JP2866701B2 - Bone formation promoter - Google Patents
Bone formation promoterInfo
- Publication number
- JP2866701B2 JP2866701B2 JP4651690A JP4651690A JP2866701B2 JP 2866701 B2 JP2866701 B2 JP 2866701B2 JP 4651690 A JP4651690 A JP 4651690A JP 4651690 A JP4651690 A JP 4651690A JP 2866701 B2 JP2866701 B2 JP 2866701B2
- Authority
- JP
- Japan
- Prior art keywords
- present
- compound
- bone formation
- bone
- formation promoter
- 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 - Fee Related
Links
- 230000011164 ossification Effects 0.000 title claims description 10
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- NUDKKGSOPWMRIK-LWKDCUQFSA-N (8R,9S,10S,13R)-17-ethenyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12-decahydro-1H-cyclopenta[a]phenanthrene Chemical compound C=CC1=CC=C2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C NUDKKGSOPWMRIK-LWKDCUQFSA-N 0.000 claims description 2
- -1 3-hydroxy-3-methylbutyloxy Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 17
- 239000011575 calcium Substances 0.000 description 12
- 210000000988 bone and bone Anatomy 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 235000019166 vitamin D Nutrition 0.000 description 3
- 239000011710 vitamin D Substances 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000037147 Hypercalcaemia Diseases 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- 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 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000148 hypercalcaemia Effects 0.000 description 2
- 208000030915 hypercalcemia disease Diseases 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 210000003455 parietal bone Anatomy 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 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 2
- 229940046008 vitamin d Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-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 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000480 effect on calcification Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、１α,3β−ジヒドロキシ−20α−（３−ヒ
ドロキシ−３−メチルブチルオキシ）−9,10−セコ−5,
7,10（19）、プレグナトリエン（以下「本発明の化合
物」と称す。−下式）を有効成分と して含有する医薬、具体的には骨形成促進剤に関す
る。The present invention relates to 1α, 3β-dihydroxy-20α- (3-hydroxy-3-methylbutyloxy) -9,10-seco-5,
7,10 (19), pregnatriene (hereinafter referred to as “compound of the present invention” —the following formula) as an active ingredient The present invention relates to a medicine, specifically an osteogenesis promoter.
従来の技術・発明が解決しようとする問題点 近年ビタミンＤ類の生理作用が逐次明らかにされてき
ているが、その中でカルシウム調節ホルモンとしての役
割が大きな位置を占めている。ビタミンＤ類、例えば１
α,25−ヒドロキシビタミンD3は小腸からのカルシウム
の吸収、腎臓でのカルシウムの再吸収、そして骨カルシ
ウムの溶出と骨形成を促進することがよく知られてい
る。しかしながらこの化合物は長期かつ連続的な投与に
より高カルシウム血症を起こすという難点を有してお
り、骨形成促進剤としては必ずしも満足のいくものでは
ない。Problems to be Solved by Conventional Techniques / Inventions In recent years, the physiological actions of vitamins D have been successively elucidated. Among them, the role of calcium-regulating hormone is dominant. Vitamin Ds, such as 1
alpha, 25-hydroxyvitamin D 3 is absorbed calcium from the small intestine, the calcium reabsorption in the kidney, and It is well known that promote dissolution and bone formation of bone calcium. However, this compound has a drawback of causing hypercalcemia by long-term and continuous administration, and is not always satisfactory as an osteogenesis promoter.
本発明者は、これらの事情を鑑み副作用のない骨形成
促進剤につき鋭意研究した結果、本発明の化合物が小腸
からのカルシウム吸収能を有していないにもかかわらず
骨形成を促進するという事実を、マウス頭頂骨より単離
された骨芽細胞様細胞株MC3T3-E1を用いた実験系で見い
だした。In view of these circumstances, the present inventors have conducted intensive studies on an osteogenesis promoter having no side effects, and as a result, have found that the compound of the present invention promotes osteogenesis despite having no ability to absorb calcium from the small intestine. Was found in an experimental system using an osteoblast-like cell line MC3T3-E1 isolated from the mouse parietal bone.
また本発明の化合物は骨粗鬆症モデルラットを用いた
実験においても骨塩量の減少を抑止する効果を示した。In addition, the compound of the present invention also showed an effect of suppressing a decrease in the amount of bone mineral in an experiment using an osteoporosis model rat.
本発明はこれらの新知見に更に検討を加え完成したも
のである。The present invention has been completed by further studying these new findings.
本発明の化合物は、例えば特開昭61-267550号公報
で、免疫調節作用および腫瘍細胞の分化誘導能を有する
化合物として知られているが、本発明の骨形成促進作用
については何ら記載されていない。The compound of the present invention is known, for example, in JP-A-61-267550 as a compound having an immunomodulatory effect and an ability to induce tumor cell differentiation, but nothing is described about the osteogenesis promoting effect of the present invention. Absent.
問題点を解決するための手段 本発明の化合物は、例えば１α,3β−ジヒドロキシ−
5,7−プレグナジエン−20α−オールを出発物質として
特開昭61-267550号公報に記載の方法に従って合成され
る。Means for Solving the Problems The compound of the present invention is, for example, 1α, 3β-dihydroxy-
It is synthesized according to the method described in JP-A-61-267550 using 5,7-pregnadien-20α-ol as a starting material.
本発明の化合物は、骨形成の促進作用を有し、骨粗鬆
症等の治療薬として有用である。The compound of the present invention has an action of promoting bone formation and is useful as a therapeutic agent for osteoporosis and the like.
本発明の化合物は常法に従い、例えば経口剤または注
射剤の形に製剤化され投与される。好ましい剤型として
は、例えばカプセル剤、錠剤等である。The compound of the present invention is formulated and administered according to a conventional method, for example, in the form of an oral preparation or an injection. Preferred dosage forms are, for example, capsules, tablets and the like.
本発明の化合物の投与量は、症状および投与方法によ
って若干異なるが、従来のビタミンＤ類と異なり高カル
シウム血症を起こすことがないため、比較的高投与量が
可能である。好ましい範囲は、ヒト成人で１日量0.01〜
10μｇである。The dose of the compound of the present invention slightly varies depending on the condition and the administration method, but unlike conventional vitamin D, it does not cause hypercalcemia, so that a relatively high dose is possible. The preferred range is 0.01 to 1 day for adult humans.
10 μg.
実験例１ マウス頭頂骨より単離された骨芽細胞様細胞株MC3T3-
E1を用い、以下Sudo等の方法〔J.Cell Biol.,96,191（1
983）〕に従い本発明の化合物の45Caの細胞への取込み
で、石灰化へ効果を見た。その結果を図面に示す。Experimental Example 1 Osteoblast-like cell line MC3T3-isolated from mouse parietal bone
Using E1, the following method such as Sudo [J. Cell Biol., 96 , 191 (1
983)], the incorporation of 45 Ca into the cells of the compound of the present invention showed an effect on calcification. The result is shown in the drawing.
実験例２ ａ）骨粗鬆症モデルラットの作製； F344/Du雌性ラット10ヶ月齢（日本チャールズリバー
より購入）を１週間普通食により馴化後、エーテル麻酔
下、OVX（卵巣摘出）術を施し、傷がほぼ回復した術後
２週間後より0.5％Ca dietに切替えた。またコントロー
ルとしてsham operation群を作成し、飼料は正常Ca含量
の1.16％Ca dietとした。この飼料切り換えの時点を０
ヶ月とする。水はCaを除去するためイオン交換水を用
い、群飼いによる動物間の成長差を均一にするため個別
飼いとし３ヶ月間飼育した。また骨代謝に大きな影響を
及ぼすビタミンD3は摂取量を各個体一定にするため、餌
をビタミンD free dietとし、別途ビタミンD3150IU/bod
yを毎週１回経口投与した。Experimental Example 2 a) Preparation of an osteoporosis model rat; F344 / Du female rats 10 months old (purchased from Charles River Japan) were acclimated with a normal diet for one week, and then subjected to OVX (ovariectomy) under ether anesthesia to remove wounds. The diet was switched to a 0.5% Ca diet two weeks after the surgery, which had almost recovered. A sham operation group was prepared as a control, and the feed was 1.16% Ca diet with normal Ca content. The time of this feed change is 0
Months. The water used was ion-exchanged water to remove Ca, and the animals were kept individually for 3 months to equalize the growth difference between the animals in the group. Since the great effect of vitamin D 3 in bone metabolism which intake to each individual constant, the feed with vitamin D free diet, vitamin D 3 separate 150 IU / bod
y was orally administered once a week.
ｂ）本発明の化合物の投与； Ca diet飼育４ヶ月後より、1.0μg/kgの本発明の化合
物をMCT（中鎖脂肪酸のトリグリセライド）に溶解し、
週３回、２ヶ月間経口投与した。なおコントロール群に
はMCTのみを与えた。一群匹数は５〜10匹とした。b) Administration of the compound of the present invention: Four months after breeding a Ca diet, 1.0 μg / kg of the compound of the present invention was dissolved in MCT (triglyceride of medium chain fatty acid),
Oral administration 3 times a week for 2 months. The control group received only MCT. The number of animals per group was 5 to 10 animals.
ｃ）骨塩量の測定； 本発明の化合物最終投与24時間後にラットをエーテル
麻酔下全採血した。その後右大腿骨を得、筋肉等をはく
離し、70％エタノールにて固定した。固定後、Dichroma
Scan DCS-600（ALOKA社製）で骨塩量を測定した。骨塩
量は各個体の大腿骨近位、骨幹、遠位の各部位について
行った。その結果本発明の化合物1.0μg/kg投与群は、
各部位の骨塩量の減少を有意に抑止することが明らかと
なった。c) Measurement of bone mineral content: 24 hours after the last administration of the compound of the present invention, rats were subjected to whole blood collection under ether anesthesia. Thereafter, the right femur was obtained, the muscles and the like were separated, and fixed with 70% ethanol. After fixing, Dichroma
Bone mineral content was measured using Scan DCS-600 (manufactured by ALOKA). The amount of bone mineral was measured for the proximal, diaphyseal and distal sites of the femur of each individual. As a result, the compound of the present invention 1.0 μg / kg administration group,
It was found that the decrease in bone mineral density at each site was significantly suppressed.
図面は、本発明の化合物のMC3T3-E1細胞への45Caの取込
みの効果を示したものである。縦軸にはDNA当りの45Ca
の取込みを、横軸には本発明の化合物の添加濃度を示
す。The figure shows the effect of the incorporation of 45 Ca into MC3T3-E1 cells by the compounds of the present invention. The vertical axis shows 45 Ca per DNA
The horizontal axis shows the concentration of the compound of the present invention.
Claims (2)
ドロキシ−３−メチルブチルオキシ）−9,10−セコ−5,
7,10（19）、プレグナトリエンを有効成分として含有す
る骨形成促進剤。(1) 1α, 3β-dihydroxy-20α- (3-hydroxy-3-methylbutyloxy) -9,10-seco-5,
7,10 (19), an osteogenesis promoter containing pregnatriene as an active ingredient.
形成促進剤。2. The bone formation promoting agent according to claim 1, which is a therapeutic agent for osteoporosis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4651690A JP2866701B2 (en) | 1989-02-28 | 1990-02-27 | Bone formation promoter |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4809889 | 1989-02-28 | ||
| JP1-48098 | 1989-02-28 | ||
| JP4651690A JP2866701B2 (en) | 1989-02-28 | 1990-02-27 | Bone formation promoter |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02289519A JPH02289519A (en) | 1990-11-29 |
| JP2866701B2 true JP2866701B2 (en) | 1999-03-08 |
Family
ID=26386609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4651690A Expired - Fee Related JP2866701B2 (en) | 1989-02-28 | 1990-02-27 | Bone formation promoter |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2866701B2 (en) |
-
1990
- 1990-02-27 JP JP4651690A patent/JP2866701B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02289519A (en) | 1990-11-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |