JPH0129184B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 1α-hydroxyvitamin _D3 . It is known that 1α-hydroxyvitamin D compounds, which also contain a 25-hydroxy group, have advantageous biochemical properties that make them quite useful in therapy. That is, they are more rapidly acting and cleared from the system than the corresponding 1α-unsubstituted compounds, and are therefore more likely to induce vitamin toxicity than normal vitamin D compounds, which are only gradually removed from the system. becomes smaller. Additionally, the hydroxylated derivatives are often effective in alleviating symptoms of vitamin D deficiency that apparently do not respond to conventional vitamin treatments. Such 1α-hydroxyvitamin D compounds can be synthesized by techniques similar to those used for the synthesis of the corresponding 1α-unsubstituted derivatives, especially 1α,3α-dihydroxysteroids of the cholestane series.
- Can be produced by photochemical decomposition of dienes using ultraviolet irradiation. 1α,3β-dihydroxysteroid-5,7-
A useful precursor to the diene starting material is the corresponding steroid-5-ene. This is because they can be easily converted into 5,7-dienes, for example by bromination at the 7-position followed by dehydrobromination. However, such 1α,3β-dihydroxysteroid-5
-ene synthesis poses many problems. This is because it is generally necessary to introduce a 1α hydroxyl group by a Michael-type addition to the ^Δ1,2-3 -ketosteroid. That is, the subsequent formation of the desired 5,6-double bond is made difficult by the tendency to remove the 1α-hydroxyl group in the β position relative to the carbonyl group, whereas the formation of the desired 5,6-double bond using known techniques is Specificity of 3-keto groups to 3-β-
Reduction to hydroxy groups is also difficult. The synthetic route to 1α-hydroxycholesterol has been described by Berg et al. (J.Chem.
Soc., 1970(c)1624). This involves epoxidation of 6β-hydroxy-5α-cholest-1-en-3-one, reduction of the product to 1,2-epoxy-3β-hydroxy derivatives using sodium borohydride, and removal of the 6β-hydroxyl group. formation of the corresponding △ ^5,6 steroid by and 1α by reduction with lithium aluminum hydride,
Including the production of 3β-diol. However, the products obtained by this method do not exhibit the expected physical properties. In other words, the optical rotation is [α] _D 0
±1° (in methanol). ^Δ5,6 sterols, on the other hand, are usually characterized by a fairly substantial negative specific rotation, typically around -30°.
Also, the actual elemental analysis values of C76.2% and H11.1% are also available.
Calculated value for C ₂₇ H ₄₆ O ₂ , 1/2H ₂ O (C78.8%,
H11.5%) does not match. The structure of this product must therefore clearly be considered questionable. One possible source of this error is borohydride reduction of the 3-keto group, which results in the desired
In addition to 3β-ol, significant amounts of 3α-ol can be produced. A somewhat similar synthetic route to the steroid precursor for 1α,25-dihydroxycholecarferol has been described by De Luca et al. [see Tetrahedron Letters 40 , 4147 (1972)]. These researchers have used appropriate steroid-1-ene-3
Epoxidation of -one-6-(ethylene ketal) and subsequent reduction of this product with lithium aluminum hydride produced a mixture from which only the 1α,3β-diol could be separated. Several additional steps, including oxidation to the 3-one and reduction with sodium borohydride, are therefore necessary to produce the 1α,3β-diol, after which the 6-ketal group is removed and the 6-hydroxyl group is removed. The compound can be reduced and dehydrated to produce the ^Δ5,6 -steroid, making the overall route somewhat cumbersome. Therefore, there is a need for a simpler process for preparing 1α,3β-dihydroxysteroid-5-enes that allows easy control of the stereochemistry of the product, especially in the 3-position, and It is an object of the present invention to provide such a method. Other objects, advantages, and features of the invention will be apparent from the following detailed description and claims. The essence of the invention is that 1α-hydroxy- and 1α,
2α-epoxy-steroid-4,6-diene-
The corresponding 6-substituted steroid-4-en-3-ones in which the 3-one and 6-substituents are reductively removable atoms or groups are reacted with alkali metal/liquid ammonia or alkali in the presence of a proton source. By reaction with a metal/liquid amine reducing agent, the directly corresponding 1α,3β-dihydroxysteroid-5
The discovery lies in the fact that it can be reduced to −ene. Under these conditions, the highly oxidized starting material undergoes a series of reductions, essentially involving double bond isomerization or removal of the substituent in the β-position of the 3-carbonyl group. The desired product is obtained without any oxidation. This method uses 1α-hydroxylated vitamin D
It is particularly applicable to the production of cholestane-based 1α-hydroxysteroids, which are precursors for derivatives. "Cholestane" as used herein
The expression refers to steroids having the _C8 chain characteristic of cholestane at position 17, as well as analogues in which this chain is unsubstituted or has one or more hydroxy or methyl groups. inclusive, these are the 17-side chains found in vitamin D. Such as Kolestan type
A suitable ketone starting material for the production of 1α-hydroxysteroids has the formula [In the formula, R ¹ represents a hydroxyl group and R ² represents a hydrogen atom, or R ¹ and R ² together represent an epoxide group.

[Formula], R ³ represents a reductively removable atom or group and R ⁴ represents a hydrogen atom, or R ³ and R ⁴ together form a carbon-carbon double bond. and
R ⁵ is based (In the formula, R ⁶ and R ⁷ each represent a hydrogen atom or a hydroxyl group, or together form a carbon-carbon double bond or an epoxy group, and R ⁸ and R ¹⁰ are the same or different and each represents a hydrogen atom or a hydroxyl group. represents an atom or a hydroxyl group, and
R ⁹ represents a hydrogen atom or a methyl or ethyl group]. Reduction of a compound of formula by the method of the invention results in [In the formula, R ⁵ is as defined for the formula]
A 1α,3β-diol is produced which can be represented by: 1α,3β-dihydroxy-25-H-cholesto-
5-ene and its hydroxyl protected derivatives are new compounds. Reductively removable substituents which may be present in the 6-position of the starting material, such as the R ³ group of the formula, include, for example, halogen atoms such as fluorine, chlorine or bromine atoms and hydrocarbon sulfonate groups such as aromatic hydrocarbons. Sulfonate groups such as p-tosylate or aliphatic hydrocarbon sulfonate groups such as mesylate groups may be mentioned. Alkali metals that can be used in reducing agents include:
Mention may be made of lithium, calcium, sodium and potassium, with lithium being the preferred metal. Liquid amines that can be used include, for example,
primary, secondary and tertiary alkylamines, such as primary lower alkyl amines such as methylamine or ethylamine, di(lower alkyl)amines such as dimethylamine or diethylamine, and tri(lower alkyl)amines such as triethylamine, diamines such as lower Mention may be made of alkenediamines such as ethylene diamine or propylene diamine, and saturated heterocyclic amines such as piperidine or piperazine. Particularly preferred reducing agents are lithium and liquid ammonia. Proton sources that can be used during the reaction include ammonium and amine salts, such as salts derived from mineral acids, such as halides such as fluorides or chlorides, nitrates or sulfates. Alcohols such as lower alkanols such as methanol or ethanol can also serve as a proton source. This reduction is conveniently carried out in a solvent, preferably an inert organic solvent such as a cyclic ether such as tetrahydrofuran or dioxane or a hydrocarbon solvent such as hexane. It may be advantageous to remove moisture and/or oxygen from the reaction system. If a solvent is used, this reduction is conveniently carried out at a temperature between the freezing point of the solvent system and 100°C.
Advantageously, it is carried out cold. Various addition schemes can be used to bring these reaction components together. Thus, for example, a solution of the steroid can be added in one or more portions to a solution of the alkali metal in liquid ammonia or a liquid amine, and then the proton source can be added in one or more portions. Alternatively, improved yields and/or easier isolation of reduced steroids may be achieved by first adding a proton source such as solid ammonium chloride to a solution of the steroid starting material and then using an alkali metal/liquid ammonia or liquid amine reducing agent. This can be achieved by adding small amounts of It is generally preferred that the 1α-hydroxy group in the steroid starting material be protected, for example with a cleavable protecting group. The reason is that reduction of steroids with free 1α-hydroxyl groups results in the formation of Δ ^6,7 -steroids as a result of internal proton transfer. Suitable protecting groups include silyl groups such as tri(lower alkyl)silyl groups such as trimethylsilyl. Such protecting groups can be introduced, for example, by reacting a 1α-hydroxysteroid with a suitable hexa(lower alkyl)disilazane. The 1α,3β-dihydroxysteroid-5-enes obtained by the process of the invention can be prepared, for example, by conventional techniques such as N-bromoamides, imides or hydantoins such as N-bromosuccinimide, N-
By brominating the 7-position using bromophthalimide or dibromodimethylhydantoin as the brominating agent, followed by dehydrobromination using, for example, an amide such as dimethylacetamide in the presence of an alkaline earth metal carbonate. ,Equivalent to
It can be converted into 1α,3β-dihydroxysteroid-5,7-diene. Or again,
This dehydrobromination can also be induced by treatment with trimethylphosphite or bases such as uridine, pyridine or diazabicyclooctane. The 7,8-double bond can also be oxidized using methods such as Dopine, e.g. 1α,3β-dihydroxysteroid-5-ene, using a chromium trioxide oxidizer, preferably a chromium trioxide/pyridine complex. to give the corresponding steroid-5-en-7-one and convert this ketone into a sulfonylhydrazine, preferably an aromatic sulfonylhydrazine, e.g. p-
tosylhydrazine to form the corresponding 7-sulfonylhydrazine, which is then subjected to Wolff-Xiyuner reduction conditions using, for example, an alkali metal alkoxide such as sodium tert-butoxide and an alkali metal halide such as sodium hydride to form the desired compound. 5,7-
It can also be introduced by forming a diene. In order to avoid undesired side reactions during the series of reactions necessary to introduce the 7,8-double bond, the 1α- and 3β- It may be advantageous to protect the hydroxy group. This steroid 5,7-diene obtained from the treatment of a compound of formula by any of the above techniques is
formula [In the formula, R ⁵ is as defined for the formula]
It can be expressed as 1α,3β-dihydroxy-25-H-cholesto-
5,7-dienes and their hydroxyl protected derivatives are new compounds. Irradiating such a compound of formula with near-ultraviolet light, preferably of a wavelength of e.g. 275-300 nm, firstly [In the formula, R ⁵ is as defined for the formula]
Promotes the production of 1α-hydroxylated previtamins, which can be expressed as: Further irradiation or treatment with iodine under mild conditions, e.g. at relatively low temperatures using small amounts of iodine, gives the corresponding formula [In the formula, R ⁵ is as defined for the formula]
promotes the conversion of 1α-hydroxytaxerol derivatives. This can be optionally reduced with eg lithium/liquid ammonia or sodium/liquid ammonia to provide novel 1α-hydroxy-
9,10-dihydrotachysterol derivatives can be produced. This 1α-hydroxy-9,
10-dihydrotachysterol itself is a novel compound and constitutes one embodiment of the present invention. Compounds of this formula also have the formula [In the formula, R ⁵ is as defined for the formula]
and which can be converted into such vitamin derivatives by heating in an alcohol or hydrocarbon solvent, for example. This vitamin has the cis form as shown in the formula. The formation of undesirable oxidation by-products during this conversion can be minimized, for example by converting to a 1,3-diacetoxy derivative, by esterifying its 1α- and 3α-hydroxy groups. can. This vitamin () can be converted into the corresponding 5,6-transvitamin derivative, if desired. Isomerization of the 5,6-double bond is easily promoted, for example, by treatment with iodine under mild conditions. That is, 1α, 3β produced by the present invention
It is clear that -dihydroxysteroid-5-enes are valuable intermediates in the synthesis of a wide range of biologically useful substances. The starting material for the reduction process of the present invention can be prepared by any convenient method, e.g. by converting the appropriate 3-hydroxysteroid-5-ene into
quinone by oxidation using an oxidizing agent such as dichlorodicyanoquinone, followed by treatment with a peroxide such as hydrogen peroxide with a base such as sodium hydroxide, conveniently in an aqueous alcoholic medium.
It can be produced by producing 1α,2α-epoxide. This can be converted if desired to the corresponding 1α-hydroxy compound, for example by reduction with zinc and an acid such as acetic acid. The present invention also provides novel compounds such as 1α-hydroxy 25-H-vitamin D derivatives, especially 1α-hydroxyvitamin _D2 and 1α-hydroxyvitamin D2.
Includes _D3 . The present invention provides vitamin (cis)
and corresponding trans compounds.
These vitamins are not only superior in their vitamin activity to vitamin D ₂ and vitamin D ₃ , but also superior to the known 1α,25-dihydroxyvitamin D compounds in their vitamin activity. Thus, for example, 1α-hydroxy-25-H compounds exhibit a much more active effect on bone metabolism. Tests in the vitamin D ₃ series have shown that 1α-hydroxy-25-H vitamin D ₃ is 10-50 times more active than unsubstituted vitamin D ₃ ;
On the other hand, 1α,25-dihydroxyvitamin _D3 has been shown to be only 2-5 times more active than the unsubstituted vitamin. These results are particularly unexpected in view of previous suggestions that the 25-hydroxy group is involved in metabolism and therefore should be activity-promoting. These new 1α-hydroxy-25-H-vitamin D compounds are also fast-acting and their biological activity is rapidly terminated, so that the problems of vitamin toxicity hitherto encountered are substantially eliminated. by using them. 1α-Hydroxy-25-H-vitamin D compounds, together with 1α-hydroxy-9,10-dihydrotachysterol, have the ability to stimulate, inter alia, intestinal calcium circulation, bone calcium mobilization, bone mineralization and bone formation. Pharmaceutical compositions which constitute an important new group of chemically active substances and which contain effective amounts of one or more of these compounds and procedures in human and veterinary medicine involving their administration. The method constitutes a further aspect of the invention. Said compounds have important prophylactic and therapeutic uses in the prevention and treatment of diseases such as rickets and osteomalacia, and these include vitamin D-responsive diseases such as hypoparathyroidism, It is of value in the treatment of hypophosphatemia, hypocalcemia and/or associated bone disease, renal disease or failure, and hypocalcemic tetany. In addition, native 1α-H vitamin D
compared to the compounds 1α-hydroxy-25-H-vitamin D and 1α-hydroxy-9,10
- The superior activity of dihydrotachysterol is associated with vitamin D-resistant rickets, renal osteodystrophy, steatorrhea, cirrhosis caused by liver, renal or gastrointestinal dysfunction. Not treatable for other resorptive dysfunctions, osteoporosis, secondary hypocalcemia and/or bone diseases, and for dilantins, barbiturates (e.g. phenylbarbitone) and related common compounds e.g. vitamin _D3 It has been proven that. This makes this 1α-hydroxy compound valuable for the treatment of secondary hypocalcemia or bone disease resulting from drug treatment. Generally, 1α-hydroxy-25-H-vitamin D compounds and 1α-hydroxy-9,10-taxerol are carried out in injectable liquid carriers such as sterile pyrogen-free water, sterile peroxide-free ethyl oleate, It can be administered parenterally in combination with dehydrated alcohol, propylene glycol or dehydrated alcohol/propylene glycol mixtures. Injectable compositions are preferably prepared in dosage unit form, such as ampoules;
Each unit advantageously contains from 0.1 to 200 μg, preferably from 0.2 to 20 μg, of the active vitamin component in the case of vitamin D ₂ and D ₃ compounds. Taxisterol compounds require dosages in the higher part of this range. Usual dosages for adult treatment generally range from 0.1 to 200 μg per day, with lower doses within this range, e.g. 0.1 to 2 μg, being used for prophylaxis, and higher doses, e.g. 5 to 50 μg.
is used for therapeutic purposes. 1α-Hydroxyvitamin D compounds and 1α-
Because of the susceptibility of hydroxy-9,10-dihydrotachysterol to oxidation, pharmaceutical compositions containing these substances should generally contain at least trace amounts of antioxidants such as ascorbic acid, butylated hydroxyanisole or hydroquinone. It is preferable. The inventors have surprisingly discovered that 1α-hydroxyvitamin D compounds and 1α-hydroxy-
It has also been discovered that 9,10-dihydrotachysterol exhibits significant activity upon oral administration. 1α
-Hydroxyvitamin _D3 is remarkable in this regard. This is completely unexpected in view of previous disclosures regarding 1α,25-dihydroxyvitamin _D3 . Previous disclosures have shown that oral administration of this dihydroxyvitamin has very low activity (as determined by e.g. antirickets activity measurements) and that parenteral administration of dihydroxyvitamin achieves effective therapeutic results. This shows that it is necessary for this purpose. In view of the similarity in the properties of the biological activity of the compounds in other respects,
It is generally expected that 1α-hydroxyvitamin D compounds will exhibit similar general behavior to the corresponding dihydroxyvitamins. However, oral administration of serum calcium and phosphorus levels in epithelial resection/thyrotomy rats (these were male Charles River rats weighing 80-100 g, and each test group consisted of 6 rats). Administered 1α-hydroxyvitamin _D3 and 1α,25-dihydroxyvitamin
The following table showing the effect of D ₃ (0.1 μg/Kg, intragastric intubation) shows that 1α-hydroxyvitamin D ₃ Orally administered 1α,25-dihydroxyvitamin _D3 is relatively inactive and does not significantly alter serum calcium levels when compared to controls. It is shown that. This table also shows that the metabolic changes induced by 1α-hydroxyvitamin _D3 are relatively short-lived;
The results show that serum calcium levels in 1α-hydroxyvitamin D3 _- treated rats become very close to that of control rats within 24 hours after vitamin administration. This means that 1α-hydroxyvitamin
This ensures that D ₃ is rapidly removed from the system and therefore has no possibility of producing unwanted vitamin toxicity side effects.

Table: The oral activity of 1α-hydroxyvitamin _D3 and its ease of administration make this compound of very important therapeutic value with a wide range of applications, and the known parenteral administrable
This considerably enhances the utility of this compound compared to 1α,25-dihydroxyvitamin D derivatives. The new 1α-hydroxy compounds can be used as food supplements or as components of food supplements, for example in combination with other vitamins. An example of such a use is in the fortification of milk. 0.1 to 1 quart of milk
The incorporation of 0.5 μg of 1α-hydroxyvitamin D ₃ is of prophylactic value, for example in the prevention of rickets, osteomalacia and other diseases. Similarly, this new 1α-hydroxy compound is
A wide range of applications, such as any of the vitamin D-responsive diseases or otherwise any 1α-
Orally administrable pharmaceutical compositions for the treatment of diseases that are hydroxyvitamin D responsive but difficult to treat with conventional vitamin D, especially for long-term treatment and prophylactic applications of diseases such as osteoporosis. It can be provided as a (multi)vitamin preparation. Orally administrable compositions containing the novel 1α-hydroxy compounds can optionally be prepared using one or more physiologically acceptable carriers and/or
Or it may contain excipients, which can also be solid or liquid. The compositions can be used, for example, as tablets, coated tablets, capsules, sweetened tablets, aqueous or oily suspensions, solutions, emulsions, syrups, elixirs and for reconstitution with water or other suitable liquid vehicles before use. It can take any convenient form, including a suitable dry product. The composition is preferably manufactured in dosage unit form, but
Each unit is advantageously 0.2 to 20 μg, preferably 0.5 to 5 μg
g of 1α-hydroxy compound. The dosage of 1α-hydroxyvitamin _D3 used for adult treatment is typically 0.2 to 20μ per day.
g range. 1α-hydroxy-vitamin D ₂
is administered in similar doses, but 1α-hydroxy-9,10-dihydrotachysterol is given in higher doses, for example up to 200 μg/day. Tablets and capsules containing the novel 1α-hydroxy compounds can optionally contain conventional ingredients such as binders such as syrup, acacia, gelatin,
sorbitol, tragacanth or polyvinylpyrrolidone, fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch or as acceptable. Wetting agents such as sodium lauryl sulfate may also be included. The tablets can be coated by methods well known in the art. The liquid 1α-hydroxyvitamin D ₃ composition is
Customary additives such as suspending agents such as sorbitol syrup, methylcellulose, glycose/sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats,
Emulsifiers such as lecithin, sorbitan monooleate or acacia, non-aqueous vehicles which may include edible oils such as vegetable oils such as peanut oil, almond oil, fractionated coconut oil, fish liver oil, oily esters such as polysorbate 80, propylene glycol or ethyl alcohol, and preservatives. eg methyl or propyl p-hydroxybenzoate or sorbic acid. Liquid compositions can be conveniently encapsulated in gelatin, for example, to provide the product in dosage unit form. The compositions of the invention may contain other therapeutically active ingredients such as calcium salts (e.g. lactate, sodium salt of lactic acid, phosphate, gluconate or hypophosphite).
and/or salts of other essential trace elements such as magnesium, manganese, iron, copper, zinc and iodine and/or other vitamins such as vitamin A, vitamin B ₁ , vitamin B ₂ , nicotinamide, pantothenic acid or its salts. For example, it may contain calcium salts, vitamin B ₆ , vitamin B ₁₂ folic acid, vitamin C and vitamin E. Multivitamin formulations containing this new 1α-hydroxy compound can be formulated in a similar manner to vitamin formulations using conventional 1-H vitamin D compounds. The activity of this new 1α-hydroxy compound also makes it suitable for rectal administration and for this purpose e.g.
Pharmaceutical compositions containing 1α-hydroxyvitamin D ₃ in a conventional suppository base, such as a mixture with cocoa butter or other glycerides, are within the scope of this invention. As mentioned above, it may be advantageous to incorporate antioxidants such as ascorbic acid, butylated hydroxyanisole or hydroquinone into the composition of the invention in order to increase its shelf life. The activity of the 1α-hydroxyvitamin compounds according to the invention when administered orally makes them valuable in veterinary applications. For example, the above-mentioned compounds can be incorporated into animal and livestock feeds for prophylactic purposes and therefore according to the invention 1α-hydroxy-25-H-
A livestock or poultry feed composition is provided containing a vitamin D compound, particularly 1α-hydroxyvitamin D ₃ or 1α-hydroxy-9,10-dihydrotachysterol. Animal feed according to the foregoing embodiments of the invention may be prepared by adding the vitamin compounds as described above in a conventional manner, for example to solid feed such as animal cake or to granular mineral supplements (e.g. flour, corn flour, soybean flour, limestone, essential minerals, etc.). It can be manufactured by mixing with feed supplements such as supplements containing ingredients such as trace element sources and other vitamins. The vitamins mentioned above can be applied in any form that allows their homogeneous distribution in the feed. For example, the vitamin compound can be applied dissolved in water or a suitable organic solvent (eg ethanol), after which the solvent can be removed from the feed if desired. Furthermore, antioxidants such as ascorbic acid, butylated hydroxyanisole or hydroquinone may also be added to improve the storage stability of the vitamin-containing feed. Said vitamins may also be applied in solid form (eg crystalline solids) and are preferably mixed intimately with the feed to ensure homogeneous distribution. The solid vitamin may be first coated with an antioxidant, such as those mentioned above, or adsorbed onto a substrate such as ground limestone or chalk by known methods, if desired, to enhance its stability. Good too. Furthermore, in certain applications it may be advantageous to use the vitamin compounds mentioned as a component of preparations that would otherwise be nothing more than ordinary multivitamin preparations. Typical supplements for preventive purposes are 0.1 to 2.0 μg per pound of supplement.
(~0.2 to 4.5 μg/Kg) of vitamins, especially 1α-
Will contain hydroxyvitamin D ₃ . This supplement is recommended for livestock such as dairy cows and pigs.
Feed at a rate of ~20 lbs (22-44 Kg)/animal/day. An important application of animal feeds containing 1α-hydroxyvitamin D- and 1α-hydroxy-9,10-dihydrotachysterol is in the prevention of hypocalcemia in livestock such as cows, especially cows, at or near calving. be. 1α-Hydroxyvitamin D ₃ is particularly valuable in this regard. This is because the high activity and low toxicity of this compound makes it possible to administer it prophylactically at low doses over long periods of time to groups of animals, including, for example, animals without a history of hypocalcemia. It is. This is in contrast to the traditional use of vitamin D compounds in this field. Because of the high drug doses required when using compounds such as vitamin _D3 , for economic reasons among others, it has traditionally been customary to administer said vitamins only to animals with a previous history of hypocalcemia. Because it was hot. Yet another application of the vitamin-containing feed according to the above-described aspect of the invention is in the prevention or treatment of milk fever in dairy cows. That is, said feed is fed to cows before calving for prophylactic purposes, and the vitamin content preferably ranges from 10 to 10% of vitamin absorption (preferably 1α-hydroxyvitamin D ₃ ).
The amount is 200 μg (for example, 15 to 100 μg)/day. Feed compositions for poultry according to the above-described aspects of the invention can generally be manufactured using the technical procedures described for animal feeds above. Compositions containing 1α-hydroxyvitamin _D3 are preferred, with typical vitamin levels ranging from 0.2 to 12 μg (e.g. 1 to 8 μg).
g)/Kg of feed. Said vitamins can be added to any conventional poultry feed composition, such as grain flour, soybean flour, fish meal, corn flour, meat and bone scraps,
It can be added to the composition consisting of one or more ingredients selected from Distillas solubulus, essential trace element sources and other vitamins. It has been found that administration of a poultry feed composition according to the invention, in particular a composition containing 1α-hydroxyvitamin _D3 , to poultry at the time of laying reduces the tendency of the poultry to produce soft shell eggs. The feed composition for this application contains a source of calcium, such as ground limestone or oyster shells, to aid mineralization of the eggshells, and the calcium level of the feed desirably ranges from about 2.5 to 5.5% by weight; Preferably it is 3 to 4%. The invention further provides 1α-hydroxy-25-H-vitamin D compounds, especially 1α-hydroxyvitamin D ₃
for example, in a content of from 0.2 to 12 micrograms, preferably from 1 to 8 micrograms, of the vitamin per kg of feed. Novel 1α-hydroxy-25-H-vitamin D
Animal applications of the compounds and 1α-hydroxy-9,10-dihydrotachysterol include the prevention of hypocalcemia in livestock such as cattle, especially cows at or near calving. 1α-Hydroxyvitamin D ₃ is particularly valuable in this regard. This is because the high activity and low toxicity of this compound makes it possible to administer it prophylactically at low doses over long periods of time to groups of animals, including for example animals without a history of hypocalcemia. be. This is in contrast to the traditional use of vitamin D compounds in this field.
This is because, due to the high doses required when using compounds such as vitamin _D3 , it has traditionally been customary, especially for economic reasons, to administer this vitamin only to animals with a history of hypocalcemia. This is because it was hot. Furthermore, 1α-hydroxy-25-H-vitamin D
It has been found that administering an effective dose of a compound, particularly 1α-hydroxyvitamin _D3 , to livestock at the time of production is effective in reducing the tendency of the livestock to produce soft shell eggs. Such measures also constitute another feature of the invention. The invention is further illustrated by the following detailed examples. All temperatures are in degrees Celsius. Reference Example 1 (a) Cholester 1,4,6-trien-3-one Cholesterol (19.3g) and dichlorodicyanoquinone (38g) were mixed with dry dioxane (500g).
ml) under reflux for 22 hours. The mixture was then cooled, filtered and the liquid was evaporated to dryness. The residue was chromatographed on alumina and eluted with benzene/hexane followed by benzene to give the title trienone as a pale oil (11.5 g).
This solidified when left to stand. The physical properties of this material were appropriate. (b) 1α,2α-Epoxycholest-4,6-dien-3-one The trienone (1 g) from (a) above was dissolved in ethanol (50 mg) at 0° with 10% aqueous sodium hydroxide (0.25 ml). and 30% _{aqueous H2O2} (2.5ml)
Processed with. The mixture was kept at 5° overnight, then the resulting epoxide was separated, washed with aqueous alcohol and dried to give the title compound (0.86 mg). Recrystallization from ethanol gave colorless needle crystals mp 107-109°. (c) 1α,3β-dihydroxycholest-5-ene To a stirred solution of liquid ammonia (80 ml) containing ammonium chloride (0.5 g) and metallic lithium (0.2 g) in dry tetrahydrofuran (50 ml) was added dry tetrahydrofuran (25 ml). ) in which a deoxygenated solution of the epoxide (4.3 g) from (b) above was added dropwise. When the blue color disappears,
The steroid addition was stopped and more lithium (0.2 g) and ammonium chloride (1 g) were added, then the epoxide solution was added again.
This series of operations was repeated until all the steroid had been added. At this point, additional pieces of lithium (0.2g, 0.8g total) were added, then more ammonium chloride (8g total)
g) was added. Most of the ammonia was then evaporated and the remaining mixture was poured into ice water and extracted with chloroform. The chloroform was concentrated to give a brown gummy material. This was chromatographed on aluminum oxide (160g). Elution with ethyl acetate/benzene gave the 1α,3β-diol as a glass-like material. This quickly crystallized upon addition of ethanol. Recrystallization from aqueous ethanol yielded the title compound (1.7 g) m.
p.161.5-163° was obtained. Actual value C80.40,
H11.39%, calculated value ( _{C27H46O2 )} C80.54 _,
H11.52%. Reference Example 2 (a) 1α-Hydroxycholester-4,6-dien-3-one Epoxydienone from Reference Example 1(b) (130 mg)
was treated with zinc dust (1 g) with stirring in ethanol (10 ml) and then 3 drops of acetic acid were added.
The mixture was then filtered and the liquid was concentrated to dryness. Chromatography on silica gel gave cholester 1,4,6-trien-3-one, which could be recovered and recycled, and then the title compound. λ _nax 3600, 3400, 1675, 1625 and 1590cm
^-1 . δ6.15 (2 protons S, H6, H7), 5.73 (1
Proton singlet, H4), δ4.15 (1 proton, thin multiplet, H1). (b) 1α,3β-dihydroxycholest-5-ene Hydroxydienone (0.6 g) from (a)
A solution in tetrahydrofuran (2 ml) and pyridine (2 ml) was dissolved in hexamethyldisilazane (1.5 ml) and trimethylchlorosilane (0.6 ml).
ml) to its trimethylsilyl ether. This crude trimethylsilyl ether was dissolved in tetrahydrofuran (10
ml) and this solution was added dropwise to a stirred solution of lithium metal (approximately 200 mg) in liquid ammonia (20 ml). After a few minutes ammonium chloride (2g) was added and the mixture was stirred. Additional lithium metal (approximately 100mg)
added. The solution was stirred again. Additional ammonium chloride was then added and the mixture was poured into cold water. The product was isolated by extraction with ether and methylene dichloride followed by column chromatography to give the title compound. When crystallized from ethanol, its mp was 158-161°. After recrystallization, its MP was 161.5-163°. [α] _D (CHCl ₃ ) −38°. This material is identical to the product of Reference Example 1(c), and upon hydrogenation it produces a 1α, identical in all respects to the standard sample.
A sample of 3β-dihydroxy-5α-cholestane was obtained. Reference example 3 (a) 1α,3β-dibenzoyloxycholest-5
-Ene 1α,3β-dihydroxycholest-5-ene (1.2g) in pyridine (10ml) containing dimethylaminopyridine (20mg) was treated with benzoyl chloride (5ml). After standing overnight at room temperature, the reaction mixture was poured into water and the product was extracted with ether, washed with dilute aqueous hydrochloric acid, saturated sodium bicarbonate solution and water. Evaporation of the ether part yields dibenzoate (1.6
g) mp147-150° was obtained. When recrystallized from ethanol, the product had a melting point of 151-153°. [α] _D +24°. Analysis calculation value (C ₄₁ H ₅₄ O ₄ ) C80.61%, H8.91%, actual value
C80.43, H8.74%. (b) 1α,3β-dibenzoyloxycholester-5,
A solution of the dibenzoate described in 7-Diene (a) (0.58g) in hexane (10ml) was treated with dibromodimethylhydantoin (0.15g) and heated under reflux for 25 minutes. After cooling, the mixture was filtered and the liquid was concentrated to a pale oil. This oil was dissolved in dry xylene (3ml) and this was dissolved in trimethylphosphite (0.4ml) in xylene (5ml).
ml) dropwise to the refluxing solution. Heating under reflux was continued for 1.75 hours. After this time the solvent was removed under reduced pressure and the residue was crystallized from acetone/methanol to give the title compound. After recrystallization from ethanol/acetone,
This product had a melting point of 161-162°.
[α] _D −8°. Analysis calculation value (C ₄₁ H ₅₂ O ₄ ) C80.88%,
H8.61% Actual value C80.69%, H8.66%. (c) 1α,3β-dihydroxycholesta-5,7-
Ethanol (30ml) containing diene KOH (0.6mg)
and the dibenzoate (300 mg) from (b) dissolved in water (0.5 ml) and kept at 80° for 0.5 h under an argon atmosphere. The reaction mixture was then cooled, diluted with water and extracted with ether.
Evaporation of the ether extract gave the title compound as a crystalline solid. Recrystallization from methanol gave a product with mp 155-158°. λ _nax (ethanol) 263 (7700), 272
(11000), 282 (11900), 295 (7000) nm. Example 1 1α, 3β in deoxygenated ether (200 ml)
-dihydroxycholester-5,7-diene (95
mg) of toluene (24 mg) per methanol for 12 minutes.
ml) and CS ₂ (4 ml) using a 200 watt Hanobia lamp surrounded by a strained solution. The cold solution was transferred to a flask filled with argon and the ether was removed at 0°. The residue was deoxidized with absolute alcohol (8
ml) and heated under reflux for 1.5 hours. Biological assays performed using vitamin D-deficient chicks show that the 1α-hydroxyvitamin _D3 [λ _nax 264 (19000)] produced is characterized by a very rapid onset of physiological activity (less than 3 hours). However, this has been tentatively shown to be 1α,
This has only been observed for the natural product characterized as 25-dihydroxyvitamin _D2 . Reference example 4 1,3-dipropionic acid ester of 1α-hydroxyvitamin D ₃ (a) 1α,3β-dipropionoxy-cholester-5,
7-Diene 1,3-dipropionic acid ester of 1α-hydroxycholesterol (130 mg) was treated with dibromatine (44 mg) in hexane (4 ml).
This material was irradiated with a 275 Watt solar lamp for 35 minutes at 74°C. The reaction mixture was cooled on ice and filtered. The filtrate was concentrated and dissolved in xylene (1 ml). A xylene solution containing the crude bromide was mixed with trimethyl phosphite (0.5 ml) in xylene (1.5 ml) at 133-140°C.
ml) solution dropwise. the solution for 2.5 hours 133~
It was maintained at 140°C. The reaction mixture was concentrated and subjected to chromatography as follows. Silica gel impregnated with 5% (by weight) silver nitrate was mixed with Celite (4 g:1 g). The column was eluted with hexane (100 ml), 2% diethyl ether in hexane (300 ml), 3% diethyl ether in hexane (100 ml), and 4% diethyl ether in hexane (100 ml). 10 ml of fraction was collected. Fractions 33-49 contained the title 5,7-diene and its 4,6-diene isomer (13 mg). Fraction 50~
60 is relatively pure 5,7-diene (4 mg)
Contained. Fractions 33 to 49 were combined and rechromatographed on the column prepared as above, in hexane (100 ml), 2% diethyl ether in hexane (100 ml), 3% diethyl ether in hexane (100 ml). ), eluted with 4% diethyl ether in hexane (100ml).
A 10ml fraction was collected. Fraction 31~
45 is relatively pure 5,7-diene (11 mg)
Contained. (b) 1α-Hydroxyprevitamin D ₃ 1,3-
Dipropionic acid ester 1α,3β-dipropionoxy-cholesta-5,7-diene (15 mg) prepared in (a) above was dissolved in diethyl ether (400 ml) at Hanobia intermediate pressure.
It was irradiated with a UV lamp at -28 to -30°C for 3 to 4 minutes. The diethyl ether was evaporated and the crude product was dissolved in hexane and applied to a chromatography column prepared as described above. The column was washed with hexane, 1% diethyl ether in hexane,
Elution was carried out with 100 ml each of 2% diethyl ether in hexane, 3% diethyl ether in hexane and 4% diethyl ether in hexane.
Fractions 28-32 are pure title compounds (λ _nax
262; 2.5 mg). When treated with iodine, the moiety underwent conversion to the corresponding tachysterol. Fractions 33-34 are the title compound
1α,3β-dipropionoxy-cholester-4,
It contained a mixture with 6-diene. Fractions 35 to 43 are 5, corresponding to the above 4,6-diene.
7-diene. Fractions 44-49 contained pure 5,7-diene starting material. (c) 1,3-dipropionic acid ester of 1α-hydroxyvitamin D ₃ The previtamin (1 mg) obtained in (b) above was dissolved in isooctane (1 ml), and this was heated at 75°C in argon for 1 hour. . The isooctane was evaporated and the product was dissolved in hexane and applied to a small silica gel chromatography column prepared by packing silica gel into a 5 cm high Pasteur pipette. The column was diluted with hexane (15
ml) and 1% diethyl ether in hexane (30ml), collecting 1.5ml fractions. Fractions 18-19 contained previtamin starting material that was not isomerized. Fraction 21
~22 contained the title compound (λ _nax 264.5, λ _nio 229). The part treated with iodine corresponds to 5,
6-transvitamin λ _nax 271, λ _nio 238). Reference example 5 (a) 1α-hydroxycholesterol bistrimethylyl ether 1α,3β-dihydroxycholest-5-ene (1.0 g) and N-trimethylsilylimidazole
10 ml was added, and the mixture was heated and stirred at 90° under a nitrogen stream.
After cooling, hexane was added and the mixture was washed twice with saturated brine. After drying over anhydrous sodium sulfate, it was filtered and concentrated. The obtained crude product was purified with 30 g of silica gel column chromatography, and the yield was 1.26 g (yield:
93%) of the desired product was obtained. As spectrum is
564 showed M ⁺ . (b) 1α,3β-bistrimethylsilyloxycholester-5,7-diene 1α-hydroxycholesterol bistrimethylsilyl ether (0.55 g) in hexane (10
ml) solution was treated with dibromomethylhydantoin (0.15g) and heated under reflux for 25 minutes.
After cooling, the filtrate was concentrated. The resulting residue was dissolved in dry xylene (3ml) and this solution was added dropwise to a refluxing solution of trimethylphosphite (0.4ml) in xylene (5ml). Heated at reflux for 1.75 hours after which time the solvent was removed under reduced pressure.
Careful purification was performed using 30 g of silica gel column chromatography to obtain 0.23 g (42% yield) of the target compound. Mass spectrum showed M ⁺ at 544. (c) 1α-Hydroxyvitamin D _{3bistrimethylsilyl} ether 1α,3β-bistrimethylsilyloxycholester-5,7-diene (230mg) deoxygenated with benzene (500ml) and ethanol (100ml)
dissolved in This solution was irradiated for 19 minutes using a 200 W Hanobia lamp surrounded by a Vycor filter. The reaction temperature was 18°C. This solution was then heated to reflux for 3.5 hours.
After completion of the reaction, the reaction solution was concentrated, and the resulting crude product was purified by silica gel thin layer chromatography (developed twice with hexane-benzene solvent) to obtain 85 mg of 1α-hydroxyvitamin D ₃ bistrimethylsilyl ether. I got it. The ultraviolet absorption (EtOH) was λ _nax ×265 nm and λ _nio 22 nm. Mass spectrum showed M ⁺ at 544. (d) 1α-hydroxyvitamin D ₃ 1α-hydroxyvitamin D ₃ bistrimethylsilyl ether (50 mg) was dissolved in anhydrous tetrahydrofuran (5 ml), tetra-n-butylammonium fluoride (100 mg) was added, and under a nitrogen stream,
The mixture was treated in a cool, dark place for 5 hours. Water was added, extracted with ethyl acetate, and washed twice with saturated brine. It was dried over anhydrous sodium sulfate and overconcentrated. The obtained crude product was purified by silica gel thin layer chromatography (developed twice with a solvent: benzene-ethyl acetate system) to obtain 29 mg of the desired product. The melting point is
141-142℃, UV absorption (EtOH) is λ _nax 265n
m, λ _nio was 228 nm. The mass spectrum is
M ⁺ was shown at 400, and peaks were also shown at 382, 364, 251, and 134. Reference Example 6 Orally administrable 1α-hydroxyvitamin D ₃ composition (a) 1α-hydroxyvitamin D ₃ capsule A low-purity composition containing 1α-hydroxyvitamin D ₃ as an antioxidant and 0.1% w/w butylated hydroxyanisole. Dissolution of the oxide in sterile peanut oil resulted in a solution with a vitamin concentration of 40 μg/ml. 1/4 ml aliquots of this solution obtained were encapsulated in gelatin by conventional techniques. The dosage is 1-2 capsules per day. Capsules were similarly prepared by the method described above from each of the solutions containing 1α-hydroxyvitamin D ₃ in an amount of 20 μg/ml. (b) Tory vitamin preparations Tablets containing the following ingredients are manufactured by conventional techniques. Vitamin A 4000 usp units Vitamin C 75 mg 1α-Hydroxyvitamin D ₃ 0.2-1 μg The preparation may optionally also contain 1 mg of fluorine as a physiologically acceptable fluoride salt. (c) Deca-vitamin preparation (for adults) Tablets containing the following ingredients are manufactured using conventional techniques. Vitamin A 25000usp unit Vitamin B ₁ 10mg Vitamin B ₂ 10mg Vitamin B ₆ 5mg Vitamin B ₁₂ 5mg Vitamin C 200mg 1α-Hydroxyvitamin D ₃ 0.2-1μg Vitamin E 15IU Calcium pantothenate 20mg Nicotinamide 100mg This tablet may also contain 1mg Fluorine as a physiologically acceptable fluoride salt and/or as a physiologically acceptable salt of a mineral complex containing the following elements: copper 2 mg, iodine 0.15 mg, iron 12 mg, magnesium 65 mg, manganese 1 mg, zinc 1.5 mg. It may be contained in the form of The dosage is one tablet per day. (d) Deca-vitamin formulation (infancy and pediatric use) Tablets containing the following ingredients are manufactured by conventional techniques: Vitamin A 5000 usp units Vitamin B ₁ 5 mg Vitamin B ₂ 5 mg Vitamin B ₆ 2 mg Vitamin B ₁₂ 10 μg Vitamin C 100 mg 1α-Hydroxyvitamin D ₃ 0.2-1 μg Calcium pantothenate 3 mg Nikonamide 30 mg This tablet may be physiologically acceptable. It may also contain fluoride salts or mineral complexes in amounts listed in (c) above. The dosage is one tablet per day. (e) Poultry feed composition 400 mcg of 1α-hydroxyvitamin D ₃ is dissolved in ethanol (100-500 ml) and the resulting solution is slurried with 2 Kg of crushed limestone. The ethanol is then removed under reduced pressure while stirring the slurry, and the resulting vitamin-containing solid is added to the poultry feed at a rate of 20 g/Kg of feed. (f) Fortified feed supplement for dairy cows, pigs and other livestock 50 μg of 1α-hydroxyvitamin D ₃ is dissolved in 500 ml of ethanol and the resulting solution is slurried with 500 g of powdered Dolomite limestone. Next, ethanol was removed from the slurry while stirring under reduced pressure, and the resulting vitamin-containing solid was converted into a standard granular mineral supplement (45.5Kg).
Mix with 100lb. The gist of the present invention and specific examples of embodiments are listed below, all of which are included within the scope of the present invention. 1 1α-hydroxy-25-H-previtamin D
Or, a method for producing 1α-hydroxy-25-H-vitamin D or its acylate, which comprises isomerizing the acylate by heating to produce a desired vitamin D compound. 2 Previtamin D is 1α-hydroxy-25-H
- The method ₃ according to the above item 1, wherein the previtamin D is 1α-hydroxy-25-hydroxy-previtamin D ₃ 1α,3β-diacetate. Method. 4 The isomerization is carried out by heating in an alcohol or hydrocarbon solvent,
The method described in any of Section 3. 5. The method according to item 1, wherein cis-1α-hydroxy-25-H-vitamin D is treated with iodine to effect isomerization to the corresponding trans isomer. 6 1α-hydroxy-25-H-previtamin D
1α,3β-dihydroxycholester corresponding to
The method according to any of the above items, which is produced by irradiating 5,7-diene or its acylate. 7. The method of item 6 above, wherein the irradiation is carried out in an ether solvent. 8 1α-hydroxy-25-H-previtamin D
7. The process according to claim 6, wherein the corresponding 1α-hydroxy-25-H-taxerol derivative is obtained by further irradiating or iodine treatment. 9. The method according to item 8, wherein the 1α-hydroxy-25-H-taxisterol derivative is subjected to reduction to produce the corresponding 1α-hydroxy-9,10-dihydrotachysterol derivative. 10. The method of claim 9, wherein the reduction is carried out using lithium or sodium in liquid ammonia. 11 1α,3β-dihydroxycholester-5,7-
1α corresponding to diene or its acylate,
A process according to any preceding clause, produced by dehydrogenation of 3β-dihydroxycholest-5-ene. 12 dehydrogenation is carried out by bromination followed by dehydrobromination of the brominated product;
The method according to item 11 above. 13 Dehydrogenation corresponds to 1α,3β-dihydroxycholest-5-ene or its acylate
1α,3β-dihydroxycholest-5-ene-
7-one or its acylate, which is then reacted with a sulfonylhydrazine to form the corresponding 7-sulfonylhydrazone;
12. The method according to item 11, which is carried out by subsequently reducing the 5,7-diene to produce the desired 5,7-diene. 14 Corresponding 1α-hydroxy- or 1α,2α-
Epoxy-steroid-4,6-diene-3-
1α-hydroxy- or 1α,2α-epoxy-steroid-4-enes or their 1α-protected hydroxyl derivatives with a 6-position or easily removable substituent in ammonia or an alkali metal in a liquid amine in the presence of a proton source. or 1α,3β-dihydroxysteroid-5- subjected to reduction with alkaline earth metals.
A method for producing ene or its 1α-protected hydroxyl derivative. 15. The method according to item 14, wherein the metal is lithium, sodium, potassium or calcium. 16. The method according to paragraph 14 or 15, wherein the liquid amine is a primary, secondary or tertiary alkyl amine or a lower alkylene diamine or a saturated heterocyclic amine. 17. The method according to any of paragraphs 14 to 16, wherein the proton source is ammonium or amine salt or alcohol. 18. The method according to any of paragraphs 14 to 17, wherein the reduction is carried out in the presence of an inert organic solvent. 19 The starting material is a 1α-silyloxy derivative,
19. The method according to any one of items 14 to 18 above. 20. The method according to any one of items 14 to 19 above, wherein the easily removable group at the 6-position is a halogen atom or a hydrocarbon sulfonate group. 21. According to any of the preceding paragraphs 14 to 20, if the target product has free hydroxyl groups in the 1α- and/or 3β-positions, such hydroxyl groups are converted into acyloxy groups. Method. 22 The above-mentioned steroid is cholestene.
The method according to any of paragraphs 14 to 21. 23 The cholesten has one or more hydroxyl groups or alkyl groups in the side chain at position 17, or has a double bond at position 22,
The method according to item 22 above. 24. The method according to item 23, wherein the _C8 chain at position 17 of cholestene is unsubstituted or has a 25-hydroxyl group. 25 The 1α-hydroxy steroids used as starting materials are produced by reduction of the corresponding 1α,2α-epoxy steroids,
The method described in any of the paragraphs. 26. The method according to paragraph 25, wherein the reduction is carried out with a zinc/acid reducing agent. 27 1α,2α-Epoxy steroid corresponds to 1,
27. The method according to item 25 or 26, which is produced by reacting a 2-dehydrosteroid with a peroxide. 28. The method according to paragraph 27, wherein the peroxide is hydrogen peroxide in the presence of a base. 29 3- corresponding to 1,2-dehydrosteroid
29. The method according to item 27 or 28, which is produced by oxidation of hydroxysteroid-5-ene. 30. The method according to paragraph 29, wherein the oxidation is carried out using dichlorodicyanoquinone. 31 1α-Hydroxyvitamin D and its acylate. 32 1α-Hydroxyvitamin D ₃ . 33 1α-Hydroxyvitamin D ₃ in crystalline form. 34 1α-Hydroxyvitamin D ₃ without isomeric impurities. 35 When recrystallized from ether-pentane, 4
1α-Hydroxyvitamin D ₃ having a melting point of 132-133° C. at a heating rate of 1° C. per second and a λ264nm/λ229nm ratio of 1.87. 35' 1α-Hydroxy-5,6-trans-vitamin _D3 . 36 1α-Hydroxy-9,10-dihydrotachysterol. 37 1,25-dihydroxycholesterol. 38 1α,3β-Dihydroxy-25-H-cholesta-5,7-diene and its ethers and acylates. 39 1α,3β-dihydroxy-cholesta-5,7
-Dienes and their diacetates. 40 Crystalline forms of 1α,25, including the chloroform solvate of _1,25- dihydroxyvitamin D3
-Dihydroxyvitamin _D3 . 41 1-Hydroxy-25-H-vitamin D compounds and 1α-hydroxy-25-H-9,10-
A vitamin-containing composition containing an effective amount of an active ingredient selected from the group consisting of dihydrotachysterol. 42. The composition according to item 41 above for oral administration. 43. The composition according to paragraph 41, wherein the active ingredient is 1α-hydroxyvitamin _D3 . 44. According to any of paragraphs 41 to 43 above, containing 0.1 to 1.0 μg of 1α-hydroxyvitamin D compound and further containing other active ingredients selected from essential trace elements and vitamins. Composition of. 45. A composition according to any of the preceding paragraphs 41 to 43 in the form of a dosage unit containing 0.2 to 20 μg of 1α-hydroxyvitamin _D3 . 46. A composition according to paragraph 45 in the form of a dosage unit containing 0.5 to 5 μg of 1α-hydroxyvitamin _D3 . 47. A composition according to any of paragraphs 41 to 46, further comprising calcium and phosphorus in physiologically effective forms. 48 Vitamin D deficiency diseases and related diseases by administering an effective dose of 1α-hydroxy-25-hydrogen-vitamin D or 1α-hydroxy-25-hydrogen-9,10-dihydrotachysterol to humans or animals. How to treat or prevent 49. A method for treating and preventing rickets by administering 0.1 to 1.0 μg of 1α-hydroxy-vitamin D ₃ per day to an individual. 50 A method for treating or preventing vitamin D-resistant rickets by administering 0.1 to 20 μg of 1α-hydroxyvitamin D ₃ per day to an individual. 51 A method for treating vitamin D-resistant hypocalcemia and/or bone disease by orally administering 0.2 to 20 μg of 1α-hydroxyvitamin D to a human individual. 52 A method for treating vitamin D-resistant hypocalcemia and/or bone disease by orally administering 1 to 5 μg of 1α-hydroxyvitamin D ₃ to an individual. 53. The method according to item 51 or 52, wherein the hypocalcemia is hypoparathyroidism, post-surgical hypocalcemia, renal osteodystrophy, liver cirrhosis, or steatorrhea. 54. A method for treating osteoporosis by administering to an individual an effective daily dose of 1α-hydroxyvitamin _D3 . 55. The method according to item 54, wherein the daily dose is 0.2 to 20 μg of 1α-hydroxyvitamin _D3 . 56 A method for preventing hypocalcemia in whole animals at or about to give birth, wherein 1α-hydroxyvitamin D ₃ is administered to the animal before birth. 57. The method of paragraph 56, wherein the 1α-hydroxyvitamin D ₃ is administered to a domestic animal that has no previous history of hypocalcemia. 58 A method for preventing the formation of soft shell eggs by poultry, comprising administering to the poultry an effective dose of 1α-hydroxyvitamin _D3 . 59 0.2 to 12 micrograms of 1α− per kg of feed
Livestock feed containing hydroxyvitamin _D3 . 60 Milk fortified with 1α-hydroxyvitamin D ₃ with a content of 0.1-0.5 micrograms per liter.

Claims (1)

[Claims] 1 formula 1α,3β-dihydroxycholesta-5,
The formula consists of irradiating the 7-diene with light in the wavelength range of 275 nm to 300 nm. A method for producing 1α-hydroxy previtamin _D3 having 2 formulas 1α,3β-dihydroxycholesta-5,
7-Diene is irradiated with light in the wavelength range of 275 nm to 300 nm, and the formula producing 1α-hydroxy previtamin D ₃ having the formula and isomerizing it to give the formula and producing 1α-hydroxyvitamin _D3 having the above formula.
Method for producing 1α-hydroxyvitamin _D3 .