JPH05221924A - Secosterol compound - Google Patents
Secosterol compoundInfo
- Publication number
- JPH05221924A JPH05221924A JP4029771A JP2977192A JPH05221924A JP H05221924 A JPH05221924 A JP H05221924A JP 4029771 A JP4029771 A JP 4029771A JP 2977192 A JP2977192 A JP 2977192A JP H05221924 A JPH05221924 A JP H05221924A
- Authority
- JP
- Japan
- Prior art keywords
- group
- het
- added
- compound
- chloroform
- 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.)
- Pending
Links
Abstract
Description
【０００１】[0001]
【産業上の利用分野】この発明は、セコステロール化合
物とこれを含有する血清脂質低下剤に関するものであ
る。TECHNICAL FIELD The present invention relates to a secosterol compound and a serum lipid lowering agent containing the same.
【０００２】[0002]
【従来の技術とその課題】従来より、動脈硬化を誘発す
る高脂血症の治療薬として種々の血清脂質低下剤が開発
され、使用されてきている。しかしながら、従来の血清
脂質低下剤は脂質代謝の改善作用が十分でなく、またそ
の副作用も無視しえないものであった。たとえば、一般
に広く使用されている血清脂質低下剤としてクロフィブ
レートが知られているが、このクロフィブレートは血清
コレステロールをある程度低下させることはできるが中
性脂肪を低下させることはできず、またその副作用も問
題となるために、結局は血清脂質低下剤として実用的に
満足できるものではなかった。そこで、その使用にあっ
ては血清脂質の変化に注意しながら長期間服用すること
を余儀なくされていた。2. Description of the Related Art Conventionally, various serum lipid lowering agents have been developed and used as therapeutic agents for hyperlipidemia that induces arteriosclerosis. However, conventional serum lipid-lowering agents have insufficient lipid metabolism-improving actions, and their side effects cannot be ignored. For example, clofibrate is known as a widely used serum lipid lowering agent, but this clofibrate can lower serum cholesterol to some extent but cannot lower triglyceride, and Since its side effect also poses a problem, it was not practically satisfactory as a serum lipid lowering agent in the end. Therefore, in its use, it was forced to take for a long period of time while paying attention to changes in serum lipids.
【０００３】このため、血清コレステロールの低下作用
とともに中性脂肪の低下作用も大きい新たな血清脂質低
下剤の開発が望まれていた。この発明は、以上のような
従来の脂質低下剤の問題点を解決し、血清中のコレステ
ロールと共に中性脂肪をも低下させることができる薬理
活性化合物等として有用な、新規セコステロール化合物
と、これを用いた血清脂質低下剤を提供することを目的
としている。Therefore, it has been desired to develop a new serum lipid-lowering agent which has a large serum cholesterol-lowering effect as well as a neutral fat-lowering effect. The present invention solves the problems of the conventional lipid lowering agents as described above, and is useful as a pharmacologically active compound or the like that can reduce neutral fat as well as cholesterol in serum, and a novel secosterol compound, It is intended to provide a serum lipid lowering agent using
【０００４】[0004]
【課題を解決するための手段】この発明は、上記の課題
を解決するものとして、次の一般式（１）The present invention has the following general formula (1) for solving the above problems.
【０００５】[0005]
【化２】 [Chemical 2]
【０００６】（式中のＲはＨｅｔ−，Ｈｅｔ−ＣＯ−，
Ｈｅｔ−Ｂ−ＣＯ−，Ａｒ−ＣＯ−，Ａｒ−Ｂ−ＣＯ−
のいずれかの官能基を示し、ここで、Ｈｅｔは、置換基
を有してもよい含窒素複素環基を、Ａｒは、置換基を有
してもよい芳香族基を、またＢは、炭素鎖もしくは異項
原子を介する炭素鎖を示す。(R in the formula is Het-, Het-CO-,
Het-B-CO-, Ar-CO-, Ar-B-CO-
Wherein Het represents a nitrogen-containing heterocyclic group which may have a substituent, Ar represents an aromatic group which may have a substituent, and B represents Indicates a carbon chain or a carbon chain through a heteroatom.
【０００７】Ａは炭化水素基を示す。）で表わされるセ
コステロール化合物を提供する。また、この発明は、こ
のセコステロール化合物もしくはその薬理的に許容しう
る塩を含有することを特徴とする血清脂質低下剤をも提
供する。この一般式（１）で表わされるセコステロール
化合物において、Ｒは、前記した通りの官能基より選択
されるが、このうちのＨｅｔ−，Ｈｅｔ−ＣＯ−もしく
はＨｅｔ−Ｂ−ＣＯ−基のＨｅｔについては、ピロー
ル、ピロリジン、インドール、ピリジン、ピペリジン、
キノリン、ジアゾール、ジアジン等の１個以上の窒素原
子を環構成原子をも有する複素環基、オキサゾール、モ
ルホリン等の他の異項原子をも有する複素環基の任意の
もの、そしてこれらの複素環にハロゲン原子、アルキル
基、アリール基、ヘテロアリール基、水酸基、アルコキ
シ基、カルボニル基、カルボキシル基、アルコキシカル
ボニル基、カルバモイル基、ニトロ基、アミノ基、シア
ノ基、Ｎ−オキシド基等の置換基の任意のものを有して
いてもよい複素環基が例示される。なお、Ｈｅｔ−基の
場合には、環構成原子の窒素原子が酸素原子と結合して
イミノエーテルを形成してもよい。A represents a hydrocarbon group. ) Is provided. The present invention also provides a serum lipid-lowering agent containing the secosterol compound or a pharmacologically acceptable salt thereof. In the secosterol compound represented by the general formula (1), R is selected from the functional groups as described above. Of these, Het-, Het-CO- or Het-B-CO- group Het Is pyrrole, pyrrolidine, indole, pyridine, piperidine,
Any heterocyclic group having one or more nitrogen atoms also having a ring-constituting atom such as quinoline, diazole or diazine, any heterocyclic group having another heteroatom such as oxazole or morpholine, and these heterocycles Of halogen atom, alkyl group, aryl group, heteroaryl group, hydroxyl group, alkoxy group, carbonyl group, carboxyl group, alkoxycarbonyl group, carbamoyl group, nitro group, amino group, cyano group, N-oxide group and the like. The heterocyclic group which may have any is illustrated. In the case of the Het-group, the nitrogen atom of the ring-constituting atom may be bonded to the oxygen atom to form an imino ether.
【０００８】Ａｒ−ＣＯ−、Ａｒ−Ｂ−ＣＯ−の場合に
も、芳香族基のＡｒは、単環、多環のいずれでもよく、
前記したような各種の置換基を有していてもよい。Ｂの
炭素鎖は、たとえばＣ1 〜Ｃ6 程度の飽和もしくは不飽
和の炭素鎖とすることができ、これらは、酸素、窒素、
硫黄原子等の異項原子を介していてもよい。In the case of Ar-CO- and Ar-B-CO-, the aromatic group Ar may be either monocyclic or polycyclic,
It may have various substituents as described above. The carbon chain of B can be, for example, a saturated or unsaturated carbon chain of about C 1 to C 6 , which includes oxygen, nitrogen,
It may be via a heteroatom such as a sulfur atom.
【０００９】また、一般式（１）におけるＡの炭化水素
基は、たとえばＣ3 〜Ｃ10のアルキル基、もしくはアル
ケニル基とすることができる。これらの一般式（１）で
表わされる化合物は、各種の公知方法をはじめとする適
宜な手段によって製造することができる。たとえば、次
式（２）The hydrocarbon group represented by A in the general formula (1) may be, for example, a C 3 -C 10 alkyl group or an alkenyl group. The compound represented by the general formula (1) can be produced by an appropriate means including various known methods. For example, the following equation (2)
【００１０】[0010]
【化３】 [Chemical 3]
【００１１】のコレステロールのＣ−５位および６位の
２重結合を酸化し、ＮａＢＨ4 等によって還元すること
によって製造することができる。この酸化にはオゾンを
使用することができる。また、前記式（２）の化合物に
おいて、ＲＯ−がＨＯ−の水酸基である化合物を同様に
酸化および還元し、これを、Ｃ−６位の水酸基をトリチ
ル基によって保護し、次式（３）It can be produced by oxidizing the double bonds at the C-5 and 6 positions of cholesterol in (1) and reducing it with NaBH 4 or the like. Ozone can be used for this oxidation. Further, in the compound of the above formula (2), a compound in which RO- is a hydroxyl group of HO- is similarly oxidized and reduced, and the hydroxyl group at the C-6 position is protected by a trityl group, and the following formula (3)
【００１２】[0012]
【化４】 [Chemical 4]
【００１３】の化合物のＣ−３位水酸基をエステル化反
応してこの発明の化合物を製造することもできる。もち
ろん、これらの反応以外に、官能基の導入反応を適宜に
行うことができる。たとえば以上のようにして製造する
ことができるこの発明の一般式（１）で表わされるセコ
ステロール化合物は血清コレストロールの低下作用及び
中性脂肪の低下作用の双方に優れており、また肝障害に
対する作用も従来の血清脂質低下剤よりも低いので、血
清脂質低下剤として有用である。その場合、血清脂質低
下剤として、５，６−セコ−ステロールの誘導体の薬学
的に許容しうる塩を用いてもよい。The compound of the present invention can also be produced by subjecting the C-3 hydroxyl group of the compound of 1 to an esterification reaction. Of course, in addition to these reactions, a reaction for introducing a functional group can be appropriately performed. For example, the secosterol compound represented by the general formula (1) of the present invention, which can be produced as described above, is excellent in both serum cholesterol lowering action and neutral fat lowering action, and also acts on liver damage. Since it is lower than conventional serum lipid lowering agents, it is useful as a serum lipid lowering agent. In that case, as the serum lipid lowering agent, a pharmaceutically acceptable salt of a derivative of 5,6-seco-sterol may be used.
【００１４】この血清脂質低下剤は経口投与、非経口投
与のいずれにも適するように調整することができる。経
口投与により使用する場合には、この発明のステロール
化合物を定法により担体、賦形剤、希釈剤等を用いて、
粉末、顆粒、錠剤、カプセル等に形成する。また、非経
口投与により使用する場合には、必要に応じてＰＨ調整
剤、保存剤、安定剤等を添加して形成することができ
る。This serum lipid lowering agent can be adjusted to be suitable for both oral administration and parenteral administration. When used by oral administration, the sterol compound of the present invention is used by a conventional method using a carrier, an excipient, a diluent, etc.
It is formed into powder, granules, tablets, capsules, etc. When used by parenteral administration, it can be formed by adding a pH adjusting agent, a preservative, a stabilizer, etc., if necessary.
【００１５】以下、この発明の実施例に基づいてさらに
具体的に説明する。Hereinafter, the present invention will be described more specifically based on the embodiments.
【００１６】[0016]
【実施例】実施例１ （ａ）コレステリルニコチネート コレステロール３ｇの塩化メチレン６０ml溶液にピリジ
ン1.9ml を加え、氷冷下ニコチン酸クロライド塩酸塩2.
1 ｇを添加し、続いて室温で１晩攪拌した。反応液を
水、希塩酸、水、希炭酸水素ナトリウム溶液、水の順に
洗浄し、無水硫酸マグネシウムで乾燥後、減圧下に溶媒
留去した。得られた残渣をメタノール−クロロホルムに
より再結晶し、無色針状晶として次の物性値のコレステ
リルニコチネートを3.5 ｇ（収率91.6％）得た。 Example 1 (a) Cholesteryl nicotinate To a solution of 3 g of cholesterol in 60 ml of methylene chloride was added 1.9 ml of pyridine, and nicotinic acid chloride hydrochloride was added under ice cooling.2.
1 g was added, followed by stirring overnight at room temperature. The reaction solution was washed with water, diluted hydrochloric acid, water, diluted sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methanol-chloroform to obtain 3.5 g (yield 91.6%) of cholesteryl nicotinate having the following physical properties as colorless needle crystals.
【００１７】[0017]
【数１】 [Equation 1]
【００１８】（ｂ） ３β−ニコチノイロキシ−５，６
−セココレスタン−５α，６−ジオール 上記（ａ）により得られたコレステリルニコチネート1.
0 ｇのクロロホルム２５ml溶液にエタノール0.5ml を加
え、内温−４３℃でオゾンガスを２時間吹き込んだ。薄
層クロマトにより原料の消失を確認後、アルゴンガスを
１０分間吹き込み過剰のオゾンガスを追い出した。次い
で、同温度でメタノール５mlを加え更にＮａＢＨ4 ２５
０mgを添加し、続いて室温で一晩攪拌した。反応液にア
セトン２mlを加え過剰のＮａＢＨ4 を分解し、減圧下に
濃縮し、得られた残渣をシリカゲルカラムクロマト（ク
ロロホルム：メタノール−３０：１〜２０：１）により
精製した。水−イソプロピルアルコールから再結晶し、
無色針状晶として次の物性値の３β−ニコチノイロキシ
−５，６−セココレスタン−５α，６−ジオール（ＳＣ
−０１）を２８０mg（収率26.1％）得た。(B) 3β-nicotinoyloxy-5,6
-Secocolestan-5α, 6-diol Cholesteryl nicotinate obtained by the above (a) 1.
0.5 ml of ethanol was added to a 25 ml solution of 0 g of chloroform, and ozone gas was blown into the solution at an internal temperature of −43 ° C. for 2 hours. After confirming the disappearance of the raw materials by thin layer chromatography, argon gas was blown for 10 minutes to drive out excess ozone gas. Next, at the same temperature, 5 ml of methanol was added and further NaBH 4 25
0 mg was added, followed by stirring overnight at room temperature. Acetone (2 ml) was added to the reaction solution to decompose excess NaBH 4, and the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol-30: 1 to 20: 1). Recrystallized from water-isopropyl alcohol,
As colorless needle-like crystals, 3β-nicotinoyloxy-5,6-secocholestane-5α, 6-diol (SC
-01) was obtained in an amount of 280 mg (yield 26.1%).
【００１９】[0019]
【数２】 [Equation 2]
【００２０】実施例２ （ａ） ５，６−セココレスタン−３β，５α，６−ト
リオール コレステロール２０ｇのクロロホルム５００ml溶液にエ
タノール１０mlを加え、内温−３５℃でオゾンガスを４
時間吹き込んだ。薄層クロマトにより原料の消失を確認
後、アルゴンガスを１０分間吹き込み過剰のオゾンガス
を追い出した。次いで、同温度でメタノール１００mlを
加え更にＮａＢＨ4 ５ｇを添加し、続いて室温で一晩攪
拌した。反応液にアセトン３０mlを加え過剰のＮａＢＨ
4 を分解し、減圧下に濃縮し、得られた残渣をシリカゲ
ルカラムクロマト（クロロホルム：メタノール＝２０：
１）により精製した後、メタノールから再結晶して、無
色針状晶として次の物性値の５，６−セココレスタン−
３β，５α，６−トリオールを14.9ｇ（収率68.2％）得
た。 Example 2 (a) 5,6-sechocholestane-3β, 5α, 6-triol 10 ml of ethanol was added to 500 ml of chloroform containing 20 g of cholesterol, and ozone gas was adjusted to 4 at an internal temperature of -35 ° C.
I breathed time. After confirming the disappearance of the raw materials by thin layer chromatography, argon gas was blown for 10 minutes to drive out excess ozone gas. Then, 100 ml of methanol was added at the same temperature, and 5 g of NaBH 4 was further added, followed by stirring at room temperature overnight. To the reaction solution, add 30 ml of acetone and add excess NaBH.
4 was decomposed and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 20:
After purification by 1), it was recrystallized from methanol to give colorless needle crystals having the following physical properties of 5,6-secocholestane-
14.9 g (yield 68.2%) of 3β, 5α, 6-triol was obtained.
【００２１】[0021]
【数３】 [Equation 3]
【００２２】（ｂ）５，６−セココレスタン−６−トリ
フェニルメトキシ−３β，５α−ジオール 前記（ａ）の生成物14.1ｇのピリジン７５ml溶液に、氷
冷下塩化トリチル9.8ｇを添加し同温度で１時間攪拌
後、室温で一晩攪拌した。次いで塩化トリチル1.0 ｇを
追加し更に室温で５時間攪拌した。反応液を減圧下に溶
媒留去した。得られた残渣をクロロホルムに溶解し、希
塩酸、飽和食塩水の順に洗浄後、無水硫酸マグネシウム
で乾燥し減圧下に溶媒留去した。得られた残渣をシリカ
ゲルカラムクロマト（ｎ−ヘキサン：酢酸エチル＝４：
１−３：１）により分離精製し、無色アモルファスとし
て５，６−セココレスタン−６−トリフェニルメトキシ
−３β，５α−ジオールを21.1ｇ（収率95.6％）得た。(B) 5,6-secocholestane-6-triphenylmethoxy-3β, 5α-diol To a solution of 14.1 g of the product of (a) above in 75 ml of pyridine, 9.8 g of trityl chloride was added under ice cooling, and the same temperature was added. After stirring for 1 hour at room temperature, the mixture was stirred at room temperature overnight. Next, 1.0 g of trityl chloride was added, and the mixture was further stirred at room temperature for 5 hours. The solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was dissolved in chloroform, washed with diluted hydrochloric acid and saturated brine in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 4:
After separation and purification by 1-3: 1), 21.1 g (yield 95.6%) of 5,6-secocholestane-6-triphenylmethoxy-3β, 5α-diol was obtained as a colorless amorphous.
【００２３】[0023]
【数４】 [Equation 4]
【００２４】（ｃ） エステル化反応生成物 原料カルボン酸（ＲＣＯ2 Ｈ）4.5mmol の塩化メチレン
２０ml溶液に、氷冷下ジメチルホルムアミド4.5 ｍｍｏ
ｌ及び塩化チオニル18.0mmolを加え室温で２時間攪拌し
た。反応液を減圧下濃縮し、得られる粗製酸クロライド
を精製することなくそのまま使用した。一方、前記
（ｂ）工程の生成物である５，６−セココレスタン−６
−トリフェニルメトキシ−３β，５α−ジオールの3.0m
mol の塩化メチレン４０ml溶液にピリジン9.0mmol を加
え、次いで氷冷下、先の粗製酸クロライドの塩化メチレ
ン３ml溶液を滴加し室温で２時間攪拌した。反応液を
水、希塩酸、水、希炭酸水素ナトリウム溶液、水の順に
洗浄し、無水硫酸マグネシウムで乾燥後、減圧下に溶媒
留去した。得られた残渣をシリカゲルカラムクロマト
（クロロホルム：メタノール）により精製し、アモルフ
ァスとして、原料カルボン酸の種類に応じて次の表１お
よび表２の各種エステル体を得た。(C) Esterification reaction product A solution of 4.5 mmol of the starting carboxylic acid (RCO 2 H) in 20 ml of methylene chloride was added to dimethylformamide (4.5 mmo) under ice cooling.
1 and thionyl chloride (18.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude acid chloride was used as it was without purification. On the other hand, 5,6-secocholestane-6, which is the product of the step (b),
-Triphenylmethoxy-3β, 5α-diol 3.0m
To a solution of 40 mol of methylene chloride in 40 ml of pyridine, 9.0 mmol of pyridine was added, and then under ice-cooling, a solution of the above crude acid chloride in 3 ml of methylene chloride was added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water, diluted hydrochloric acid, water, diluted sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol) to obtain various ester compounds shown in Tables 1 and 2 below as amorphous depending on the kind of raw material carboxylic acid.
【００２５】[0025]
【表１】 [Table 1]
【００２６】[0026]
【表２】 [Table 2]
【００２７】（ｄ） トリチル基の脱離 前記（ｃ）工程の各々の生成物の5.7mmol のメタノール
４０mlとクロロホルム１０ml溶液に、氷冷下ｐ−トルエ
ンスルホン酸１水和物（前記生成物に対し１０％w/w
良）を加え室温で３０分間攪拌した。反応液にクロロホ
ルムを加え飽和食塩水、希炭酸水素ナトリウム溶液、飽
和食塩水の順に洗浄し、無水硫酸マグネシウムで乾燥
後、減圧下に溶媒留去した。得られた残渣をシリカゲル
カラムクロマト（クロロホルム：メタノール）により精
製し、無色アモルファスとして、次の表３および表４の
化合物を得た。ＳＣ−０２，ＳＣ−０４およびＳＣ−０
５の３化合物は再結晶により更に精製し、スクリーニン
グサンプルとした。なお、５ｃおよび５ｆ，５ｇの２化
合物はアモルファスのまま次の反応に使用した。(D) Removal of trityl group To a solution of 5.7 mmol of each product of the above step (c) in 40 ml of methanol and 10 ml of chloroform, p-toluenesulfonic acid monohydrate (to the above product) was added under ice cooling. 10% w / w
Good) was added and stirred at room temperature for 30 minutes. Chloroform was added to the reaction solution, which was washed with saturated saline, a dilute sodium hydrogen carbonate solution, and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol) to give the compounds shown in Tables 3 and 4 below as colorless amorphous. SC-02, SC-04 and SC-0
The 3 compounds of 5 were further purified by recrystallization and used as a screening sample. The two compounds, 5c, 5f, and 5g, were used in the next reaction as amorphous.
【００２８】[0028]
【表３】 [Table 3]
【００２９】[0029]
【表４】 [Table 4]
【００３０】実施例３ 前記実施例２（ｄ）により得られた脱トリチル体（５
ｃ）はカラム精製することなく粗製のまま使用した。粗
製５ｃ化合物2.0 ｇのベンゼン３０ml溶液に、氷冷下0.
1 Ｎ−ＫＯＨ／ＭｅＯＨ１０mlを１０分間かけて滴加し
た。反応液に水を加え２Ｎ−塩酸にて酸性とし、クロロ
ホルムで抽出した。有機層を飽和食塩水で洗浄し、無水
硫酸マグネシウムで乾燥後、減圧下に溶媒留去した。得
られた残渣をシリカゲルカラムクロマト（クロロホル
ム：メタノール４０：１−３０：１）により精製し更に
イソプロピルアルコール−水により再結晶して、無色針
状晶として次の物性値の３β−（４−ヒドロキシ−３−
メトキシシンナモイルオキシ）−５，６−セココレスタ
ン−５α，６−ジオール（ＳＣ−０３）を５８０mg（２
stepで46.6％）得た。 Example 3 Detritylated product (5) obtained in Example 2 (d) above
c) was used as crude without column purification. To a solution of 2.0 g of the crude 5c compound in 30 ml of benzene, under ice cooling,
10 ml of 1 N-KOH / MeOH was added dropwise over 10 minutes. Water was added to the reaction solution, acidified with 2N-hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol 40: 1-30: 1) and recrystallized from isopropyl alcohol-water to give colorless needle crystals with the following physical properties of 3β- (4-hydroxy). -3-
580 mg (2) of methoxycinnamoyloxy) -5,6-secocholestane-5α, 6-diol (SC-03)
46.6% in step).
【００３１】[0031]
【数５】 [Equation 5]
【００３２】実施例４ 前記実施例２（ｄ）より得られた脱トリチル体（５ｆ）
（５ｇ）はカラム精製することなく粗製のまま使用し
た。粗製の化合物（５ｆ）（５ｇ）の各々3.0mmol のベ
ンゼン２０mlとクロロホルム５ml溶液に0.1 Ｎ−ＫＯＨ
／ＭｅＯＨ１０mlを室温で１５分間かけて滴加した。反
応液にクロロホルム及び水を加え、２Ｎ−塩酸にて水層
を酸性とし有機層を分取した。更に水層をクロロホルム
で抽出し、有機層を併せて飽和食塩水で洗浄し、無水硫
酸マグネシウムで乾燥後、減圧下に溶媒留去した。得ら
れた残渣をシリカゲルカラムクロマト（クロロホルム：
メタノール＝４０：１−３０：１）により精製して無色
結晶として次の物性値を有する化合物、すなわち、３β
−〔２−ヒドロキシ−４−（２，２，２−トリクロルエ
トキシカルボニルアミノ）ベンゾイロキシ〕−５，６−
セココレスタン−５α，６−ジオール（ＳＣ−１２）を
得た（収率、５ｆより２stepで68.8％）。 Example 4 Detritylated product (5f) obtained from the above Example 2 (d)
(5 g) was used as crude without column purification. To a solution of the crude compound (5f) (5g) in an amount of 3.0 mmol each in 20 ml of benzene and 5 ml of chloroform is added 0.1 N-KOH.
10 ml of / MeOH was added dropwise at room temperature over 15 minutes. Chloroform and water were added to the reaction solution, the aqueous layer was made acidic with 2N-hydrochloric acid, and the organic layer was separated. The aqueous layer was extracted with chloroform, the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform:
A compound having the following physical properties as colorless crystals obtained by purification with methanol = 40: 1-30: 1, that is, 3β
-[2-hydroxy-4- (2,2,2-trichloroethoxycarbonylamino) benzoyloxy] -5,6-
Secocholestane-5α, 6-diol (SC-12) was obtained (yield: 68.8% in 2 steps from 5f).
【００３３】[0033]
【数６】 [Equation 6]
【００３４】また、同様にして、無色結晶の次の物性値
を有する化合物、すなわち、３β（４−エトキシカルボ
ニルアミノ−２−ヒドロキシベンゾイロキシ）−５，６
−セココレスタン−５α，６−ジオール（ＳＣ−１３）
を得た。Similarly, a compound having the following physical properties as colorless crystals, namely, 3β (4-ethoxycarbonylamino-2-hydroxybenzoyloxy) -5,6
-Secocholestane-5α, 6-diol (SC-13)
Got
【００３５】[0035]
【数７】 [Equation 7]
【００３６】実施例５ 実施例４の化合物（ＳＣ−１３）の1.19ｇのメタノール
１５mlとジメチルスルホキサイド3.5ml 溶液にアセチル
アセトン2.5ml 及び亜鉛粉末1.2 ｇを加え、８０℃で２
時間攪拌した。亜鉛粉末を濾去し、濾液にクロロホルム
を加え希炭酸水素ナトリウム溶液、水、飽和食塩水の順
に洗浄し、無水硫酸マグネシウムで乾燥後、減圧下に溶
媒留去した。得られた残渣をシリカゲルカラムクロマト
（クロロホルム：メタノール＝３０：１）により精製
し、更にメタノール−水により再結晶して、無色薄片晶
として次の物性値を有する３β−（４−アミノ−２−ヒ
ドロキシベンゾイロキシ）−５，６−セココレスタン−
５α，６−ジオール（ＳＣ−０７）を４４０mg（収率4
8.7％）得た。 Example 5 To a solution of the compound of Example 4 (SC-13) (1.19 g) in methanol (15 ml) and dimethyl sulfoxide (3.5 ml) was added acetylacetone (2.5 ml) and zinc powder (1.2 g).
Stir for hours. The zinc powder was filtered off, chloroform was added to the filtrate, and the mixture was washed with a dilute sodium hydrogen carbonate solution, water and saturated brine in that order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and recrystallized from methanol-water to give 3β- (4-amino-2-3) having the following physical properties as colorless flaky crystals. Hydroxybenzoyloxy) -5,6-secocholestane-
440 mg of 5α, 6-diol (SC-07) (yield 4
8.7%).
【００３７】[0037]
【数８】 [Equation 8]
【００３８】実施例６ アルゴン置換下、２−ピラジンカルボン酸９３３mgとカ
ルボニルジイミダゾール1.10ｇの混合物にテトラハイド
ロフラン２０mlを加え室温で１時間攪拌した。次いで、
氷冷下に、実施例２（ｂ）工程より得た５，６−セココ
レスタン−６−トリフェニルメトキシ−３β，５α−ジ
オールの2.50ｇのテトラハイドロフラン２０ml溶液を滴
加し室温で一晩攪拌した。反応液を減圧下濃縮し、得ら
れた残渣にクロロホルムを加え、水、希塩酸、水、希炭
酸水素ナトリウム溶液、水の順に洗浄し、無水硫酸マグ
ネシウムで乾燥後、減圧下に溶媒留去した。得られた残
渣をシリカゲルカラムクロマト（ｎ−ヘキサン：酢酸エ
チル＝３：１）により精製し、次の物性値の３β−（２
−ピラジンカルボニルオキシ）−５，６−セココレスタ
ン−６−トリフェニルメトキシ−５α−オールを無色ア
モルファスとして1.6 ｇ（収率55.2％）得た。 Example 6 20 ml of tetrahydrofuran was added to a mixture of 933 mg of 2-pyrazinecarboxylic acid and 1.10 g of carbonyldiimidazole under argon substitution, and the mixture was stirred at room temperature for 1 hour. Then
A solution of 5,6-secocholestane-6-triphenylmethoxy-3β, 5α-diol (2.50 g) in tetrahydrofuran (20 ml) was added dropwise under ice-cooling and the mixture was stirred at room temperature overnight. did. The reaction mixture was concentrated under reduced pressure, chloroform was added to the obtained residue, and the mixture was washed with water, diluted hydrochloric acid, water, diluted sodium hydrogen carbonate solution and water in this order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), and 3β- (2
-Pyrazinecarbonyloxy) -5,6-secocholestane-6-triphenylmethoxy-5α-ol was obtained as colorless amorphous in an amount of 1.6 g (yield 55.2%).
【００３９】[0039]
【数９】 [Equation 9]
【００４０】次いで、5.7mmol のメタノール４０mlとク
ロロホルム１０ml溶液に氷冷下ｐ−トルエンスルホン酸
１水和物（前記生成物に対し１０％w/w 量）を加え室温
で３０分間攪拌した。反応液にクロロホルムを加え飽和
食塩水、希炭酸水素ナトリウム溶液、飽和食塩水の順に
洗浄し、無水硫酸マグネシウムで乾燥後、減圧下に溶媒
留去した。得られた残渣をシリカゲルカラムクロマト
（クロロホルム：メタノール）により精製し、さらにメ
タノールによって再結晶してこの発明の化合物である３
β−（２−ピラジンカルボニルオキシ−５，６−セココ
レスタン−５α，６−ジオール（ＳＣ−１１）を得た。
その物性値は次の通りであった。Then, p-toluenesulfonic acid monohydrate (10% w / w amount based on the above product) was added to a solution of 5.7 mmol of methanol (40 ml) and chloroform (10 ml) under ice cooling and the mixture was stirred at room temperature for 30 minutes. Chloroform was added to the reaction solution, which was washed with saturated saline, a dilute sodium hydrogen carbonate solution, and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol), and recrystallized from methanol to give the compound of the present invention 3.
β- (2-Pyrazinecarbonyloxy-5,6-secocholestane-5α, 6-diol (SC-11) was obtained.
The physical properties were as follows.
【００４１】[0041]
【数１０】 [Equation 10]
【００４２】実施例７ アルゴン置換下、ＤＣＣ3.72ｇの塩化メチレン５０ml溶
液に５−メチル−２−ピラジンカルボン酸1.66ｇを添加
し、次いでビリジン1.79ml及び実施例６と同様の実施例
２（ｂ）工程より得たジオール体4.0 ｇを加え室温で6.
5 時間攪拌した。反応液中の不溶物を濾別し、炉液を飽
和食塩水、希塩酸、飽和食塩水、希炭酸水素ナトリウム
溶液、飽和食塩水の順に洗浄し、無水硫酸マグネシウム
で乾燥後、減圧下に溶媒留去した。得られた残渣をシリ
カゲルカラムクロマト（クロロホルム：メタノール＝５
０：１）により精製し、淡黄色アモルファストとして次
の物性値を有するエステル体を4.5 ｇ（収率95.4％）得
た。 Example 7 Under argon substitution, 1.66 g of 5-methyl-2-pyrazinecarboxylic acid was added to a solution of 3.72 g of DCC in 50 ml of methylene chloride, followed by 1.79 ml of viridine and Example 2 (b) similar to Example 6. ) Was added at room temperature and 4.0 g of the diol derivative obtained in step 6) was added.
Stir for 5 hours. The insoluble matter in the reaction solution was filtered off, and the furnace solution was washed with saturated saline, dilute hydrochloric acid, saturated saline, dilute sodium hydrogen carbonate solution, and saturated saline in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Left. The obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 5).
Purification by 0: 1) gave 4.5 g (yield 95.4%) of an ester having the following physical properties as a pale yellow amorphous substance.
【００４３】[0043]
【数１１】 [Equation 11]
【００４４】次いで5.7mmol のメタノール４０mol とク
ロロホルム１０ml溶液に、氷冷下ｐ−トルエンスルホン
酸１水和物（前記生成物に対し１０％W/W 量）を加え室
温で３０分間攪拌した。反応液にクロロホルムを加え飽
和食塩水、希炭酸水素ナトリウム溶液、飽和食塩水の順
に洗浄し、無水硫酸マグネシウムで乾燥後、減圧下に溶
媒留去した。得られた残渣をシリカゲルカラムクロマト
（クロロホルム：メタノール）により精製し、３β−
（５−メチル−２−ピラジンカルボニルオキシ）−５、
６−セココレスタン−５α、６−ジオール（ＳＣ−１
４）を次の物性値を有するものとして得た。Then, p-toluenesulfonic acid monohydrate (10% W / W amount based on the product) was added to a solution of 5.7 mmol of methanol (40 mol) and chloroform (10 ml) and the mixture was stirred at room temperature for 30 minutes. Chloroform was added to the reaction solution, which was washed with saturated saline, a dilute sodium hydrogen carbonate solution, and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (chloroform: methanol) to give 3β-
(5-methyl-2-pyrazinecarbonyloxy) -5,
6-secocholestane-5α, 6-diol (SC-1
4) was obtained having the following physical properties.
【００４５】[0045]
【数１２】 [Equation 12]
【００４６】実施例８ 前記実施例７の生成物（ＳＣ−１４）の1.7 ｇのクロロ
ホルム２０ml溶液にｍ−クロロ過安息香酸６２１mgを加
え、５０℃で１時間攪拌した。次いで、ｍ−クロロ過安
息香酸２４８mgを追加し、同温度で４０分攪拌した。反
応液にクロロホルムを加え、１０％炭酸ナトリウム溶
液、水、飽和食塩水の順に洗浄し、無水硫酸マグネシウ
ムで乾燥後、減圧下に溶媒留去した。得られた残渣をシ
リカゲルカラムクロマト（クロロホルム：メタノール＝
２０：１）により精製し、更にメタンノールクロロホル
ムにより再結晶して、無色プリズム晶として次の物性値
を有する３β−（５−メチルー４−オキシド−２−ピラ
ジンカルボニルオキシ）−５，６−セココレスタン−５
α、６−ジオール（ＳＣ−０９）を８８７mg（収率50.8
％）得た。 Example 8 621 mg of m-chloroperbenzoic acid was added to a solution of the product of Example 7 (SC-14) (1.7 g) in 20 ml of chloroform, and the mixture was stirred at 50 ° C. for 1 hour. Then, 248 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at the same temperature for 40 minutes. Chloroform was added to the reaction solution, which was washed with a 10% sodium carbonate solution, water, and saturated saline in this order, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform: methanol =
20: 1) and further recrystallized from methanol / chloroform to give 3β- (5-methyl-4-oxide-2-pyrazinecarbonyloxy) -5,6-secocholestane having the following physical properties as colorless prism crystals. -5
887 mg of α, 6-diol (SC-09) (yield 50.8
%)Obtained.
【００４７】[0047]
【数１３】 [Equation 13]
【００４８】実施例９ 実施例２（ｂ）で得たジオール体の2.5 ｇ、トリフェニ
ルホスフィン1.18ｇ及びN-ヒドロキシフタルイミドのテ
トラハイドロフラン25ml溶液に、アゾジカルボン酸ジエ
チル0.71mlのテトラハイドロフラン７ml溶液を添加し、
室温で３０分間攪拌した。反応液を減圧下濃縮し、得ら
れた残渣をシリカゲルカラムクロマト（ｎ−ヘキサン：
酢酸エチル＝７：１−３：１）により精製した。無色ア
モルファスとして次の物性値を有する３α−フタルイミ
ジルオキシ−５，６−セココレスタン−６−トリフェニ
ルメトキシ−５α−オ−ルを2.62ｇ（収率85.9％）得
た。 Example 9 2.5 g of the diol obtained in Example 2 (b), 1.18 g of triphenylphosphine and 25 ml of tetrahydrofuran containing N-hydroxyphthalimide were added to 0.7 ml of diethyl azodicarboxylate and 7 ml of tetrahydrofuran. Add the solution,
Stir for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:
Purified by ethyl acetate = 7: 1-3: 1). 2.62 g (yield 85.9%) of 3α-phthalimidyloxy-5,6-sececholestane-6-triphenylmethoxy-5α-ol having the following physical properties was obtained as a colorless amorphous substance.
【００４９】[0049]
【数１４】 [Equation 14]
【００５０】次いでこの化合物2.5 ｇのメタノール20ml
とクロロホルム１５ml溶液に、氷冷下ｐ−トルエンスル
ホン酸１水和物２５０mgを加え室温で３０分間攪拌し
た。反応液にクロロホルムを加え飽和食塩水、希炭酸水
素ナトリウム溶液、飽和食塩水の順に洗浄し、無水硫酸
マグネシウムで乾燥後、減圧下に溶媒留去した。得られ
た残渣をシリカゲルカラムクロマト（クロロホルム：ア
セトン＝１０：１）により精製し、メタノール−水によ
り結晶化した。無色薄片晶として次の物性値を有する３
α−フタルイミジルオキシ−５，６−セココレスタン−
５α、６−ジオール（ＳＣ−０８）を1.22ｇ（収率69.7
％）得た。Then, 2.5 g of this compound, 20 ml of methanol
To a solution of 15 ml of chloroform and 250 mg of p-toluenesulfonic acid monohydrate under ice cooling, the mixture was stirred at room temperature for 30 minutes. Chloroform was added to the reaction solution, which was washed with saturated saline, a dilute sodium hydrogen carbonate solution, and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: acetone = 10: 1) and crystallized from methanol-water. Colorless flaky crystals having the following physical properties 3
α-phthalimidyloxy-5,6-secocholestane-
1.22 g of 5α, 6-diol (SC-08) (yield: 69.7
%)Obtained.
【００５１】[0051]
【数１５】 [Equation 15]
【００５２】実施例１０ 以上の実施例１〜９によって製造したこの発明の化合物
のうちのＳＣ−０１〜０２、ＳＣ−０４〜０５、および
ＳＣ−０７〜０９について、高コレステロール食（ＨＣ
Ｄ）負荷ラットにおける脂質低下作用を評価した。 （１）化合物について 上記化合物の投与容量が３０mg／５ml／kg（ｂ．ｗ．）
となるように、0.5 ％メチルセロルース溶液に懸濁して
調製した。 Example 10 Among the compounds of the present invention prepared according to the above Examples 1-9, SC-01-02, SC-04-05, and SC-07-09 were tested for high cholesterol diet (HC
D) The lipid lowering effect in loaded rats was evaluated. (1) Compound The dose of the above compound is 30 mg / 5 ml / kg (bw).
Was prepared by suspending it in a 0.5% methyl cellulosic solution.
【００５３】なお、対照群およびＨＣＤ対照群には、0.
5 ％メチルセルロース溶液５ml／kg（ｂ．ｗ．）を経口
投与した。 （２）使用動物 ５週齢のWistar系雄性ラット（日本クレア）を購入（１
９８９．４．１１）後、ＴＰＸ樹脂製ケージに５匹ずつ
収容し、室温２２±１℃、湿度５５±１０％、照明時間
８：００〜の２０：００の飼育室で固型飼料（ＣＥ−
２，日本クレア）および水道水を自由に摂取させ、６日
間予備飼育した。The control group and the HCD control group had 0.
A 5% methylcellulose solution (5 ml / kg (bw)) was orally administered. (2) Animals used Purchase 5 week-old male Wistar rats (CLEA Japan, Inc.) (1
989.4.11), 5 animals each were housed in a TPX resin cage, and the solid feed (CE) was placed in a breeding room at room temperature 22 ± 1 ° C., humidity 55 ± 10%, and lighting time 8:00 to 20:00. −
(2, CLEA Japan, Inc.) and tap water were freely ingested and preliminarily reared for 6 days.
【００５４】予備飼育終了後、動物を体重により層化
し、各群の平均体重が均一になるように１群５匹ずつ１
３群に分けた。群構成は、対照群、ＨＣＤ対照群、ＳＣ
−０１〜０２、ＳＣ−０４〜０５およびＳＣ−０７〜０
９の化合物投与群の合計９群とした。なお、使用動物の
群分け時の体重は、１３１〜１４５kgであった。 （３）試験方法 ＣＥ−２飼料（普通固型飼料）に1.0 ％コレステロー
ル、0.5 ％コール酸および12.0％ココナッツオイルを添
加した固型の高コレステロール飼料（日本クレア）を、
対照群を除くすべての投与群に１０日間自由に摂取させ
るとともに、被検化合物３０mg／kgまたは0.5 ％メチル
セルロース溶液を１日１回１０日間連続経口投与した、
最終投与１８時間前より、動物を絶食状態にし、最終投
与４時間後にエーテル麻酔下で下大静脈より採血し、放
血致死させた。その後、肝、胸腺、両精巣および両副腎
を摘出し湿重量を測定した。採取した静脈血は、直ちに
血液生化学検査を行った。検査項目は、血清総コレステ
ロール（totalcholesterol；ＴＣ）、中性脂肪（trigly
ceride；ＴＧ）、ＨＤＬ−コレステロール（ＨＤＬ−
Ｃ）および血清ＧＯＴ・ＧＰＴの５項目とし、（ＶＬＤ
Ｌ＋ＬＤＬ）・コレステロール値は、ＴＣからＨＤＬ−
Ｃを差し引いて求め、動脈硬化指数（athrogenicinde
x；ＡＬ）は、ＴＣ−ＨＤＬ−Ｃ／ＨＤＬ−Ｃ比より算
出した。After the preliminary breeding, the animals were stratified according to their body weights, and one group of 5 animals was prepared so that the average body weight of each group was uniform.
It was divided into 3 groups. Group composition is control group, HCD control group, SC
-01-02, SC-04-05 and SC-07-0
There were a total of 9 compound administration groups. The weight of the used animals when divided into groups was 131 to 145 kg. (3) Test method A solid high-cholesterol feed (CLEA Japan, Inc.) prepared by adding 1.0% cholesterol, 0.5% cholic acid and 12.0% coconut oil to CE-2 feed (normal solid feed).
All administration groups except the control group were allowed to freely ingest for 10 days, and a test compound of 30 mg / kg or 0.5% methylcellulose solution was orally administered once a day for 10 consecutive days.
The animals were fasted from 18 hours before the final administration, and 4 hours after the final administration, blood was collected from the inferior vena cava under ether anesthesia and killed by exsanguination. Then, the liver, thymus, both testes and both adrenal glands were removed and the wet weight was measured. The collected venous blood was immediately subjected to a blood biochemical test. Test items include serum total cholesterol (TC), triglyceride (trigly)
ceride; TG, HDL-cholesterol (HDL-
C) and serum GOT / GPT as 5 items, (VLD
L + LDL) / cholesterol level from TC to HDL-
Calculated by subtracting C, atherosclerosis index (athrogenicinde
x; AL) was calculated from the TC-HDL-C / HDL-C ratio.
【００５５】なお、試験期間中毎日、体重および摂餌量
を測定した。 （４）統計学的処理 Ｆ検定をＰ＜0.05で行い、等分散の場合はStudent のｔ
検定を用い、不等分散の場合はCochran-Cox 検定を用い
て有意差検定を行った。 （５）試験結果 表５および表６に示したように、ＴＣに関しては、対照
群の65.6mg／dlに対し、ＨＣＤ対照群は96.8mg／dlと約
1.4 倍の増加傾向を示した。ＳＣ−０５投与群では、１
６％の増加抑制傾向を示した。このＳＣ−０５は脂質低
下に適用するに有用である。またＳＣ−０８も増加抑制
傾向を示した。The body weight and food intake were measured every day during the test period. (4) Statistical processing Student's t in the case of equal variance when F-test was performed with P <0.05.
A significant difference test was performed using the test and the Cochran-Cox test in the case of unequal variance. (5) Test results As shown in Table 5 and Table 6, the TC was 65.6 mg / dl in the control group, while the TC group was 96.8 mg / dl, which was about 66.8 mg / dl.
It showed a 1.4-fold increase. 1 in the SC-05 administration group
It showed a 6% increase suppression tendency. This SC-05 is useful in lipid lowering applications. Further, SC-08 also showed a tendency of suppressing increase.
【００５６】ＨＤＬ−Ｃに関しては、対照群の37.4mg／
dlに対し、ＨＣＤ対照群では23.6mg／dlの有意な減少を
示した。ＳＣ−０１およびＳＣ−０２投与群はそれぞれ
２７および２５％の有意な増加を示した。ＳＣ−０１お
よびＳＣ−０２は、血清ＴＣには作用を示さなかったも
のの、ＨＤＬ−Ｃを有意に増加し、（ＶＬＤＬ＋ＬＤ
Ｌ）−Ｃを低下したことによりＡＩを低下した。リボ蛋
白の一種であるＨＤＬ−Ｃは、体内のコレステロール量
と負の相関を有すること、および抹消組織に蓄積したコ
レステロールを異化臓器である肝に運搬し、抗動脈硬化
作用を発現するが、その指標である（ＶＬＤＬ＋ＬＤ
Ｌ）−ＣとＨＤＬ−Ｃの比（ＡＩ）を低下させることの
重要性が指摘されている。これら両化合物は、ＨＤＬ−
Ｃの著明な増加を示し、抗動脈硬化作用を有する化合物
として期待される。Regarding HDL-C, 37.4 mg / control group
In contrast to dl, the HCD control group showed a significant decrease of 23.6 mg / dl. The SC-01 and SC-02 treated groups showed significant increases of 27 and 25%, respectively. SC-01 and SC-02 had no effect on serum TC, but significantly increased HDL-C (VLDL + LD
L) -C was lowered to lower AI. HDL-C, which is a kind of riboprotein, has a negative correlation with the amount of cholesterol in the body, and transports cholesterol accumulated in peripheral tissues to the liver, which is a catabolic organ, and exhibits an anti-atherogenic effect. It is an index (VLDL + LD
The importance of reducing the ratio of L) -C to HDL-C (AI) has been pointed out. Both of these compounds are HDL-
It shows a marked increase in C and is expected as a compound having an anti-atherogenic effect.
【００５７】（ＶＬＤＬ＋ＬＤＬ）−Ｃに関しては、対
照群の28.2mg／dlに対し、ＨＣＤ対照群では73.2mg／dl
と有意な増加を示した、ＳＣ−０５投与群では、２８％
の増加抑制傾向を示した。また、ＳＣ−０１、ＳＣ−０
８も抑制傾向を示した。ＡＩに関しては、対照群の0.75
7 に対し、ＨＣＤ対照群では3.138 と有意な増加を示し
た。ＳＣ−０１およびＳＣ−０５投与群ではそれぞれ２
３および３６％の増加抑制傾向を示した。ＳＣ−０２も
抑制傾向を示している。Regarding (VLDL + LDL) -C, 28.2 mg / dl in the control group, and 73.2 mg / dl in the HCD control group.
28% in the SC-05 administration group, which showed a significant increase
There was a tendency to suppress the increase. Also, SC-01, SC-0
8 also showed a tendency to be suppressed. For AI, 0.75 of the control group
7, the HCD control group showed a significant increase of 3.138. 2 in SC-01 and SC-05 administration groups
3 and 36% showed the tendency of suppressing increase. SC-02 also shows a tendency for suppression.
【００５８】ＴＧに関しては、対照群の30.4mg／dlに対
し、ＨＣＤ対照群で同値を示した。ＳＣ−０９投与群
は、２６％の有意な低下を示した。ＧＯＴおよびＧＰＴ
に関しては、ＳＣ−０１，−０７およびＳＣ−０９投与
群で、ＨＣＤ投与群に比べそれぞれ１３，２２および１
３％のＧＯＴの有意な低下を示し、ＧＰＴではいずれの
投与群においても有意な作用を示さなかった。Regarding TG, the same value was shown in the HCD control group as compared with 30.4 mg / dl in the control group. The SC-09 treated group showed a significant decrease of 26%. GOT and GPT
Regarding, regarding SC-01, -07 and SC-09 administration groups, 13, 22 and 1 respectively compared to the HCD administration group.
GOT showed a significant decrease of 3%, and GPT showed no significant effect in any administration group.
【００５９】なお、ＧＯＴの有意な減少が認められたも
のの、いずれも生理的正常変動内の変化であり、薬物性
肝障害に対し関与している可能性はないと思われる。Although a significant decrease in GOT was observed, all were within normal physiological changes, and it is unlikely that they are involved in drug-induced liver injury.
【００６０】[0060]
【表５】 [Table 5]
【００６１】[0061]
【表６】 [Table 6]
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/59 ＡＤＮ 7252−4Ｃ Ｃ０７Ｃ 69/712 Ｚ 9279−4Ｈ 69/76 Ｚ 9279−4Ｈ Ａ 9279−4Ｈ 69/80 Ａ 9279−4Ｈ 69/84 9279−4Ｈ 69/94 9279−4Ｈ 69/96 Ｚ 9279−4Ｈ 229/64 8930−4Ｈ 233/73 7106−4Ｈ 271/28 6917−4Ｈ Ｃ０７Ｄ 207/20 7019−4Ｃ 209/48 213/80 241/24 8615−4Ｃ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Office reference number FI Technical indication location A61K 31/59 ADN 7252-4C C07C 69/712 Z 9279-4H 69/76 Z 9279-4H A 9279 -4H 69/80 A 9279-4H 69/84 9279-4H 69/94 9279-4H 69/96 Z 9279-4H 229/64 8930-4H 233/73 7106-4H 271/28 6917-4H C07D 207/20 7019-4C 209/48 213/80 241/24 8615-4C
Claims (2)
ＣＯ−，Ａｒ−ＣＯ−，Ａｒ−Ｂ−ＣＯ−のいずれかの
官能基を示し、ここで、Ｈｅｔは、置換基を有してもよ
い含窒素複素環基を、Ａｒは、置換基を有してもよい芳
香族基を、またＢは、炭素鎖もしくは異項原子を介する
炭素鎖を示す。Ａは炭化水素基を示す。）で表わされる
セコステロール化合物。1. The following general formula (1): (R in the formula is Het-, Het-CO-, Het-B-
CO-, Ar-CO-, or Ar-B-CO- represents any functional group, wherein Het represents a nitrogen-containing heterocyclic group which may have a substituent, and Ar represents a substituent. An aromatic group which may be possessed, and B represents a carbon chain or a carbon chain through a hetero atom. A represents a hydrocarbon group. ) A secosterol compound represented by
的に許容しうる塩を含有することを特徴とする血清脂質
低下剤。2. A serum lipid-lowering agent comprising the sterol compound according to claim 1 or a pharmacologically acceptable salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4029771A JPH05221924A (en) | 1992-02-17 | 1992-02-17 | Secosterol compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4029771A JPH05221924A (en) | 1992-02-17 | 1992-02-17 | Secosterol compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05221924A true JPH05221924A (en) | 1993-08-31 |
Family
ID=12285305
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4029771A Pending JPH05221924A (en) | 1992-02-17 | 1992-02-17 | Secosterol compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05221924A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7999010B2 (en) | 2003-04-15 | 2011-08-16 | Aquinox Pharmaceuticals Inc. | Indene derivatives as pharmaceutical agents |
| US9765085B2 (en) | 2013-03-14 | 2017-09-19 | Aquinox Pharmaceuticals (Canada) Inc. | SHIP1 modulators and methods related thereto |
| US9944590B2 (en) | 2015-06-26 | 2018-04-17 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of the acetate salt of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol |
| US10053415B2 (en) | 2016-01-20 | 2018-08-21 | Aquinox Pharmaceuticals (Canada) Inc. | Synthesis of a substituted indene derivative |
| US10100056B2 (en) | 2013-03-14 | 2018-10-16 | Aquinox Pharmaceuticals (Canada) Inc. | SHIP1 modulators and methods related thereto |
-
1992
- 1992-02-17 JP JP4029771A patent/JPH05221924A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7999010B2 (en) | 2003-04-15 | 2011-08-16 | Aquinox Pharmaceuticals Inc. | Indene derivatives as pharmaceutical agents |
| US8084503B2 (en) | 2003-04-15 | 2011-12-27 | Aquinox Pharmaceuticals Inc. | Indene derivatives as pharmaceutical agents |
| US8673975B2 (en) | 2003-04-15 | 2014-03-18 | Aquinox Pharmaceuticals Inc. | Indene derivatives as pharmaceutical agents |
| US9765085B2 (en) | 2013-03-14 | 2017-09-19 | Aquinox Pharmaceuticals (Canada) Inc. | SHIP1 modulators and methods related thereto |
| US10100056B2 (en) | 2013-03-14 | 2018-10-16 | Aquinox Pharmaceuticals (Canada) Inc. | SHIP1 modulators and methods related thereto |
| US10174046B2 (en) | 2013-03-14 | 2019-01-08 | Aquinox Pharmaceuticals (Canada) Inc. | SHIP1 modulators and methods related thereto |
| US9944590B2 (en) | 2015-06-26 | 2018-04-17 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of the acetate salt of (1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexanol |
| US10065920B2 (en) | 2015-06-26 | 2018-09-04 | Aquinox Pharmaceuticals (Canada) Inc. | Crystalline solid forms of the acetate salt of (1S,3S,4R)-4-((3AS,4R,5S,7AS)-4-(aminomethyl)-7A-methyl-1-methyleneoctahydro-1H-inden-5-YL)-3- (hydroxymethyl)-4-methylcyclohexanol |
| US10053415B2 (en) | 2016-01-20 | 2018-08-21 | Aquinox Pharmaceuticals (Canada) Inc. | Synthesis of a substituted indene derivative |
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