JPS59190962A - 24-oxo-25-dehydrovitamin d3, its production and calcium regulating agent containing the same as active constituent - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is H or OH). EXAMPLE:24-Oxo-25-dehydrovitamin D3. USE:A calcium regulating agent, having the activity of promoting the calcium absorption ability from the intestinal tracts, increasing the calcium concentration in blood and dissolving action on bone salts, and useful as a treating and preventing agent for diseases, e.g. osteoporosis or osteomalacia, caused by the abnormal calcium metabolism. PREPARATION:A 24-oxo-3beta-hydroxycholesta-5,7,25-triene expressed by formulaII (R<1> is H, OH or protected OH group; R<2> is H or a protecting group) is irradiated with ultraviolet light to produce 24-oxo-25-dehydroprevitamin D3, which is isomerized with heat energy and if necessary subjected to the protecting group removing reaction to give the aimed compound expressed by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION ff' Industrial Field of Application The present invention relates to a method for producing 24-oxo-25-dehydrovitamins r) 3 and 2, which are novel ntrl-type vitamins 1 and 3, and their use as active ingredients. The present invention relates to a calcium regulator. More specifically, the present invention has an excellent pharmacological effect, an effect of promoting calcium uptake from the intestinal tract, an effect of increasing calcium regulators in the blood, and a bone mineral dissolving effect, and has an effect of increasing the calcium cost by 11! i'j Various diseases that always occur,
The present invention relates to 24-oxo-dehydrovitamin D3 which is effective for the treatment or prevention of bone lesions such as skeletal condyle and osteomalacia, a method for producing the same, and a calcium regulator containing the same as an active ingredient.

Conventional technology As active vitamin D3, 1α,25-dihydro[]
Kinvitamin D3,1α, 24-Dihydroquinvitamin D3. Alternatively, 1α-hydroxy-24-oxovitamin D3 and the like are known. Such compounds have the effect of promoting calcium absorption from the intestinal tract, and are effective as therapeutic agents for bone lesions and the like.

However, 24-oxo-24-dehydrovitamin D3, which has an oxo group at the 24th position and a double bond between the 25th and 26th positions, is a new compound that has not been described in any literature, and there are no details regarding its production method, pharmacological activity, etc. was previously completely unknown.

OBJECTS OF THE INVENTION An object of the present invention is to provide 24-oxo-dehydrovitamin D3, which is a novel compound and has excellent pharmacological action, a method for producing the same, and a calcium regulator containing the same as an active ingredient.

Structure and Effects of the Invention The present invention provides 24-oxo-25-dehydro [wherein R represents a hydrogen atom or a hydroxyl group].

The 24-oxo-25-dehydrovitamin 1 type 3 with the above formula "■" has an oxo group at the 24th position and a double bond between the 25th and 26th positions, and has a completely unknown structure. have.

”-Closed formula [11, R represents a hydrogen atom or a water group. A specific example of the compound represented by the above formula [King] is 24-oxo-25-dehydrovitamin D3.24-oxo-25-dehydro-1α-hydroquine vitamin D3.

24-oxo-25-dehydrovitamin D3 is 24-oxo-3β- represented by [wherein R1 represents a hydrogen atom, a hydroxyl group, or a protected water M group, and R2 represents a hydrogen atom or a protective group] By irradiating hydroxycholester-5,7,25-trienes with ultraviolet rays, isomerizing the generated 24-oxo-25-dehydrovitamin D3 with thermal energy, and then subjecting it to a deprotection reaction as necessary. Manufactured.

In the above formula [JT], which is a raw material compound, R1 represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. The following groups can be mentioned as protecting groups for the hydroxyl group protected here.

(1) Acyl groups such as acedel group, propanoyl group, butanoyl group, pentanoyl group, noJ broyl group, cyclohext nanoyl group, chloroacetal group, bromoacedel group, benzoyl group, p-bromobenzoyl group.

p-nitrobenzoyl group, ethylbenzoyl group.

C1-CI2 aliphatic or aromatic carboxylic acid residues such as tolyl group, or their nitro, halogen, or alkokene equivalent derivatives are preferably used.

Among these, particularly preferred are acedel group, benzoyl group, propanoyl M, and the like.

(2) A group that forms an ether bond with a human n-xyl group, such as hrimedylsilyl group, lameblue t-butyl-
Trialgylsilyl group such as silyl group, 2-7 tolahydride [
Examples include 2-cyclic ether groups such as 1-pyranyl group and 2-detrahydrofuranyl group.

(3) Alkoxycarbonyl group Examples include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonylcarbonyl group, and pentoxycarbonyl group.

Among IMs, acyl groups and alkoxycarbonyl groups are particularly preferred, but are not limited to these.

In the above formula [■], R2 represents a hydrogen atom or a protective group. Such protecting groups include the same protecting groups as those mentioned above.

Such raw material compounds are synthesized, for example, according to the reaction formula shown below.

O OR3 q g In this reaction formula, the synthesis of compound 3 is described in JP-A-54-4
The June 1856 bulletin is used as a reference.

The production method of the present invention is carried out by irradiating 24=oxo-3β-hydroxycholest-5.7.25-trienes of the formula [IT] as described above with ultraviolet rays. Here, ultraviolet rays are known to have a wavelength range of about 200 to 360 nm, and in the method of the present invention, especially 2
Those having a wavelength of 60 to 310 nm are preferably used.

When irradiating with ultraviolet rays, it is preferable to carry out the irradiation in an inert organic solvent.

Examples of inert organic solvents include hexane.

Heptane, cyclohexane, ligroin, benzene, toluene, xylene, bromobenzene, chlorobenzene,
Hydrocarbons or halogenated hydrocarbons such as nitrobenzene, carbon tetrachloride, 1,2-dichloroethane, 1,2-dibromoethane; ether.

Tetrahydrofuran, dioxane, methyl cellosolve,
Ether solvents such as phenyl cellosolve; methanol,
Alcohol solvents such as ethanol, propatool, hexanol, and cyclohexanol are often used as suitable solvents.

The temperature during ultraviolet irradiation is -20 to -80℃, especially -10 to
A range of 20°C is preferred. Further, it is preferable to carry out the reaction in an inert atmosphere in which oxygen does not exist, such as an argon or nitrogen atmosphere.

Thus, when exposed to ultraviolet irradiation, the 9 and 10 positions of the starting material 24-oxo-3β-hydroxycholesta-5,7,25-trienes are cleaved to form 24-oxo-25-dehydroprevitamins D3. is generated. By isomerizing this previtamin D3 using thermal energy, 24-oxo-25-dehydrovitamin D3 or its hydroquine-protected vitamin D3 can be obtained. The isomerization reaction is carried out at 20°C to 120°C, preferably 40°C to 100°C.
It will be held in This isomerization reaction can be carried out as it is in the inert organic solvent used. Therefore, for example, the ultraviolet irradiation to obtain the above-mentioned previtamins D3 can be carried out at, for example, 40°C. In cases where this is carried out,
Simultaneously with the production of previtamin D3, a reaction occurs in which the produced previtamin D3 is gradually isomerized into vitamin D3 in the reaction system.

As is clear from the above, the isomerization reaction using thermal energy in the method of the present invention does not necessarily mean heating the reaction yarn.

The product thus obtained is subjected to a deprotection reaction if its water M group is protected. Such deprotection reaction may be performed after the product is isolated and purified, or may be performed subsequent to the above-mentioned isomerization reaction.

The deprotection reaction of hydroxyl groups is a known reaction per se, and can be carried out, for example, as follows.

When the protecting group is an acyl group or an alkoxycarbonyl group, it may be treated in an alkaline solution of a lower aliphatic alcohol such as methanol or ethanol, or with a metal hydride such as LiApH4 in ether. The temperature may be 0°C to 50'C. If the protecting group combines with the oxygen atom of the hydroxyl group to form an ether group)
! It can be easily removed originally or by contacting with acid or alkali.

Thus, 24-oxo-25-dehydrovitamin r) 3 represented by the above formula [+] can be obtained by the production method of the present invention.

24-oxo-25-dehydrovitamin 03 has the effect of regulating the calcium level during condensation. That is, it has the effect of promoting calcium absorption from the intestinal tract, increasing the calcium concentration in the surface, and has a bone mineral dissolving effect. Therefore, the 24-oxo-25-dehydrovitamin D3 of the present invention is extremely useful for the treatment or prevention of various diseases caused by abnormal calcium metabolism, such as osteohyperia, osteomalacia, and bone lesions in patients with renal failure. It is something.

Therefore, according to the present invention, 2 represented by the above formula III
A calcium regulator containing 4-oxo-25-dehydrovitamin D3 as an active ingredient is provided.

24-oxo-25-dehydrovitamin D3 may be administered either orally or parenterally, and parenteral administration includes intramuscular, subcutaneous, intravenous, and rectal administration.

Among these, oral administration is preferred. Calcium regulators containing this compound as the active ingredient are available in tablets, powders, and granules.

It is used in dosage forms such as suppositories, capsules, alcoholic solutions, oily solutions, and aqueous suspensions.

When forming into tablet form, for example, lactose.

Excipients such as starch, calcium carbonate, crystalline cellulose, silicic acid; carboxymethyl cellulose.

Binders such as methylcellulose, potassium phosphate, polyvinylpyrrolidone; sodium alginate.

Sodium bicarbonate, sodium lauryl sulfate.

It can be molded by a conventional method using a disintegrant such as stearic acid monoglyceride; a humectant such as glycerin; an adsorbent such as carrion or colloidal silicic acid; a lubricant such as purified talc or boric acid powder. Powders and granules can also be formed using the above-mentioned excipients and the like in a conventional manner. When molding into the form of a suppository, it can be molded by a conventionally known method using, for example, polyethylene glycol, cacao butter, higher alcohol, gelatin, or the like.

Capsules can be obtained by forming soft capsules etc. using an oily solution of the present compound. As solvents for oily solutions, vegetable oils such as corn [I], cottonseed oil, coconut oil, almond oil, fallen beef oil, fish liver oil, oily T.
You can use files such as

Alcohol solutions, oil fl solutions, aqueous suspensions, etc. can be obtained by known methods.

Antioxidants such as ascorbic acid, butylated hydroxyanisole, hydroquinone, etc. can also be incorporated into the formulation in order to extend the shelf life of the compound.

The dosage of 24-oxo-dehydrovitamin D3 of the present invention is appropriately selected depending on the patient's age, sex, degree of disease, etc., but is usually 2 to 200n9/Kg/day, more preferably 5 to 10n9/Kg/day. Kg/day.

It takes a throw! jm J: The amount of 24-oxo-dehydrovitamin D3 to be included in a formulation in unit dosage form is determined.

The present invention will be explained in more detail below with reference to Examples.

Reference example 1゜24-oxocholester-5,7-dinine-1α, 3β
- 60g of diol was dissolved in tetrahydrofuran-methylene chloride (1:1) 200IIrIlkm11jli'
L,4-”) enyl-1,2,4-triazoline-3,
An acetone solution of 5-dione was added dropwise until the red color of the reaction solution disappeared.

After stirring for 1 hour, the solvent was concentrated under reduced pressure, and the resulting crude product was applied to a silica gel column (solvent: benzene-acetone system) to obtain 24-oxo-5α,8α-(4
-phenyl-1,2-urazolo)choles] to-6-nin-1α-ol 7.79% was obtained.

The physical properties of this product were as follows.

h Reference example 2゜Synthesis of cose-1--6-ene (5) 24-oxo-5α,8β-(4-phenyl-1,2-
Urazoro) Trust-6-J-1α-all 7.5
9 was suspended in 50% of dry Hp-containing methylene and washed with N.

6.7 g of N-diisopropyl amine was added.

The reactor was cooled to 0° C., and 4.15 g of lurnatyl methyl ether was slowly added dropwise under a nitrogen stream. After Ihr, the temperature was returned to room temperature, and the reaction was continued until the T L Ct' raw material disappeared.

After the reaction was completed, T N m MW was added and the mixture was extracted with ethyl acetate. After washing successively with an aqueous sodium hydrogen carbonate solution and a saturated saline solution, it was dried over anhydrous sulfuric acid.

The solvent was concentrated under reduced pressure, and the resulting crude product was purified with a silica gel column (solvent: benzene-acetone system) to obtain 1α,
3β-di(methoxymethoxy)-24-oxo-5α,
8β-(4-)T-nyl-1,2-urazolo)cholesto-
5.8g of 6-ene was obtained. The physical properties of this product were as follows.

NMR (CD (J3:a, ppm), 0.85
(3+-1,8), 1.00 (31-1,S
).

1.09 (6M, d, J = 7.
2H7).

3.37 (61-1, S), 4.3-5.0
<48. m).

6.35 (2H, AB q ),
7.37 < 58. S)h Reference example 3゜1α,3β-di(methoxymethoxy)-24-oxo-
5α, 8β-(4-phenyl-1,2-urazolo)]]
Dissolve 30 ml of Resto 6-ene in 90 ml of diglyme-1-butanol (1:1), and dissolve t-butoxypotassium L95.
g, oxygen absorption at -20℃ under oxygen atmosphere becomes I
Stir until smooth. 1.16 g of triphenylphosphine was added and stirred for a while, then 411 N-hydrochloric acid and ethyl acetate were added and the mixture was mixed. The d layer was washed successively with IN-hydrochloric acid, aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified with a silica gel column (solvent: benzene-acetone system) to 1.919 1α, 3β-di(methoxine 1-xy) -24-A = Sohachi 5α, 8β-(
4-) Chonyl-1,2-urazo11) -J reply 1~
-6-en-25-ol is 141. 1J of this thing
Uniformity values were as follows.

NMR (CD (J3: 8.ppm) 0.85
(3H,S), 1.00 (3+-1,S)
.

1.35 (61-l, S), 4.3-5
．． 0(4H,m).

6.37 (2H, ΔBq), 7.3-7.
9(51-1,m)h Reference Example 4゜11h+9 1α,3β-di(methoxymethoxy)-2
4-oxo-5α,8β-(4-phenyl-1,2-urazolo)choles 1--6-en-25-ol was dissolved in 10 m of benzene, and methyl(carboxysulfamoyl)triethylammonium hydroxy- Reid 11
0 mg was added thereto, and the mixture was heated under reflux for 1.5 hours under a nitrogen atmosphere.

Water was added, extracted with ethyl acetate, and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure and applied to a silica gel column (solvent: benzene-T-tyl acetate system).
It was purified with 34 mg of 1α,3β-di(methoxymethoxy)-24-oxo-5α,8β-(4-phenyl-1,2-urazolo)cholesta-6,25-diene was obtained. The physical properties of this product were as follows.

NMR (CDCf3: 8.ppm >0.83 (
3H,S), 0.98 (3H,S).

1.87 (3+-LS), 3.33 (
61-1, S).

4.35 ~ 5.0 (4 tons 1.m),
5.73 (1 to 1. br, s) 5.93
(Month 1. br, s), 6.35 (21
-(,ABQ)7.3~7.9 (51-1, m
) h Reference example 5゜24-oxo-1α3β-dihydroxycholesta-5,
Synthesis of 7,25-triene (8) 1α,3β-di(methoxymethoxy)-24-oxo5α,8β-(4-)T-nyl-1,2-urazolo)] Lester 6,25-diene 180■ Tetrahydrofuran methanol (1:1) was dissolved in 18 mF, a catalytic amount of concentrated hydrochloric acid was added, and the mixture was heated and stirred at 50°C. 15
After avoiding the reaction for an hour, the solvent was removed under reduced IT and the resulting residue was mixed with S-]lysine 18#lI! and heated under reflux for 15 minutes. After the reaction was completed, 6N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. After sequentially washing with 1N hydrochloric acid, aqueous sodium bicarbonate solution, and saturated brine, it was dried over anhydrous sodium sulfate/rum. The solvent was concentrated under reduced pressure, and the resulting crude product was purified twice by ilica gel thin layer chromatography (
Solvent system: benzene-acetone system and n-hexane-2
-22 to 24- by [1 panol system]
Oxo-1α, 3β-dihydroxycholesta-5,7,
25-triene was obtained. The physical properties of this product were as follows.

UV (λmax, nm): 294. 282. 271. 262 (sh)
, 217.5MS (m/e):
412 (M”) Example 1゜24-oxo-1α 3β-dihydroxycholesta-5
, 600 deoxygenated 22 mg of 7,25-triene
Benzene m: [dissolved in ethanol (5:1). The resulting solution was irradiated using a 200 W Panobia lamp surrounded by a Vycor filter for 3 minutes while stirring and controlling the temperature at 5°C. This solution was then heated to reflux for 3.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure at 30° C. or lower. The obtained crude product was purified twice by silica gel thin layer chromatography (solvent system: benzene-acetone system and n-hexylene-2-propertool system).

Next, the purified product obtained was further purified by high performance liquid chromatography using a Zorbax-3I column using 1.6% methanol/dichloromethane as the eluent, and both fractions were eluted with a retention time of 17.2 minutes. 24-oxo-25-dehydro-1α-hydroxyvitamin D3? [? is. The fi value of this object is as follows.

(]V-(Eton, nm):
λ maX264. λ min237MS(m/
e): 412(M''), 394,376.
361,269,251,152,13. INMR(C
DCfa, 8ppm) 0.54 (3+-
1, S).

0.94 (31-1, d, , J =
6.4117).

1.87 (31,8), 4.2
3 (11-l, m).

4.43 (IH, m), 5.00
(11-1, 8).

5.33 (IN, S), 5.76 (
11-1, S).

5.95 (11-l, S).

6.01 (11-1, d, J = 11.3
117).

6.38 (IH, d, J = 11.3
Hz) Example 2゜Calcium absorption activity from the intestinal tract [and bone 1n dissolution activity f1
Immediately weaned male Wistar rats were fed a vitamin D-deficient, low-calcium diet (Ca, 0.0) for 8 weeks.
036%; p, 0.3%). 2 for this rat! 24-oxo-25-dehyde []- of inn 7
]1α-Hydroxyvitamin D 0.2%”rrtto
It was dissolved in 0.2 mfl of n
lylartin, D, t, and1')
e1-uca, H, F, Δrn, J, P
hysiol, 216°13!1l-1359 (196
9), and bone mineral dissolution activity was determined from the increase in serum calcium content. Serum calcium level was measured using the OCPC method (C
onety, l-1, V, and Briggs,
△, R, Am, J, Cl1m, Patho
l.

290-296 (19661).

The results are shown in FIGS. 1 and 2.

Example 3 The binding affinity of Lirebuta and 24-oxo-25-dehydro-1α-hydroxyvitamin D3 is E isman3
The method [1yoisman, J.A., l-1am
stra, A., J.;

1 (ream, B, E, and l) e ju
ca, l-1, F, Arch.

Biochem, BioI) hVs, 176.2
35-243 (1976) [15hizuk
a, S., Bannai, K., Naruch
i.

T, and 1-1a1-1ashi, Y, 3
The procedure was carried out according to J. T. teroids, 37.33-4323- (1981)). That is, the Lii 1 hesol fraction (0.3 mg protei
n/mf! ) 1mg to 10,000dpm [3
1-l 1 1α, 2! i-(Ol-1) 2D3
(S, Δ 163 (1′/mmfl I ) was added, and various concentrations of 24-oxo-25-dehyde [
1-1α-Hydroxyvitamin []3 was added and incubated at 25° C. for 60 minutes. Reaction 4940% (W/
1 d of polyethylene glycol 6,000 (V) was added, stirred well, and centrifuged at 2.260 x g for 60 minutes.
31-1] 1α.

25- (011) 2 D3 skewers were measured. From this measurement value, 24-oxo-2 has an affinity for 1α, 25- (OH) 2D3 glue zepter of 1
The affinity of 5-dehydro-1α-hydroxyvitamin 1]3 was 1.74, indicating high affinity.

Example 4 24-oxo-24i-dehydro-1α-hydrococonut vitamin D3 was dissolved in coconut oil to give 7/l G/
An mQ electrical oil + J1 solution was obtained.

Geradine, glycerin, paraoxic benzoate, 24-methyl, and purified water were moistened and dissolved to make a coating agent, and the above oil f[solution was used, and 24-oxo-25-dehydro-1α-hydroxyvitamin D3 was added to 1 capsule per capsule. Soft capsules were made using a continuous soft capsule making machine so as to contain 1 g/1 g.

[Brief explanation of the drawing]

Figure 1 shows the calcium absorption activity of 24-oxo-25-dehydro-1α-hydroxyvitamin D3 from the intestinal tract, and Figure 2 shows the bone mineral dissolution activity (bone mineral dissolution activity).
calcium mobilizaNon). Procedural amendment dated February 7, 1980, to the Commissioner of the Patent Office 1. Indication of the case, Patent Application No. 58-62372, 2. Title of the invention: 24-oxo-25-dehydrovitamin DJ, its production method, and its use as an active ingredient. Calcium regulator 3 Relationship with the case of the person making the amendment Patent applicant Sashibe Okamoto (1), Representative of Teijin Limited, 1-11 Minamihonmachi, Higashi-ku, Osaka (1) " 24-oxo-dehydrovitamin DJLJ Correct to read [24-oxo-25-dehydrovitamin D, etc.]. (2) [1α in the 17th to 19th lines of the third trace. 25-dihydroquine vitamin D 3,1α, 24 dihydroquine vitamin D, J. Correct it to "1α. 25-dihydroxyvitamin D1,1α, 24-dihydroxyvitamin D." (3) On page 4, lines 4 to 5, K “24-oxo-24-dehydrovitamin D1” was replaced with “24-oxo-24-dehydrovitamin D1”.
"Oxo-25-dehydrovitamin D," is corrected. (4) [24-
"Oxo-dehydrovitamin D, etc." should be corrected to "24-oxo-25-dehydrovitamin D." (5) “24-
oxo-25-dehydeq-1α-hydroquine vitamin D,” should be corrected as [24-oxo-2-25-dehydro-1α-hydroxyvitamin DsJ. (6) On page 5, line 14, “24-oxo-25
-Dehydrovitamin D3” is replaced with “24-oxo-2
Corrected to 5-dehydrovitamin 03 class J. (7) On page 6, line 5, the phrase “24-oxo-25 dehydrovitamin D,” was replaced with “24-oxo-25 dehydrovitamin D,”
-Dehydroprevitamin D3”. (8) "Chloracetal group" on page 6, line 16 of the same
I corrected it to say "chloroacetyl group". (9) On page 13, line 6 of the same page, it says “in serum” [
Correct as J in serum. α1 The button on page 14, line 11 of the same page says ``Karion''.
Kaolin,” he corrected. (b) On page 15, line 8, K "compound" is corrected to "this compound." (b) On page 15, line 12 of the same page, the phrase "24-oquine-dehydrovitamin D, etc." is corrected to "24-oquine-25-dehydrohitamine D3." (b) On page 15, line 17 of the same page, the phrase "24-oxo-dehydro-vitamin D3" is corrected to "24-oxo-25-dehydro-vitamin D,". α◆ On page 16, lines 2 and 3, the text “124-oxo-5α,8α-(4-phenyl-1,2-urazo,)cholesto-6-en-1α-ol” was replaced with “ 24-oxo-5α,8α-(4-phenyl-1,2-urazolo)cholest-6-ene-1α,3β-diol”. (2) In the 6th line of page 16, K rs o gJ is corrected to r 6.0 # J. 0 → "24-oxo-5α,8α-(4-phenyl-1°2-urazolo)fres)-6-,:X-7-1α-ol" on page 16, lines 12 to 14 " is corrected to "24-oxo-5α. 8α-(4-phenyl-1,2-urazo I:I) 4-cholest-6-ene-1α,3β-diol." αη From page 16, line 18 to page 17, line 1, “1
α,3β-di(methoxymethoxy)-24-oxo-5
α,8β-(4-phenyl1,2-urazolo)cholest-6-ene” -Urazoro) Cholest-6-en'' is corrected. α→ On page 17, lines 2 and 3, “24-okine-5α,8β-(4-phenyl-1゜2-uran I:l
)Cholest-6-enet,1α-ol” is replaced with “24-oxo-5α.8α-(4-phenyl1,2-urazolo)cholesto-6
-nin-lα,3β-diol”. α groan On page 17, lines 14 to 16 of the same page, “Work α, 3
β-di(methoxymethoxy)-24-oxo-5α,8
β-(4-phenyl-1゜2-urazolo)cholesto-6
-en" θ) with [lα,3β-di(methoxymethoxy)-24-oxo-5α,8α-(4-fer-
1,2-Uranium p) Correct as Cholest-6-Nin-1. (20) Kr8, page 17, line 18. pprnJ is corrected to [δ+PpmJ. (21) On page 18, lines 5 to 7, “lα. 3β-di(methoxymethoxy)-24-oxo-5α,
8β-(4-phenyl-1,2-urazolo)Frest-
6-en-25-ol" is replaced by [1α,3β-di(methoxymethoxy)-24-oxo-5α,8α-(
4-phenyl-1,,2-IJ7razolo)cholesto-6
-en-25-ol). (22) [1α] on page 18, lines 8 to 10. 3β-di(methoxymethoxy)-24-oxo-5α,
8β-(Ephenyl-1,2-Uzoro)Frest-
6-ene, 1 is corrected to [1α, 3β-di(methoxymethoxy)-24-oxo-5α, 8α-(4-phenyl-1°2-urazolo)cholest-6-ene”. (23) On page 19, lines 1 to 4, "'1α. 3β-di(methoxymethoxy)-24-oxo-5α,
8β-(4-7enyl-1,2-uranium p)cholesto-
6-en-25-ol" is replaced by [1α,3β-di(methoxymethoxy)-24-oxo-5α,8α-(
Corrected as 4-phenyl-1,2-urazolo (cholest-6-en-25-ol l). (24) On page 19, line 6 of the same page, r8+ppmJ is corrected as ``δIPpmJ.'' (25) K r1α, page 19, lines 12 to 14
. 3β-di(methoxymethoxy)-24-oxo-5α,
8β-(4-phenyl-1,2-urazoI=)Frester 6,25-diene” is replaced by “1α,3β-di(methoxymethoxy)-24-oxo-5α,8α-(4-
Phenyl-1,2-uranium p) Flester 6° 7-25-Diene-1. (26) Same full 19 Sadame 1 (lines 15 to 17: “
1α. jβ-di(methoxymethoxy)-24-okine-5α,
8β-(4-):・-nyl-1,2-urazolo)frest-CI-en-25-t-l” is replaced by [1α,3
β-di(methoxymethoxy)-24-oxo-5α,8
α-(4-phenyl-1,2-urasolo)Frest-6
-en-25-ol”. (27) 20th line 6th line and 9th line vcrxa23
β-di(methoxymethoxy)-24-oxo-5α,8
β-(4-phenyl-1,2-urazolo)cholester-6
,25-diene" is "]α,3β-di(methoxymethoxy)-24-oson-5α,8α-(4-phenyl-1,2-uranium p)cholesta-6゜25-diene.” I am corrected. (28) In the second to fourth lines of the 21st member, “lα. 3β-di(methoxymethoxy)-24-okine-5α,
8β-(4-7enyl-1,2-8-urazolo)cholester-6,25-diene"
1α,Jβ・-di(methynemethoxy)-2cy4-oxo-5α,8α-(4-phenyl-1,2-uranjJ
) Correster-6゜25-diene'' is corrected. (29) I- on page 25, line 4] 63α/ mn
na (!j and r ] 63 C4/mmo/J
I am corrected. (:(o) Figures 1 and 2 of the drawings are corrected as shown in the attached sheet. 9-

Claims (1)

[Scope of Claims] 24-oxo-25-dehydrovitamin D3 represented by the formula [wherein R represents a hydrogen atom or a hydroxyl group]. In formula 1, R1 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and R2 represents a hydrogen atom or a protective group. It is characterized by irradiating ultraviolet rays, isomerizing the generated 24-oxo-25-dehydroprevitamin O3 with thermal energy, and then subjecting it to a deprotection reaction as necessary [wherein R is a hydrogen atom or A method for producing 24-oxo-25-dehydrovitamin D3 represented by [representing a hydroxyl group]. 3) Calcilam regulator containing 24-oxo-25-dehydrovitamin D3 represented by the above formula [I] as an active ingredient.