JPH05222089A - 1alpha,3beta,25-trihydroxy-24-homocholesta-5,22- diene compound - Google Patents

Abstract

PURPOSE: To provide a compd. comprising a 1α,3β,25-trihydroxy-24- homocholesta-5,22-diene compd. as an intermediate for the synthesis of 1α,25- dihydroxy-24-homovitamin D₃ deriv. for the treatment for bone diseases.

CONSTITUTION: A bisnorcholanic acetate expressed by formula I (Ac is acetyl) is reduced by using hydrogenated aluminum lithium and then oxidized to obtain 1,4,6-trien-3-one, which is treated with an alkali hydrogen peroxide to obtain 1a,2a-epoxide. Then the compd. is reduced and then treated with chloromethyl methyl ether to obtain a dimethyloxymethyl ether, from which protecting groups of hydroxyl groups is removed. The compd. subjected to Swern oxidation to obtain an aldehyde expressed by formula II (MOMO is methoxymethoxy), which is then allowed to react with a vinyl bromide magnesium. Then the reaction product is allowed to react with an ortho-triethyl acetate and propionic acid to remove MOM groups for acetylation. Thus, the objective compd. expressed by formula III (R is H, a 1 to 4C acyl, benzoyl, etc.), is obtd.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an intermediate used in the synthesis of a novel vitamin D derivative. More specifically, the invention relates to intermediates used in the synthesis of 24-homovitamins. Even more particularly, the invention relates to intermediates 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 the living body, vitamin D ₃ is hydroxylated to 25-hydroxyvitamin D ₃ in the liver and then converted to 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.
Because of its biological activity of promoting calcification and mineralization, it is an important medicinal 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 Patent 3,78
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, osteomalacia, immediately a new vitamin D ₃ derivatives that can be used has been found for the treatment of various disease states representing the imbalance of calcium and phosphorus, such as 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-homo vitamin D ₃ derivatives expressed by the following equation.

[0005]

[Chemical 2]

(Wherein R ₁ , R ₂ and R ₃ are each 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. Represents or bond with each other to form a double bond of a carbon atom and a carbon atom). The present invention is the above 24
- providing an intermediate member used in homo vitamin D ₃ derivative synthesis. More specifically, the present invention relates to 1α, 3β, 25-
A trihydroxy-24-homocholesta-5,22-diene compound is provided. 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 hydrogen, an acyl group having 1 to about 4 carbon atoms, a benzoyl group and a methoxymethyl group).

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 ( 7 ), ( 8 ) and ( 9 ).

[0010]

[Chemical 4]

In accordance with the process of the present invention, bisnorcolenic acid 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 obtain 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, aldehyde ( 4 ) was obtained in 81% yield 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 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, followed by hydrolysis 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 a yield of 92%. 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 diluting with water, extracting with the organic solvent shown in parentheses, washing the extract to neutrality, drying over anhydrous magnesium sulfate, filtering, and removing 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
To a solution of 8.04 mmol) in THF (20 ml) was added lithium aluminum hydride (3.0 g, 78.95 mmol). 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 [deg.] Over 30 minutes and the mixture was stirred at -78 [deg.] 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 ° at 45 ° with chloro-methyl methyl ether (2.0 ml, 26.34 mmol) and N, N-diethylcyclohexylamine (4.6 ml, 24.93 mmol) for 24 hours. Normal 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) at room temperature for 2 hours. .. 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 dimethyl sulfoxide (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 6 1α, 3β-dimethoxymethoxycola-5,23-die
N-22-ol (5) Magnesium (70 mg, 2.9 ) in THF (3 ml).
2 mmol) to vinyl bromide in THF (0.42 ml,
2.98 mmol) 50% solution was added. To the resulting Grignard reagent was added aldehyde ( 4 ) (595 mg, 1.37 mmol) in THF (6 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. The usual work up (ether) gave the crude product which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (3: 1) gave the arylic alcohol ( 5 ) (595 mg, 94%) as an amorphous solid. ¹ H-NMR δ: 0.70 (3H, s, 18-H ₃ ), 1.02 (3H, s, 19
-H ₃ ), 3.35 (3H, s, -O-CH ₃ ), 3.38 (3H, s, -O-CH ₃ ),
3.69 (1H, m, 1β-H), 4.20 (1H, m, 22-H), 4.64 (2H,
ABq, J = 7Hz, ΔAB = 11Hz 1α-O-CH ₂ -O-), 4.65 (2H, s, 3
β-O-CH ₂ -O-), 5.52 (1H, m, 6-H), 4.90-6.0 (3H, m, 23-
H and 24-H ₂ ).

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 treatment with iodine. That is, the compound ( 6 ) in ether is treated with a catalytic amount of iodine (2%) relative to the amount of ( 6 ) in diffusive sunlight for 1 hour, and the product of the isomerization reaction from trans form to cis form is analyzed by HPLC. Purification by (Zorbax-Sil column 4.6 x 25 cm 6% 2-propanol / hexane) gives the 22Z stereoisomer.

Example 1 (22E) -1α, 3β-dimethoxymethoxy-24-
Homo-cholester 5,22-diene-25-ol
(7) T of ester ( 6 ) (605 mg, 1.14 mmol)
To HF (6 ml) solution THF of methylmagnesium bromide
(4.5 ml, 4.5 mmol) 1M solution was added at room temperature. The mixture was stirred at room temperature for 1 hour. Usual work-up gives the crude product which is purified by silica gel (30
g) column. Hexane-ethyl acetate (3:
Elution with 1) gave alcohol ( 7 ) (548 g,
93%) as an oil. ¹ H-NMR δ: 0.68 (3 H, s, 18-
H ₃ ), 0.97 (3H, d, J = 6Hz, 21-H ₃ ), 1.01 (3H, s, 19-H
₃ ), 1.21 (6H, s, 26-H ₃ and 27-H ₃ ), 3.33 (3H, s,-
O-CH ₃ ), 3.38 (3H, s, -O-CH ₃ ), 3.70 (1H, m, 1β-H),
4.64 (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) and 5.50 (1H, m, 6-H).

Example 2 (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).

Example 3 (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 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).

Reference Example 8 (22E) -1α, 3β-diacetoxy-25-hydro
Xy-24-homocholester 5,7,22-triene
(10) 5-ene- ( 9 ) (51 m in carbon tetrachloride (3 ml)
A mixed solution of g, 0.0992 mmol) and N-bromosuccinimide (21 mg, 0.118 mmol) was refluxed for 20 minutes under an argon atmosphere. After cooling the mixture to 0 ° C., the precipitate was filtered off. The filtrate was concentrated below 40 ° C. until a residue was obtained. THF (5m
In l) was treated with a catalytic amount of tetra-n-butylammonium bromide at room temperature for 50 minutes. The mixture is then treated with tetra-n-butylammonium fluoride in THF (3.5 m
1, 3.5 mmol) at room temperature for 30 minutes. The usual work-up (ethyl acetate) gave the crude product which was subjected to preparative thin layer chromatography (hexane-ethyl acetate, developed 4:15 times). Rf value 0.4
The band portion of 8 was scraped off and eluted with ethyl acetate. Removal of the solvent allowed 5,7-diene ( 10 ) (12.
5 mg, 24%) was obtained. UV λ _max ^EtOH : 293, 282 and 271.

Reference Example 9 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 exposed to a medium pressure mercury lamp light through a Vicol filter for 5 minutes at 0 ° C. under argon atmosphere. The solvent was removed under reduced pressure to give 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 analogue ( 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 : 22
8 nm, MS m / z: 428 (M ⁺ ), 410, 392 (base peak),
374, 287, 269, 251, 152, 134, 123, 59, ¹ HN
MR (360MHz) 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 ), 2.3
2 (1H, dd, J = 13.2 and 6.7 Hz), 2.60 (1H, dd, J = 13.0
And 3.0Hz), 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
= 16.9Hz, 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 10 1α, 3β-diacetoxy-24-homocholest-5-
5,22-Diene ( 9 ) (4) in ene-25-ol (12) ethyl acetate (2 ml)
0 mg, 0.0778 mmol) and 10% Pd-C (4
(mg) mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The Pd catalyst was filtered off, the filtrate was concentrated until a residue was obtained, which was applied to a column of silica gel (5 g). 5-by elution with hexane-ethyl acetate (4: 1)
The ene ( 12 ) (37 mg, 92%) was obtained as an oil. ¹ H
-NMR δ: 0.66 (3H, s, 18-H ₃ ), 1.08 (3H, s, 19-H ₃ ), 1.20
(6H, s, 26-H ₃ and 27-H ₃ ), 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). Reference Example 11 1α, 3β-diacetoxy-24-homocholester 5,
7-Dien-25-ol (13) 5-ene ( 12 ) (19 mg, 0.037 mmol) was added to 5,7-diene ( 1 in the same manner as described in ( 10 ).
3 ) (5.8 mg, 31%). UVλ _max
^EtOH : 293, 282, 271 nm

Reference Example 12 1α, 25-dihydroxy-24-homovitamin D ₃
(14) Vitamin D was added to 5,7-diene ( 13 ) (5.8 mg, 0.0113 mmol) in the same manner as described in ( 11 ).
Converted to ₃ analogs ( 14 ) (890 μg, 19%).
The retention time of ( 14 ) under the above-mentioned HPLC conditions 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, 5
9. If desired, compounds ( 11 ) and ( 14 ) can be readily obtained in crystalline form by crystallization with a suitable solvent such as hexane, ethers, alcohols, or mixtures thereof well known to those skilled in the art. ..

Biological activity 1α, 25- (OH) ₂ -24-Homo-D ₃ compound
Lucium fluidization activity Bone calcium fluidization activity was evaluated by measuring the increase in serum calcium content corresponding to the compound administered. Low weaning rats (Holtzmann, Madison, WI) low calcium vitamin D deficient diet (Suda et al., Journal of Nutrients,
100, 1049-1050, 1970) and water ad libitum for 3 weeks. After that, the rats were divided into 3 groups of 5 to 6 each, and 95% ethanol 0.05m
It was dissolved in l 1,25- gave (OH) ₂ D ₃ or the test compound. Rats in the control group were similarly fed with 0.05 ml 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, Conn.). The results obtained are shown in Table 1.

[0029]

[Table 1]

From the data shown in Table 1 above, in the vitamin D responsive system of vitamin D deficient animals, the compounds ( 11 ) and ( 14 ), although the doses of the 22-dehydro derivative ( 11 ) were very high, 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 gastrointestinal tract, or as a suppository or transdermal agent. 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.
If a liquid carrier is used, the dosage form may be a soft gelatin capsule, syrup or suspension, emulsion or solution. Further, the dosage form may contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, and dissolution accelerators. 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 skilled in the art in the therapeutic use of those pharmaceuticals.

[0031]

The compound 1α, 3β, 25-trihydroxy-24-homocholesta-5,22-diene compound of the present invention is a compound showing excellent vitamin D-like activity, namely 1α, 25-dihydroxy-22E (or Z). ) -Dehydro-24-homovitamin D ₃ and 1α, 25-dihydroxy-24-homovitamin D ₃ are suitable as synthetic intermediates.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Nobuo Ikegawa 2-21-5 Kichijoji Higashimachi, Musashino City, Tokyo, Japan (72) Inventor Yoko Tanaka United States 12054 New York, Delmar, Paxwood Road 72

Claims (1)

[Claims] 1. A compound having the following general formula: [Chemical 1] (In the formula, R is selected from the group consisting of hydrogen, an acyl group having 1 to about 4 carbon atoms, a benzoyl group, and a methoxymethyl group.)