JPH0377173B2 - - Google Patents
Info
- Publication number
- JPH0377173B2 JPH0377173B2 JP17507183A JP17507183A JPH0377173B2 JP H0377173 B2 JPH0377173 B2 JP H0377173B2 JP 17507183 A JP17507183 A JP 17507183A JP 17507183 A JP17507183 A JP 17507183A JP H0377173 B2 JPH0377173 B2 JP H0377173B2
- Authority
- JP
- Japan
- Prior art keywords
- vitamin
- calcium
- hydroxyvitamin
- intestinal
- binding
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000011710 vitamin D Substances 0.000 claims description 12
- 229940046008 vitamin d Drugs 0.000 claims description 12
- 230000003167 anti-vitamin Effects 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
- 229930003316 Vitamin D Natural products 0.000 description 9
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 9
- 239000011575 calcium Substances 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 235000019166 vitamin D Nutrition 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000000968 intestinal effect Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 239000002775 capsule Substances 0.000 description 3
- 210000000172 cytosol Anatomy 0.000 description 3
- GMRQFYUYWCNGIN-ZVUFCXRFSA-N 1,25-dihydroxy vitamin D3 Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-ZVUFCXRFSA-N 0.000 description 2
- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 208000022458 calcium metabolism disease Diseases 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000007442 rickets Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
【発明の詳細な説明】
Ｋ本発明は、1α−フルオロ−25−ヒドロキシ
ビタミンD3の新規な用途に関し、更に詳しくは、
該化合物の抗ビタミンD3活性を利用することに
関する。
古くから、動物のカルシウム代謝障害、例えば
クル病などを治療するために、ビタミンＤ類が使
用されることは知られていたが、近年になつて、
それらが体内において活性な化合物に変換され利
用されることが知られて来た。そして更に、最近
になつて、それがビタミンＤ類のヒドロキシル化
によるものであることがわかり、そのようなヒド
ロキシル化されたビタミンＤ類例えば25−ヒドロ
キシビタミンD3や1α，25−ジヒドロキシビタミ
ンD3が合成され、それを動物類に与えることに
よつて、カルシウムや燐のアンバランスを含めた
代謝障害が治療されることによつて裏付けられ
た。
さらに種々のアナログが合成されたが、それら
の活性は或る程度の比較として、トリの小腸
cytosol receptor 蛋白への結合性をみることに
よつて可能であることも知られた。
そして、ごく最近になつて、全く新しい作用を
有するビタミンＤ誘導体が見出された。これら
は、それを動物類に投与することによつて、ビタ
ミンＤの腸内カルシウム輸送効果や骨カルシウム
移動効果を阻止するような作用、即ち、抗ビタミ
ンＤ活性を示すものであつて、これによつて動物
類のカルシウム障害のうち、過カルシウム血症、
ビタミンＤ過多症、ビタミンＤ過敏症或いは転移
性石灰化の治療に使用されることになる（特開昭
54−119858号、特開昭54−154747号）。これらは、
ビタミンD2およびビタミンD3の生物学的活性の
発現が、上記ビタミンＤの動物体内における25位
のヒドロキシル化体への転換によるものであるこ
とに基いてなされた発明であつた。
本発明者等は、全く異なつた観点より抗ビタミ
ンＤ化合物について鋭意研究を重ね、１位のヒド
ロキシル化を阻止することが抗ビタミン作用の発
現をもたらすことを見出して本発明を完成した。
即ち、本発明は、1α−フルオロ−25−ヒドロ
キシビタミンD3を有効成分とする抗ビタミンＤ
剤である。この化合物は、本発明者等の１人によ
つて合成され（日本薬学会第103年会、5D−３−
３）、式
で表わされる。
上記式（）を有する化合物は、腸内カルシウ
ム輸送および血清カルシウム濃度に対しては何等
影響を与えず、小腸cytosol receptor 蛋白質へ
の強い結合を示すので、ビタミンＤ代謝異常によ
る前記諸症に顕著な効果を示すものである。
前記式（）を有する化合物をヒトに投与する
に当つては、常法によつて所望の製剤形態例えば
注射剤、錠剤、カプセル剤、シロツプ剤などに製
剤化して投与することができ、投与量は年令、病
状等によつて異なるが、通常は投与量が１日当り
約0.2μｇ乃至約2μｇのように非常に少量であるた
め、カプセル剤とくに軟カプセル剤として投与す
るのが好ましい。
実施例 １
カルシウム代謝
低カルシウム・ビタミンＤ欠乏食（J.Nutr.
100，1045〜1052）で雄の離乳子ラツトを、３週
間飼育する。１群６匹のラツトを３群用意し、対
照群には95％エタノールの0.05mlを静注し、第２
群には25−ヒドロキシビタミンD3〔25（OH）D3〕
（250nｇ／ラツト）そして第３群には1α−フルオ
ロ−25−ヒドロキシビタミンD3〔1αF，25（OH）
D3〕（1.3μｇ／ラツト）を夫々95％エタノールの
0.05ml溶液として静注する。24時間後、夫々の群
について腸管カルシウム吸収についてはMartine
およびDeLucaの方法〔Am.J.Physiol.216 1351
〜1359（1969）〕によつて、骨カルシウム移行につ
いては田中等の方法〔Biochemistry，14 3293
〜3296（1969）〕によつて測定した。結果は第１表
に示す通りである。25（OH）D3は明らかに腸管
カルシウムの吸収を促進せしめているが、1αF，
25（OH）D3は殆んど影響を有しない。
【表】
実施例 ２
トリ腸管細胞のサイトソールに存在する１，25
（OH）2D3に対するリセプター蛋白質に対する
結合能
１，25（OH）2D3〔26，27− 3H〕の結合したリ
セプター蛋白に、試験化合物を添加し、置換され
る１，25（OH）2D3を測定することによつて結合
能を測定することができる。Eisman等の報告
〔Arch.Biochem.Biophys.176 235〜243（1976）〕
に準じ、１，25（OH）2D3〔26，27− 3H〕の存在
下、50μの95％エタノールに溶かした種々の濃
度の1αF，25（OH）D3および25（OH）D3を添加
する。結果は第１図の通りであり、これから明ら
かなように、1αF，25（OH）D3は25（OH）D3に
比較して約30倍強い結合能を有している。
実施例 ３
1αF，25（OH）D3をトリグリセライド（日本
油脂社製：パナセート800）に1μｇ／mlの濃度に
溶かし、次のような剤皮処方により１カプセル当
り0.1μｇを含むような軟カプセル剤を製造する。
剤皮処方
ゼラチン 100
グリセリン 30
EHB 0.2
水 130 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel use of 1α-fluoro-25-hydroxyvitamin D3 , more specifically,
It relates to exploiting the anti-vitamin D3 activity of said compounds. It has been known for a long time that vitamin D is used to treat disorders of calcium metabolism in animals, such as rickets, but in recent years,
It has been known that they are converted into active compounds and utilized within the body. Furthermore, it has recently been found that it is due to hydroxylation of vitamin D, and such hydroxylated vitamin D such as 25-hydroxyvitamin D 3 and 1α,25-dihydroxyvitamin D 3 was synthesized and given to animals to treat metabolic disorders, including calcium and phosphorus imbalances. In addition, various analogs have been synthesized, and their activity has been tested in the avian small intestine for some comparison.
It has also been found that this is possible by looking at the binding properties to cytosol receptor proteins. Very recently, vitamin D derivatives with completely new effects have been discovered. When administered to animals, these substances inhibit the intestinal calcium transport effect and bone calcium movement effect of vitamin D, that is, exhibit anti-vitamin D activity. Among the calcium disorders in animals, hypercalcemia,
It will be used in the treatment of vitamin D hypersensitivity, vitamin D hypersensitivity, and metastatic calcification.
No. 54-119858, Japanese Patent Application Publication No. 54-154747). these are,
This invention was based on the fact that the biological activity of vitamin D 2 and vitamin D 3 is due to the conversion of vitamin D to a hydroxylated form at position 25 in the animal body. The present inventors have conducted extensive research on anti-vitamin D compounds from completely different viewpoints, and have completed the present invention by discovering that blocking hydroxylation at the 1-position brings about the expression of anti-vitamin effects. That is, the present invention provides antivitamin D containing 1α-fluoro-25-hydroxyvitamin D3 as an active ingredient.
It is a drug. This compound was synthesized by one of the inventors (103rd Annual Meeting of the Pharmaceutical Society of Japan, 5D-3-
3), formula It is expressed as The compound having the above formula () does not have any effect on intestinal calcium transport or serum calcium concentration, and shows strong binding to small intestinal cytosol receptor protein, so it is prominent in the above-mentioned diseases caused by vitamin D metabolic disorders. It shows the effectiveness. When administering the compound having the above formula () to humans, it can be formulated into a desired dosage form such as injections, tablets, capsules, syrups, etc. by a conventional method, and the dosage can be adjusted accordingly. The amount varies depending on the age, medical condition, etc., but the dose is usually very small, about 0.2 μg to about 2 μg per day, so it is preferable to administer it in the form of capsules, especially soft capsules. Example 1 Calcium metabolism Low calcium/vitamin D deficient diet (J. Nutr.
Male weanling rats (100, 1045-1052) are raised for 3 weeks. Three groups of 6 rats per group were prepared, and 0.05 ml of 95% ethanol was intravenously injected into the control group, and the second
The group contains 25-hydroxyvitamin D3 [25(OH)D3 ]
(250 ng/rat) and the third group received 1α-fluoro-25-hydroxyvitamin D 3 [1αF, 25(OH)
D 3 ] (1.3 μg/rat) in 95% ethanol.
Administer intravenously as a 0.05 ml solution. After 24 hours, intestinal calcium absorption was determined by Martine for each group.
and DeLuca's method [Am.J.Physiol. 216 1351
~1359 (1969)], and Tanaka's method for bone calcium transfer [Biochemistry, 14 3293
~3296 (1969)]. The results are shown in Table 1. 25(OH) D3 clearly promotes intestinal calcium absorption, but 1αF,
25(OH)D 3 has little effect. [Table] Example 2 1,25 present in the cytosol of avian intestinal cells
Binding ability of (OH) 2 D 3 to receptor protein A test compound is added to the receptor protein to which 1,25 (OH) 2 D 3 [26,27- 3 H] is bound, and the amount of 1,25 (OH) that is substituted is ) Binding ability can be determined by measuring 2D3 . Report by Eisman et al. [Arch.Biochem.Biophys. 176 235-243 (1976)]
Various concentrations of 1αF, 25 (OH)D 3 and 25(OH)D dissolved in 50 μ of 95% ethanol in the presence of 1,25(OH) 2 D 3 [26,27− 3 H] Add 3 . The results are as shown in Figure 1, and as is clear from this, 1αF,25(OH)D 3 has a binding ability about 30 times stronger than 25(OH)D 3 . Example 3 1αF, 25(OH)D 3 was dissolved in triglyceride (Panasate 800, manufactured by NOF Corporation) to a concentration of 1 μg/ml, and soft capsules containing 0.1 μg per capsule were prepared using the following shell formulation. Manufacture the agent. Shell prescription gelatin 100 Glycerin 30 EHB 0.2 Water 130
第１図は25−（OH）D3（線Ｂ）および1αF，25
（OH）D3（線Ａ）のリセプター蛋白結合能を示し
もので、縦軸は 3H−１，25（OH）2D3の結合量
（cpm）を示し、横軸は上記２種のD3誘導体の量
を示す。
Figure 1 shows 25-(OH)D 3 (line B) and 1αF, 25
It shows the receptor protein binding ability of (OH)D 3 (line A), the vertical axis shows the binding amount (cpm) of 3 H-1,25(OH) 2 D 3 , and the horizontal axis shows the binding amount of 3 H-1,25(OH) 2 D 3 (cpm). The amount of D3 derivative is shown.
Claims (1)
を有効成分とする抗ビタミンＤ剤。1 1α-fluoro-25-hydroxyvitamin D 3
An anti-vitamin D agent containing as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17507183A JPS6064924A (en) | 1983-09-21 | 1983-09-21 | Anti-vitamin d agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17507183A JPS6064924A (en) | 1983-09-21 | 1983-09-21 | Anti-vitamin d agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6064924A JPS6064924A (en) | 1985-04-13 |
| JPH0377173B2 true JPH0377173B2 (en) | 1991-12-09 |
Family
ID=15989718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17507183A Granted JPS6064924A (en) | 1983-09-21 | 1983-09-21 | Anti-vitamin d agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6064924A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180265463A1 (en) * | 2014-12-24 | 2018-09-20 | Kyoto University | Vitamin D3 Derivatives and Pharmaceutical Use Thereof |
| US11932595B2 (en) | 2020-09-17 | 2024-03-19 | KYOTO UNIVERSITY, NATIONAL UNIVERSITY CORPORATION TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY, TEIKYO UNIVERSITY and THE UNIVERSITY OF TOKYO | VDR-silent vitamin D derivative as inhibitors of SREBP and pharmaceutical use thereof |
-
1983
- 1983-09-21 JP JP17507183A patent/JPS6064924A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6064924A (en) | 1985-04-13 |
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