JPH01228999A - Novel podophyllotoxin glycoside - Google Patents
Novel podophyllotoxin glycosideInfo
- Publication number
- JPH01228999A JPH01228999A JP5355688A JP5355688A JPH01228999A JP H01228999 A JPH01228999 A JP H01228999A JP 5355688 A JP5355688 A JP 5355688A JP 5355688 A JP5355688 A JP 5355688A JP H01228999 A JPH01228999 A JP H01228999A
- Authority
- JP
- Japan
- Prior art keywords
- glucopyranosyl
- podophyllotoxin
- tetra
- galactopyranosyl
- group
- 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
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960001237 podophyllotoxin Drugs 0.000 title claims abstract description 27
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229930182470 glycoside Natural products 0.000 title claims abstract description 10
- -1 podophyllotoxin glycoside Chemical class 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 abstract description 28
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 abstract description 21
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 150000002338 glycosides Chemical class 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 abstract description 3
- 208000032839 leukemia Diseases 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 229910052765 Lutetium Inorganic materials 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009036 growth inhibition Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- MOQOOKGPCBQMCY-UHFFFAOYSA-N acetic acid;hexane Chemical compound CC(O)=O.CCCCCC MOQOOKGPCBQMCY-UHFFFAOYSA-N 0.000 description 2
- 125000003550 alpha-D-galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 125000001488 beta-D-galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 101001074571 Homo sapiens PIN2/TERF1-interacting telomerase inhibitor 1 Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100036257 PIN2/TERF1-interacting telomerase inhibitor 1 Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- RJBIAAZJODIFHR-UHFFFAOYSA-N dihydroxy-imino-sulfanyl-$l^{5}-phosphane Chemical compound NP(O)(O)=S RJBIAAZJODIFHR-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 208000010576 undifferentiated carcinoma Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
新規な抗腫瘍活性を有するポドフィロトキシン配糖体に
関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a podophyllotoxin glycoside having novel antitumor activity.
ポドフィロトキシン類およびポドフィロトキシン配糖体
類は、制癌活性を示すことが知られている。その中で、
ｖＰ−１６−２１３（エトポシド）〔■〕およびＶＭ−
２６（テニボニド）〔■〕は白血病、悪性リンパ腫、肺
癌（扁平上皮癌、小細胞未分化癌）、逼九腫瘍、肝臓癌
等に有効で有リ、すでに日本、ヨーロッパにおいて広く
臨床利用されている。Podophyllotoxins and podophyllotoxin glycosides are known to exhibit anticancer activity. among them,
vP-16-213 (etoposide) [■] and VM-
26 (Tenibonide) [■] is effective against leukemia, malignant lymphoma, lung cancer (squamous cell carcinoma, small cell undifferentiated carcinoma), Takashi tumor, liver cancer, etc., and has already been widely used clinically in Japan and Europe. .
（ＩＩ） ［１１１）しか
し、この例に見られるように、ポドフィロトキシン−タ
イプよりエピポドフィロトキシン−ポドフィロトキシン
エピポドフィロトキシンタイプ
タイプ
タイプの配糖体類が多く知られている。その理由として
、ポドフィロトキシン−タイプの配糖体は、合成しにく
いからとされている。従って、天然にないポドフィロト
キシン−タイプの配糖体類が得られれば、それらの新し
い生理活性作用が期待されている。(II) [111] However, as seen in this example, epipodophyllotoxin-podophyllotoxin-type rather than podophyllotoxin-type
Many types of glycosides are known. The reason for this is said to be that podophyllotoxin-type glycosides are difficult to synthesize. Therefore, if podophyllotoxin-type glycosides that are not found in nature are obtained, new physiologically active effects are expected.
本発明は、本発明者らが発明した置換グリコシルホスホ
ロイミ・ドチオエートを用いて、従来の方法に比べより
緩和な条件で、高選択的に１．２−シス−グリコジル化
合物をつくる方法を用いて、新規なポドフィロトキシン
配糖体を合成することが出来ることを見出し完成させた
ものである。The present invention utilizes a method for highly selectively producing 1,2-cis-glycodyl compounds using substituted glycosylphosphoroimide dothioates invented by the present inventors under conditions that are milder than those of conventional methods. , discovered and completed the ability to synthesize a new podophyllotoxin glycoside.
本発明は、−殺伐〔Ｉ〕 〔式中、Ｒは１−ｏ−（２，
３，４，６−テトラ−０−ベンジルーα−Ｄ−グルコピ
ラノシル）基、１−０−（２，３，４，６−テトラ−０
−ベンジルーβ−Ｄ−グルコピラノシル）基、１−０−
（４，６−０−エチリデン−α−Ｄ−グルコピラノシル
）基、１−０−（４，６−０−エチリデン−β−Ｄ−グ
ルコピラノシル）基、１−０−（２，３，４，６−テト
ラ−０−ベンジルーα−Ｄ−ガラクトピラノシル）基、
１−０− （２，３，４，６−テトラ−０−ベンジルー
β−Ｄ−ガラクトピラノシル）基、１−０−（α−Ｄ−
ガラクトピラノシル）基、１−０−（β−Ｄ−ガラクト
ピラノシル）基、１−〇−（４，６−０−エチリデン−
α−Ｄ−ガラクトピラノシル）基及び１−０−（４，６
−０−エチリデン−β−Ｄ−ガラクトピラノシル）基を
表す〕で表される新規なポドフィロトキシン配糖体に関
するものである。The present invention provides -salt [I] [wherein R is 1-o-(2,
3,4,6-tetra-0-benzyl-α-D-glucopyranosyl) group, 1-0-(2,3,4,6-tetra-0
-benzy-β-D-glucopyranosyl) group, 1-0-
(4,6-0-ethylidene-α-D-glucopyranosyl) group, 1-0-(4,6-0-ethylidene-β-D-glucopyranosyl) group, 1-0-(2,3,4,6 -tetra-0-benzyl-α-D-galactopyranosyl) group,
1-0-(2,3,4,6-tetra-0-benzyl-β-D-galactopyranosyl) group, 1-0-(α-D-
galactopyranosyl) group, 1-0-(β-D-galactopyranosyl) group, 1-〇-(4,6-0-ethylidene-
α-D-galactopyranosyl) group and 1-0-(4,6
-0-ethylidene-β-D-galactopyranosyl) group].
本発明の新規なポドフィロトキシン配糖体を得る反応は
次の式で表される。即ち、ホスボロイミドチオエート〔
■〕 〔式中、Ｒは１−３−（２，３，４，６−テトラ
−０−ベンジルーＤ−グルコピラノシル）基および１−
５−（２，３，４，６−テトラ−０−ベンジルーＤ−ガ
ラクトピラノシル）基を表す〕とポドフィロトキシンを
２．６−ルチジニウムトシラート（ＬＰＴＳ）等の反応
促進剤の存在下に適当な有機溶媒中で反応させると−Ｍ
式（１）Ｃ式中、Ｒは１−０−（２，３，４，６−テト
ラ−０−ベンジルーα−Ｄ−１’ルコビラノシル）基、
１−０−（２，３，４，６−テト（ＴＶ） ポ
ドフィロ （１）トキシン
シー０−ベンジルーβ−Ｄ−グルコピラノシル）基、１
−０− （２，３，４，６−テトラ−０−ベンジルーα
−Ｄ−ガラクトピラノシル）基、１−〇−（２，３，４
，６−チトラー０−ベンジルーβ−Ｄ−ガラクトピラノ
シル）基を表す〕で表される本発明の化合物を得ること
が出来る。又、所望により脱ベンジル化、さらに続いて
エチリデン化することによって本発明化合物を得ること
が出来る。The reaction for obtaining the novel podophyllotoxin glycoside of the present invention is represented by the following formula. That is, phosphoroimidothioate [
■] [In the formula, R is a 1-3-(2,3,4,6-tetra-0-benzy-D-glucopyranosyl) group and a 1-
5-(2,3,4,6-tetra-0-benzy-D-galactopyranosyl) group] and podophyllotoxin using a reaction accelerator such as 2,6-lutidinium tosylate (LPTS). When reacted in a suitable organic solvent in the presence of -M
Formula (1)C In the formula, R is a 1-0-(2,3,4,6-tetra-0-benzyl-α-D-1'lucobyranosyl) group,
1-0-(2,3,4,6-tet(TV)podophyllo(1)toxic0-benzy-β-D-glucopyranosyl) group, 1
-0- (2,3,4,6-tetra-0-benzyru α
-D-galactopyranosyl) group, 1-〇-(2,3,4
, 6-chitler-0-benzyl-β-D-galactopyranosyl) group] can be obtained. The compound of the present invention can also be obtained by debenzylation and subsequent ethylideneation, if desired.
本発明の化合物としては、例えば次の様な物があげられ
る。（１）１−０− （２，３，４，６−テトラ−０−
ベンジルーα−Ｄ−グルコピラノシル）ポドフィロトキ
シン、（２）１−０− （２，３，４，６−テトラ−０
−ベンジルーβ−〇−グルコピラノシル）ポドフィロト
キシン、（３） １−Ｏ−（２，３，４，６−テトラ
−０−ベンジルーα−Ｄ−ガラクトピラノシル）ポドフ
ィロトキシン、（４）１−０− （２，３，４，６−テ
トラ−０−ベンジルーβ−Ｄ−ガラクトピラノシル）ポ
ドフィロトキシン、（５）１−０− （４，６−〇−エ
チリデンーα−Ｄ−グルコピラノシル）ポドフィロトキ
シン、 （６）１−０− （４，６−〇−エチリデン
ーβ−Ｄ−グルコピラノシル）ポドフィロトキシン、（
７）１−０− （α−Ｄ−ガラクトピラノシル）ポドフ
ィロトキシン、（８） １−Ｏ−（β−Ｄ−ガラクト
ピラノシル）ポドフィロトキシン、（９）１−０− （
４，６−０−エチリデン−α−Ｄ−ガラクトピラノシル
）ポドフィロトキシン、及び（１０）１−０− （４，
６−０−エチリデン−β−Ｄ−ガラクトピラノシル）ポ
ドフィロトキシン
本発明の化合物の抗腫瘍活性は細胞増殖阻害活性を用い
て測定した０次に、細胞増殖阻害活性の測定法について
述べる。Examples of the compounds of the present invention include the following. (1) 1-0- (2,3,4,6-tetra-0-
Benzyl-α-D-glucopyranosyl)podophyllotoxin, (2) 1-0-(2,3,4,6-tetra-0
-benzy-β-〇-glucopyranosyl)podophyllotoxin, (3) 1-O-(2,3,4,6-tetra-0-benzy-α-D-galactopyranosyl)podophyllotoxin, (4 )1-0-(2,3,4,6-tetra-0-benzyl-β-D-galactopyranosyl)podophyllotoxin, (5)1-0-(4,6-〇-ethylidene-α- D-glucopyranosyl)podophyllotoxin, (6) 1-0-(4,6-〇-ethylidene-β-D-glucopyranosyl)podophyllotoxin, (
7) 1-0- (α-D-galactopyranosyl)podophyllotoxin, (8) 1-O-(β-D-galactopyranosyl)podophyllotoxin, (9) 1-0- (
4,6-0-ethylidene-α-D-galactopyranosyl)podophyllotoxin, and (10)1-0-(4,
6-0-ethylidene-β-D-galactopyranosyl) podophyllotoxin The antitumor activity of the compounds of the present invention was measured using cell growth inhibitory activity.Next, the method for measuring cell growth inhibitory activity will be described. .
方 法
）１ｅＬａ ３３１１胞を７．５ｘｌＯ”ｃｅｌｌｓノ
ー１に調整し、９６ｗｅｌｌ平底ｐｌａｔｅに０．２＋
＊１ずつ播く、３７℃、５χＣＯ。Method) 1eLa 3311 cells were adjusted to 7.5xlO”cells No. 1 and placed in a 96-well flat bottom plate at 0.2+
*Sow one at a time, 37℃, 5χCO.
インキュベーター内で２４時間培養した後、薬剤を添加
し７２時間培養する。培養後、アスピレータ−を用いて
各−ｅｌｌの培養液を抜き取り、ＭｅＯ）１で固定した
後、０．０５χのｍｅｔｈｙｌｅｎｅｂｌｕｅ／１０ｍ
Ｍ Ｔｒｉｓ−ＨＣＩ（ｐｈ８．５）溶液を０．２ｍｌ
／ｗｅｌｌずつ加え、３０分間室温にて染色する。各ｗ
ｅｌｌの染色液をアスピレータ−を用いて抜き取り、純
水で３回洗浄する。３χＨＣＩを０．２＋ａｌ／ｗｅ１
１の割合で添加後、シールで密封して約２４時間室温放
置し細胞から色素を抽出する。各抽出液の６６０ｎ−で
の吸光度（＾ｈ６．）をダイナチックマイクドブレート
リーダーで測定し、下式より各農度の増殖阻害％を算出
し、対数確率紙にプロ７）し、５０９Ａ阻害の濃度を求
める。After culturing in an incubator for 24 hours, a drug is added and cultured for 72 hours. After culturing, the culture solution from each cell was taken out using an aspirator, fixed with MeO)1, and then fixed with 0.05χ methylene blue/10 m
0.2 ml of M Tris-HCI (ph 8.5) solution
/well and stain for 30 minutes at room temperature. Each w
The staining solution from the cells is taken out using an aspirator and washed three times with pure water. 3χHCI 0.2+al/we1
After adding at a ratio of 1:1, the cells are sealed and left at room temperature for about 24 hours to extract the pigment from the cells. The absorbance at 660n- (^h6.) of each extract was measured using a dynamic microphone plate reader, and the growth inhibition % of each agricultural grade was calculated from the formula below, and the percentage of growth inhibition was calculated on logarithmic probability paper. Find the concentration of
Ａｉｎｏ（薬剤処理細胞）
増殖阻害％＝ １００− ｘｌ
ＯＯＡｂｉａ（薬剤無処理細胞）
本発明の化合物の内、代表的化合物の細胞増殖５０％阻
害の濃度（ＩＣｓ。）を表１に示す０本発明の化合物は
強い細胞増殖阻害活性を示し、制癌剤としての有用性が
期待される。Aino (drug-treated cells) growth inhibition % = 100-xl
OOAbia (drug-free cells) Among the compounds of the present invention, the concentrations of 50% inhibition of cell proliferation (ICs) of representative compounds are shown in Table 1.0 The compounds of the present invention exhibit strong cell proliferation inhibitory activity and are used as anticancer agents. is expected to be useful.
表 １ 細胞増殖阻害活性（ＩＣＳ。値：μｇ／ｍｌ）
次に、実施例によって具体的に本発明を説明する。Table 1 Cell proliferation inhibitory activity (ICS. Value: μg/ml)
Next, the present invention will be specifically explained with reference to Examples.
実施例 １）１−０− （２，３，４，６−テトラ−０
−ベンジル−α−１およびβ−Ｄ−グルコピラノシル）
ポドフィロトキシンの合成〔化合物Ｎ０（１）および（
２）〕
脱気、乾燥した反応管にポドフィロトキシン（５００ｗ
ａｇ、 １．２ｓ＋ｖ＋ｏｌ）、すりつぶしたモレキエ
ラーシーブ４Ａ （３００腸ｇ）を入れ、アルゴン雰囲
気、０℃にて無水トルエン（７鴎ｌ）に溶かした１−３
−（２，３，４，６−テトラーＯ−ベンジルーＤ−グル
コピラノシル）−Ｎ−フェニル−Ｎ’ 、Ｎ’ −ビ
ス（ジメチル）ホスホロイミドイミデート（９３０−ｇ
、１．２−ｍｏｌ）をシリンジを用いてゆっくり加えた
。Example 1) 1-0- (2,3,4,6-tetra-0
-benzyl-α-1 and β-D-glucopyranosyl)
Synthesis of podophyllotoxin [compounds N0(1) and (
2)] Add podophyllotoxin (500W) to a degassed and dry reaction tube.
ag, 1.2s + v + ol), ground Molecule Sieve 4A (300g) was added, and 1-3 was dissolved in anhydrous toluene (7ml) at 0°C in an argon atmosphere.
-(2,3,4,6-tetra-O-benzy-D-glucopyranosyl)-N-phenyl-N',N'-bis(dimethyl)phosphoroimidoimidate (930-g
, 1.2-mol) was slowly added using a syringe.
すばやくガラス管を封じ１５時間室温で攪拌した。The glass tube was quickly sealed and stirred at room temperature for 15 hours.
反応液を濾過し、エーテル１０ｍ１で薄めて、飽和重炭
酸ソーダ水（１０ｍｌｘ２）、飽和食塩水（１０ｍｌｘ
２）で洗浄し無水硫酸ナトリウムで乾燥後、溶媒を暦表
し残金をシリカゲルクロマトグラフィー（ｎ−へキサン
ー酢酸エステル３：１）にて精製し、目的物のα、β混
合物（３６０ｍｇ、収率３２χ）を得た。The reaction solution was filtered, diluted with 10 ml of ether, and mixed with saturated sodium bicarbonate water (10 ml x 2) and saturated brine (10 ml x 2).
After washing with 2) and drying with anhydrous sodium sulfate, the solvent was removed and the remaining residue was purified by silica gel chromatography (n-hexane-acetate 3:1) to obtain a mixture of α and β of the target product (360 mg, yield 32χ ) was obtained.
）１−ＮＭＲδ（ｐｐｍ） ＣＤＣｌ３ニア、２０（Ｌ
Ｈ，３，８−８）６．４７（ＬＨ，ｓ、Ｈ−５）
６．３８（２Ｈ，ｓ、Ｈ−１’、Ｈ−２’）５．９５（
２Ｈ，ｓ、）Ｉ−７）
３．７５（３Ｈ，Ｓ、ＣＨ３０）
３．７２（６８，！、Ｃ）１３０）
２．７８（ＩＨ９−、Ｈ−２）
所望により、さらに精製することによってα一体とβ一
体を分離することが出来る。)1-NMRδ (ppm) CDCl3 near, 20(L
H, 3, 8-8) 6.47 (LH, s, H-5) 6.38 (2H, s, H-1', H-2') 5.95 (
2H,s,)I-7) 3.75(3H,S,CH30) 3.72(68,!,C)130) 2.78(IH9-,H-2) Optionally by further purification It is possible to separate α-integrated and β-integrated.
実施例 ２）１−０−（４，６−０−エチリデン−α−
およびβ−Ｄ−グルコピラノシル）ポドフィロトキシン
〔化合物Ｎ０（５）および（６）〕の合成
実施例 １）で得られた化合物（１）および（２）の混
合物（３５（１ｍｇ １０．３８ｍｍｏｌ）を無水エタ
ノール３１似溶解し、２０χＰｄ （ＯＨ） ！／Ｃを
加え室温で１０時間攪拌し水素化分解を行った０反応終
了後、触媒を濾別し溶媒を減圧下に暦表した。得られた
残金（２００ｍｇ）を無水アセトニトリル３ｍｌに溶解
し、１、ｌ−ジェトキシエタン（１，１ｍ１）、バラト
ルエンスルフォン酸く２０−ｇ）加え２時間室温で攪拌
した０反応終了後、トリエチルアミンを加え溶媒を暦表
した。残金をシリカゲルクロマトグラフィー（塩化メチ
レン−メタノール、３０：１）にて精製し、目的物のα
一体〔化合物Ｎｏ（５））とβ一体〔化合物Ｎｏ（６）
）を得た。Example 2) 1-0-(4,6-0-ethylidene-α-
and β-D-glucopyranosyl) podophyllotoxin [Compounds N0 (5) and (6)] Synthesis Example A mixture of compounds (1) and (2) obtained in 1) (35 (1 mg 10.38 mmol) was dissolved in 31 ml of absolute ethanol, 20 χ Pd (OH) !/C was added, and the mixture was stirred at room temperature for 10 hours to perform hydrogenolysis. After the reaction was completed, the catalyst was filtered off and the solvent was evaporated under reduced pressure. The remaining residue (200 mg) was dissolved in 3 ml of anhydrous acetonitrile, and 1,1-jethoxyethane (1,1 ml) and valatoluenesulfonic acid (20 g) were added and stirred at room temperature for 2 hours. After the reaction was completed, triethylamine was added and the solvent was removed. Calendar chart. The residue was purified by silica gel chromatography (methylene chloride-methanol, 30:1) to obtain the target product α.
Integral [Compound No. (5)] and β Integral [Compound No. (6)
) was obtained.
α一体（化合物Ｎｏ（５））
（α）”−６５，５° （ｃ Ｏ，４２，ＣＨＣｈ）ｍ
ｐ １３６−１３７．５℃
Ｉ Ｒ（ＣＨＣＩｓ）： １ ７ ７ ０ ｃｍ
−１、３４６０ｃｍ＋−″１Ｈ−ＮＭＲδ （ｐｐｍ）
ＣＤＣｌ３；７．２７（１Ｂ、ｓ、Ｈ−８）６．５
１（ＩＨ，ｓ、Ｈ−５）
６．３９（２Ｈ，ｓ、Ｈ−１’、Ｈ−２’）５．９８（
２Ｈ，ｓ、Ｈ−７）
５．１５（１）１．ｄ、Ｊ−３，８，Ｈ−１’”）４．
６９（ＩＨ，ｄ、Ｊ−８，９，Ｈ−１）４．５８（ＩＨ
，ｄ、Ｊ＝４．３．Ｈ−４）３．８３（３Ｈ，ｓ、ＣＨ
ｉＯ）
３．７７（６Ｈ，Ｓ、ＣＨ３０）
２．８８（１８，ｗｇ、）ｌ−２）
２．８２（ＩＨ，ｄｄ、Ｊ＝４．３゜
Ｊ、１４．０．８−３）
１．３５（３ｎ、ｄ、Ｊ−５，１，ｃｏｉＣＨ）β一体
〔化合物Ｎ０（６））
（α）”−７９，０° （ｃ Ｏ，２８，ＣＨＣｌ３）
ｍｐ １７２−１７４ ℃
Ｉ Ｒ（ＣＨＣｌり；１ ７ ７ ０Ｃ１１−’、
３ ４ ６ ０ｃｍ −息１１−ＮＭＲδ（ｐｐｍ
） ＣＤＣｌ３；７．２２（ｌＨ，ｓ、Ｈ−８）６．５
０（ＩＨ，ｓ、Ｈ−５）
６．３２（２）１．ｓ、Ｈ−１’、Ｈ−２’）５．９５
，５．９７（２８，ｓ、）ｌ−７）４．９０（ＩＨ，ｄ
、Ｊ−８，７，）ｌ−１）４．４２（ＩＨ，ｄ、Ｊ−７
，８，Ｈ−１”）３．７８（９Ｈ，ｄ、ＣＨ３０）
２．９０（１）１．１１．）ｌ−２）
２．８０（ＩＨ，ｄｄ、Ｊ−５，２゜
Ｊ、１４．０．Ｈ−３）
１．３５（３ｏ、ｄ、Ｊ、５．１．ｃｏ＊ｃＨ）実施例
３）１−０− （２，３，４，６−テトラ−０−ベン
ジル−α−１およびβ−Ｄ−ガラクトピラノシル）ポド
フィロトキシンの合成〔化合物Ｎｏ （３）および（４
）〕
脱気、乾燥した反応管にポドフィロトキシン（１８Ｂ、
ｍｇ、０．４５ｍｗｏｌ） 、すりつぶした％ Ｌ／
＋ エラーシーブ４Ａ （１２０ｍｇ）を入れ、アルゴ
ン雰囲気、０℃にて無水トルエン（７１）に溶かした１
−３−（２，３，４，６−テトラーＯ−ベンジルーＤ−
グルコピラノシル）−Ｎ−フェニル−Ｎ’ 、Ｎ’ −
ビス（ジメチル）ホスホロイミドイミデート（２００＋
ｓｇ 、 ０．３６ｍｍｏｌ）をシリンジを用いてゆっ
くり加えた。すばやくガラス管を封じ６０時間室温で攪
拌した０反応液を濾過し、エーテル７ｍｌで薄めて、飽
和重炭酸ソーダ水（５ｓｌｘ２）、飽和食塩水（５ｍ１
ｘ２）で洗浄し無水硫酸ナトリウムで乾燥後、溶媒を暦
表し残金をシリカゲルクロマトグラフィー（ｎ−ヘキサ
ン−酢酸エステル４：１）にて精製し、目的物のα一体
（１５６＋Ｂ 、収率４６χ）、β一体（５６ｍｇ。α integral (compound No. (5)) (α)”-65,5° (c O,42,CHCh)m
p 136-137.5℃ IR (CHCIs): 1770 cm
-1, 3460cm+-''1H-NMRδ (ppm)
CDCl3; 7.27 (1B, s, H-8) 6.5
1 (IH, s, H-5) 6.39 (2H, s, H-1', H-2') 5.98 (
2H, s, H-7) 5.15 (1) 1. d, J-3,8, H-1''')4.
69 (IH, d, J-8, 9, H-1) 4.58 (IH
, d, J=4.3. H-4) 3.83 (3H,s, CH
iO) 3.77 (6H, S, CH30) 2.88 (18, wg, )l-2) 2.82 (IH, dd, J=4.3°J, 14.0.8-3) 1 .35 (3n, d, J-5,1, coiCH) β integral [Compound N0 (6)) (α)”-79,0° (c O, 28, CHCl3)
mp 172-174 °C IR (CHCl; 1 7 7 0C11-',
3 4 6 0cm - breath 11 - NMR δ (ppm
) CDCl3; 7.22 (lH, s, H-8) 6.5
0 (IH, s, H-5) 6.32 (2) 1. s, H-1', H-2') 5.95
,5.97(28,s,)l-7)4.90(IH,d
, J-8,7,)l-1)4.42(IH,d,J-7
, 8, H-1") 3.78 (9H, d, CH30) 2.90 (1) 1.11.) l-2) 2.80 (IH, dd, J-5, 2° J, 14 .0.H-3) 1.35 (3o, d, J, 5.1.co*cH) Example 3) 1-0- (2,3,4,6-tetra-0-benzyl-α- 1 and β-D-galactopyranosyl) podophyllotoxin [Compound No. (3) and (4)
)] Add podophyllotoxin (18B,
mg, 0.45 mwol), ground % L/
+ Error Sieve 4A (120 mg) was added and dissolved in anhydrous toluene (71) in an argon atmosphere at 0°C.
-3-(2,3,4,6-tetra O-benzyruD-
glucopyranosyl)-N-phenyl-N', N'-
Bis(dimethyl)phosphoroimidoimidate (200+
sg, 0.36 mmol) was slowly added using a syringe. The glass tube was quickly sealed and the reaction solution was stirred at room temperature for 60 hours. The reaction solution was filtered, diluted with 7 ml of ether, and mixed with saturated sodium bicarbonate water (5 sl x 2) and saturated brine (5 ml).
After washing with x2) and drying with anhydrous sodium sulfate, the solvent was removed and the residue was purified by silica gel chromatography (n-hexane-acetic acid ester 4:1) to obtain the target α-integrated product (156+B, yield 46χ), β unit (56 mg.
１７χ）をえた。17χ).
α一体〔化合物Ｎｏ（３））
（α） ” １５． ０ （ｃｌ、１５ 、ＣＨＣ
ｌ３ ）Ｉ Ｒ（ＣＨＣｌｘ）； １７７０ ｃｍ−’
Ｈ−Ｎ？ＩＲδ （ｐｐｍ） ＣＤＣｌ５；６．４８
（１８，ｓ、Ｈ−５）６．３８（２Ｈ，ｓ、Ｈ−１’、
Ｈ−２’）５．９６．５．９８（２Ｈ，ｓ、Ｈ−７）４
．８９（ＩＨ，ｄ、Ｊ＝３．８．８−１”）４．４５（
ＩＨ，ａ、Ｊ＝８．７．Ｈ−１）３．７６（３Ｈ，ｓ、
ＣＨＪ）
３．７２（６Ｈ，ｓ、ｃＨ３０）
３．３０−３．５０（２Ｂ、ｍ ）
２．７０−２．８５（２Ｈ，ｎ、）Ｉ−３，Ｈ−２）β
一体〔化合物Ｎｏ（４））
（α）”、’−５１，０° （ｃ Ｏ，８２，ＣＨＣｌ
ｘ）Ｉ Ｒ（ＣＤＣ１３）； １ ７ ７ ０ ｃ
ｍ−’Ｈ−ＮＭＲδ（ｐｐｍ） ＣＤＣ１，：６．４８
（ＩＨ，ｓ、Ｈ−５）６．４０（２Ｈ，ｓ、Ｈ−１’、
Ｈ−２’）５．９６．５．９７（２）１．ｓ、Ｈ−７
）３．７６（３Ｈ，ｓ、ＣＨｉＯ）
３．７２（６Ｈ，ｓ、ＣＨ３０）
２．９０（１）１．ｍ、Ｈ−２）
２．７８（ＩＨ，ｄｄ、Ｊ富５．３゜
Ｊ−１４，０）１−３）
実施例 ４）１−０−（α−Ｄ−ガラクトピラノシル）
ポドフィロトキシンの合成〔化合物Ｎ０７〕実施例 ３
）で得うレタ化合物（３） （１２０ｍｇ、０．１３
＋ｍｏｌ）を無水エタノール３ｍｌ似溶解し、２０χＰ
ｄ （ＯＨ）工／Ｃを加え室温で６時間攪拌し水素化分
解を行った０反応終了後、触媒を濾別し溶媒を減圧下に
溜去して目的物（７） （６１ｍｇ、 ８２χ）を得
たα一体〔化合物Ｎ０（７））
（α） ２ｏ １６− ９° （ｃ Ｏ，６８，Ｍｅ
ＯＨ））１−ＮＭＲδ （ｐｐｍ） ＣＤ３０Ｄ；７
．６０（ＩＨ，３，８−８）６．４８（ＩＨ，ｓ、Ｈ−
５）
６．４０（２Ｈ，ｓ、Ｈ−１’、Ｈ−２’）５．９５．
５．９６（２Ｂ、ｓ、Ｈ−７）５．１５（１Ｂ、ｄ、Ｊ
＝３．８．Ｈ−１”）４．７５（ＩＨ，ｄ、Ｊ＝８．７
．１（−１）３．７３（３Ｈ，ｓ、ｃＨｘｏ）
３．７０（６Ｍ、Ｓ、ＣＨ３０）
３．００（ＩＨ，ｄ、Ｊ、５．１゜
Ｊ＝１４．Ｏ，Ｈ−３）
２．８５（ＩＨ，■、Ｈ−２）
実施例 ５）１−０− （β−Ｄ−ガラクトピラノシル
）ポドフィロトキシンの合成〔化合物Ｎ０８）実施例３
）で得られた化合物（４）を用いて、実施例 ４）と同
様にして行うと化合物８が得られる。α integral [Compound No. (3)) (α)” 15.0 (cl, 15, CHC
l3)IR(CHClx); 1770 cm-'
H-N? IRδ (ppm) CDCl5; 6.48
(18,s, H-5)6.38(2H,s,H-1',
H-2') 5.96.5.98 (2H, s, H-7) 4
．． 89 (IH, d, J = 3.8.8-1”) 4.45 (
IH,a,J=8.7. H-1) 3.76 (3H,s,
CHJ) 3.72 (6H, s, cH30) 3.30-3.50 (2B, m) 2.70-2.85 (2H, n,) I-3, H-2) β
Integral [Compound No. (4)) (α)”,'-51,0° (c O,82,CHCl
x) I R (CDC13); 1 7 7 0 c
m-'H-NMRδ (ppm) CDC1,: 6.48
(IH, s, H-5) 6.40 (2H, s, H-1',
H-2')5.96.5.97(2)1. s, H-7
) 3.76 (3H, s, CHiO) 3.72 (6H, s, CH30) 2.90 (1) 1. m, H-2) 2.78 (IH, dd, J wealth 5.3° J-14,0) 1-3) Example 4) 1-0-(α-D-galactopyranosyl)
Synthesis of podophyllotoxin [Compound N07] Example 3
) Reta compound (3) (120 mg, 0.13
+ mol) in 3 ml of absolute ethanol, 20χP
d(OH)/C was added and stirred at room temperature for 6 hours to perform hydrogenolysis. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain the desired product (7) (61mg, 82χ) The obtained α monolithic [compound N0(7)) (α) 2o 16-9° (c O,68,Me
OH))1-NMRδ (ppm) CD30D;7
．． 60 (IH, 3, 8-8) 6.48 (IH, s, H-
5) 6.40 (2H, s, H-1', H-2') 5.95.
5.96 (2B, s, H-7) 5.15 (1B, d, J
=3.8. H-1”) 4.75 (IH, d, J=8.7
．． 1 (-1) 3.73 (3H, s, cHxo) 3.70 (6M, S, CH30) 3.00 (IH, d, J, 5.1°J = 14.O, H-3) 2 .85 (IH, ■, H-2) Example 5) Synthesis of 1-0- (β-D-galactopyranosyl)podophyllotoxin [Compound N08) Example 3
) Compound 8 is obtained in the same manner as in Example 4) using Compound (4) obtained in Example 4).
β一体〔化合物Ｎ０（８））
（α） ” −５８、３（ｃ Ｏ，４７，ＭｅＯＨ））
１−ＮＭＲδ （ｐｐｍ） ＤＭＳＯ；７．５５（Ｉ
Ｈ，ｓ、Ｈ−８）（Ｄｉ） ６．７０（ＩＨ，Ｓ、Ｈ
−５）６．６０（２Ｈ，ｓ、Ｈ−１’、 Ｈ−２’）６
．１５，６．１７（２）１．ｓ、Ｈ−７）５．２５（ｌ
Ｈ，ｄ、Ｊ＝８．７．Ｈ−１）４．５５（ＩＨ，ｄ、Ｊ
＝７−８．）ｌ−１’”）３．９８（３Ｈ，Ｓ、ＣＨ３
０）
３−９０（６Ｈ，ｓ、ｃＨｉＯ）
３．１０（１）１．＋ｍ、）ｌ−２，Ｈ−３）実施例
６）１−０− （４，６−０−エチリデン−α−Ｄ−ガ
ラクトピラノシル）ポドフィロトキシン〔化合物Ｎ０（
９））の合成
実施例 ４）で得られた化合物（７）（５０ｍｇ、０．
０９■曽ｏ１）を無水アセトニトリル３ｍｌに溶解し、
１．１−ジェトキシエタン（０，４ｍ１）、パラトルエ
ンスルフォン酸（５ｍｇ）加え２時間室温で攪拌した０
反応終了後、固体重炭酸ソーダを加え溶媒を溜去した。β integral [compound N0(8)) (α) ”-58,3(cO,47,MeOH))
1-NMRδ (ppm) DMSO; 7.55 (I
H, s, H-8) (Di) 6.70 (IH, S, H
-5) 6.60 (2H, s, H-1', H-2')6
．． 15, 6.17 (2) 1. s, H-7) 5.25 (l
H, d, J=8.7. H-1) 4.55 (IH, d, J
=7-8. )l-1'”)3.98(3H,S,CH3
0) 3-90(6H,s,cHiO) 3.10(1)1. +m,)l-2,H-3) Example
6) 1-0-(4,6-0-ethylidene-α-D-galactopyranosyl)podophyllotoxin [Compound N0(
Synthesis Example of 9)) Compound (7) obtained in 4) (50 mg, 0.
09■so1) was dissolved in 3 ml of anhydrous acetonitrile,
1.1-Jethoxyethane (0.4ml) and para-toluenesulfonic acid (5mg) were added and stirred at room temperature for 2 hours.
After the reaction was completed, solid sodium bicarbonate was added and the solvent was distilled off.
残金をシリカゲルクロマトグラフィー（塩化メチレン−
メタノール、３０：１）にて１１！ＩＬ、目的物の化合
物Ｎｏ ９ （１４ｍｇ、 ２４χ）を得た。The residue was purified by silica gel chromatography (methylene chloride).
methanol, 30:1) at 11! IL, the target compound No. 9 (14 mg, 24χ) was obtained.
Ｔ Ｒ（ＣＨＣＩｓ）： １７７０ ｃｍ−’、３４０
０ｃ＋ｓ″″′）１−ＮＭＲδ（ｐｐｍ） ＣＤＣｌ３
ニア、４０（ＩＨ，３，Ｈ−８）６、５０ （１８，ｓ
、 Ｈ−’５）
６．３８（２８，ｓ、Ｈ−１°、Ｈ−２’）５．９７．
５．９９（２Ｈ，ｓ、Ｈ−７）５．２８（１）１．ｄ、
Ｊ＝３．８．８−１”）４．６８（ＩＨ，ｄ、Ｊ＝８．
２，１（−１）３．８０（３４１，ｓ、ＣＨ３０）
３．７０（６Ｈ，Ｓ、ＣＨ３０）
２．７０−２．９０（２Ｈ，諺、Ｈ−２，１ｌ−３）１
．４０（３）１．ｄ、Ｊ−５，１，ＣＨ，ＣＨ）特許出
願人 日本化薬株式会社T R (CHCIs): 1770 cm-', 340
0c+s″″′)1-NMRδ(ppm) CDCl3
Near, 40 (IH, 3, H-8) 6, 50 (18, s
, H-'5) 6.38 (28,s, H-1°, H-2') 5.97.
5.99 (2H, s, H-7) 5.28 (1) 1. d,
J=3.8.8-1”)4.68(IH,d,J=8.
2,1 (-1) 3.80 (341, s, CH30) 3.70 (6H, S, CH30) 2.70-2.90 (2H, proverb, H-2, 1l-3) 1
．． 40(3)1. d, J-5,1, CH, CH) Patent applicant Nippon Kayaku Co., Ltd.
Claims (1)
ベンジル−α−Ｄ−グルコピラノシル）基、１−Ｏ−（
２、３、４、６−テトラ−Ｏ−ベンジル−β−Ｄ−グル
コピラノシル）基、１−Ｏ−（４、６−Ｏ−エチリデン
−α−Ｄ−グルコピラノシル）基、１−Ｏ−（４、６−
Ｏ−エチリデン−β−Ｄ−グルコピラノシル）基、１−
Ｏ−（２、３、４、６−テトラ−Ｏ−ベンジル−α−Ｄ
−ガラクトピラノシル）基、１−Ｏ−（２、３、４、６
−テトラ−Ｏ−ベンジル−β−Ｄ−ガラクトピラノシル
）基、１−Ｏ−（α−Ｄ−ガラクトピラノシル）基、１
−Ｏ−（β−Ｄ−ガラクトピラノシル）基、１−Ｏ−（
４、６−Ｏ−エチリデン−α−Ｄ−ガラクトピラノシル
）基及び１−Ｏ−（４、６−Ｏ−エチリデン−β−Ｄ−
ガラクトピラノシル）基を表す〕で表される新規なポド
フィロトキシン配糖体。[Claims] General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, R is 1-O-(2,3,4,6-tetra-O-
benzyl-α-D-glucopyranosyl) group, 1-O-(
2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl) group, 1-O-(4,6-O-ethylidene-α-D-glucopyranosyl) group, 1-O-(4, 6-
O-ethylidene-β-D-glucopyranosyl) group, 1-
O-(2,3,4,6-tetra-O-benzyl-α-D
-galactopyranosyl) group, 1-O-(2,3,4,6
-tetra-O-benzyl-β-D-galactopyranosyl) group, 1-O-(α-D-galactopyranosyl) group, 1
-O-(β-D-galactopyranosyl) group, 1-O-(
4,6-O-ethylidene-α-D-galactopyranosyl) group and 1-O-(4,6-O-ethylidene-β-D-
A novel podophyllotoxin glycoside represented by [representing a galactopyranosyl group].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5355688A JPH01228999A (en) | 1988-03-09 | 1988-03-09 | Novel podophyllotoxin glycoside |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5355688A JPH01228999A (en) | 1988-03-09 | 1988-03-09 | Novel podophyllotoxin glycoside |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01228999A true JPH01228999A (en) | 1989-09-12 |
Family
ID=12946080
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5355688A Pending JPH01228999A (en) | 1988-03-09 | 1988-03-09 | Novel podophyllotoxin glycoside |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01228999A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5081234A (en) * | 1990-04-30 | 1992-01-14 | Bristol-Myers Squibb Co. | 4'-demethylepipodophyllotoxin glycosides |
-
1988
- 1988-03-09 JP JP5355688A patent/JPH01228999A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5081234A (en) * | 1990-04-30 | 1992-01-14 | Bristol-Myers Squibb Co. | 4'-demethylepipodophyllotoxin glycosides |
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