JPH02167295A - Triterpene compound - Google Patents
Triterpene compoundInfo
- Publication number
- JPH02167295A JPH02167295A JP62299041A JP29904187A JPH02167295A JP H02167295 A JPH02167295 A JP H02167295A JP 62299041 A JP62299041 A JP 62299041A JP 29904187 A JP29904187 A JP 29904187A JP H02167295 A JPH02167295 A JP H02167295A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- represented
- formula
- compound
- carboxylic acid
- 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
- -1 Triterpene compound Chemical class 0.000 title description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 23
- 235000012000 cholesterol Nutrition 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 abstract description 7
- BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 abstract description 6
- CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 abstract description 6
- XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 abstract description 6
- FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 abstract description 6
- BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 abstract description 6
- LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 abstract description 6
- CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 abstract description 6
- 229940058690 lanosterol Drugs 0.000 abstract description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 abstract description 3
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006809 Jones oxidation reaction Methods 0.000 abstract description 2
- KPVWDKBJLIDKEP-UHFFFAOYSA-L dihydroxy(dioxo)chromium;sulfuric acid Chemical compound OS(O)(=O)=O.O[Cr](O)(=O)=O KPVWDKBJLIDKEP-UHFFFAOYSA-L 0.000 abstract description 2
- 150000004965 peroxy acids Chemical class 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 239000005515 coenzyme Substances 0.000 description 2
- JSEMUSFPVZYRSG-UHFFFAOYSA-N ethyl 3-(triphenyl-$l^{5}-phosphanylidene)propanoate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CCC(=O)OCC)C1=CC=CC=C1 JSEMUSFPVZYRSG-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MBZYKEVPFYHDOH-UHFFFAOYSA-N (10S)-3c-Hydroxy-4.4.10r.13t.14c-pentamethyl-17t-((R)-1.5-dimethyl-hexyl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(C)CCCC(C)C)CCC21C MBZYKEVPFYHDOH-UHFFFAOYSA-N 0.000 description 1
- MBZYKEVPFYHDOH-BQNIITSRSA-N 24,25-dihydrolanosterol Chemical compound C([C@@]12C)C[C@H](O)C(C)(C)[C@@H]1CCC1=C2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@]21C MBZYKEVPFYHDOH-BQNIITSRSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 1
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 108091027881 NEAT1 Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 229940127226 anticholesterol agent Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000008687 biosynthesis inhibition Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- GGCLNOIGPMGLDB-GYKMGIIDSA-N cholest-5-en-3-one Chemical compound C1C=C2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 GGCLNOIGPMGLDB-GYKMGIIDSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000008365 organ synthesis Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、新規なトリテルペン化合物、さらに詳細には
コレステロール生合成阻害作用を有し医薬品として有用
な（２４Ｅ）−ラノスタ−３−オキソ−８，２４−ジエ
ン−２６−カルボン酸に関スる。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel triterpene compound, more specifically (24E)-lanosta-3-oxo-8,24, which has a cholesterol biosynthesis inhibitory effect and is useful as a pharmaceutical. -Relates to diene-26-carboxylic acid.
従来の技術
従来、生体内で生成される幾つかの酸化ステロールにコ
レステロール生合成の阻害作用が認められている。この
事実をもとに、酸化コレステロールまたは酸化ラノステ
ロール型の種々のトリテルペン化合物が合成され、それ
らについてコレステロール生合成阻害作用が検討されて
いる。このうち、５α−コレスト−８（１４）−エン−
３β−才一ルー１５−オン［Ｐｒｏｃ、 Ｎａｔｌ、
Ａｃａｄ、 Ｓｃｉ、 ＵＳＡ 、第８１巻、第６８６
１頁（１９８４年）］や］７−オキソー２４．２５−ジ
ヒドロラノステロール Ｊ、Ｐｈａｒｍａｃｏｂｉｏ−
Ｄｙｎ、 。BACKGROUND OF THE INVENTION Conventionally, several oxidized sterols produced in vivo have been recognized to have an inhibitory effect on cholesterol biosynthesis. Based on this fact, various triterpene compounds of the oxidized cholesterol or oxidized lanosterol type have been synthesized, and their cholesterol biosynthesis inhibitory effects have been investigated. Among these, 5α-cholest-8(14)-ene-
3β-Saiichirou 15-one [Proc, Natl,
Acad, Sci, USA, Volume 81, No. 686
1 (1984)]7-oxo24.25-dihydrolanosterol J, Pharmacobio-
Dyn, .
第８巻、第５１８頁（１９８５年〉］は、猿やラットに
対する経口投与において血清コレステロールを低下させ
ることが明らかにされている。一方、植物の成分として
単離されたトリテルペンおよびその誘導体に血清コレス
テロールを低下させるものが、たとえば、特開昭５８−
１０６０００号公報に記載されている。Vol. 8, p. 518 (1985)] has been shown to lower serum cholesterol when orally administered to monkeys and rats.On the other hand, triterpenes and their derivatives isolated as plant components For example, a substance that lowers cholesterol is disclosed in JP-A-58-
It is described in Japanese Patent No. 106000.
今日、高コレステロール血症およびこれに起因する動脈
硬化症は増加の傾向にあり、それゆえ、コレステロール
生合成阻害活性を有する新規なトノテルペン化合物を見
出し、これを利用したより効果的なコレステロール低下
剤を開発することが望まれている。Nowadays, hypercholesterolemia and the arteriosclerosis caused by it are on the rise. Therefore, we have discovered a new tonoterpene compound that has cholesterol biosynthesis inhibitory activity, and have developed a more effective cholesterol-lowering agent using this compound. It is hoped that it will be developed.
発明が解決しようとする問題点
本発明の目的は、コレステロール生合成阻害活性を有す
る新規な（２４Ｅ）−ジノスター３−オキソ−８，２４
−ジエン−２６−カルボン酸を提供することにある。Problems to be Solved by the Invention The object of the present invention is to provide a novel (24E)-dinoster 3-oxo-8,24 having cholesterol biosynthesis inhibitory activity.
-Diene-26-carboxylic acid.
問題点を解決するための手段
本発明者は、入手容易なラノステロールを出発原料にし
て新規な（２４Ｅ）−ジノスター３−オキソ−８，２４
−ジエン−２６−カルボン酸を製造することに成功し本
発明を完成した。すなわち、本発明により提供される化
合物は、（２４Ｅ）−ジノスター３−オキソ−８，２４
−ジエン−２６−カルボン酸［化合物（Ｉ）］である。Means for Solving the Problems The present inventor has developed a novel (24E)-dinoster 3-oxo-8,24 using readily available lanosterol as a starting material.
-Diene-26-carboxylic acid was successfully produced and the present invention was completed. That is, the compound provided by the present invention is (24E)-dinoster 3-oxo-8,24
-diene-26-carboxylic acid [compound (I)].
本発明の化合物は、ラノステロールを出発原料として、
下記反応式にしたがって立体選択的に製造することがで
きる（反応式中、Ｒは低級アルキル基を示す、）。The compound of the present invention uses lanosterol as a starting material,
It can be stereoselectively produced according to the reaction formula below (in the reaction formula, R represents a lower alkyl group).
すなわち、ラノステロール［化合物（１）コの側鎖２４
位の二重結合を、たとえばｍ−クロロ過安息香酸などの
過酸でエポキシ化し、過ヨウ素酸で分解して２４−アル
デヒド［化合物（名）コとする。化合物（２）を、たと
えばカルボエトキシエチリデントリフェニルフォスフオ
ランなどのカルボアルコキシエチリデントリフェニルフ
ォスフオランとのウィツテイヒ（Ｗｉｔｔｉｇ ）反応
により選択的にトランスエステル［化合物〈３）コに導
き、次に３位の水酸基をクロム酸−硫酸を用いるジョー
ンズ酸化とアルカリ加水分解を行って、目的の（２４Ｅ
）−ジノスター３−オキソ−８，２４−ジエン−２６−
カルボン酸［化合物（Ｉ）］を製造することができる。That is, the side chain 24 of lanosterol [compound (1)]
The double bond at position is epoxidized with a peracid such as m-chloroperbenzoic acid, and decomposed with periodic acid to give 24-aldehyde (compound (name)). Compound (2) is selectively converted into a transester [compound (3)] by a Wittig reaction with a carboalkoxyethylidene triphenylphosphorane such as carboethoxyethylidene triphenylphosphorane, and then 3 Jones oxidation using chromic acid-sulfuric acid and alkaline hydrolysis were performed to obtain the desired (24E
)-Gynoster 3-oxo-8,24-diene-26-
Carboxylic acid [compound (I)] can be produced.
発明の効果
本発明の（２４Ｅ）−ジノスター３−オキソ−８，２４
−ジエン−２６−カルボン酸は、コレステロール生合成
阻害作用を有し医薬品として有用である。Effects of the invention (24E)-ginoster 3-oxo-8,24 of the present invention
-Diene-26-carboxylic acid has a cholesterol biosynthesis inhibitory effect and is useful as a pharmaceutical.
実施例
次に、実施例および試験例により本発明をさらに具体的
に説明する。EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples.
実施例
（１）ラノステロール（２０〜３０％のジヒドロラノス
テロールを含む）５０ｇを塩化メチレン１１に懸濁させ
、氷冷下、ｍ−クロロ過安息香酸２５．３ ｇの塩化メ
チレン溶液５００−を１時間かけて滴下した０滴下終了
後、水冷下で３０分間攪拌し、飽和チオ硫酸ナトリウム
水溶液３００ｄを加え、室温で１時間攪拌した。有機層
を分け、飽和重曹水、飽和食塩水で順次洗浄し、無水硫
酸ナトリウム上で乾燥した。溶媒留去後、残渣をシリカ
ゲルカラムクロマトグラフィー（Ｒ開溶媒；ベンゼン、
次いでベンゼン：酢酸エチル−２０：１）で９製シ、ｚ
ａ。Example (1) 50 g of lanosterol (containing 20-30% dihydrolanosterol) was suspended in 11 methylene chloride, and a solution of 25.3 g of m-chloroperbenzoic acid in 500 g of methylene chloride was added for 1 hour under ice cooling. After the completion of the 0 dropwise addition, the mixture was stirred for 30 minutes under water cooling, 300 d of a saturated aqueous sodium thiosulfate solution was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (R opening solvent: benzene,
Then, with benzene:ethyl acetate-20:1),
a.
２５−エボキシラノスター８−エン−３β−オールを２
２．０６ ｇ得た。25-Eboxylanostar8-en-3β-ol 2
2.06 g was obtained.
ｍ、ｐ、 １２９〜１３０℃（アセトンから再結晶）’
Ｈ−ＮＭ Ｒ（ＣＤＣ１１３） Ｓ ：０．６９（３Ｈ
，ｓ） 、 ０．８１（３Ｈ，ｓ） 、 ０．８８（３
Ｈ，ｓ） 。m, p, 129-130℃ (recrystallized from acetone)'
H-NMR (CDC113) S: 0.69 (3H
,s), 0.81(3H,s), 0.88(3
H,s).
０、９２（３１，ｄ、Ｊ＝６Ｈｚ＞ 、 ０．９８（３
Ｈ，ｓ） 。0,92(31,d, J=6Hz>, 0.98(3
H,s).
１．００（３Ｈ，ｓ） 、 １．２７（３Ｈ，ｓ） 、
１．３１（３Ｈ，ｓ） 。1.00 (3H, s), 1.27 (3H, s),
1.31 (3H, s).
２、７１（ＩＨ，ｔ、Ｊ＝６Ｈｚ） 、 ３．２６（Ｌ
Ｈ，ｄｄ、Ｊ＝６Ｈｚ、２Ｈｚ＞Ｉ ＲＬ７ ＫＢ”ｃ
ｒｎ−’ ：
ａｘ
３２３０ 、２９４０ 、１４５０ 、１３７２Ｍ Ｓ
ｍ／ ｚ ：
４４２（Ｍ”） 、 ４２７ 、４０９ 、２１２（２
）上記（１）で得た２４．２５−エボキシラノスター８
−エン−３β−才一ル４．２２ｇをテトラヒドロフラン
２００ｄに溶解し、過ヨウ素酸５．４３ ｇを加え、室
温で１時間攪拌した。不溶物を濾過し、濾液を酢酸エチ
ルで希釈後、飽和重曹水、飽和食塩水で順次洗浄し、無
水硫酸ナトリウム上で乾燥した。2,71 (IH, t, J=6Hz), 3.26 (L
H, dd, J=6Hz, 2Hz>I RL7 KB”c
rn-': ax 3230, 2940, 1450, 1372M S
m/z: 442 (M”), 427, 409, 212 (2
) 24.25-Eboxylanoster 8 obtained in (1) above
4.22 g of -ene-3β-thalene was dissolved in 200 d of tetrahydrofuran, 5.43 g of periodic acid was added, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was filtered, and the filtrate was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate.
溶媒留去後、残渣をシリカゲルカラムクロマトグラフィ
ー（展開溶媒；ヘキサン：酢酸エチル−２０： １−１
０： １ ）で精製し、２５．２６．２７− トリスノ
ルジノスター８−エン−３β−才−ルー２４−アール２
、８０ ｇを得た。After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent: hexane:ethyl acetate-20: 1-1
0:1) and purified with 25.26.27-trisnordinoster8-ene-3β-x-24-al2
, 80 g was obtained.
ｍ、ｐ、 １５０〜１５２℃（アセトンから再結晶）’
Ｈ−ＮＭ Ｒ（ＣＤＣｊ２．）δ：
０、６９（３Ｈ，ｓ） 、 ０．８１（３Ｈ，ｓ） 、
０．８８（３Ｈ，ｓ） 。m, p, 150-152℃ (recrystallized from acetone)'
H-NMR (CDCj2.) δ: 0, 69 (3H, s), 0.81 (3H, s),
0.88 (3H, s).
０、９２（３）１．ｄ、Ｊ＝６Ｈｚ） 、 ０．９８（
３８，ｓ） 。0,92(3)1. d, J=6Hz), 0.98(
38, s).
１．００（３Ｈ，ｓ） 、 ２．４２（２Ｈ，ｍ） 。1.00 (3H, s), 2.42 (2H, m).
３．２６（ＬＨ，ｄｄ、Ｊ＝１１Ｈｚ、４）１ｚ）、
９．８０（ＩＨ，ｔ＋ Ｊ＝２Ｈｚ）Ｉ Ｒｖ ＫＢ
ｒａｍ−’ ：
ａＸ
３３５０ 、２９２０ 、１７３０ 、１４４０ 、１
３６５Ｍ５ｍ／ｚ：
４００（Ｍ”）、３８５，３６７．３４９．２３９（３
）上記で得た２５，２６．２７− トリスノルジノスタ
ー８−エン−３β−才一ルー２４−アール２，４ｇと（
カルボエトキシエチリデン）トリフェニルホスホラン３
．８ｇを乾燥ベンゼン２Ｍに溶解し、室温、窒素気流下
で２日間攪拌した０反応液を飽和食塩水で洗浄後、無水
硫酸ナトリウム上で乾燥した。溶媒留去後、残渣をシリ
カゲルカラムクロマトグラフィー（展開溶媒；ヘキサン
：酢酸エチル冨１０：１）で精製し、（２４Ｅ）−ラノ
スタ−８．２４−ジエン−３β−オールーｚ６−カルボ
ン酸エチルエステル２．４１２ｇを得た。3.26 (LH, dd, J=11Hz, 4)1z),
9.80 (IH, t+ J=2Hz) I Rv KB
ram-': aX 3350, 2920, 1730, 1440, 1
365M5m/z: 400 (M”), 385,367.349.239 (3
) 2.4 g of 25,26.27-trisnorginoster-8-ene-3β-saiichiru-24-ar obtained above and (
Carboethoxyethylidene) triphenylphosphorane 3
．． 8 g of the solution was dissolved in 2M dry benzene and stirred for 2 days at room temperature under a nitrogen stream. The reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (developing solvent: hexane: ethyl acetate concentration 10:1) to obtain (24E)-lanosta-8.24-diene-3β-ol-z6-carboxylic acid ethyl ester 2. .412g was obtained.
ｍ、ｐ、 １２２〜１２４℃（アセトンから再結晶）’
Ｈ−ＮＭＲ（ＣＤＣＩＩ） Ｓ ：
０、６９（３Ｈ，ｓ） 、 ０．８１（３Ｈ，ｓ） 、
０．８７（３Ｈ，ｓ） 。m, p, 122-124°C (recrystallized from acetone)'
H-NMR (CDCII) S: 0, 69 (3H, s), 0.81 (3H, s),
0.87 (3H, s).
０、９４（３Ｈ，ｄ、Ｊ＝６Ｈｚ） 、 ０．９８（３
Ｈ，ｓ） 。0,94(3H,d,J=6Hz), 0.98(3
H,s).
１．００（３Ｈ，ｓ） 、 １．８３（Ｈ，ｓ） 。1.00 (3H, s), 1.83 (H, s).
３、２４（ＩＨ，ｄｄ、Ｊ＝１１Ｈｚ、４Ｈｚ） 。3, 24 (IH, dd, J=11Hz, 4Hz).
４、１９（２Ｈ，ｑ、Ｊ＝６Ｈｚ） 、 ６．７６（Ｉ
Ｈ，ｔ、Ｊ＝７Ｈｚ）Ｉ Ｒｌ／ ＫＢｒａｍ−’ ：
ａｘ
３２４０．２９３０．１７ｉ０．１４５０，１３７０．
１２６５Ｍ５ｍ／ｚ：
４８４（Ｍ”） 、 ３８５ 、３６７ 、３４９ 、
２３９（４）上記で得た（２４Ｅ）−ラノスタ−８．２
４−ジエン−３β−才一ルー２６−カルボン酸エチルエ
ステル２０４ｇをアセトン２００ｄに溶解し、水冷下、
ジョーンズ試薬［リエージェンッ ホア オーガニック
シンセシス（Ｒｅａｇｅｎｔｓ ｆｏｒ Ｏｒｇａｎ
ｉｃ ５ｙｎ−ｔｈｅｓｉｓ ） 、第１巻、第１４２
頁（１９６７年）コ１．５５−を滴下した。反応混合物
を水冷下５分間攪拌し、不溶物を濾過し、アセトンで洗
浄した。濾液および洗液を合わせ、約１００ｄ程度に濃
縮し、酢酸エチルで希釈し、飽和食塩水、飽和重曹水、
飽和食塩水で順次洗浄後、無水硫酸ナトリウム上で乾燥
した。溶媒留去後、残渣をシリカゲルカラムクロマトグ
ラフィー（展開溶媒；ヘキサン：酢酸エチル−２０：１
）で精製し、（２４Ｅ）−ジノスター８．２４−ジエン
ー３−オンー２６−カルボン酸エチルエステル１．８３
ｇを得た。4, 19 (2H, q, J = 6Hz), 6.76 (I
H,t,J=7Hz)I Rl/KBram-': ax 3240.2930.17i0.1450,1370.
1265M5m/z: 484 (M”), 385, 367, 349,
239(4) (24E)-Lanostar-8.2 obtained above
204 g of 4-diene-3β-saiichi-26-carboxylic acid ethyl ester was dissolved in 200 d of acetone and cooled with water.
Jones Reagent [Reagents for Organ Synthesis]
ic 5yn-thesis), Volume 1, No. 142
Page (1967) 1.55-mL was added dropwise. The reaction mixture was stirred for 5 minutes under water cooling, and insoluble materials were filtered and washed with acetone. The filtrate and washing solution were combined, concentrated to about 100d, diluted with ethyl acetate, and mixed with saturated brine, saturated sodium bicarbonate solution,
After washing successively with saturated brine, it was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography (developing solvent: hexane:ethyl acetate-20:1
) to give (24E)-Dynoster 8.24-dien-3-one-26-carboxylic acid ethyl ester 1.83
I got g.
’Ｈ−ＮＭＲ（ＣＤＣム） Ｓ ： ０、７２（３Ｈ，ｓ） 、 ０．９０（３Ｈ，ｓ） 。'H-NMR (CDC) S: 0, 72 (3H, s), 0.90 (3H, s).
０．９５（３Ｈ，ｄ、Ｊ＝６Ｈｚ） 、 １．０７（３
Ｈ，ｓ） 。0.95 (3H, d, J=6Hz), 1.07 (3
H,s).
１．１０（３Ｈ，ｓ） 、 １．１２（３Ｈ，ｓ） 。1.10 (3H, s), 1.12 (3H, s).
１．２９（ＬＨ，ｔ、Ｊ＝７Ｈｚ＞ 、 １．８４（３
Ｈ，ｓ） 。1.29 (LH, t, J = 7Hz>, 1.84 (3
H,s).
４、２０（２８，ｑ、 Ｊ：６Ｈｚ） 、 ６．７８（
ＬＨ，ｔ、 ＪニアＨｚ）ｎｅａｔ −１゜
ＩＲνｆｆｌａｘｃｍ。4, 20 (28, q, J: 6Hz), 6.78 (
LH, t, J near Hz)neat −1°IRνfflaxcm.
２９４０ 、１７２０ 、１７０５ 、１４５５ 、１
３７０ 、１２７０Ｍ Ｓ ｍ／ ｚ ：
４８２（Ｍ＋） 、 ４６７ 、４５３ 、４２１ 、
３９３ 、２５７（５） （２４Ｅ）−ラノスタ−８，
２４−ジエンー３−オンー２６−カルボン酸エチルエス
テル１．６６ ｇをテトラヒドロフラン５０ｄおよびメ
タノール５０ｄの混合溶媒に溶解し、１規定水酸化ナト
リウム１０ｍＮを加え、１０時間加熱還流した０反応液
を２規定塩酸で中和後、酢酸エチルで抽出した。抽出し
た有機層を飽和食塩水で洗浄し、無水硫酸ナトリウム上
で乾燥した。溶媒留去後、残渣をシリカゲルヵラムクロ
マトグラフイー（Ｒ開溶媒；クロロホルム）で精製し、
アセトンから再結晶することにより、（２４Ｅ）−ラノ
スタ−８．２４−ジエンー３−オンー２６−カルボン酸
１．２３ｇを得た。2940, 1720, 1705, 1455, 1
370, 1270M S m/z: 482 (M+), 467, 453, 421,
393, 257(5) (24E)-Lanostar-8,
Dissolve 1.66 g of 24-dien-3-one-26-carboxylic acid ethyl ester in a mixed solvent of 50 d of tetrahydrofuran and 50 d of methanol, add 10 mN of 1N sodium hydroxide, and heat under reflux for 10 hours. After neutralization, the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (R opening solvent: chloroform),
By recrystallizing from acetone, 1.23 g of (24E)-lanosta-8,24-dien-3-one-26-carboxylic acid was obtained.
ｍ、ｐ、 １２２〜１２４℃
’Ｈ−ＮＭＲ（ＣＤＣ党、） Ｓ ：０．７２（３Ｈ
，ｓ） 、 ０．８９（３Ｈ，ｓ） 。m, p, 122-124℃ 'H-NMR (CDC,) S: 0.72 (3H
,s), 0.89(3H,s).
０、９５（３Ｈ，ｄ、Ｊ＝６Ｈｚ） 、 １．０６（３
Ｈ，ｓ） 。0,95(3H,d,J=6Hz), 1.06(3
H,s).
１．０９（３Ｈ，ｓ） 、 １．１２（３Ｈ，ｓ） 、
１．８５（３Ｈ，ｂｒｓ） 。1.09 (3H, s), 1.12 (3H, s),
1.85 (3H, brs).
２、４２（１Ｈ，ｄｄｄ、 Ｊ＝１６Ｈｚ、 １２）１
ｚ、 ７Ｈｚ＞ 。2, 42 (1H, ddd, J=16Hz, 12) 1
z, 7Hz>.
２、５８（ＩＨ，ｍ） 、 ６．９３（ＩＨ，ｔ、Ｊ＝
７１（ｚ）■Ｒ、ＫＢｒｏＩｎ−＋ 。2,58 (IH, m), 6.93 (IH, t, J=
71(z)■R, KBroIn-+.
ａｘ
２９２０ 、１７００ 、１６７０ 、１３７０ 、１
２７５Ｍ５ｍ／ｚ：
４５４（Ｍ＋）、 ４３９ 、４２１ 、３９３試験例
［コレステロール生合成阻害活性コ２００ｇ前後のウィ
スター系ラット肝をホモジネートし、１０．０００Ｘ
ｇ上清を調製した。この上清０、５ｍｆｆ１、本発明化
合物のメタノール溶液２０ハ（最終濃度５）Ｉｇ／献お
よび２５ ＩＪｇ／ Ｎ ）、生理食塩水８０バ、補酵
素液（３０ｍＭアデノシン トリホスフェ−） 、 ３
０ｎ＋Ｍ Ｄ−グルコース−６−ホスフェート、１０ｍ
Ｍβ−ニコチンアミドアデニン ジヌクレオチド リ／
ｖ 酸、 ３０ｍＭニコチンアミドおよび５ｍＭ塩化マ
グネシウムを含む０．１Ｍりん酸緩衝液、ｐＨ７，５）
１００−および■ｃ−メバロン酸溶液１００４ （０，
２５μＣｉ）を加え、３７”Ｃで３時間反応させた。こ
の間１時間毎に補酵素液１００）ＬＱを加えた。１０％
水酸化カリウム／メタノール溶液１ｄを加え反応を停止
させ、７０℃の温浴中で１時間振盪したのち２ｄの石油
エーテルで２回抽出した０石油エーテル抽出液を合わせ
、石油エーテルを留去し、残渣を石油エーテル１００ハ
に溶解してシリカゲルプレートにスポットし、ジクロロ
メタンで展開した。ラジオクロマトスキシナ−（アロカ
株式会社製ＪＴＣ−６０１）により生成したコレステロ
ールの放射能を測定した。対照は、本発明化合物のメタ
ノール溶液２０−の代わりにメタノール２０−を加え、
同様に処理し、放射能を測定した。ax 2920, 1700, 1670, 1370, 1
275M5m/z: 454 (M+), 439, 421, 393 Test Examples [Cholesterol biosynthesis inhibitory activity: around 200 g of Wistar rat liver was homogenized, 10.000X
g supernatant was prepared. This supernatant 0.5 mff1, 20 methanol solution of the compound of the present invention (final concentration 5 Ig/N and 25 IJg/N), 80 mg physiological saline, coenzyme solution (30 mM adenosine triphosphate), 3
0n+M D-glucose-6-phosphate, 10m
Mβ-nicotinamide adenine dinucleotide li/
v acid, 0.1M phosphate buffer containing 30mM nicotinamide and 5mM magnesium chloride, pH 7,5)
100- and ■c-mevalonic acid solution 1004 (0,
25 μCi) was added and the reaction was carried out at 37"C for 3 hours. During this time, coenzyme solution 100) LQ was added every hour. 10%
The reaction was stopped by adding 1 d of potassium hydroxide/methanol solution, and after shaking in a 70°C hot bath for 1 hour, 2 d of petroleum ether extracts extracted twice with petroleum ether were combined, and the petroleum ether was distilled off to form a residue. was dissolved in 100% petroleum ether, spotted on a silica gel plate, and developed with dichloromethane. The radioactivity of the cholesterol produced was measured using radiochromatoxina (JTC-601, manufactured by Aloka Co., Ltd.). For the control, 20-methanol was added instead of 20-methanol solution of the compound of the present invention,
It was treated in the same manner and radioactivity was measured.
コレステロール生合成阻害率は下式より算出した。The cholesterol biosynthesis inhibition rate was calculated using the following formula.
測定の結果は皮表の如くであった。The measurement results were similar to those on the skin surface.
表 （註） ａ；実施例の（５〉で得た化合物 １；検体の最終濃度table (Note) a; Compound obtained in Example (5) 1; Final concentration of sample
Claims (1)
ジエン−２６−カルボン酸。(1) (24E)-Lanostar-3-oxo-8,24-
Diene-26-carboxylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62299041A JPH02167295A (en) | 1987-11-27 | 1987-11-27 | Triterpene compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62299041A JPH02167295A (en) | 1987-11-27 | 1987-11-27 | Triterpene compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02167295A true JPH02167295A (en) | 1990-06-27 |
Family
ID=17867446
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62299041A Pending JPH02167295A (en) | 1987-11-27 | 1987-11-27 | Triterpene compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02167295A (en) |
-
1987
- 1987-11-27 JP JP62299041A patent/JPH02167295A/en active Pending
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