JPH02288854A - 1alpha, 25-dihydroxylated vitamin d2 - Google Patents

Abstract

NEW MATERIAL: A compound represented by formula I (wherein K is O, ethylenedioxy; R₁, R₂ are each H, an acyl) or by formula II.

EXAMPLE: 1α-25-Dihydroxy-24-epivitamin D₂ wherein K is ethylene-dioxy.

USE: A precursor of 1α,25-dihydroxylated compounds of the vitamin D₂ series such as 1α,25-dihydroxyvitamin D₂ and (24R)-epimer thereof, etc.

PREPARATION: A vitamin D-ketal derivative of formula III (wherein R is H, tosyl) is subjected to solvolysis in an alcoholic medium to form a novel compound of formula IV (wherein Z is CH₃) and this compound is added to a CH₂Cl₂ solution containing anhydrous pyridine of SeO₂ and t-BuOOH to obtain a compound of formula V wherein R₁ is H. This compound is acetylated with pyridine and an acetic anhydride solution to form a compound of formula V wherein R₁ is an acyl, which is then reacted with p-toluenesulfonic acid in a dioxane/H₂O mixed solution to obtain a compound of formula I wherein K is ethylenedioxy.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to precursors of 1α,25-dihydroxylated compounds of the vitamin D2 series.

More specifically, the present invention relates to lα,25-dihydroxyvitamin'D2 and its (24R)-epimer counterpart 5.6
-) lance-isomers, certain 025-alkyl or aryl derivatives as well as precursors of the acyl derivatives of these compounds.

(Prior Art and Problems to be Solved by the Invention) The importance of the hydroxylated form of vitamin D as a regulator of calcium and phosphate metabolism in animals and humans is
By now, it has been well recognized through numerous disclosures in patents and general literature, and as a result of these, hydroxyvitamin D
Derivatives are finding increasing clinical and veterinary use as agents for the treatment and treatment of diseases of calcium metabolism and related bone diseases. Vitamin D3 is known to be hydroxylated in vivo to 25-hydroxyvitamin D3 and then to lα,25-dihydroxyvitamin D3, where the latter is generally accepted as the active hormonal form of vitamin D3. It is something. Similarly, a highly effective vitamin D2 metabolite, 1α,25-dihydroxyvitamin D? (1α, 25- (OH)2 D2
) is vitamin D2 to 25-hydroxyvitamin D2
(250H-D2). Both of these hydroxylated forms of vitamin D2 compounds have been isolated and identified (Dell-Power et al., US Pat. No. 3,585).

No. 221, No. 3,880,894). These metabolites derived from vitamin D2 are characterized by (S)-stereochemistry at carbon 24.

Is this invention vitamin D? It is assumed that l=I provides a precursor of the lα,25-dihydroxylated compound of the system.

Means for Solving the Problems Precursors of 1α,25-dihydroxylated compounds of the vitamin D2 family have now been developed. Here, the lα,25-dihydroxylated vitamin Dz-based compound is a compound having the general structure shown below.

(wherein R,, R2 and R3 are selected from the group consisting of hydrogen and acyl groups, and X is an alkyl or aryl group.

In these structures, the erratic center of carbon 24 may have a (double) or (altitudinal) arrangement. is an oxy group, R1
and R2 may be the same or different and are hydrogen and an acyl group. ), 2, the compound of the above formula is lα,25-dihydroxy-24
- said first epivitamin D2, wherein K is an oxygen group;
3. The compound of the above formula is lα,25-dihydroxy-24
- The compound according to the above item 1, which is epivitamin D2 and K is an ethylenedioxy group, 4, the compound of the above formula is l
α-Hydroxy-25-oxo-27-norvitamin D
? and the compound according to item 1 above, which is an acetate thereof;
and 5. provides the compound according to item 1 above, wherein the compound of the above formula is lα-hydroxy-25-oxo-27-true 24-epivitamin D2.

Specific examples of compounds using the compound of the present invention as a precursor include 1α
, 25-dihydroxyvitamin D2. Compatible (24R)
- epimer, 1α, 25-dihydroxy-24-epivitamin D2, each 5.6-) lance-isomer,
That is, 5,6-trans-1α,25-dihydroxyvitamin D2 and 5,6-trans-1α,25-dihydroxy24-epivitamin D2, as well as C-25-alkyl or aryl analogs of these compounds, That is, compounds in which X in the formula shown above is an ethyl, propyl, isopropyl or phenyl group are included.

The term "acyl" herein refers to aliphatic acyl groups (alkanoyl groups) having 1 to 6 carbon atoms, including all possible isomeric forms, such as formyl, acetyl, butyryl, imbutyryl, valeryl, aromatic acyl groups (aroyl groups), etc. , for example vinylyl or a methyl, halo or nitro substituted benzoyl group or -formula R00C(CH2)ncO- or R
means an acyl group derived from a dicarboxylic acid having OOCCH2-0-GH2GO- (where n is an integer having a value of O to 4 (including O and 4), and R is hydrogen or an alkyl group) . Representative of such dicarboxylic acyl groups are oxalyl, malonyl, succinoyl, glutaryl, adipyl and diglycolyl.

The term "alkylpa" includes all isomeric forms and refers to hydrocarbon radicals having 1 to 6 carbon atoms, such as methyl, ethyl,
Means propyl, inpropyl, butyl, isobutyl, etc. The term "aryl" refers to phenyl, benzyl or alkyl-substituted phenyl group isomers.

A specific example of a chemical process for obtaining the compounds according to the invention is depicted in the attached process φ scheme. In the following description of this process, numbers (eg, 1.2.3, etc.) indicate the specific products so numbered in the process scheme. The wavy line for the substituent (methyl) at C-24 indicates that this substituent is R or S
This indicates that any array is acceptable. In Process Scheme I, compounds of the invention have structure 6.
8.7 and 10.

Suitable starting materials for obtaining the compounds according to the invention are vitamin D-ketal derivatives of structure (1). in general,
Compound (1) is used as a mixture of 24R and S epimers (such as when both C-24-epimers of a lα,25-dihydroxyvitamin D2 compound are required) and the individual 24R and S epimers are separated. is conveniently carried out at a later stage of the method. However, pure 24- or pure 24-fold epimers of (1) are equally suitable as starting materials, whereby the former compound can be processed by the indicated synthetic steps to (243)-1α, 25
-dihydroxy product, the latter compound being similarly treated to yield the corresponding (24R)-1α,25-dihydroxylated product.

The starting material (1) is converted to the desired 1α-hydroxylated form via a cyclovitamin D derivative (Dell-Riki et al., U.S. Pat. Nos. 4,195,027 and 4,260,54).
No. 9). Thus, treatment of compound (1) with toluenesulfonyl chloride in a conventional manner yields the corresponding C-3-1 sylated product (2), which is subjected to solvolysis in an alcoholic medium to form a novel 3,5 -Produces cyclovitamin D derivative (3). Solvolysis in methanol yields a Z-methyl cyclovitamin in structure (3). However, when other alcohols such as ethanol, 2-propanol, butanol, etc. are used in this reaction, similar cyclovitamin D compounds (3) where Z is an alkyl group derived from the alcohol, such as ethyl, isopropyl, butyl, etc. give. Allyl oxidation of intermediate (3) with selenium dioxide and hydroperoxide yields the lα-hydroxy-analogue of structure (4). Compound (4) was subsequently acetylated to form the structure (5, R1=
gives 1-acetate of (acetyl). If you wish,
Other 1-0-acylated compounds (Structure 5, where R1=acyl, e.g. formate, propionate, butyrate,
benzoates, etc.) are prepared by analogous conventional acylation reactions. This 1-0-acylated derivative is then subjected to acid-catalyzed solvolysis.

When this solvolysis is performed in a solvent containing water, the structure (6,
5.6-cis-vitamin D of R,=acyl, R2=H)
Intermediates and corresponding 5.6-) lance-compounds (structure 7, R
1=acyl, R2=H) in a ratio of about 3-4:1. These 5,6-z and 5,6-) lance isomers can be separated at this stage, for example by high performance liquid chromatography. If desired, the C-1-0-acyl group can be removed by basic hydrolysis to yield compounds (6) and (7) with R1 and R2=H.

Alternatively, if desired, these 1-0 monoacylates can be further acylated at the C-3-hydroxy group using conventional acylation conditions to form structures (6) or (7), where R1 and R2 are mutually The corresponding 1,3-di-0-acylated product of (indicating an acyl group) which may be the same or different can be obtained. Alternatively, the hydroxycyclovitamin of structure (4)'' can be subjected to acid-catalyzed solvolysis in a medium containing a low molecular weight organic acid to form structures (6) and (7).
) (where R1=H, R2=acyl, where the acyl group is derived from the acid used in the solvolysis reaction)
, 6-'yZ and trans compounds are obtained.

The next step in this method is to remove the ketal protecting group and produce the corresponding 25-ketone.

The conversion of ketals to ketones occurs under the acidic conditions required for ketal hydrolysis.
24) - This step is very important since the isomerization to the conjugated position must be achieved without concomitant effects. Furthermore, conditions must be chosen to avoid leaving off the unstable allyl C-1-oxygen function. This conversion can be successfully achieved by careful hydrolysis at mild temperatures using organic acid catalysts.

Thus, 5,6-cis-compound (6) is treated with P-)luenesulfonic acid in aqueous alcohol to give the corresponding ketone (8). To avoid unintended detachment of the C-1 oxygen functional group during this reaction, the C-1-
Protecting hydroxy groups (e.g. R,=acyl, R2
=hydrogen or acyl).

Subsequent reaction of the ketone (8) with a methyl Grignard reagent yields 1α of the desired structure (9).

25-dihydroxyvitamin D? give the compound. If the starting material used in the above method contains two C-24
-Epi-, compound (9) is a mixture of 24S and R-
A mixture of epimers (9a and 9b, respectively) would be obtained. Separation of this epimer mixture can be carried out by chromatographic methods, and it is possible to separate lα,25-dihydroxyvitamin D2 (structure 9a, 243-stereochemistry) and its 24R-epibo, structure! ! 19b, lα, 25-dihydroxy-24-epivitamin D2 are both obtained in pure form. Such separation of epimers is, of course, unnecessary if the compounds are used as a mixture.

When the 5,6-trans-25-ketal intermediate of structure (7) is subjected to ketal hydrolysis in an analogous manner, structure (
10) gives the 5.6-) lance ketone intermediate, which Grignard reaction with reagents with methylmagnesium bromide or similar provides the 5.6-) lance-1α of structure (11),
25-dihydroxyvitamin D2 is provided as the 243 or 24R-epimer or as a mixture of both epimers, depending on the nature of the starting material (1) used in the process. If obtained as an epimer mixture, the epimers can be separated by chromatography and 5.6
-trans-1α.

25-dihydroxyvitamin D2 (lla) and its 24R-epimer, 5°6-trans-1α, 25-dihydroxy-24-epitavitamin D2 of structural formula (llb) are obtained. The reaction steps using these 5,6-trans-intermediates can be carried out in exactly the same way as can be applied to the 5,6-cis compounds described above.

The novel side chain ketone structure (8) or (10) of the present invention is the most important and versatile intermediate in that it can be used to prepare various 1α,25-dihydroxyvitamin D2 side chain analogs. (precursor). In particular, these keto-intermediates can be useful in preparing 5,6-cis- or 5,6-trans-1α,25-dihydroxyvitamin D2 analogs having the side chain formulas below.

(where X is an alkyl or aryl group). For example, treatment of the ketone (8) with ethylmagnesium bromide results in a reaction similar to the corresponding hydroxyvitamin D2, where X is an ethyl group in the side chain shown above. Give your body. Similarly, treatment of (8) with inpropylmagnesium or phenylmagnesium bromide provides side chain analogs where X is isopropyl or phenyl, respectively. Structure (1
Treatment of the 5,6-trans-25-ketone intermediate of 0) with a furkyl or aryl Grignard reagent in a similar manner yields 5.6 with a side chain where X is an alkyl or aryl group derived from the Grignard reagent used. -) Lance - provides a vitamin D2 analogue.

Isotopically labeled Grignard reagents (e.g. 03 R3MgBr, 14
cH3MgBr, C2R3MgBr, etc.), 1α,25-dihydroxyvitamin D2 or its trans isomer and the corresponding C-24-epimer in isotopically labeled form, i.e. X is C
It is also clear that it provides convenient means for preparing compounds which are selected from 3R3, "CH3, C2R3, l"CH3 or other isotopically labeled alkyl or aryl groups.

The alkyl or aryl analogs of the above 5.6-'yZ or trans-1α,25-dihydroxy-vitamin D2 are useful substituents of acute compounds in cases where very high lipophilicity is required; On the other hand, the isotopically labeled compounds mentioned above may find use as reagents in analytical applications.

Additionally, for therapeutic applications, free hydroxy compounds represented by structures A and B above (where R, , R2 and R3 = H) are used in - boat fishing; , the corresponding hydroxy-protected derivatives would be effective and preferred. Such hydroxy-protected derivatives are, for example, represented by formulas A and B above and R1,
It is an acylated compound in which one or more of R2 and R3 represents an acyl group.

Such acyl derivatives can be prepared by converting the free hydroxy compound using conventional acylation techniques such as hydroxyvitamin D.
It can be conveniently prepared by treating either of the two products with an acyl compound or acid anhydride in a suitable solvent such as pyridine or alkylpyridine. By appropriate selection of reaction time, acylating agent, temperature and solvent, partially or fully acylated acylated derivatives of structure A or B above can be obtained, as is well known in the art. For example, 1α, 25-
Treatment of dihydroxyvitamin D2 (9a) with acetic anhydride in pyridine solvent at room temperature gives the 1,3-diacetate, whereas the same reaction carried out at elevated temperature gives the corresponding 1.3.25-) diacetate. Produces acetate. This 1,3-
The diacetate can be further acylated at the C-25 position with different acyl groups. For example, treatment with benzoyl chloride or succinic anhydride gives l,3-diacetyl-25benzoyl- or l-,3-diacetyl-25-succinoyl derivatives, respectively. The 1,3,25-triazyl derivative is subjected to selective hydrolysis in mild base to give 1,3
-dihydroxy-250-acyl compounds. The free hydroxy groups here can be reacylated with different acyl groups if desired. Similarly, 1,3-diacyl derivatives can be subjected to partial acyl hydrolysis to obtain 1-0-acyl and 3-0-acyl compounds, which can be further reacylated with different acyl groups. Other hydroxyvitamin D2 products (
9b, 1laZ, or their corresponding 25-alkyl or aryl analogues) of structure A or B, where any or all of R1, R2, and R3 are acyl. gives the corresponding desired acyl derivative.

Similar to previously known vitamin D2 metabolites, 1α,
25-Dihydroxyvitamin I) 7B (, di'', ) exhibits significant vitamin D-like activity and thus has a wide range of therapeutic or veterinary applications compared to the known vitamin D2.
or a desirable alternative to D3. Particularly preferred products in this regard are structures 9b and lla and llb or acylated derivatives thereof. This new compound can be used to treat various diseases such as vitamin D-resistant rickets, osteomalacia, hypoparathyroidism, osteodystrophy, pseudohypoparathyroidism,
It can be used to improve or correct a variety of calcium and phosphorus imbalance conditions resulting from osteoporosis, Purget's disease, and similar bone and mineral related disease conditions known in the medical profession. The compounds can also be used in the treatment of mineral imbalance conditions in animals such as lactation fever conditions, foot weakness in poultry or eggshell quality improvement in chickens. Their use in the treatment of osteoporosis is of particular interest.

During menopause, women suffer significant wear and tear on their bones, ultimately leading to bone deficiency diseases, which eventually result in spontaneous compression of the vertebrae, fractures, and fractures of long bones. This disease, commonly known as postmenopausal osteoporosis, is a significant medical problem in the United States and other countries where women live to at least 60 to 70 years.

Generally, the disease is often accompanied by bone pain and decreased physical activity and is diagnosed by a compression fracture of one or more vertebrae along with x-ray evidence of bone loss. This disease is known to occur with a decreased capacity for calcium absorption, decreased levels of sex hormones, especially estrogens and androgens, and a negative calcium balance.

There have been significant changes in the way this disease is treated.

For example, supplementing calcium itself has not been successful in preventing or treating the disease. sex hormones, especially
Estrogen injections, which have been reported to be effective in preventing the rapid bone loss experienced by postmenopausal women, have been difficult due to fears about their carcinogenic potential. Other treatment methods have again been reported with mixed results, including the combination of large doses of vitamin D, calcium, and fluoride.

The main problem with this approach is that fluoride induces structurally unfavorable bone, so-called focal bone;
It produces a number of side effects such as increasing the incidence of bone fractures and causing gastrointestinal reactions due to high doses of fluoride.

Similar symptoms are found in senile osteoporosis and steroid-induced osteoporosis, the latter of which is recognized to result from glucocorticoid (corticosteroid) therapy for a long-term disease state. There is.

Various metabolites of vitamin D3 increase calcium absorption and maintenance in mammals that exhibit evidence of, or are physiologically predisposed to, bone wasting, but do not respond to physiological demands. It is also characterized by complementary vitamin D-like properties that mobilize calcium in bones.

Shrimp compounds of the compounds according to the present invention, especially 24-shrimp-1α
, 25-dihydroxyvitamin D2 (24-shrimp-1,
25-(OH) 2 D2 ) is outstandingly suitable for the prevention or treatment of mammalian physiological diseases characterized by bone wasting. This is because they exhibit some of the properties recognized as vitamin D-like, affecting calcium substance metabolism, such as increasing intestinal calcium transport and affecting bone mineralization, but even at high doses they do not affect serum calcium levels. This is because it does not increase This observed property makes it clear that administration of this compound does not fluidize bone. This fact, along with the ability of this compound to mineralize bone when administered, supports widespread calcium diseases evidenced by bone wasting, e.g.
It has been shown to be an ideal compound for the prevention or treatment of postmenopausal osteoporosis, senile osteoporosis, and steroid-induced osteoporosis. The compound is useful for the prevention or treatment of other disease states where bone wasting is an indicator, e.g. as a result of dialysis,
It is clear that it can be easily applied for the treatment of patients undergoing renal dialysis who are faced with bone wasting.

(Examples) Next, the present invention will be explained in more detail based on Examples. The following reference examples will help to explain the properties of 24-shrimp-1,25-(OH)2D2 according to the invention, which contribute to its outstanding suitability for the prevention or treatment of disease states exhibiting bone wasting. Dew.

Reference example 1 A newly weaned male rat was placed in the journal of Sudha et al.
Journal of Nut
rition) Zoo, 1049-1052 (
0.02 of the vitamin D-deficient diet described in (1970)
The mice were placed on a special diet modified to contain % calcium and 0.3% phosphorus. After two weeks on this special diet, the animals were given 1,25-dihydroxyvitamin D2 or 24-shrimp-1,25-dihydroxyvitamin D2 by subcutaneous injection of 0.1 mJl of propanediol in 5% ethanol daily. . 12 hours after the last dose, animals were sacrificed;
Blood calcium and intestinal calcium transport were measured.

The results of these measurements are shown in Figures 1 and 2 for the indicated levels of compound administered. The measurements of intestinal calcium transport shown in Figure 2 are based on Martin and Dell-Power's American Journal of Physiology.
Journal of Physiology)2
16.1351-1359 (1969).

Reference Example 2 Newly weaned male rats were treated with high calcium (1.2% calcium), low phosphorus (calcium) as described in Suda et al.
They were placed on a special diet containing 0.1% phosphorus). Rats were fed this special diet for three weeks and divided into two groups. One group has 1, 25 (0)1)
2 D2 is given, and the other side is given 24-shrimp-1, 2
5(OH) 2 D2, but both groups received 0.1 m of 5% ethanol in propanediol! Dose levels of compound indicated by the data points in Figure 3 were given subcutaneously in L. After continuing this medication daily for 7 days, the animals were sacrificed and serum inorganic phosphorus levels were measured. 3rd result
As shown in the figure.

Rat femurs were removed and the ash content of the bones was measured. The femurs were cut free of attached connective tissue and extracted using a Soxhlet extractor in absolute alcohol for 24 hours and in diethyl nityl for 24 hours. This bone is 600"
It was incinerated in F for 24 hours. Ash weight was determined by measuring constant weight. The results are shown in Figure 4.

The results of the two studies described in Reference Examples 1 and 2 above are:
24-Shrimp-1,25-(OH)2D2 is lα for the occurrence of bone mineralization and stimulation of intestinal calcium transport.
, 25-dihydroxyvitamin D3 (1,25-(
In short, there are no substantively meaningful differences between the two groups in Figures 2 and 4. That means no. On the other hand, in the case of a low-phosphorus special diet, the increase in serum inorganic phosphorus resulting from bone fluidization is 1.25-(O
H)2 Very significantly affected by D224
-Shrimp-1,25(OH)2D2 causes almost no stimulation. Similarly, about 750 pool/
The 24-shrimp compound did not show any effect on calcium mobilization from bone, as noted even at extremely high doses of serum calcium levels (Figure 1). On the other hand, the mobilizing effect of l,25-dihydroxyvitamin D2 is evident even at much lower doses. The increase in serum calcium in rats on a low-calcium special diet is a measure of bone mobilization potential, and the increase in blood phosphorus in animals on a low-phosphorus special diet is also a measure of bone mobilization. , these results are 2
4-Shrimp-1,25(OH)2D2 has unexpected properties i.e. can fully stimulate intestinal calcium transport and new bone mineralization but has minimal effectiveness in bone calcium mobilization. and exhibit properties that make this compound particularly suitable for the treatment of disease states in which bone wasting is evident.

The unique properties of 24-shrimp-1,25-(OH)2 D2, as described above, can be used to improve various vitamin D response processes (intestinal calcium absorption, bone provides a rare opportunity to control mineral mobilization and bone mineralization. This possibility suggests that the shrimp compounds of the present invention may be administered to mammals alone (with suitable and acceptable excipients) or in combination with other vitamin D derivatives exhibiting a full spectrum of D-oleaginous properties. It arises from the true reality of being. Such measures therefore make it possible to combine the active properties of 24-epi-analogues with the general activity of other vitamin D metabolites or analogues. Administration of 24-shrimp-1゜25-(OH)2D2 alone stimulates intestinal calcium transport and bone mineralization, as shown above, but causes no or minimal bone mineral mobilization. be. However, the latter activity is limited by known vitamin D derivatives (e.g. 1,25-(OH)2
D3.1α, 2'5- (OH),! D2.1α-0
HD3 and related analogs) can be induced by co-administering one or more of them.

By adjusting the relative amounts of compounds administered, a degree of control over the relative strength of intestinal calcium absorption versus bone mineral fluidization processes can be exerted in a way not previously possible with known vitamin D derivatives. . 24-
Bone mobilization activity by co-administration of shrimp compounds and other vitamin D compounds is particularly advantageous in conditions where some degree of bone mobilization is required. For example, under certain circumstances,
The bone must first be fluidized before the new bone is sacrificed. Under such conditions, vitamin D or vitamin D derivatives that induce bone fluidization, such as 1α-hydroxyvitamin D3 or D2.1α, 25-dihydroxyvitamin D3 or D2.25-hydroxyvitamin D3
or D2.24.24-difluoro-25-hydroxyvitamin-D3.24.24-difluoro-1α.

25-dihydroxy-vitamin D3.24-fluoro-
25-hydroxyvitamin D3.24-fluoro-1α
, 25-dihydroxyvitamin D3.2β-fluoro-
1α-hydroxyvitamin D3.2β-fluoro-25
-Hydroxyvitamin D3.2β-Fluoro-1α,2
5-dihydroxy-vitamin D3.26,26,26°27.27.27-hexafluoro-1α, 25-dihydroxy-vitamin D3.26.26°26.27,2
7.27-hexafluoro-25-hydroxyvitamin D3,24.25-dihydroxyvitamin-D3.1α
, 24.25-) dihydroxyvitamin D3, 25.2
6-cyhydroxyvitamin D3.1α, 25.26
-) Dihydroxyvitamin D3 24-shrimp-1,25
A treatment regimen that adjusts the ratio of 24-shrimp compound and bone fluidizing vitamin D compound in combination with (OH)2D2 will improve the degree of bone fluidization until the desired medical and physiological objectives are achieved. can be adjusted. Suitable and effective mixtures are, for example, lα.

25-dihydroxyvitamin D2 and 1α,25-dihydroxy-24-epivitamin D3 (9a and 9b)
, the corresponding 5.6-trans compounds (11a and 11
b) or other combinations of the four compounds as their free hydroxy compounds or their acylated forms. The compounds according to the invention or their conjugates with other vitamin DM conductors or other therapeutic agents can be easily administered orally as a sterile parenteral solution by injection or infusion, through the skin or from the gastrointestinal tract in the form of herbal medicines. be done. Advantageously, the compound is given in a dosage of 0.1 to 100 gram per day. About skeletal slope disease, it is about 0.5 to 25. A dosage of 100 g is generally effective. The compounds may be administered alone or in combination with other vitamin D derivatives, the proportion of each compound being combined depending on the particular disease state directed and the degree of bone mineralization and/or bone fluidization desired. . Preferred compounds are 24-shrimp lα,
25-(OH)202 The actual amount of the 24-shrimp compound used in the treatment of osteoporosis is not critical. In all cases, the compound should be used in an amount sufficient to induce bone mineralization. Using an excess of more than about 25 JLg of 24-epi-compound or that compound in combination with bone mobilization-inducing vitamin D derivatives per day is unnecessary to achieve the desired results in boat fishing; It is not an economically sound implementation. In practice, higher doses of the compound are used when the purpose is to treat a disease state, whereas lower doses are generally used for prophylactic purposes. However, in any case, the dosage given will depend on the specific compound being administered, as is well known to those skilled in the art! ! It is to be understood that the activity of the drug and the patient's response will be adjusted depending on the disease being treated, the patient's condition, and other appropriate medical realities that require modification of the drug's activity and patient response.

Medicaments of the compounds according to the invention can be prepared by combining the compounds according to the invention with non-toxic pharmaceutically acceptable carriers. Such carriers can be either solid or liquid, such as corn starch, lactose, sucrose, peanut oil, olive oil, sesame oil and propylene glycol. If a solid support is used,
Dosage forms of the medicaments of the invention can be tablets, capsules, powders, troches, or lozenges. If a liquid carrier is used, the dosage form can be a soft gelatin capsule, syrup or suspension, emulsion or solution. The dosage form may also contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solubility enhancers, and the like. They may also contain therapeutically valuable substances, such as other vitamins, salts, saccharide-1 proteins, hormones or other pharmaceutical compounds.

Reference example 3 1α-hydroxy-3,5-cyclovitamin D (4, Z
-Methyl) A solution of compound (1) (50 mg) (as a mixture of 24R and S epimers) in dry pyridine (300 ml) was prepared by p.
-Toluenesulfonyl chloride 50 mg for 30 hours at 4°C. Stir the mixture under water/saturated NaH.
Poured onto CO3 and extracted the product with benzene. -The combined organic layers were added to NaHCO3 aqueous solution, H20, CuSO4
Washed with aqueous solution and water, dried over Mg5O4J1 and evaporated. The crude 3-tosyl derivative (2) was diluted with anhydrous methanol (10 methanol) and NaHCO3 (150 mg) under stirring for 55 minutes.
The mixture was heated at ℃ for 8.5 hours and subjected to solvolysis. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to ~2 mcm. Benzene (80 mb) was then added and the organic layer was washed with water, dried and evaporated. The generated cyclovitamin (
3, Z-methyl) can be used in the next oxidation without further purification.

The crude product (preliminary) in CH2C12 (4,5 mJlj) was ice-cooled, Seo2 (5,05 mg) and t-BuO
OH (16,5 g JL) (7), anhydrous pyridine (50 J
Ln) was added to a CH2C12 (8 mJ1) solution. After stirring for 15 minutes at 0°C, the reaction mixture was warmed to room temperature. After an additional 30 minutes, the mixture was transferred to a separatory funnel and shaken with 10% NaOH (30 ml). Ether (150 mJj) was added to reduce the separated organic phase to 10%.
Washed with 1 aqueous NaOH, dried and evaporated. The oily residue was purified on a silica gel thin layer plate (20X20 cm plate, Ac0Et/Hex 74:6) and 1α
-20 mg of a hydroxy derivative (迭, Z=methyl) was obtained. Mass spectrum m/e: 470 (14”, 5),
438 (20), 8? (100); NMR (C
I) CI3) 80.53 (3H, s.

18-H3), 0. f13 (IH, m, 3-H)
, 4.18(1)1. d, J=9.5Hz, 8
-H), 4.2 (IH, m, 1-H), 4.9
5 (IH, d, JJ, 5 Hz, ?-H), 5
．． 17 and 5.25 (2)1. Each m, , 19-H2
).

5.35 (2H, m, 22-H and 23-H).

Reference Example 4 A solution of acetylated cyclovitamin (4, Z-methyl) (18 mg) of compound (4) in pyridine (1 mJlj) and acetic anhydride (0.33 mJlj) was heated at 55°C for 2 hours. The mixture was cooled in water with saturated NaH.
Poured into CO3 and extracted with benzene and ether. The organic extracts were combined with water, saturated CuOa and NaHC.
Washed with aqueous O3, dried and evaporated to give 1-acetoxy derivative (5, Z = methyl, acyl niacetyl) (19 mg
) was obtained. Mass spectrum m/e: 512 (M,
5), 420 (5).

87 (100); NMR (CDCh) δ0.53
(3H,s, 18-H3).

4.18 (IH,, d, J=9.5 Hz, fi
-H), 4.97 (2H, m, 7H and 19-H)
, 5.24 (2H,m, 1-H and 19-H),
5.35 (2H, wr, 22-H and 23-H)
.

Example 1 1α-7 setoxy 3,5-cyclovitamin (5) (R
+ = acetyl) solvolysis cyclovitamin (5)
(4.5 mg) of dioxane/H20 in a 3=1 mixture (1
, 5 mJL) was heated at 55°C. p-) Luenesulfonic acid (1 mg in 20 JL water, Q) was then added and heating continued for 15 minutes. The mixture was saturated with NaCHO
3/Pour into ice and extract benzene and ether. The organic phase was washed with NaHCO3 and water and dried over Mg5Oa. Evaporation of the solvent yields compound (6) (where R1=
acetyl, R2=H) and (7) (where R1=acetyl, R2=H) was obtained, which was analyzed by HPL using 2% 2-propanol in hexane as eluent.
C (6, 2mmX 25cm Zorbax-3i
l) separated by chromatography above. If necessary, the product can be further purified by re-chromatography.

Example 2 Ketone (8) is obtained by ketal hydrolysis of compound (6).

Ketal (6, R, = acetyl, R2 = H) (1,35
p-toluenesulfone (0.34 mg in 45 U of water) in a solution of ethanol (1.5 mg) in ethanol (1.5 mg)
was added and the mixture was heated under reflux for 30 minutes. The reaction mixture was poured into diluted NaHCO3 and extracted with benzene and ether. The organic extracts were combined, washed with water, and M
Dry over gSO4 and evaporate. High pressure liquid chromatography of the crude mixture (4% 2-propanol/hexane, 6,2 m m x 25 cm Zor
bax-3il) is the unreacted ketal (6)(0,1
2 mg, collected in 48 ml) and the desired ketone (8, R,=acetyl and R2=H) (0.36 mg, collected in 52 mM) characterized by the following data. Mass spectrum m/e: 454 (M・,
11), [4(17), 37111 (10),
134 (23), 43 (100); NMR (CD
Cl2) δ0.53 (3H,s, 18-R3).

1.03 (3H, d, J=8.5 R2,2l-R
3), 1.13 (3Hd, J=7, OR2,28
-83), 2.03 (3)1. s, CH3CO
0), 2.12 (3H,s, CH3CO), 4
．． 111 (IH, m, 3-H), 5.03 (1M
, m, 1ll-H), 5.33 (3H, broad m, 1B-) 1.22-H and 23-H), 5.
48 (IH, ra, 1-H), 5.93 (
IH, d, J=11 Hz, ? -H), 8
．． 37 (IH, d, J-11Hz, 8-H)
; UV (EtOH) λ5ax2E18 n
m, 250 nm, λ1n255 2I
11゜Reference Example 5 Reaction of ketone (Dan) with methylmagnesium bromide to obtain products (and 1) and (di) Ketone (Dan, R
1 = acetyl, R2 = 'H) in anhydrous ether with excess CH3MgBr (2.85M solution in ether). The reaction mixture was stirred at room temperature for 30 minutes, then quenched with aqueous NH4CJL and extracted with benzene, ether and CH2C12. Dilute the organic phase with diluted NaH
Washed with CO3, dried over Mg5OJ and evaporated.

The mixture of (Dan 1) and (9b) thus obtained was subjected to high performance liquid chromatography (6% 2-propanol/hexane, 4.6 mm x 25 cm, Zorba
x-Si I), the pure epimer (9
a) and (9b) were obtained. 1(X,25-dihydroxyvitamin 7D2 (9a): UV (EtOH)λ
wax2B5.5n+w, mix 227.5
Hm; Mass spectrum ll/e42B (M.,
8), 410 (4), 352 (4), 287 (
it), 289(10), 251(10),
152 (42), 134 (100), 59 (
119).

NMR (CDCl2) 60.58 (3H,s,
18-H), 1.01 (3H, d.

J=8.5 Hz, 28-H), 1.04 (3
8, d, J=8.5 Hz, 21-H).

1.14 and 1.18 (8H, each 3.2B-H and 27-
H), 4.24 (IH.

m, 3-H), 4.43 (18, m, 1-H), 5
．． 01 (IH, m.

19-H), ~5.34 (3B, broad m, 1
9-H, 22-H and 23-H), 8.02 (IH,
d, J=11 Hz, 7-H), 8.39
(IH.

d, J=11 Hz, 8-H).

1α,25-dihydroxy-24-epivitamin D (f
llb): UV (EtOH) containing wax 285.
5Hm, λwin 277.5Hm; Mass spectrum, m/e 42B (M., 13), 410'
(9), 352(7), 2B? (11), 28
13 (15), 251 (13), 152 (5
2).

134 (100), 59 (117).

Example 3 5.6-) Lance-1α of compound (7).

25-dihydroxyvitamin D2 compound (lla) and (
When hydrolysis of the ketal intermediate (1, R, = acetyl, R2 = H) is carried out using the conditions described in Reference Example 2, the structure of the corresponding 5,6-trans-25-ketone is obtained. (Yo O, R,
=acetyl, R2=H), and this ketone is then reacted with methylmagnesium bromide using conditions similar to Reference Example 3 to provide shrimp-y-(lla) and (1l
b), which is separated by high performance liquid chromatography (HPLC) to give pure 1α, 25
-dihydroxy-5,6-)lance-vitamin D2 (
lla) and 1α,25-dihydroxy-5,6-) lance-24-epivitamin D2 (llb). If required, structural designations can be made for each 5,6-cis compound (9a,
This can be confirmed by isomerization to 9b).

5.8-) Lance-1α, 25-dihydroxyvitamin Dz (lla): wax with UV (EtOH) 27
3.5 nm, 1n 230IB; "'F soot vector m/e 428 (M, 8), 410
(3).

28? (3), 289 (7), 251 (34
), 134 (100), 59 (78).

5.8- trans-1α,25-dihydroxy-2
4-Epivitamin D2 (llb): uv (EtOH
) λmay 273.5nm λwin 230nm
;-v soot vector m/e 428 (M.

10), 410 (4), 352 (4), 2
8? (5), 2B9 (9), 251(8
), 152 (37), 134 (100
), 59 (82).

Reference Example 6 Preparation of alkyl and aryl analogs of 1α,25-dihydroxyvitamin D2 compound Ketone intermediate (Dan) (R+
= acetyl, R2 = H) respectively with (a) ethylmagnesium bromide (b) propylmagnesium bromide (C) isopropylmagnesium bromide (d) butylmagnesium bromide (e) phenylmagnesium bromide and in Reference Example 5. When the correspondence is made using conditions similar to those described, the corresponding hydroxy represented by the following formula, in the above formula,
are as follows.

(a) Ethyl (b) Propyl (e) Isopropyl (d) Butyl (e) Phenyl 5.6-Doransuketone intermediate (10) (R1=acetyl, R2=H) in the same manner as above using the Grignard reagent. , the corresponding 5.6-
) A lance-hydroxyvitamin D2 product is obtained.

(b) Propyl (C) Isopropyl (d) Butyl (e) Phenyl A preferred starting material for the compounds according to the invention is a vitamin D-ketal derivative of structure (1), which is described in British Patent Specification No. 2,127; No. 023 or U.S. Pat. No. 4,448
, No. 721, according to process scheme II and ■. Generally, compound (1) is used as a mixture of 24R and 24S epimers (e.g. when both C-24-epimers are desired), and individual 24R and 24S epimers are used.
It is convenient to carry out the separation of the epimers later. However, pure 24S- or pure 24D-epimers of (1) are also suitable, the former providing the 24S-1α,25-dihydroxy product and the latter providing the corresponding 24-R-product.

In the above formula, or each as follows.

(a) Ethyl Process love Process rich scheme III Mutual = 24 and Process scheme■

[Brief explanation of drawings]

Figure 1 is a graph showing the relationship between the compound dose of 1.25-(OH)2D2 or 24-shrimp-1,25-(OH)2D2 and the amount of serum calcium; (OH)202 or 24-shrimp-
1,2-5-(OH)2D2 is a graph showing the relationship between the compound dose and the amount of intestinal calcium transport.
25- (O)() 2D2 or 24-Shrimp-1,25
A graph showing the relationship between the compound dose of -(OH)2D2 and serum inorganic phosphorus, Figure 4 is 1.25-(OH)2D
2 is a graph showing the relationship between the compound dosage of 2 or 24-shrimp-1,25-(OH)2D,2 and the total bone ash content. Patent Applicant Rice Consin Alumni Research Fundamentals Agent Patent Attorney Takao Kawasaki (and 1 other person) (Tsu 00T
/n) l h candy lined reason (Poor/n) Y4 Otsu/l/q station training (n)ze Y good hand

Claims (1)

[Claims] 1. A compound selected from the following group. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, K is oxygen or ethylenedioxy group, R_
1 and R_2 may be the same or different and are hydrogen and an acyl group. ) 2. The compound of the above formula is 1α,25-dihydroxy-24
-Epivitamin D_2, and K is an oxygen group. 3. The compound of the above formula is 1α,25-dihydroxy-24
-Epivitamin D_2, and K is an ethylenedioxy group. 4. The compound according to claim 1, wherein the compound of the above formula is 1α-hydroxy-25-oxo-27-nor-vitamin D_2 and its acetate. 5. The compound according to claim 1, wherein the compound of the above formula is 1α-hydroxy-25-oxo-27-nor-24-epivitamin D_2.