JPH0689022B2 - 1α, 3β, 25-trihydroxy-24-homocholesta-5,7-diene analogue - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to precursors used in the synthesis of novel vitamin D derivatives. More specifically, the invention relates to precursors used in the synthesis of 24-homovitamins. Even more particularly, the present invention relates to precursors used in the synthesis of hydroxylated 24-homovitamins.

[0002]

BACKGROUND OF THE INVENTION Vitamin D is known to regulate the metabolism of calcium and phosphorus in animals and humans, and the biological efficacy of vitamin D is its in vivo hydroxylation. It is now a dogma to rely on metabolic conversion to derivatives. That is, in vivo, vitamin D ₃ is hydroxylated in the liver to 25-hydroxyvitamin D ₃ and then converted into 1α, 25-dihydroxyvitamin D ₃ in the kidney.
It is the latter compound that is currently recognized as the circulating hormone form of vitamin D. This form of vitamin D transports calcium and phosphorus in the intestine and mobilizes bone.
Due to its biological activity of promoting calcification and mineralization, it is an important pharmaceutical product which is outstandingly suitable for the treatment of various bone diseases.

Vitamin D derivatives and their preparation and uses are extensively described in patents and other literature. For example, in US Pat. No. 3,565,924, 25
-Dihydroxycholecalciferol, US Patent 3,6
1,25-dihydroxycholecalciferol in 97,559 and 1α-in US Pat. No. 3,741,996.
Hydroxycholecalciferol, US Pat. No. 3,783
No. 6,062 is 22-dehydro-25-hydroxycholecalciferol, US Pat. No. 3,880,894 is 1,25-dihydroxyergocalciferol, and US Pat. No. 4,201,881 is 24,24-difluoro-1α. , 25-dihydroxycholecalciferol,
US Pat. No. 4,196,133 teaches each of 24,24-difluoro-1α, 25-dihydroxycholecalciferol.

[0004]

It exhibits here excellent vitamin D-like activity and is therefore known for its use as an alternative to vitamin D ₃ and its various derivatives, such as hypoparathyroidism, bone dystrophy, New vitamin D ₃ derivatives have been found that can be used immediately for the treatment of various medical conditions that exhibit calcium and phosphorus imbalances such as osteomalacia and osteoporosis. These derivatives are 24-homovitamins, in particular 1α, 25-dihydroxy-22E (or Z) -dehydro-24-homovitamin D ₃ and 1α, 25-dihydroxy-24-homovitamin D ₃ . These 24-homovitamin D ₃ derivatives are represented by the following formula.

[0005]

[Chemical 2] (Wherein each of R ₁ , R ₂ and R ₃ is selected from the group consisting of hydrogen, an acyl group having 1 to about 4 carbon atoms, and a benzoyl group, and R ₄ and R ₅ are each a hydrogen atom. Or bond to each other to form a double bond of a carbon atom and a carbon atom).

The present invention provides the precursor used in the synthesis of the 24-homovitamin D ₃ derivative. More specifically, the present invention provides 1α, 3β, 25-trihydroxy-24-homocholesta-5,7-diene analogs. The compound of the present invention is preferably represented by the following chemical formula.

[0007]

[Chemical 3]

Wherein R is selected from the group consisting of an acyl group having 1 to about 4 carbon atoms and a benzoyl group ;
₃ is a hydrogen atom, an acyl group having 1 to about 4 carbon atoms,
And R ₄ and R selected from the group consisting of
₅ represents a hydrogen atom or is bonded to each other to form a carbon-carbon double bond. )

The best mode for carrying out the present invention will be described below. The compounds of the present invention can be prepared according to the steps and process instructions shown in the schemes below. Like numbers refer to like compounds in the process schematics and detailed description. In the following description, the compound of the present invention is represented by ( 10 ) and ( 13 ).

[0010]

[Chemical 4]

In accordance with the process of the present invention, bisnorcolenate acetate ( a ) is reduced with lithium aluminum hydride and then oxidized with dichlorodicyanobenzoquinone to give 1,4,6-trien-3-one ( b ). Was produced in a yield of 47%. The 22-THP-ether of b was treated with alkaline hydrogen peroxide to give 1α, 2α-epoxide ( 1 ) in a yield of 41%. ( 1 ) was reduced with lithium and ammonium chloride in liquid ammonium-tetrahydrofuran at -78 ° and then treated with chloromethyl methyl ether to give dimethyoxymethyl ether ( 2 ) in 38% yield. After removing the THP group, the aldehyde ( 4 ) was obtained in a yield of 81% by Swern oxidation. This was reacted with vinylmagnesium bromide to obtain allyl alcohol ( 5 ) in a yield of 94%.
The alcohol was heated in refluxing xylene with triethyl orthoacetate and a catalytic amount of propionic acid to produce the ester ( 6 ) in 93% yield. The ester ( 6 ) was then reacted with methylmagnesium bromide to give the alcohol ( 7 ) in 93% yield. After removal of MOM, acetylation leads to (22E) -1α, 3β-diacetoxy-2.
5-Hydroxy-24-homo-cholester 5,22-diene ( 9 ) was obtained with a yield of 73%.

After allyl bromination of ( 9 ) with N-bromosuccinimide, it was treated with tetra-n-butylammonium bromide and then with tetra-n-butylammonium fluoride to give 5,7,22-triene ( 10). ) Was obtained as the main product in a yield of 24%. 5,7-diene ( 1
0 ) in a benzene-ethanol solution for 5 minutes with a medium-pressure mercury lamp and then refluxed for 1 hour, and then hydrolyzed to (22E) -1α, 25-dihydroxy-22-dehydro-24-homovitamin D ₃ 22% yield of ( 11 )
Got with. 5,22-Diene ( 9 ) was selectively hydrogenated to give 5-ene ( 12 ) in 92% yield. This compound was converted to 1α, 2 via 5,7-diene ( 13 ) as described above.
It was changed to 5-dihydroxy-24-homovitamin D ₃ ( 14 ) (total yield 12%).

[0013]

EXAMPLES In the examples of the present invention described below, the melting points are uncorrected as measured by using a thermal stage microscope. Unless otherwise specified, the ¹ H-NMR spectrum is Hitachi R
Me _{4 in} CDCl _{3 with} −24 A (60 MHz)
Si was measured as an internal standard. Mass spectrum is Shimadzu Q
Obtained at 70 eV by P-1000 mass spectrometer. UV spectra were obtained in an ethanol solution by a Shimadzu UV-200 double beam spectrophotometer. Column chromatography is performed on silica gel (E. Merck Kieselgel 60, 7
0-120 mesh). Preparative thin layer chromatography was carried out on a plate pre-coated with silica gel (E-Merck Kieselgel 60F _254, thickness 0.25 mm). Normal work-up means dilution with water, extraction with the organic solvent indicated in parentheses, washing of the extract until neutral, drying over anhydrous magnesium sulfate, filtration, and removal of the solvent under reduced pressure. To do. The following abbreviations were used. THP-tetrahydropyranyl, THF-tetrahydrofuran, ether-diethyl ether, MeO
H-methyl alcohol, MOM-methoxymethyl. The temperature is ° C.

Reference Example 1 22-hydroxy-23,24-dinorcola-1,4
6-trien-3-one (b) 3β-acetoxydinorcholenic acid ( a ) (7.0 g, 1
Lithium aluminum hydride (3.0 g, 78.95 mmol) was added to a solution of 8.04 mmol) in THF (20 ml). The mixture was stirred at 60 ° C. for 14 hours. Water and ethyl acetate were added carefully to the reaction mixture. The residue (5.2 by filtration and removal of solvent)
g) was obtained. It was treated with dichlorodicyanobenzoquinone (11.7 g, 51.54 mmol) in dioxane (140 ml) under reflux for 14 hours. After cooling to room temperature, the reaction mixture was filtered, the filtrate was evaporated until a residue was obtained, and the residue was applied to an alumina column (200g). Elution with dichloromethane gave trienone ( b ) (2.8g, 47%). Melting point 156-15
7 ° (ether), UV _max ^EtOH nm (ε): 299 (1300
0), 252 (9200), 224 (12000) ¹ H-NMR (CDCl
₃ ) δ: 0.80 (3H, s, 18-H ₃ ), 1.04 (3H, d, J = 6Hz, 21-H
₃ ), 1.21 (3H, s, 19-H ₃ ), 3.10-3.80 (3H, m, 22-H ₂
And OH ), 5.90-6.40 (4H, m, 2-H, 4-H, 6-H, and 7-H), 7.05 (1H, d, J = 10Hz, 1-H), MS m / z : 326 (M ⁺
), 311, 308, 293, 267 112.

Reference Example 2 1α, 2α-epoxy-22-tetrahydropyranylio
Xy-23,24-dinorcola-4,6-diene-3-
On (1) Alcohol ( b ) in dichloromethane (50 ml)
(2.7 g, 8.28 mmol) was treated with dihydropyran (1.5 ml, 16.42 mmol) and p-toluenesulfonic acid (50 mg) at room temperature for 1 hour. The usual work-up (ethyl acetate extraction) gave the crude product. To a solution of this product in MeOH (70 ml) 30
% H ₂ O ₂ (4.8 ml) and 10% NaOH / Me
OH (0.74 ml) was added and the mixture was 1 at room temperature.
Stir for 4 hours. The usual work-up (ethyl acetate extraction) gave the crude product which was applied to a column of silica gel (50 g). Epoxide ( 1 ) (1.45 g, 41 by elution with benzene-ethyl acetate (100: 1)
%) Was obtained. Melting point 113-115 ° (hexane) UVλ
_max ^EtOH nm (ε): 290 (22000), ¹ H-
NMR (CDCl ₃ ) δ: 0.80 (3H, s, 18-H ₃ ), 1.07 (3H,
d, J = 6 Hz, 21-H ₃ ), 1.18 (3H, s, 19-H ₃ ) 3.38 (1H, dd,
J = 4 and 1.5Hz, 1-H), 3.55 (1H, d, J = 4Hz, 2-H), 3.3
0-4.10 (4H, m, 22-H ₂ and THP), 4.50 (1H, m, TH
P), 5.58 (1H, d , J = 1.5Hz, 4-H), 6. 02 (2H, s, 6-H and
7-H), MS m / z : 342 (M ⁺ -DHP), 324 (M ⁺ -THPOH)
, 309, 283, 85.

Reference Example 3 1α, 3β-dimethoxymethoxy-23,24-dinor
Col-5-ene-22-tetrahydropyranyl ether
(2) Lithium (5.00 g) was added portionwise into liquid ammonium (200 ml) at -78 ° under an argon atmosphere over 30 minutes. After stirring at -78 ° for 1 hour, dry TH
1α, 2α-epoxy-22-tetrahydropyranyl-oxy-23,24-dinorcola-4,6-dien-3-one ( 1 ) (2.00 g, 4.
69 mmol) was added dropwise at -78 ° over 30 minutes and the mixture was stirred at -78 ° for 1 hour. Anhydrous NH ₄ Cl (60 g) was added to the reaction mixture in small portions at −78 ° over 1 hour. After 1.5 hours, the cooling bath was removed and most of the ammonium was removed by bubbling argon. The usual work-up (using ether as solvent) gave the crude product. Dioxane (20m
l) at 45 ° in chloro-methyl methyl ether (2.0 ml, 26.34 mmol) and N, N-diethylcyclohexylamine (4.6 ml, 24.93 mmol) for 24 hours. The usual work-up (ethyl acetate) gave the crude product which was purified by silica gel (40
g) applied to the column. Hexane-ethyl acetate (5: 1)
By elution with dimethoxymethyl ether ( 2 )
(922 mg, 38%) was obtained as an oil. ¹ H-NMR δ
0.70 (3H, s, 8-H ₃ ), 1.02 (3H, s, 19-H ₃ ), 1.04 (3H, d, J =
_{6Hz, 21-H 3),} 3.34 (3H, s, -O-CH 3) 3.37 (3H, s, -O-CH 3)
, 4.63 (2H _, ABq _, J = 7Hz, ΔAB = 11Hz _, 1 α-O-CH ₂ -O
-), 4.64 (2H, s, 3β-O-CH ₂ -O-), and 5.50 (1H, m, 6
-H).

Reference Example 4 1α, 3β-dimethoxymethoxy-23,24-dinor
Col-5-en-22-ol (3) THP ether ( 2 ) (922 mg, 1.77 mmol) in THF (8 ml) and MeOH (8 ml) was treated with 2M HCl (1 ml) for 2 hours at room temperature. . The usual work-up (ethyl acetate) gave the crude product which was applied to a column of silica gel (40 g). Elution with hexane-ethyl acetate (2: 1) gave the alcohol ( 3 ) (678 mg, 88%) as an amorphous solid. ¹ H-NMR δ 0.70 (3H _, s, 18-H ₃ ), 1.02 (3H, s, 19-
_{H 3), 1.04 (3H,} d, J = 6Hz, 21- H 3), 3.34 (3H, s, -OC
H ₃ ), 3.38 (3H, s, -O-CH ₃ ) 4.65 (2H, ABq, J = 7Hz, ΔAB
= 11Hz, 1α-O-CH ₂ -O-) 4.66 (2H, s, 3β-O-CH ₂ -O-) 5.5
3 (1H, m, 6-H).

Reference Example 5 1α, 3β-dimethoxymethoxy-23,24-dinor
Col-5-en-22-al (4) Oxalyl chloride (0.27 ml, 3.09 millimolar) in dichloromethane (8 ml) was added to dimethylsulfoxide (0.44 ml, 6.21 mmol) at -78 ° C and argon gas. Added below. The mixture was stirred at -78 ° C for 10 minutes. Alcohol ( 3 ) (660 mg, 1.51 mmol) in dichloromethane (5 ml) was added to the solution at -78.
Added at ° C. The mixture was stirred at −78 ° C. under argon for 5 minutes and allowed to warm to room temperature. Normal finish (ether)
Gave a crude product which was applied to a column of silica gel (30 g). Aldehyde ( 4 ) (607 mg, 92) by elution with hexane-ethyl acetate (4: 1).
%) Was obtained as crystals. Melting point 71-72 ° C (hexane), ¹
H-NMR δ 0.74 (3H, s, 18-H ₃ ), 1.04 (3H, s, 19-H ₃ ), 1.12 (3
H, d, J = 6Hz, 21-H 3), 3.35 (3H, s, -O-CH 3), 3.39 (3H, s,
-O-CH ₃ ), 3.7 (1H, m, 1 β-H), 4.65 (2H, ABq, J = 7
Hz, ΔAB = 11Hz, 1α-O-CH ₂ -O-), 4.66 (2H, s, 3β-OC
HO-), 5.52 (1H, m, 6-H), and 9.61 (1H, d, J = 3H
z, -CHO), calculated as elemental analysis C ₂₆ H ₄₂ O ₅ : C, 71:85;
H, 9.74. Results: C, 71.71; H, 9.68.

Reference Example 61α, 3β-dimethoxymethoxycola-5,23-die
N-22-all (5) Magnesium (70 mg, 2.9 in THF (3 ml)
2 mmol) vinyl bromide in THF (0.42 ml,
2.98 mmol) 50% solution was added. Of the result
Aldehyde in THF (6 ml) to Grignard reagent
(Four) (595 mg, 1.37 mmol) at room temperature
Added. The mixture was stirred at room temperature for 1 hour. Normal
Workup (ether) gave the crude product which was
The gel was loaded onto a column of kagel (30 g). Hexane-acetic acid
Elution with Chill (3: 1) to elute Allylic Alcohol
Le (5) (595 mg, 94%) as an amorphous solid
Obtained. ¹ H-NMR δ: 0.70 (3H, s, 18-H₃), 1.02 (3H, s, 19-H
₃ ), 3.35 (3H, s, -O-CH₃), 3.38 (3H, s, -O-CH₃), 3.6
9 (1H, m, 1β-H), 4.20 (1H, m, 22-H), 4.64 (2H, AB
q, J = 7Hz, ΔAB = 11Hz 1α-O-CH₂-O-), 4.65 (2H, s, 3β
-O-CH₂-O-), 5.52 (1H, m, 6-H), 4.90-6.0 (3H, m, 23-H
And 24-H₂).

Reference Example 7 (22E) -1α, 3β-dimethoxymethoxy-27-
Norcholester 5,22-diene-26-oic acid
Chill ester (6) Triethyl orthoacetate ( 10 ml, 5.46) of allyl alcohol ( 5 ) (550 mg / 1.28 mmol)
A solution of (mmol), propionic acid (4 drops), and xylene (8 ml) was refluxed under argon for 2 hours. Removal of the solvent under reduced pressure gave a residue which was applied to a column of silica gel (30g). Ester ( 6 ) by elution with hexane-ethyl acetate (4: 1)
(630 mg, 93%) was obtained as an oil. ¹ H-NMR δ: 0.
68 (3H, s, 18-H ₃ ), 0.97 (3H, d, J = 6Hz, 21-H ₃ ), 1.03 (3
H, s, 19-H ₃ ), 1.24 (3H, t, J = 7Hz -CO ₂ CH ₂ C H ₃ ), 3.35
(3H, s, -O-CH ₃ ), 3.39 (3H, s, -O-CH ₃ ), 3.70 (1H,
m, 1β-H), 4.11 (2H, q, J = 7Hz, -CO ₂ C H ₂ CH ₃ ), 4.6
4 (2H, ABq, J = 7Hz, ΔAB = 11Hz, 1α-O-CH ₂ -O-), 4.6
5 (2H, s, 3β-O-CH ₂ -O-) 5.29 (2H, m, 22-H and 23-
H), 5.52 (1H, m, 6-H). If necessary, the 22E stereoisomer, compound ( 6 ), can be readily converted to the 22Z stereoisomer by iodine treatment. That is, the compound ( 6 ) in ether ( 6 )
The product of the isomerization reaction from trans form to cis form treated with diffusive sunlight for 1 hour using a catalytic amount of iodine (2%) relative to the amount of
Purification by 25 cm 6% 2-propanol / hexane) gives the 22Z stereoisomer.

Reference Example 8(22E) -1α, 3β-dimethoxymethoxy-24-
Homo-cholester 5,22-diene-25-ol
(7) ester(6) (605 mg, 1.14 mmol) T
To HF (6 ml) solution THF of methylmagnesium bromide
(4.5 ml, 4.5 mmol) 1M solution at room temperature
Added. The mixture was stirred at room temperature for 1 hour. Normal cut
Raising gave the crude product which was purified by silica gel (30
g) column. Hexane-ethyl acetate (3:
By elution with 1) alcohol (7) (548 g,
93%) as an oil.¹H-NMR δ: 0.68 (3H, s, 18-
H₃), 0.97 (3H, d, J = 6Hz, 21-H₃), 1.01 (3H, s, 19-H
₃), 1.21 (6H, s, 26-H₃ And 27-H₃), 3.33 (3H, s,-
O-CH₃), 3.38 (3H, s, -O-CH₃), 3.70 (1H, m, 1β-H),
4.64 (2H, ABq, J = 7Hz, ΔAB = 11Hz, 1α-O-CH₂-O-), 4.6
5 (2H, s, 3β-O-CH₂-O-), 5.29 (2H, m, 22-H and 23-
H) and 5.50 (1H, m, 6-H).

Reference Example 9 (22E) -24-Homocholester 5,22-diene-
1α, 3β, 25-triol (8) dimethoxymethyl ether ( 7 ) (540 mg, 1.0
4 mmol) in THF (15 ml) was added to 6M HCl.
(3 ml) at 50 ° C. for 2.5 hours. The usual work-up (ethyl acetate) gave the crude product which was applied to a column of silica gel (20 g). Elution with hexane-ethyl acetate (1: 1) gave the triol ( 8 ) (428 mg, 95%) as crystals. Melting point 164 to 166 ° C (hexane-ethyl acetate) ¹ H-NMR
δ: 0.68 (3H, s, 18-H ₃ ) 0.95 (3H, s, J = 6Hz, 21-H ₃ ), 1.00
(3H, s, 19-H ₃ ), 1.20 (6H, s, 26-H ₃ and 27-H ₃ ), 3.80 (1
H, m, 1 β-H), 3.92 (1H, m, 3 α-H), 5.30 (2H, m, 22-H
And 23-H), and 5.53 (1H, m, 6-H).

Reference Example 10 (22E) -1α, 3β-diacetoxy-25-hydro
Xy-24-homocholesta-5,22-diene (9) triol ( 8 ) (395 mg, 0.919 mmol)
Solution of pyridine (2 ml) in acetic anhydride at room temperature for 16
Time processed. The usual work-up (ethyl acetate) gave the crude product which was applied to a silica gel (20 g) column. Elution with hexane-ethyl acetate (2: 1) gave the diacetate ( 9 ) (361 mg, 77%) as an oil. ¹ H-NMR δ: 0.67 (3H, s, 18-H ₃ ), 0.97 (3H, d, J =
_{6Hz, 21-H 3),} 1.07 (3H, s, 19-H 3), 1.21 (6H, s, 26-H
₃ and 27-H ₃ ), 2.01 (3H, s, acetyl), 2.04 (3H,
s, acetyl), 4.98 (1H, m, 3α-H), 5.05 (1H, m,
1β-H), 5.31 (2H, m, 22-H and 23-H) and 5.52 (1
H, m, 6-H).

Example 1(22E) -1α, 3β-diacetoxy-25-hydro
Xy-24-homocholester 5,7,22-triene
(10) 5-ene- (in carbon tetrachloride (3 ml)9) (51m
g, 0.0992 mmol) and N-bromosuccinimine
Solution (21 mg, 0.118 mmol)
The mixture was refluxed for 20 minutes under a gong atmosphere. The mixture is heated to 0 ° C.
After cooling with, the precipitate was filtered off. Filtrate below 40 ° C
Concentrate until a residue is obtained. THF (5m
l) a catalytic amount of tetra-n-butylammonium bromide in
Was used for 50 minutes at room temperature. Then add the mixture
THF of tetra-n-butylammonium chloride (3.5 m
solution for 30 minutes at room temperature.
did. Normal work-up (ethyl acetate) gave crude product
Preparative thin layer chromatography (hexane-vinegar
Ethyl acetate, developed 4: 1 5 times). Rf value 0.4
Scrape band 8 and elute with ethyl acetate
It was Removal of the solvent resulted in 5,7-diene (10) (12.
5 mg, 24%) was obtained. UV λ_max ^EtOH : 293, 282 and 271.

Reference Example 11 1α, 25-dihydroxy-22E-dehydro-24-
Homovitamin D ₃ (11) 5,7-diene ( 10 ) (7.3 mg, 0.0143 mmol) benzene (90 ml), ethanol (40 m
l) The solution was irradiated with a medium pressure mercury lamp light through a Vicol filter at 0 ° C. under argon for 5 minutes. Removal of the solvent under reduced pressure gave a crude product which was subjected to preparative thin layer chromatography (hexane-ethyl acetate, 4:15).
Times). The band portion having an Rf value of 0.38 was scraped off and eluted with ethyl acetate. Removal of the solvent gave vitamin D ₃ diacetate (1.8 mg, 25%). The band portion having an Rf value of 0.43 was scraped off and eluted with ethyl acetate. The solvent was removed to recover 5,7-diene ( 10 ) (2.1 mg, 29%). Vitamin D ₃ diacetate (1.8 mg, 2.15 μmol) in THF (4 ml) was added to 5% KOH / MeOH.
(1 ml) at room temperature for 20 minutes. The usual work-up (ethyl acetate) gave the crude product which was subjected to preparative thin layer chromatography (hexane-ethyl acetate, 1:
(Deployed a few times). A band with an Rf value of 0.43 was scraped off and eluted with ethyl acetate. Vitamin D ₃ analog ( 11 ) by removal of solvent (1.4 mg, 90%)
Got The product purity is high performance liquid chromatography (Shimadzu LC-3A, column, Zorbax ZIL normal phase, inner diameter 4.6 mm x 1.5 cm, solvent, MeOH-C.
It was confirmed to be 100% by H ₂ Cl ₂ , 1:49, flow rate 3 ml / min, retention time 11.5 minutes). The spectral data of the vitamin D ₃ analog ( 11 ) was as follows. UV λ _max ^EtOH : 265 nm, λ _min ^EtOH : 228 nm, MS m / z:
428 (M ⁺ ), 410, 392 (base peak), 374, 287, 26
9, 251, 152, 134, 123, 59, ¹ H-NMR (360 MHz) δ:
0.55 (3H, s, 18-H ₃ ), 1.02 (3H, d, J = 6.6 Hz, 21-H
₃ ), 1.22 (6H, s, 26-H ₃ and 27-H ₃ ), 2.32 (1H, dd, J
= 13.2 and 6.7 Hz), 2.60 (1H, dd, J = 13.0 and 3.0
Hz), 2.83 (1H, dd, J = 12.0 and 3.0Hz), 4.23 (1H, m, W
_1/2 ) = 18.4Hz, 3α-H), 4.43 (1H, m, W _1/2 = 16.9H
z, 1β-H), 5.00 (1H, bs, W _1/2 = 3.2Hz, 19-H), 5.30
(1H, dd, J = 15.0 and 7.1Hz, 22-H or 23-H), 5.
33 (1H, bs, W _1/2 = 3.2Hz, 19-H), 5.37 (1H, dd, J = 15.
0 and 5.8Hz, 22-H or 23-H), 6.01 (1H, d, J = 11.
0Hz, 7-H), 6.32 (1H, d, J = 11.0Hz, 6-H).

Reference Example 121α, 3β-diacetoxy-24-homocholest-5-
En-25-all (12) 5,22-diene (in ethyl acetate (2 ml)9) (4
0 mg, 0.0778 mmol) and 10% Pd-C (4
(mg) mixture was stirred at room temperature under hydrogen atmosphere for 3 hours.
It was The Pd catalyst was filtered off and the filtrate was concentrated until a residue was obtained.
Shrink and apply it to a column of silica gel (5 g). F
5-by elution with xane-ethyl acetate (4: 1)
EN (12) (37 mg, 92%) was obtained as an oil.¹ H-NMR δ: 0.66 (3H, s, 18-H₃), 1.08 (3H, s, 19-H₃), 1.2
0 (6H, s, 26-H₃ And 27-H₃), 2.02 (3H, s, acetyl
), 2.05 (3H, s, acetyl), 4.97 (1H, m, 3α-H), 5.
07 (1H, m, 1β-H), 5.53 (1H, m, 6-H). Example 21α, 3β-diacetoxy-24-homocholester 5,
7-Dien-25-ol (13) 5-en (12) (19 mg, 0.037 mmol)
(10) 5,7-diene (1
Three) (5.8 mg, 31%). UV λ_max
^EtOH : 293, 282, 271 nm

Reference Example 131α, 25-dihydroxy-24-homovitamin D ₃
(14) 5,7-diene (Thirteen) (5.8 mg, 0.0113 mi
Rimol) (11) Vitamin D as described in
₃ Analog (14) (890 μg, 19%).
Under the above HPLC conditions (14) Retention time is 1
It was 1.0 minutes. UV λ_max ^EtOH : 265 nm, λ_min ^EtOH : 228 nm. MS m / z 430 (M⁺), 412, 394 (base peak), 376,
287, 269, 251, 152, 134, 59. If desired, the compound (11)as well as(14) Is appropriate
Solvents such as hexane, ethers, acetic acid, well known to those skilled in the art.
By crystallization using rucors, or a mixture thereof.
It can be easily obtained as a crystalline form.

Biological activity 1α, 25- (OH) ₂ -24-Homo-D ₃ compound
Lucium fluidization activity Bone calcium fluidization activity was assessed by measuring the increase in serum calcium content corresponding to the compound administered. Low weaning diets (Suda et al., Journal of Nutrients) in male weanling rats (Holtzmann, Madison, Wis.).
100, 1049-1050, 1970) and water ad libitum for 3 weeks. After that, the rats were divided into three groups of 5 to 6 each, and 95% ethanol 0.05m
1,25- (OH) ₂ D ₃ or test compound dissolved in 1 was given. Rats in the control group were similarly given 0.05 ml of ethanol vehicle. 18 after administration
After a while, the rat was killed, its blood was collected, and serum was obtained by centrifugation. Serum calcium concentration in the presence of 0.1% lanthanum chloride was measured with an atomic absorption spectrometer Model 403 (Perkin Elmer, Norwalk, CT). The results obtained are shown in Table 1.

[0029]

[Table 1]

From the data in Table 1 above, in the vitamin D responsive system of vitamin D deficient animals, the compounds ( 11 ) and ( 14 ) are very high in the dose of the 22-dehydro derivative ( 11 ), It can be concluded that it exhibits similar activity to the circulating hormone form 1α, 25-hydroxyvitamin D ₃ . Compounds ( 11 ) and ( 14 ) can be easily administered by injection or intravenous injection as a sterile parenteral solution, or as an oral dosage form into the digestive tract, or as a suppository or transdermal drug. A daily maintenance dose of about 0.1 μg to about 0.5 μg is appropriate. To obtain a physiological calcium balance corresponding to the vitamin D-like activity profile, about 0.1 μg
To about 2.5 μg is effective. Dosage forms for the compounds may be prepared in combination with non-toxic pharmaceutically acceptable carriers well known in the art. Such carriers may be solid or liquid and include, for example, corn starch, lactose, sucrose, peanut oil, sesame oil and water. Tablets if a solid carrier is used as the dosage form of the compound,
It could be a capsule, powder or drop.
When a liquid carrier is used, the dosage form can be a soft gelatin capsule, syrup or suspension, emulsion or solution. The dosage form may also contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters and the like. It may also contain other therapeutically effective substances. The dose range is defined as the specific amount to be administered to the recipient, but for each medical condition to be treated,
It is to be understood that the envisioned results will depend on the physical size of the recipient and other factors well known to those of skill in the art in the therapeutic use of those pharmaceuticals.

[0031]

The compound 1α, 3β, 25-trihydroxy-24-homocholesta-5,7-diene analogue of the present invention is a compound showing excellent vitamin D-like activity, namely 1
It is suitable as a precursor used in the synthesis of α, 25-dihydroxy-22E (or Z) -dehydro-24-homovitamin D ₃ and 1α, 25-dihydroxy-24-homovitamin D ₃ .

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Nobuo Ikegawa 2-21-5 Kichijoji Higashimachi, Musashino City, Tokyo, Japan (72) Inventor Yoko Tanaka USA 12054 New York, Delmar, Paxwood Road 72 (56) References Special JP-A-59-176250 (JP, A) JP-A-59-167552 (JP, A) JP-A-59-501746 (JP, A) US patent 4226770 (US, A) US patent 3880894 (US, A) US patent 4163744 (US, A) U.S. Pat. No. 4225596 (US, A) CHEMICAL PHARMACEU TICAL BULLETIN VOL. 33 NO. 2 (1985) P. 878-881

Claims (1)

[Claims] 1. A compound having the following general formula: [Chemical 1] (In the formula, R is selected from the group consisting of an acyl group having 1 to about 4 carbon atoms and a benzoyl group, and R ₃ is a hydrogen atom.
Child, an acyl group having 1 to about 4 carbon atoms, and benzo
Selected from the group consisting of yl groups, R ₄ and R ₅ represent hydrogen atoms or are bonded to each other to form a carbon-carbon double bond. )