JPS5867700A

JPS5867700A - Hippuristanols

Info

Publication number: JPS5867700A
Application number: JP16745981A
Authority: JP
Inventors: Hiroyuki Kikuchi; 博之菊地; Yasumasa Tsukitani; 築谷　康柾
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1981-10-19
Filing date: 1981-10-19
Publication date: 1983-04-22

Abstract

NEW MATERIAL:The compound of formulaI or formula II (R1-R3 are H or acyl; the steric configuration at 22-position may be R- or S-configuration, however, when R1 is acetyl and R2 is H in the formulaI, the configuration is 22S). USE:It has antitumor activity and is useful as a carcinostatic agent. PROCESS:Isis hippuris which is a kind of Octocorallia belonging to Anthozoa class of Coelenterata is extracted with methanol, and the extract is further extracted with ethyl acetate. The extract is subjected to the silica gel column chromatography, and eluted with n-hexane-acetone gradient. The fractions containing hippuristanol are collected, and the compound of formulaI or formula II is separated from the fractions.

Description

【発明の詳細な説明】本発明はヒプリスタノール類、さらに詳しくは、腔腸動
物、花虫類、へ放サンゴに属するヤギ（Ｉｓｉｓ　ｈｉ
ｐｐｕｒｉｓ　）から抽出、単離された新規ステロイド
化合物およびその誘導体であるヒプリスタノール類に関
する。これらのヒスリスタノール類は抗腫瘍作用を有し
、制がん剤として有用であり、したがって、本発明はま
たヒブリスタノール類を含有する医薬組成物にも関する
。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to hypristanols, more specifically to coelenterates, anthozoans, and Isis hi
The present invention relates to a novel steroid compound extracted and isolated from S. ppuri and hipristanols, which are derivatives thereof. These hisristanols have antitumor effects and are useful as anticancer agents, and the invention therefore also relates to pharmaceutical compositions containing the hisristanols.

本発明のヒプリスタノールは式：〔式中、Ｒ，、Ｒ２お工びＲ８は、同一または異なって
、各々、水素またはアシルを意味する。ただし、２２位
における立体配置はＲ−配置でもＳ−配置でもよいが、
弐１）において、Ｒ１がアセチル、Ｒ２が水素の場合は
２２８である〕で示される。Hipristanol of the present invention has the formula: [In the formula, R, , R2 and R8 are the same or different and each represents hydrogen or acyl. However, the configuration at position 22 may be R-configuration or S-configuration, but
In 21), when R1 is acetyl and R2 is hydrogen, it is 228].

Ｒ，、Ｒ２およびＲ８におけるアシル基としては・アセ
チル・プロピオニル、ブチリル、イソバレリル、バレリ
ル、イソバレリル、ピバロイルなどのような炭素数２〜
５の。アシル基が挙げられる。The acyl group in R, R2 and R8 is ・Acetyl, propionyl, butyryl, isovaleryl, valeryl, isovaleryl, pivaloyl, etc. having 2 or more carbon atoms;
5. Examples include acyl groups.

本発明のヒプリスタノール類の代表的な例としてはつぎ
の化合物が挙げられる。Representative examples of hipristanols of the present invention include the following compounds.

化合物−ｉ：Ｒ，ｙａ２およＱ：Ｒｓが共に水素で、２
２Ｒの式［１１〕の化合物。Compound-i: R, ya2 and Q: Rs are both hydrogen, 2
2R compound of formula [11].

化合物−２：　Ｒｓ　、　ＲｚおよびＲ８が共に水素で
、２２８の式Ｃ１１〕の化合物。Compound-2: A compound of formula C11 of 228, in which Rs, Rz and R8 are all hydrogen.

化合物−３：Ｒ１がアセチル、Ｒ２が水素で、２２８の
式〔１〕の化合物。Compound-3: A compound of formula [1] of 228, in which R1 is acetyl and R2 is hydrogen.

化合物−４：Ｒ，およびＲ２が共に水素で、２２Ｒの式
（１）の化合物。Compound-4: A compound of formula (1) where R and R2 are both hydrogen and 22R.

一化合物−５：　Ｒ，およびＲ２が共にアセチルで、２
２Ｒの式〔Ｉ〕の化合物。One compound-5: R and R2 are both acetyl, 2
2R compound of formula [I].

化合物−６：Ｉ’Ｌｔがアセチル、Ｒ２およびＲ５が共
に水素で、２２Ｒの式〔■〕の化合物。Compound-6: A compound of the formula [■] of 22R, where I'Lt is acetyl, R2 and R5 are both hydrogen.

化合物−７：Ｒ１およびＲ２がアセチル、Ｒ５が水素で
、２２Ｒの式（Ｉｔ）の化合物。Compound-7: A compound of formula (It) of 22R, where R1 and R2 are acetyl, R5 is hydrogen.

化合物−８：Ｒ＋がアセチル、Ｒ３およびＲ３が共に水
素で、２２８の式（Ｕ）の化合物。Compound-8: A compound of formula (U) of 228, where R+ is acetyl, R3 and R3 are both hydrogen.

化合物−９：もおよびＲ２が共にア毛チル、Ｒ３が水素
で、２２８の式（１）の化合物。Compound-9: A compound of formula (1) of 228, in which both R2 and R2 are acholythyl, and R3 is hydrogen.

化合物−１０：　Ｒ１、Ｒ２およびＲ１が共にアセルチ
ルで、２２８の式（Ｉｌ〕の化合物。Compound-10: A compound of formula (Il) of 228, where R1, R2 and R1 are all acertyl.

このうち、化合物−１、化合物−２、化合物゛−３およ
び化会ｅ）−４がヤギから抽出、゛単離されるヒプリス
タノール類であり、化合物−５、化合物−６、化合物−
７、化合物−８、化合物−９および化合物−ＩＯはそれ
らのアセチル化誘導体である。Of these, Compound-1, Compound-2, Compound-3 and Chemical Society e)-4 are hipristanols extracted and isolated from goats, Compound-5, Compound-6, Compound-4
7, Compound-8, Compound-9 and Compound-IO are their acetylated derivatives.

かくして、本発明のヒプリスタノール類には、ヤギから
抽出、単離されたものおよびそのアシル化誘導体が包含
される。Thus, the hipristanols of the present invention include those extracted and isolated from goats and acylated derivatives thereof.

ヤギからのヒプリスタノール類の抽出、単離を行なうに
は、例えば、まず、常法に従ってヤギをメタノールで抽
出してエキスを得、さらに、このエキスを酢酸エチルで
抽出して酢酸エチル抽出物を得る。ついで、得られた酢
酸エチル抽出物をシリカゲルカラムクロマトグラフィー
に付し、ｎ　−ヘキサン−アセトン゛・グレデイエント
で溶出し、ヒプリスタノール類を含有する両分を分取す
る。To extract and isolate hipristanols from goats, for example, first extract goats with methanol to obtain an extract according to a conventional method, and then extract this extract with ethyl acetate to obtain an ethyl acetate extract. get. The obtained ethyl acetate extract is then subjected to silica gel column chromatography, eluted with an n-hexane-acetone gradient, and both fractions containing hipristanols are separated.

得られん画分を、さらに、シリカゲルカラムクロマトグ
ラフィーに付し、薄層クロマトグラフィーでモニターし
ながら所望の化合物を分画し、これを精製し、メタノー
ルのごとき適当な溶媒から再結晶させて目的とする化合
物を単離する。The unobtained fraction is further subjected to silica gel column chromatography, and while monitoring with thin layer chromatography, the desired compound is fractionated, purified, and recrystallized from a suitable solvent such as methanol to obtain the desired compound. isolate the compound that

得られた化合物のアシル化誘導体は、常法に従って、適
当なアシル化剤を用い、該ヒプリスタノール類の骨格構
造に影響を及ぼさない温和な条件下でアシル化を行なう
ことにより得られる。例えば、ピリジン中、室温にて無
水酢酸で該アシル化を行なう。The resulting acylated derivative of the compound can be obtained by carrying out acylation according to a conventional method using a suitable acylating agent under mild conditions that do not affect the skeletal structure of the hipristanols. For example, the acylation is carried out with acetic anhydride in pyridine at room temperature.

本発明のヒグリスタノール類は抗腫瘍作用を有する。該
化合物の抗腫瘍作用はつぎのような方法でｉｎ　ｖｉｔ
ｒｏ　　において示すことができる。The hyglistanols of the present invention have antitumor effects. The antitumor effect of the compound can be demonstrated in vitro by the following method.
It can be shown in ro.

ＤＢＡマウス（雄）Ｋメチルコランスレンヲ皮下注射し
て生成させた線維芽肉腫のクローン化した細胞をイーグ
ル＋ウシ血清（２０％）、ラクトアルブミンヒドロリゼ
ート（０，４％）およびグルタミン（１％）からなり、
１０％炭酸水素ナトリウム水溶液でｐＨを中性に導いた
組成の培地に懸濁り、７１クロブレート（フアシヨン８
０４２）へ５　Ｘ　１０３ノ０．２ｍ／／ｍ／外の量で
まく。８７１Ｚ’で炭酸ガス培養器にて２４時間培養後
、培地を新たなものに変え、被験薬剤を所定濃度添加し
、混合し、さらに４８時間培養する。培養後、培地°を
捨で、・・ンクス（Ｉ（ａｎｋｓ’　）液で１〜２回洗
浄し、メタノールで３〜５分間固定する。その後ギムザ
液にて３０分間染色し、水洗、乾燥し、鏡検して被験薬
剤による該細胞の増殖抑制状態を観察する。DBA mice (male) Cloned cells of fibroblastosarcoma generated by subcutaneous injection of K-methylcholanthrene were treated with Eagle + bovine serum (20%), lactalbumin hydrolysate (0.4%) and glutamine ( 1%),
71 clobrate (Fashion 8
042) in an amount of 0.2 m//m/5 x 103. After culturing for 24 hours in a carbon dioxide incubator with 871Z', the medium is replaced with a new one, the test drug is added at a predetermined concentration, mixed, and further cultured for 48 hours. After culturing, discard the medium, wash once or twice with anks' solution, and fix with methanol for 3 to 5 minutes.Then, stain with Giemsa solution for 30 minutes, wash with water, and dry. , and observe the state of inhibition of proliferation of the cells by the test drug by microscopic examination.

この方法に従って、Ｒ，、Ｒ，およびＦＬ３が共に水素
で、２２Ｒの式（Ｉｔ）の化合物（前記化合物−１）と
、Ｒ２およびＲ３が共に水素で、２２ＦＬの式〔■）の
化合物（前記化合物−４）の抗腫瘍作用を試験したとこ
ろ、各々、４および０．５μｇ／−の濃度で細胞の増殖
を完全に抑制した。According to this method, a compound of the formula (It) of 22R (the above compound-1) in which R, , R, and FL3 are all hydrogen, and a compound of the formula [■] of 22FL (the above-mentioned When the antitumor effect of compound-4) was tested, cell proliferation was completely inhibited at concentrations of 4 and 0.5 μg/-, respectively.

本発明はまた、式〔ｌ）または式（Ｉｔ）で示されるヒ
プリスタノール類を有効成分とする制がん剤組成物も包
含する。かかる医薬組成物は、例えば、錠剤、カプセル
剤、顆粒剤、細粒剤、粉剤、シロップ剤、生薬、注射剤
などの経口または非経口投与用の通常の医薬製剤の形に
することができ、その製剤化には通常の医薬用賦形薬、
稀釈剤などが用いられる。さらに、注射剤には通常のｐ
Ｈ調節剤、等張化剤などが適宜配合される。ヒブリスタ
ノール類の用量は実際に用いる化合物の種類、患者の年
令、疾病の程度などによって異なるが、通常１０〜１０
００〜／ｋｙ程度である。The present invention also includes anticancer compositions containing hipristanols represented by formula [1] or formula (It) as an active ingredient. Such pharmaceutical compositions can be in the form of conventional pharmaceutical preparations for oral or parenteral administration, such as tablets, capsules, granules, granules, powders, syrups, herbal medicines, injections, etc. For its formulation, common pharmaceutical excipients,
Diluents and the like are used. In addition, injectables contain normal p
A H regulator, an isotonizing agent, and the like are appropriately added. The dose of hybristanols varies depending on the type of compound actually used, the age of the patient, the severity of the disease, etc., but is usually 10 to 10
It is about 00~/ky.

つぎに実施例を挙げて本発明をさらに詳しく説明する。Next, the present invention will be explained in more detail with reference to Examples.

実施例１沖縄県小浜島で採集したヤギ５ｋｙ（含水重量）をメタ
ノール１５ｋｐ中で粉砕し、−夜放置後、沖過する。残
渣を再びメタノール１５ｋｐに浸し、−夜放置後、濾過
する。Ｆ液を合して減圧下で濃縮してエキスを得る。こ
のエキスを水２′ｔに懸濁し、酢酸エチル２ｔで２回抽
出する。酢酸エチル抽出液を合し、減圧下で濃縮して酢
酸エチル抽出物３７ｇを得る。Example 1 5 ky of goats (water-containing weight) collected on Kohama Island, Okinawa Prefecture, were pulverized in 15 kp of methanol, left overnight, and filtered. The residue is soaked again in 15 kp of methanol and, after standing overnight, is filtered. Combine the F solutions and concentrate under reduced pressure to obtain an extract. This extract was suspended in 2't of water and extracted twice with 2t of ethyl acetate. The ethyl acetate extracts are combined and concentrated under reduced pressure to obtain 37 g of ethyl acetate extract.

得られた酢酸エチル抽出物８’ｌをシリカゲルカラム（
メルク社製シリカゲル、５ｘ８０ｍ）上でクロマトグラ
フィーに付し、容量比２０：ｌ、１０：１．５：１．８
：１．２：１および１：１のｎ−ヘキサン−アセトン混
液各ｌｔづつで溶出させる。各溶出液を減圧下で蒸発乾
固させて、各々、画分１（８，８Ｊ？）−、画分２（５
，’ｌ）、画分８（２，８，！ｉ＋）、画分４　（９，
１ｇ）　、画分５（１，ＩＩ）および画分６（２，０，
ｌを得る。目的とするヒプリスタノール類は画分４およ
び画分６に含有される。8'l of the obtained ethyl acetate extract was transferred to a silica gel column (
Chromatography on Merck silica gel, 5x80 m), volume ratio 20:l, 10:1.5:1.8
:1.Elute with 1 liter each of 2:1 and 1:1 n-hexane-acetone mixtures. Each eluate was evaporated to dryness under reduced pressure to separate fraction 1 (8,8 J?) and fraction 2 (5 J?), respectively.
,'l), fraction 8 (2,8,!i+), fraction 4 (9,
1g), fraction 5 (1,II) and fraction 6 (2,0,
get l. The target hipristanols are contained in fractions 4 and 6.

（ａ）画分４からの目的化合物の単離まず、脱色のため、画分４（９，１，９）をポリスチレ
ンゲルカラム（８，５，Ｘ　２１　ｃｍ　）にのせ、メ
タノールで溶出し、初期の溶出液　１４を捕集し、減圧
−下で蒸発乾固させて５．６Ｉの両分を得る。この画分
をシリカゲルカラム（メルク社製シリカゲル、２３０〜
４００メツシユ、８．５Ｘ８５ｃｒｎ）上でクロマトグ
ラフィーに付し、ｎ−ヘキサン−アセ）７（５：　１　
）混液、ついで、ｎ−ヘキサン−アセトン（４：１）混
液で溶出させる。溶出液を薄層クロマトグラフィー（シ
リカゲル、ｎ−ヘキサン−アセトン（２：１））でモニ
ターＬ　す７５ｒ　ラ分画する。ローヘキサン−アセト
ン（４：１）混液での溶出により、まず、Ｒ７がアセチ
ル、Ｒ２が水素て、２２８の式〔１〕の化合物（前記化
合物−８）を主成分とする粗両分５ｔｏｎｙ、ついで、
Ｒ１、＆曹およびＲｓが共に水素で、！！２８０式〔夏
〕の化合物（前記化合物−２）を主成分とする粗画分９
００ｗ９、さらに、Ｒ１、Ｊ　ｉＭ　ＡＤ　Ｒｓが共に
水素で、２２Ｒの式〔璽〕の化合物（前記化合物−１）
を主成分とする粗画分２．２Ｉが得られる。各両分を、
各々、リクロプレブＲＰ−，ｇ（メルク社製ＬｊＣｈｒ
ｏｐｒｅｐ　ＲＰ　−８（ＧｒｔｌβｅＢ））のカラム
にのせ、８ＯＮ水性メタノールで溶出して精製し、さら
にメタノールから再結晶させ、各々、化合物−２１４５
ｗ９、化合物−８１５８呼および化合物−１５７Ｑｑを
得る。各化合物の諸物性はつぎのとおりである。(a) Isolation of target compound from fraction 4 First, for decolorization, fraction 4 (9,1,9) was placed on a polystyrene gel column (8,5, x 21 cm) and eluted with methanol. The initial eluate 14 is collected and evaporated to dryness under reduced pressure to yield both portions of 5.6I. This fraction was applied to a silica gel column (Merck silica gel, 230~
400 mesh, 8.5 x 85 crn) and n-hexane-acetate) 7 (5:1
) mixture and then n-hexane-acetone (4:1) mixture. The eluate was fractionated using thin layer chromatography (silica gel, n-hexane-acetone (2:1)). By elution with a mixture of rhohexane and acetone (4:1), first, 5tony of the crude compound containing the compound of formula [1] of 228 (the above compound-8), where R7 is acetyl and R2 is hydrogen, Then,
R1, &so and Rs are both hydrogen,! ! Crude fraction 9 containing the compound of formula 280 [summer] (above compound-2) as the main component
00w9, and further, a compound of the formula [seal] of 22R where R1 and J iM AD Rs are both hydrogen (the above compound-1)
Crude fraction 2.2I is obtained, the main component of which is . Both parts of each
Licropreb RP-, g (LjChr manufactured by Merck & Co., Ltd.), respectively.
oprep RP-8 (GrtlβeB)), purified by elution with 8ON aqueous methanol, and further recrystallized from methanol to obtain compound-2145.
w9, Compound-8158 and Compound-157Qq are obtained. The physical properties of each compound are as follows.

化合物−１分子量：Ｍ＋１　４６８．８分子式：Ｃ社ボ番・Ｏｌ融点：１ｇ８〜１９０ＣＩＲ，訂：　８４６０．２９２０．１００９　。Compound-1 Molecular weight: M+1 468.8 Molecular formula: C company bo number/Ol Melting point: 1g8~190C IR, Edit: 8460.2920.1009.

９７９．９８２国−１Ｎ　Ｍ　Ｒ（ＣＤＣ４）　　：　δ−０，９８（ｄ、Ｊ
＝７Ｈｚ　　）；１．０３（ｓ）：１．２０（ｓ）；１
．２’２（ｌｉ）；１．８２（Ｓ）；１．：１１８；４
．０４；４．１０結晶形二針状化合物−２分子量：Ｍ　　　４６２分子式’　Ｃ２ｇ’４６０１１融点：２４８〜２４９Ｃ曽ＩＴ’Ｌ　　：８６４０，８４８０，２９００．１０
２８．９６８，９１６菌ＮＭＲ（ｉ０％ＣＤ３０Ｄ　／　ＣＤ’Ｃ１３）　：δ
−０゜９４　（ｄ　、８１１）；　０．９８（Ｓ　、８
Ｈ）；　１．０８（Ｓ、８Ｈ）；１．２７（Ｓ、８Ｈ）
；１．８０（Ｉｉ。979.982 country-1 NMR (CDC4): δ-0,98 (d, J
=7Hz);1.03(s):1.20(s);1
．． 2'2 (li); 1.82 (S); 1. :118;4
．． 04; 4.10 Crystal form bineedle compound-2 Molecular weight: M 462 Molecular formula 'C2g'46011 Melting point: 248-249C So IT'L: 8640, 8480, 2900.10
28.968,916 bacteria NMR (i0%CD30D/CD'C13): δ
-0°94 (d, 811); 0.98 (S, 8
H); 1.08 (S, 8H); 1.27 (S, 8H)
;1.80 (Ii.

８１（）；１．８４（ｓ、８Ｈ）；４．０１（ｂｓ）；
４゜２８（ｍ、Ｉ（）；４，４３（ｄｄｄ、Ｈ）結晶形
：針状化合物−３分子量：Ｍ　　５２０分子式”　３０”４４０？融点：２４３〜２４５ＣＩＲＫＢｒ：１０２０〜ＩＯ２８，９６８〜９７２，９
１５〜９２８　ｃｍ−１結晶形二針状（ｂ）画分６からの目的化合物の単離光のシリカゲルカラムクロマトグラフィーで得られたｎ
−ヘキサン−アセトン（に１）溶出画分６（２，０，９
）を再度シリカゲルカラムクロマトグラフィーに付し、
ｎ−ヘキサン−アセトン（３：ｌ）混液で溶出させる。81 (); 1.84 (s, 8H); 4.01 (bs);
4゜28(m, I(); 4,43(ddd,H) Crystal form: Acicular compound-3 Molecular weight: M 520 Molecular formula "30" 440? Melting point: 243-245C IRKBr: 1020-IO28,968-972 ,9
15-928 cm-1 Crystal form biacicular (b) Isolation of target compound from fraction 6 Obtained by optical silica gel column chromatography
-hexane-acetone (ni 1) elution fraction 6 (2,0,9
) was again subjected to silica gel column chromatography,
Elute with a mixture of n-hexane-acetone (3:l).

溶出液を薄層クロマトクラフィーでモニターしながら分
画し、Ｒ，およびＲ２が共に水素で、２２Ｒの式〔１〕
の化合物（前記化合物−４）を主成分とする粗画分９５
０■を得る。この画分をポリスチレンゲルカラム（８，
５Ｘ２０ｃｒｎ）にのせ、メタノールで溶出して脱色し
、溶出液を減圧下に蒸発乾固して白色粉末６３０■を得
る。これを、さらに、シリカゲルカラム（メルク社製シ
リカゲル１０１ｔ、ｌＸ５０ｃＷ１）上でクロマトグラ
フィーに付し、ベンゼン−酢酸エチル・グレデイエント
（２：１〜１：ｌ）で溶出し、化合物−４を含着する両
分を捕集し、減圧下に蒸発乾固して白色粉末状の化合物
−４２４０■を得る。The eluate was fractionated while being monitored by thin layer chromatography, and R and R2 were both hydrogen and the formula of 22R [1]
Crude fraction 95 containing the compound (above compound-4) as the main component
Get 0 ■. This fraction was transferred to a polystyrene gel column (8,
5×20 crn) and decolorized by elution with methanol, and the eluate was evaporated to dryness under reduced pressure to give 630 μm of white powder. This was further subjected to chromatography on a silica gel column (Silica gel 101t, 1X50cW1 manufactured by Merck & Co., Ltd.) and eluted with benzene-ethyl acetate gradient (2:1 to 1:1) to impregnate compound-4. Both fractions were collected and evaporated to dryness under reduced pressure to obtain compound-4240 in the form of a white powder.

分子量；　Ｍ　＋　’ｌ　　４７９．８分子式：　０２
８”４６０６％式％：（２）前記実施例１で得られた化合物−４をピリジン中、室温
で無水酢酸と１７時間反応させてガラス状の、Ｒ１およ
びＲ２が共にアセチルで、２２Ｒの式〔１〕の化合物（
前記化合物−５）を得る。収率８７％、融点１２０〜１
３０Ｕ。Molecular weight: M+'l 479.8 Molecular formula: 02
8"4606% Formula %: (2) The compound-4 obtained in Example 1 was reacted with acetic anhydride in pyridine at room temperature for 17 hours to form a glassy product, R1 and R2 both being acetyl, and having the formula of 22R. Compound [1] (
The above compound-5) is obtained. Yield 87%, melting point 120-1
30U.

実施例８前記実施例１で得られた化合物−１をピリジン中、室温
で無水酢酸と１３日間反応させて、各々、無定形固体の
、Ｒ１がアセチル、Ｒ７およびＲ８姑共に水素で、２２
１’ｔの式Ｃｍ）Ｑ化合物（前記化合物−６、収率７８
％、融点８０〜１００Ｃ）ならびにＲ，およびＲ２が共
にアセチル、Ｒ８が水素で、２２Ｒの式（ＩＩ）の化合
物（前記化合物−７、収率１４％）を得る。Example 8 Compound-1 obtained in Example 1 was reacted with acetic anhydride in pyridine at room temperature for 13 days to form an amorphous solid, R1 is acetyl, R7 and R8 are both hydrogen, and 22
1't Formula Cm) Q compound (said compound-6, yield 78
%, melting point 80 to 100 C), R and R2 are both acetyl, R8 is hydrogen, and a compound of formula (II) of 22R (the above compound-7, yield 14%) is obtained.

実施例４前記実施例１で得られた化合物−２をピリジン中、室温
で無水酢酸と１３日間反応させて、各々、Ｒ１がアセチ
ル、Ｒ２およびＲ３が水素で、２２Ｓの式（１〕の化合
物（前記化合物−８、収率８１％、融点１９８．５〜１
９５Ｃ）ならびにＲ８およびＲ１が共にアセチル、Ｒ３
が水素で、２２８の　式［１）の化合物（前記化合物−
９、収率１４％、融点２５２〜２５８ｔｌ’）を得る。Example 4 Compound-2 obtained in Example 1 was reacted with acetic anhydride in pyridine at room temperature for 13 days to obtain a compound of formula (1) of 22S, where R1 is acetyl, R2 and R3 are hydrogen, respectively. (Said compound-8, yield 81%, melting point 198.5-1
95C) and R8 and R1 are both acetyl, R3
is hydrogen, and the compound of formula [1] of 228 (the above compound -
9, yield 14%, melting point 252-258 tl').

実施例５前記実施例１で得られた化合物−２を、無水酢酸お！び
ｐ−）ルエンスルホン酸を用い、室温で３日間アセチル
化して化合物−９（収率５８％）ならびに無定形固体の
、Ｒ，、Ｒ，およびＲ３が共にアセチルで、２２８の式
［１］の化合物（前記化合物−１０、収率２４％、融点
９５〜ｉｉ。Example 5 Compound-2 obtained in Example 1 was mixed with acetic anhydride! Compound-9 (yield 58%) and amorphous solid were acetylated using p-)luenesulfonic acid for 3 days at room temperature, and R, R, and R3 were all acetyl, and the formula [1] of 228 was obtained. (Compound-10, yield 24%, melting point 95-ii.

Ｃ）を得る。C) is obtained.

特許出願人藤沢薬品工業株式会社代理人弁理士青山　葆し２名Patent applicant Fujisawa Pharmaceutical Co., Ltd. Representative Patent Attorney Aoyama Boshi 2 people

Claims

[Claims] Formula (1): [In the formula, R, , R2 and R8 are the same or different and each means hydrogen or acyl. However, the configuration at position 22 may be R-configuration or S-configuration, but
In formula [I], when R is acetyl and R2 is hydrogen, it is 228]. (2) R1', R2 and R3 are both hydrogen, 221
The compound of item (1) above, represented by the formula CI) of L. (8) R+, R2 and R8 are both hydrogen, 228
The compound of the above item (1) represented by the formula [U]. (4) The compound of item (1) above, where R1 is acetyl/kj·R2 is hydrogen and is represented by the 2280 formula [1]. (5) Both TL+ and R2 are hydrogen, and the formula of 22R [1
] The compound according to item (1) above. (6) Both R1 and R2 are acetyl, and the formula of 22R (
1) The compound according to item (1) above. (71R1 is acetyl, R2 and R5 are both hydrogen,
The compound of the above item (1), which is represented by the formula (Il) of 22R. An accompaniment. (9) "t is acetyl, R and R8 are both hydrogen,
The compound of the above item (1) represented by formula (H) of 228. Qo) The compound of item (1) above, represented by formula (1) of 228, in which both Rt and R2 are acetyl, and R8 is hydrogen. (11) The compound of item (1) above, where Rt , Rt and R3 are all acetyl, and is represented by the formula 2280 [■]X. (12) Formula: [In the formula, R, , R2 and R3 are the same or different and each means hydrogen or acyl. However, the configuration at position 22 may be R-configuration or S-configuration, but
An anticancer drug composition containing a compound represented by the formula (r), in which R1 is acetyl and R2 is hydrogen, 22S] as an active ingredient.