-1): 3400 (br), 29
70,2890 UVλ_max(EtOH) nm: 294, 282, 27
1 MS m / z: 472 (M⁺), 59 (100%) Ii)2β-butyl-1α, 3β, 25-
Trihydroxy-9,10-secocholesta-5,7,1
Synthesis of 0 (19) -triene 2β-butyl-1α, 3β, 25-Trich
9.5 mg of droxycholesta-5,7-diene in ethanol
In 200 ml of water, and bubbling argon gas under ice-cooling.
While ringing, 400W high-pressure mercury lamp
After irradiating with light for 80 seconds, heat and reflux for 3 hours
Was. The solvent is distilled off under reduced pressure, and the residue obtained is
Chromatography (silica gel; ethyl acetate: n-hex
Purification by sun = 1: 1) gave 1.36 mg of the title compound.
(14% yield). [0087]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.92 (3H, t, J = 6.8H
z), 0.94 (3H, d, J = 6.3 Hz), 1.2
2 (6H, s), 4.01-4.10 (1H, m),
4.15 (1H, brs), 5.02 (1H, s),
5.38 (1H, s), 6.04 (1H, d, J = 1)
0.9Hz), 6.35 (1H, d, J = 10.9H)
z) IR (neat, cm^-1): 3400 (br), 2
930,2880 UVλ_max(EtOH): 264 nm. λ_mim
228 nm MS m / z: 472 (M⁺), 55 (100%) [0088] Embodiment 131α, 3β, dihydroxy-2β-pen
Chill-9,10-secocholesta-5,7,10 (19)
-Triene synthesis i)1α, 3β-dihydroxy-2β-pentylcholes
Synthesis of ter-5,7-diene In an argon atmosphere, magne
127mg of iodine and a small amount of iodine are added, and the color of iodine
After stirring until disappearing, 674 μl of 1-bromopentane was added.
Then, the mixture was stirred at room temperature for 1.5 hours. Add 1 to this reaction mixture.
α, 2α-epoxy-5α, 8α- (3,5-dioxo
-4-phenyl-1,2,4-triazolidino) -6
100 mg of cholesten-3β-ol in THF (5 m
l) Add the solution and heat to reflux for 2 hours. Saturated salt in reaction mixture
Pour an aqueous ammonium chloride solution and extract with ethyl acetate.
Washed with aqueous sodium chloride solution. Anhydrous magnesium sulfate
The residue obtained by evaporating the solvent under reduced pressure after drying with
Preparative thin-layer chromatography (silica gel; dichloro
Rough purification with methane: ethanol = 20: 1)
Layer chromatography (silica gel; ethyl acetate: n-
Hexane = 1: 2) to give the title compound as a colorless oil
18.8 mg (23% yield) were obtained. [0090]¹H-NMR (CDCl₃) Δ: 0.62
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.94 (3H, d, J = 6.3 Hz), 1.0
1 (3H, s), 3.77 (1H, brs), 4.10
-4.22 (1H, m), 5.32-5.40 (1H,
m), 5.67 (1H, brd, J = 5.6 Hz) IR (neat, cm^-1): 3400 (br), 29
40,2920,2870 UVλ_max(EtOH) nm: 292, 282, 27
1 MS m / z: 470 (M⁺), 55 (100%) Ii)1α, 3β-dihydroxy-2β-
Pentyl-9,10-Secocolesta-5,7,10 (1
9) Synthesis of triene 1α, 3β-dihydroxy-2β-pliers
18.8 mg of lucoresta-5,7-diene in ethanol
Dissolve in 200 ml, and under ice-cooling, bubbling argon gas
400W high pressure mercury lamp-Vycor filter
After light irradiation for 110 seconds, the mixture was heated under reflux for 3 hours.
The residue obtained by evaporating the solvent under reduced pressure is purified by preparative thin-layer chromatography.
Chromatography (silica gel; ethyl acetate: n-hexane)
= 1: 3), followed by preparative thin-layer chromatography
(Silica gel; ethyl acetate: n-hexane = 1: 3)
Purification gave 3.38 mg (18% yield) of the title compound.
Was. [0093]¹H-NMR (CDCl₃) Δ: 0.55
(3H, s), 0.87 (6H, d, J = 6.6H
z), 0.92 (3H, d, J = 6.0 Hz), 4.0
1-4.10 (1H, m), 4.15 (1H, br)
s), 5.02 (1H, s), 5.37 (1H, s),
6.03 (1H, d, J = 11.1 Hz), 6.34
(1H, d, J = 11.1 Hz) IR (neat, cm^-1): 3400 (br), 29
60,2940,2880 UVλ_max(EtOH): 264 nm. λ_mim
228 nm MS m / z: 470 (M⁺), 133 (100%) [0094] [Reference example]Inhibitory effect on bone mineral loss in ovariectomized rats SD female rats produced by Charles River Japan (8
Month) undergoes ovariectomy (OVX) under ether anesthesia,
The compound of Example 2 was administered from the second week after the surgery, when the wound was almost recovered.
Oral administration twice a week at a dose of 0.1 μg / kg for 3 months
Was given. The chemicals are edible oils and fats (O.I.
D. O). In addition, the untreated group (OVX
Not O. D. O group) and OVX group (after OVX)
O. D. O alone). The bone mineral density was measured every month after the start of administration.
Is fixed on the back under phenobarbital anesthesia.
The average bone density from the lumbar vertebra to the 5th lumbar vertebra was determined by Aloka
X-ray bone mineral content was measured using a DCS-600 eyebrow.
Changes in bone mineral density in the drug-administered group, untreated group, and OVX group
As shown in FIG. [0096] FIG. 1. Clearly, the compound of Example 2 reduces bone mineral loss
Suppressed.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows changes in bone density in a drug-administered group, an untreated group, and an OVX group.

Continuation of the front page (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 401/00 A61K 31/59 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] General formula (1) (In the formula, R ₁ represents a hydrogen atom or a hydroxyl group; R ₂ represents a linear or branched lower alkyl group, a lower alkenyl group, or a lower alkynyl group, and these are a hydroxyl group, a halogen atom, a cyano group, a lower alkoxy group, an amino , Which may be substituted with an acylamino group).