KR810000199B1 - Process for the preparation of 5,6-cis and 5,6-trans-10,19-dihydro-vitamin d derivatives - Google Patents

Abstract

Title 5,6-cis and 5,6-trans-10,19-dihydro-vitamin D derivatives were prepd. by the catalytic hydrogenation of the corresponding vitamin D derivs. in the presence of ligand-coordinated homogeneous transition metal catalyst. Thus, the hydrogenation of vitamin D3 over tris(triphenylphosphine)-rodium chrolide gave 10,19-dihydro-5,6-cis-vitamin D3.

Description

Method for preparing 5,6-cis- and 5,6-trans-10,19-dihydro-vitamin D derivatives

The present invention relates to 5,6-trans-10,19-dihydro-vitamin D compounds (ie, 9,10-dihydrotachisterol compounds) and corresponding methods of preparing 5,6-cis-isomers.

The 10,19-dihydro-vitamin D compound is closely related to vitamin D compounds having methyl groups instead of the methylene group at the C-19 position in vitamins, for example, maintenance of serum calcium and prevention of rickets during epithelial dysfunction. It is useful in medicine for a variety of purposes, including the treatment of dystonia, osteoporosis, osteoporosis and similar vitamin D-reactive diseases. In general, they are more stable than the vitamin D compounds themselves and are less sensitive to oxidation.

However, in the past, the preparation of such 10,19-dihydro-vitamin D compounds has proved to be a difficult task, since previous methods tended to produce mixtures of isomers that were difficult to separate. Thus, for example, attempts to selectively reduce the C-19 methylene group of a vitamin D compound using an Adams catalyst or a conventional catalyst such as platinum or palladium on charcoal may result in cis-trans-isomerism for 5,6-double bonds. As well as other double bonds being reduced resulting in an isomer mixture. The method of reducing the triene system to a metal dissolved in an amine also provides a mixture of other dihydrovitamin D isomers, although it is commercially useful for the preparation of dihydrotachisterol. Furthermore, both of these methods yielded significantly lower yields when applied to 1α-hydroxy vitamin D compounds, as shown in British Patent No. 1443585, because the hydrogenation of C-19 methylene groups is also to some extent 1α-hydroxy groups. This also led to reductive removal of.

It is an object of the present invention to provide a novel and advantageous method for preparing 10,19-dihydro-vitamin D compounds that are 5,6-trans- or 5,6-cis-coordinated.

The inventors can easily convert the vitamin D compound to the corresponding 10,19-dihydro vitamin D compound by hydrogenating the vitamin D compound in the presence of a ligand-coordinated homogeneous transition metal catalyst. Figured out. Thus, 10,19-dihydro-vitamin D derivatives can be easily obtained in a relatively good yield from vitamin D compounds which are relatively changeable.

According to a preferred feature of the present invention, the present invention provides 5,6-cis-, characterized by converting the C-19 methylene group of the vitamin D compound to a methyl group by hydrogenating the corresponding vitamin D compound in the presence of a ligand-coordination homogeneous transition metal catalyst. And 5,6-trans-10,19-di hydro-vitamin D derivatives.

The metal component of the catalyst used in the aforementioned method is advantageously selected from Group VIII of the periodic table, with rhodium and ruthenium being preferred. The metal is conveniently used in the form of a salt, for example a halide such as chloride.

The transition metal is advantageously coordinated with a trisubstituted phosphine ligand, with the substituent on the phosphine molecule being preferably an alkyl (eg C _1-8 ) group or an aromatic (eg phenyl) group, which may be substituted as desired. . Triphenylphosphine is preferred as the ligand, and the transition metal is advantageously coordinated with three molecules of ligand per metal atom.

Particularly preferred catalysts for use in the process of the invention are tris- (triphenylphosphine) rhodium chloride.

Hydrogenation is generally carried out in an organic medium containing one or more organic solvents, such as for example hydrocarbons such as benzene or alkanols such as ethanol. Hydrogenation can conveniently be carried out at ambient temperature.

The foregoing method applies to the preparation of the corresponding 5,6-cis-derivatives as well as the 10,19-dihydro-5,6-trans-vitamin D derivatives (ie 9,10-dihydrotachisterol derivatives). The 10,19-dihydro-vitamin D derivatives that can be prepared by the novel method preferably have a 17-side chain of the general formula:

Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom or a hydroxy or protective hydroxy group or together form a carbon-carbon bond or an epoxy group, and R ³ and R ⁵ are the same or different and are each hydrogen An atom or hydroxy or a protective hydroxy, and R ⁴ represents a hydrogen atom or a methyl or ethyl group.

The 10,19-dihydrovitamin D compounds which can be prepared by the novel method can thus be represented, for example, by the general formula:

(Wherein R ⁶ represents a 17-side chain as defined above)

The compounds of the general formulas 1A and 1B may have different ring substitutions and generally have a hydroxy or protective hydroxy group at the 3-position. This compound may have a hydroxy or protective hydroxy group in the 1-position and is preferably in the α-coordination. Protective hydroxyl groups present in the molecule include, for example, an acyloxy group (e.g., an alkanoyloxy group having 1-6 carbon atoms or an aroyloxy group having 7-10 carbon atoms) or an ethyl group (e.g., Silyloxy groups such as trimethylsilyloxy groups).

Although such protective forms are generally physiologically active, free hydroxy group forms are preferred for use in medicine. If the hydroxyl-protected vitamins are hydrogenated, the protecting groups may subsequently be deprotected, for example by conventional methods. Thus, the acyloxy group can be removed by basic hydrolysis, for example using an alkali metal alkoxide in alkanol. The silyloxy group can be removed by acid hydrolysis.

The general formulas 1A and 1B represent 5,6-trans and 5,6-cis forms, respectively.

The novel methods of the present invention include 10,19-dihydro-cis and 5,6-trans-vitamin D ₂ and D ₃ ; And particularly useful for the preparation of 1α-hydroxy-substituted and 1α, 25-dihydroxy-substituted derivatives thereof.

As a result of the hydrogenation of the 5,6-cis vitamin D compounds according to the process of the invention described above, for example, 10 containing anti-isomers and syn-isomers (ie corresponding epi-compounds) Heterogeneous mixtures of, 19-dihydro-vitamin D compounds can be produced, which generally consist mostly of anti-isomers. As used herein, the terms “cinine” and “antianthine” are intended to indicate the comparative configuration of 3-hydroxy and 19-methyl groups. Similarly, the hydrogenation of 5,6-trans vitamin D can result in the formation of hetero- and anti-compound isomeric mixtures. In general, the latter compound (9,10-zihydrotachisterol) is responsible for the major portion of the mixture. Form. Thus, for example, hydrogenation of vitamin D ₃ (5,6-cis) according to the present invention may produce a mixture of compounds of the formula

On the other hand, hydrogenation of 5,6-trans-vitadine D ₃ can produce a mixture of a compound of the following formula.

Group R in the above formulas represents vitamin D ₃ 17-side chain.

Similarly, hydrogenation of 1α-hydroxy-vitamin D ₃ (5,6-cis) according to the present invention may produce a mixture of compounds of the formula

On the other hand, hydrogenation of 5,6-trans 1α-hydroxy vitamin D ₃ can produce a mixture of a compound of the following formula.

Group R in the above formulas represents vitamin D ₃ 17-side chain.

In the above formulas the 1- and 3-hydroxy groups can be protected, for example as acetoxy groups. However, when anti-isomers are desired, it has been found to use unprotected 1α-hydroxy vitamin D.

Hydrogenation catalysts have been shown to complex with 1-hydroxy groups, leading to much slower reactions than when 1-hydroxyl was protected, but to more stereospecific reductions to antiisomers. This finding does not extend to 1-desoxy compounds.

If desired, the epimeric mixtures obtainable by this method can be separated by conventional blubber, such as by chromatography. However, if desired, a mixture of neo- and anti-compounds may be used in medical or veterinary applications where individual isolated isomers are not essential.

The method according to the invention is particularly suitable for the production of anti-epimers of 1α-hydroxy-10,19-dihydro-5,6-trans vitamin D ₃ and the latter epimers are relatively high compared to the corresponding shin-epimers. Can be obtained in yield.

When 10,19-dihydro-5,6-trans-vitamin D compounds (ie 9,10-dihydrotachisterol compounds) are required, the corresponding 5,6-trans-vitamin D compounds used as starting materials For example, the corresponding 5,6-cis-vitamin D compounds can be prepared by isomerization by treatment in an organic solvent such as iodine, preferably hexane.

The following specific compounds are novel and can be prepared according to the present invention:

1) Sin- and anti-epimer of 10,19-dihydro-5,6-cis-1α-hydroxy-vitamin D ₃

Neo-isomers of 10,19-dihydro-5,6-trans-1α-hydroxy-vitamin D ₃ and mixtures of one or more thereof

2) syn- and anti-epimers of 10,19-dihydro-5,6-cis and 5,6-trans-1α, 25-dihydroxy-vitamin D ₃ , and one or more mixtures of such analogs

The neo-epimer of 1α-hydroxy-10,19-dihydro-5,6-cis-vitamin D ₃ exhibits a particularly rapid increase in serum calcium concentrations in rats, indicating that the compound can be used to treat vitamin D disorders. Of special value in medical therapy.

The present invention extends especially to such compounds when a double bond other than a C-19 methylene group is separated from the reduced hydrogenated vitamin D compound.

It has been found that these new compounds and mixtures have significant practical advantages over corresponding vitamin D compounds in that they tend to be more stable, less sensitive to oxidation and less sensitive to acid-catalysed allylic dehydration. lost.

The novel compounds and mixtures thereof have vitamin D-like activity and above all are important for biological activity with the ability to stimulate intestinal calcium transport, bone calcium metabolism, bone mineralization and bone formation. It constitutes a novel class of substances and also enables the treatment of pharmaceutical compositions containing an effective amount of one or more of these compounds or mixtures thereof and treatment in humans and veterinary medicine with their administration.

This novel compound and mixtures thereof, particularly those having hydroxyl groups at the 1α-position, have significant prophylactic and therapeutic effects in preventing or treating disorders such as rickets and osteomalacia, epithelial dysfunction, hypophosphatemia, and low calcium. It is of value for the treatment of vitamin D reactivity and vitamin D resistant diseases such as hypertension or associated bone diseases, kidney disorders or renal failure and hypocalcemia tetany. Further, the activity of these novel compounds and mixtures and the rapid onset and end of activity similar to 1α-hydroxy-vitamin D ₃ may be due to cumulative toxicity where vitamin D cannot be used, in particular vitamin D-resistant Grow disease, necrobiosis, fat Etiology, biliary cirrhosis and other malabsorption, osteoporosis, bone disease or secondary hypocalcemia due to liver, kidney, or gastrointestinal dysfunction, and steroids such as corticoids, diphenylhydantoin, phenyl Value for treating disorders that have proven to be untreatable to conventional compounds such as vitamin D ₃ as secondary hypokalemia, osteoporosis or other bone diseases resulting from treatment with barbiturates such as barbitone and related drugs There is.

In general, the novel compounds and mixtures thereof are parenterally, in combination with liquid carriers for injection such as pyrogen-free sterile water, peroxide-free sterilization, such as ethyl lesate, dehydrated alcohol, alcohol propylene glycol or dehydrated alcohol / propylene glycol mixtures. Can be administered. Such compositions may be injected intravenously, intraperitoneally or intramuscularly. Injectable compositions are preferably prepared in unit dosage form, such as ampoules, each unit advantageously containing 0.02-200 μg, preferably 0.1-200 μg, more preferably 0.02-20 μg; Sin- (ie epi-) compounds generally require 2-3 times the capacity of the corresponding anti-compound. Normal dosages for adult treatment generally use a daily dose in the range of 0.O2-200 μg, preferably 0.1-200 μg, and for prophylaxis low doses within this range, eg 0.02-5 μg, Preferably 0.1-2 μg is used and high doses such as 5-50 μg are used for therapeutic applications.

If desired, the pharmaceutical composition may contain an antioxidant such as ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene or hydroquinone.

The novel compounds and mixtures thereof can be used, for example, in combination with other vitamins as food supplements or as components of food supplements. Such food supplements or components thereof may, for example, be mixtures of novel 10,19-dihydro-vitamin D derivatives, for example 5,6-trans- or 5,6-cis 1α-hydroxy or 1α, 25-dihydroxy It may contain an epimeric mixture of 10,19-dihydro analogs of -vitamin D ₃ .

The novel compounds and mixtures thereof also have a wide range of applications as desired, for example the treatment of conventional vitamin D treatment refractory diseases of the aforementioned vitamin D reactivity or 1α-hydroxy vitamin D reactivity, in particular for long-term treatment of diseases such as osteoporosis and Pharmaceutical compositions for oral administration may be provided for prophylactic applications such as vitamins and multivitamin preparations.

Oral pharmaceutical compositions containing novel compounds may, if desired, contain one or more physiologically acceptable carriers or excipients and may be solid or liquid. The composition may be in a convenient form including, for example, tablets, tablets, capsules, lozenges, aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, and dry products suitable for reforming with water or other suitable liquid medium prior to use. It can manufacture. The composition is preferably prepared in unit dosage form, with each unit advantageously containing 0.02-20 μg, preferably 0.2 μg, more preferably 0.5-5 μg of a novel compound. Tablets and capsules containing the novel compounds may optionally contain binders such as syrup, acacia, gelatin, sorbitol, tragicanth or polyvinyl-pyrrolidone; Excipients 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 conventional ingredients such as acceptable wetting agents, such as sodium lauryl sulfate. Purification can be avoided according to methods well known in the four seasons. Liquid compositions include suspending agents, such as sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose, carboxymethyl cellulose, aluminum stearate or hydrogenated edible fats; Emulsifiers such as lecithin, sorbitan monooleate or acacia; Non-aqueous media which may include edible oils, such as peanut oil, ton oil, vegetable oils such as fractionated coconut oil, oily esters such as polysorbate 80, propylene glycol or ethyl alcohol; Preservatives may contain conventional additives such as, for example, P-hydroxybenzoic acid methyl or propyl or sorbic acid. Liquid compositions can conveniently be encapsulated in gelatin, for example, to form a unit product.

Compositions according to the present invention may comprise calcium salts (e.g., lactates, sodium lactates, phosphates, gluconates or hypophosphites) or salts of other essential trace elements such as magnesium, manganese, iron, copper, zinc and iodine or vitamin A, Other useful therapeutic ingredients such as vitamin B ₁ , vitamin B ₂ , nicotinamide, pantothenic acid or salts thereof (such as calcium salts), vitamin B ₆ , vitamin B ₁₂ , hydrochloric acid, vitamin C and non-amine E can do. Complex vitamin preparations incorporating the novel compounds can be formulated in a similar manner to vitamin preparations using conventional 1-hydrovitamin D compounds. Depending on the type intended to be used, the composition may also contain, for example, steroids such as prednisolone or beta metason, such as anti-inflammatory steroids, or estrogens such as methylstilbestrol, 17α-ethynylestradiol, estrone, estradiol, es Triol and conjugated quinine estrogens).

The activity of the novel compounds also makes them suitable for rectal administration, and for this purpose, pharmaceutical compositions may be used in which an effective amount of a novel compound is mixed with a conventional suppository such as cocoa butter or other glycerides.

As noted above, it is advantageous to incorporate an antioxidant such as, for example, ascorbic acid, butylated hydroxyanisole or hydroquinone into the compositions of the present invention to increase shelf life.

The following examples illustrate the invention in detail.

Example 1

Hydrogenation of Vitamin D ₃

A solution of tris (triphenylphosphine) rhodium chloride (925 mg) dissolved in ethanol (35 ml) / benzene (35 ml) was hydrogenated and stirred for 30 minutes. The next vitamin D ₃ (384 mg) was added and hydrogenation continued for 140 minutes during which about 1 mole of hydrogen was consumed by the substrate. The solvent was then removed under reduced pressure, and the residue was triturated with methylene chloride and filtered to wash the red insoluble filtrate twice with a small amount of methylene chloride. The filtrates were combined and evaporated to dryness and chromatographed to give two products: the main product, the anti-epimer (292 mg) of 10,19-dihydro-5,6-cis-vitamin D ₃ , was the starting material (vitamin). It was a pale yellow oil with a slightly larger Rf value. In order to measure the properties of this substance, it was treated with paranitrobenzoyl chloride (200 mg) in anhydrous pyridine. After 24 hours, an additional 100 mg of acid chloride was added. The aqueous phase was taken and chromatographed to give paranitrobenzoate and crystallized from acetone / methanol. Melting point is 55-60 ° UVλ max ether: (ε = 32,300), 243 (ε = 42,500, 250.5 (ε = 47,500), 260 (ε = 34,200)

Analytical Value: Theoretical value for C ₃₄ H ₄₉ NO ₄ : C, 76.22: H, 9.22: N, 2.61%

Found: C, 76.54: H, 9.18: H, 2.68%

The by-product of hydrogenation, ie, the neo-epimer (71 mg) of 10,19-dihydro-5,6-cis-vitamin D ₃ , had a slightly smaller Rf than the vitamin and treated in the same way to produce paranitrobenzoate. Got it. Melting point is 143-144. 5 ° UVλ max ether: 236.5 (ε = 30,200, 243 (ε = 43,000), 251 (ε = 53,200), 260.5 (ε = 43,600).

Analytical Value: Theoretical value for C ₃₄ H ₄₉ NO ₄ : C, 76.22: H, 9.22: N, 2.61%

Found: C, 76.46: H, 9.22: N, 2.76%

Example 2

[Hydrogenation of 5,6-trans Vitamin D ₃ ]

Iodine (2 mg) was added to a solution of vitamin D ₃ (750 mg) dissolved in hexane (20 ml). After stirring for 1 h at 20 ° the solution was washed with aqueous sodium thiosulfate solution and water and dried over sodium sulfate. After removing the solvent, chromatography was carried out to give trans-vitamin D ₃ (460 mg).

A mixture of 5,6-trans-vitamin D ₃ (400 mg) and tris (triphenylphosphine) rhodium (1.0 g) in benzene (35 ml) / ethanol (35 ml) was hydrogenated as in Example 1. After the same operation as in Example 1, the material was chromatographed to obtain approximately the same amount of two products. The less polar product, ie the neo-epimer (10 epi-dihydrotachisterol, 193 mg) of 10,19-trans-vitamin D ₃ , had the following physical constants.

UVλ max 242 (0.86), 250.5 (1.0), 260 (0.67), numbers in parentheses are comparative absorbances. This was treated with paranitrobenzoyl chloride as in Example 1 to give paranitrobenzoate. Melting point solidified as 45-60 ° and remelted at 79-80 °.

Analytical Value: Theoretical value for C ₃₄ H ₄₉ NO ₄ : C, 76.22: H, 9.22: N, 2.64%

Found: C, 76.35: H, 9.09: N, 2.61%

In all respects the second product of hydrogenation (203 mg) identified as 9,10-dihydrotachisterol (ie, 10,19-dihydro-5,6-trans-vitamin D ₃ ) was higher than the parent vitamin. Slightly smaller polarity.

Example 3

[Hydrogenation of 1α-hydroxy Vitamin D ₃ Diacetate]

1α-hydroxy vitamin D ₃ diacetate (22 mg) in ethanol (4 ml) / benzene (4 ml) containing tris (triphenylphosphine) rhodium chloride (42 mg) was hydrogenated as in Example 1. After operation as in Example 1, the residue was chromatographed on a thin plate to obtain two products as described above. The more polar main product (18.5 mg) showed UVλ max 236.5 (0.64), 342.5 (0.88), 251 (1.00) and 260.5 (0.67).

Byproducts (4.2 mg) showed UVλ max 236 (0.66), 242 (0.88), 250.5 (1.00), 259. 5 (0.68). Each extinction coefficient at 251 nm was approximately 40,000. The main and by-products were anti- and syn-epimers of 10,19-dihydro-1α-hydroxy-5,6-cis-vitamin D ₃ diacetate, respectively. The main and by-products were each hydrolyzed by treatment with KOH in 0.5% methanol at 20 ° for 2.5 hours.

Example 4

[Isomerization of 1α-hydroxyvitamin D ₃ to Trans-1α-hydroxyvitamin D ₃ Diacetate and Hydrogenation thereof]

1α-hydroxyvitamin D ₃ diacetate (55 mg) was operated as in Example 2 to obtain 5,6-trans-1α-hydroxyvitamin D ₃ diacetate (30 mg). UVλ max 273 nm was dissolved in ethanol (5 ml) / benzene (5 ml) containing tris (triphenylphosphine) rhodium chloride (60 mg) and hydrogenated as in Example 1. The more polar main product, 1α-hydroxy dihydrotachisterol diacetate (17 mg), was isolated from the more polar byproduct, 10-eth-dihydro-1α-hydroxydihydrotachisterol diacetate (10 mg). . As before, when hydrolyzed with KOH / methanol, the main product of diacetate is 1α-hydroxy 9,10-dihydrotachisterol (ie, 10,19-dihydro-5,6-trans-1α-hydroxy vitamin D ₃ anti-epimer), which showed the same melting point 175.5-178 °, α _D + 71 ° as the real sample. By-products during hydrolysis are amorphous oils 10-epi-1α-hydricsi-9,10-dihydrotachisterol (ie, 10,19-dihydro-5,6-trans-1α-herdoxy-). Vitamin D ₃ ) was formed.

UVλ max 237 (0.65), 243.5 (0.86), 251.5 (1.0), 261 (0,67)

Example 5

[Hydrogenation of 1α, 25-dihydroxy Vitamin D ₃ ]

A solution of 1α, 25-dihydroxy vitamin D ₃ (128 mg) was treated with iodine as in Example 2. After 20 minutes at room temperature, the reaction was carried out as in Example 2. It was not possible to separate the vitamins into cis- and trans-isomers by chromatography, but crystallized from methylene chloride and twice more from ethanol to give 5,6-transvitamin (22 mg). This material dissolved in ethanol (5 ml) benzene (5 ml) containing UV lambda max 273 nm tris (triphenylphosphine) rhodium was hydrogenated as in Example 1. The more polar main product, 1α, 25-dihydroxy 9,10-dihydrotachysterol (ie, 10,19-dihydro-5,6-trans-1α, 25-di, was operated as in Example 1). Anti-epimer of hydroxy-vitamin D ₃ ) and less polar byproducts, 1α, 25-dihydroxy 10-epi-9,10-dihydrotachisterol (ie, 10,19-dihydro-5) , 6-trans-1α, 25-dihydroxy-vitamin D3 syn-epimer).

Example 6

[Hydrogenation of 5,6-trans-1α-hydroxy-vitamin D ₃ ]

5,6-trans-1α-hydroxy-vitamin D ₃ (41 mg) dissolved in benzene (8 cc) and ethanol (8 cc) containing tris- (triphenylphosphine) rhodium (1.05 molecule equivalent) was stirred overnight with stirring. Exposed to hydrogen. Anti-epimer of 10,19-dihydro-5,6-trans-1α-hydroxy-vitamin D ₃ (1α-hydroxy-9,10-dihydrotaquistitol) as in Example 1 35 mg and 8-14% of the shin-epimer were obtained.

The following examples illustrate pharmaceutical adjustments or veterinary compositions according to the present invention. Unless otherwise stated, references to 1α-hydroxy-10,19-dihydrovitamin D ₃ and 1,25-dihydroxy-10,19-dihydro vitamin D ₃ are given to syn- and anti-, cis- and Either a trans-epimer or a mixture thereof.

Where 1a-hydroxy-10,19-dihydrovitamin Da is specified, it may be substituted with 1,25-dihydroxy-10,19-vitamin D3.

Example 7

Compositions for Oral Administration

(a) capsules

1α-hydroxy-10,19-dihydrovitamin D ₃ was dissolved in sterile peanut oil containing less peroxide containing 0.1% W / W butylated hydroxyanisole as an antioxidant to obtain a vitamin solution of 40 μg / ml concentration. 1/4 ml portion of the resulting solution is encapsulated in gelatin by conventional techniques. Dose-1-2 capsules daily

In addition, by the above method, a capsule is prepared in a solution containing 2.Og / ml and 4.Og / ml of 1α-hydroxy-10,19-dihydro-vitamin D ₃ , respectively.

(b) tri-vitamin preparations

Tablets containing the following ingredients are prepared by conventional techniques:

0.2-1 μg of 1α-hydroxy-10,19-dihydrovitamin D ₃ . The formulation may also optionally contain 1 mg of fluorine as a physiologically acceptable fluoride salt.

Capacity-1 tablet daily

(c) Deca-Vitamin Formulation (Adult)

Tablets containing the following ingredients are prepared by conventional techniques:

0.2-lμg of 1α-hydroxy-10,19-dihydroxyl vitamin D ₃

The tablet may also optionally contain an inorganic complex comprising 1 mg of fluorine as the physiologically acceptable complex salt and / or the following element in the form of a physiologically acceptable salt:

Capacity-1 tablet daily

Example 8

[Poultry Dietary Composition]

40 μg of 1α-hydroxy-10,19-dihydro-vitamin D ₃ is dissolved in ethanol (100-500 ml) and the resulting solution is slurried with 2 kg of crushed limestone. Next, ethanol is removed under reduced pressure while stirring the slurry, and the resulting tachysterol-containing solid is added to the feed at a rate of 20 g per kg of poultry feed.

If desired, mixtures of 10,19-dihydro-vitamin D ₃ compounds can be used in the compositions. Such mixtures may for example consist of mixtures of cis- and trans-compounds as well as epimer mixtures of such compounds.

The side right dietary composition can be prepared by a method similar to the poultry diet.

Example 9

[Capsules]

20 μg 1α-hydroxy-10,19-dihydro-vitamin D ₃

100ml peanut oil

100 mg butylated hydroxytoluene

5g micronized prednisolone usp

The ingredients are mixed in a high speed equalizer and filled with 1000 0.1 ml gelatin capsules containing 0.02 μg vitamin D ₃ compound and 5 mg steroid, respectively. One to four capsules are administered daily.

A similar composition can be prepared by replacing prednisoline with 0.6 g betamethasone.

Example 10

[Capsules]

20 μg 1α-hydroxy-10,19-dihydro-vitamin D ₃

100ml peanut oil

100mg Butylated Hydroxytoluene

20mg 17α-ethyniloestradiol

The ingredients are mixed in a high speed equalizer and filled into 1000 0.1 ml gelatin capsules containing 0.02 μg vitamin D ₃ compound and 0.02 mg steroid, respectively. 1-3 capsules daily.

Example 11

[Capsules]

Capsules each containing the following ingredients were prepared as in Example 4.

0.25 μg 1α-hydroxy-10,19-dihydro-vitamin D ₃

0.25mg ethyl steel

0. O1mg Butylated Hydroxytoluene

0.1ml peanut oil

1-4 capsules daily

Example 12

[refine]

0.67 mg 1α-hydroxy-10,19-dihydro-vitaman D ₃ and 0.1 g butylated hydroxytoluene are dissolved in 5 ml ethanol and 5 g lactose is added. The solvent was removed and the powder was mixed with 192.75 g lactose, 1.Og stearic acid and 1.25 g conjugated Equine Estrogen USP to tablet 1000 tablets of 200 mg. 1-3 tablets daily.

Claims (1)

5,6-cis- and 5 by converting the corresponding vitamin D compound to a methyl group by hydrogenating the corresponding vitamin D compound in the presence of a phosphine ligand-coordinating periodic table Group VIII transition metal catalyst trisubstituted with an alkyl or aromatic group. To prepare a 6-trans-10,19-dihydro-vitamin D derivative.