JPH052650B2 - - Google Patents
Info
- Publication number
- JPH052650B2 JPH052650B2 JP58107827A JP10782783A JPH052650B2 JP H052650 B2 JPH052650 B2 JP H052650B2 JP 58107827 A JP58107827 A JP 58107827A JP 10782783 A JP10782783 A JP 10782783A JP H052650 B2 JPH052650 B2 JP H052650B2
- Authority
- JP
- Japan
- Prior art keywords
- specific example
- diosgenin
- methanol
- rhamnopyranosyl
- glycoside
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 claims description 32
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 claims description 32
- -1 Diosgenin glycoside Chemical class 0.000 claims description 16
- 229930182470 glycoside Natural products 0.000 claims description 14
- 239000004480 active ingredient Substances 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 210000000577 adipose tissue Anatomy 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 19
- 239000003814 drug Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- YDZWHGJRWMQCDP-NKILCQAGSA-N (2s,3s,4s,5r,6r)-6-[[(3s,4ar,6ar,6bs,8as,12as,14ar,14br)-8a-carboxy-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3-yl]oxy]-3-hydroxy-4-[(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-5-[(2s,3r,4 Chemical compound O([C@H]1[C@H](O)[C@H](O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@]1(CCC(C[C@H]14)(C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O YDZWHGJRWMQCDP-NKILCQAGSA-N 0.000 description 11
- 239000002775 capsule Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000006188 syrup Substances 0.000 description 8
- 235000020357 syrup Nutrition 0.000 description 8
- YSCJAYPKBYRXEZ-HZPINHDXSA-N (2s,3s,4s,5r,6r)-6-[[(3s,4ar,6ar,6bs,8as,12as,14ar,14br)-4,4,6a,6b,11,11,14b-heptamethyl-8a-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxycarbonyl-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3-yl]oxy]-3-hydroxy-4-[(2s,3r,4s, Chemical compound O([C@H]1[C@H](O)[C@H](O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@]1(CCC(C[C@H]14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)C(O)=O)[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O YSCJAYPKBYRXEZ-HZPINHDXSA-N 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 206010003445 Ascites Diseases 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 241000244987 Daiswa polyphylla Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000401 methanolic extract Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000234280 Liliaceae Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- LSQLKWFLOZNABG-UHFFFAOYSA-N butan-1-ol chloroform methanol hydrate Chemical compound O.OC.ClC(Cl)Cl.CCCCO LSQLKWFLOZNABG-UHFFFAOYSA-N 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000003808 methanol extraction Methods 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は式（）
〔式中、Ｒはα−Ｌ−ラムノピラノシル−（１
→２）−〔α−Ｌ−アラビノフラノシル（１→４）〕
−β−Ｄ−グルコピラノシル基、あるいはα−Ｌ
−ラムノピラノシル−（１→４）−α−Ｌ−ラムノ
ピラノシル−（１→４）−〔α−Ｌ−ラムノピラノ
シル−（１→２）〕−β−Ｄ−グルコピラノシル基
を示す〕
で表されるジオスゲニン配糖体を有効成分として
含有する制癌剤である。
本発明者等は、種々の生薬の抗腫瘍作用につい
てのスクリーニングテストを行つた結果、ユリ科
（Liliaceae）のParis polyphylla Sm.の乾燥根茎
である草河車にすぐれた制癌作用があることを認
め、この事実に着目し、その有効成分を分離、研
究していくうちに、草河車中に含有されるジオス
ゲニン配糖体が強い制癌作用を示すことを見い出
し、この新知見に基ずき本発明を完成するに到つ
た。
本発明の薬剤の有効成分であるジオスゲニン配
糖体を得るには、たとえばParis polyphylla
Sm.の根茎をメタノールで抽出し、抽出液を乾燥
して得られたエキスをｎ−ヘキサンを加えて脱脂
した後、エキスを水とｎ−ブタノールで分配す
る。ｎ−ブタノール層を減圧濃縮してシロツプ状
とした後、メタノールを加え、メタノール不溶物
（ジオスゲニン配糖体含有粗製物）を採取し、こ
のメタノール不溶物をシリカゲルカラムクロマト
グラフイーに付し、クロロホルム−メタノール−
水（８：２：1.1）にて溶出しすることにより精
製物を得ることができる。
原料生薬である草河車のメタノール抽出は室温
あるいは加温して行うことができるが、本発明の
薬剤の有効成分の抽出率を期待する上において、
30〜80℃に加熱して行うことが望ましい。
本発明の薬剤の有効成分であるジオスゲニン配
糖体の製造の具体例を示すと、次の通りである。
具体例 １
草河車を粉砕し、粉末とした後、100gを取り、
還流冷却器を着けたフラスコに入れ、500mlのメ
タノールを加えて75℃の水浴上で１時間加温抽出
した。抽出液を過した後、残渣に再び500mlの
メタノールを加えて75℃の水浴上で１時間加温抽
出した。抽出液を過し、前の抽出液とあわせ、
減圧下で濃縮乾固してメタノールエキス18gを得
た。このメタノールエキスを150mlのｎ−ヘキサ
ンで抽出した後、エキスを水とｎ−ブタノールで
分配した。ｎ−ブタノール層を取り、減圧下で濃
縮してシロツプ状とし、これに200mlのメタノー
ルを加え、メタノール不溶物を採取し、減圧下で
濃縮乾固して7.0gの粉末を得た。
上記具体例１で得られた粉末は、本発明の薬剤
の有効成分であるジオスゲニン配糖体を含有し、
このままでも制癌剤として用いることができる
が、不純物を含むため、さらに精製することが望
ましい。
具体例 ２
具体例１において得られた粉末をｎ−ブタノー
ル20mlに溶解した後、シリカゲル40を使用したシ
リカゲルカラムクロマトグラフイーに付し、クロ
ロホルム−メタノール−水（８：２：1.1）にて
溶出し、溶出順に３つの分画（Fr〜）とす
る。Frを減圧下で10mlまで濃縮した後、さら
にシリカゲルカラムクロマトグラフイーに付し、
クロロホルム−ｎ−ブタノール−メタノール−水
（40：10：５：１）にて溶出し、溶出順に２つの
分画（Fr−１、Fr−２）とした。Fr−１
を濃縮し、メタノールを加えて再結晶することに
より、本発明の薬剤の有効成分である式（）で
表されるＲがα−Ｌ−ラムノピラノシル−（１→
２）−〔α−Ｌ−アラビノフラノシル−（１→４）〕
−β−Ｄ−グルコピラノシル基である白色針状晶
のジオスゲニン３−Ｏ−α−Ｌ−ラムノピラノシ
ル−（１→２）−〔α−Ｌ−アラビノフラノシル−
（１→４）〕−β−Ｄ−グルコピラノサイド（以下、
ジオスゲニン配糖体Ａと称する）800mgを得た。
具体例 ３
具体例２において得られたフラクシヨンFr
を濃縮し、乾燥した後、メタノールを加えて、不
溶物を取り、ｎ−ブタノールで溶解した後にメタ
ノールで再結晶することにより、本発明の薬剤の
有効成分である式（）で表されるＲがα−Ｌ−
ラムノピラノシル−（１→４）−α−Ｌ−ラムノピ
ラノシル−（１→４）−〔α−Ｌ−ラムノピラノシ
ル−（１→２）〕−β−Ｄ−グルコピラノシル基で
ある白色針状晶のジオスゲニン３−Ｏ−α−Ｌ−
ラムノピラノシル−（１→４）−α−Ｌ−ラムノピ
ラノシル−（１→４）−〔α−Ｌ−ラムノピラノシ
ル−（１→２）〕−β−Ｄ−グルコピラノサイド
（以下、ジオスゲニン配糖体Ｂと称する）750mgを
得た。
具体例 ４
具体例２において得られたフラクシヨンFr
と具体例３において得られたFrのメタノール
可溶分画を合せ、減圧下で濃縮した後、シリカゲ
ル40を使用したシリカゲルカラムクロマトグラフ
イーに付し、クロロホルム−メタノール−水
（（８：２：0.15）にて溶出し、溶出順に２つの分
画（Fr−１，Fr−２）とし、Fr−２を減
圧下で濃縮し５mlとした後、メタノールを加えて
再結晶することにより、白色針状晶のジオスゲニ
ン配糖体B230mgを得た。
具体例２、具体例３および具体例４において得
られたジオスゲニン配糖体Ａおよびジオスゲニン
配糖体Ｂの性状は次の通りであつた。
ジオスゲニン配糖体Ａ
色・性状 白色針状晶
融 点 278℃（測定値） 276〜278℃（文
献値）
比旋光度〔α〕20 D＝−132.5°（ｃ＝0.56，MeOH）
（測定値）
〔α〕20 D＝−133.0°（ｃ＝0.56，MeOH）
（文献値）
ジオスゲニン配糖体Ｂ
色・性状 白色針状晶
融 点 206℃（測定値） 203〜206℃（文
献値）
比旋光度〔α〕20 D＝−113.8°（ｃ＝0.57，MeOH）
（測定値）
〔α〕20 D＝−113.4°（ｃ＝0.57，MeOH）
（文献値）
〔文献名：Chem.Pharm.Bull.21（６）1240−
1247（1973）〕
次に、本発明の薬剤が制癌作用を示すこと、お
よびその安全性について、実験例をあげて説明す
る。
実験例 １
ICR系アルビノマウスにエーリツヒ腹水癌を移
植し、１週間後、腹水を採取し、別のマウスに一
匹当りエーリツヒ腹水癌細胞１×107個を腹腔中
に移植した。１群５匹とし、被験薬（ジオスゲニ
ン配糖体Ａおよびジオスゲニン配糖体Ｂ）をそれ
ぞれ癌移植の翌日より１日１回５日間腹腔内投与
した。移植７日後に開腹して腹水を取り出し、こ
れを2000Gで５分間遠心分離して癌細胞を分離し
た。この癌細胞の容積（Packed Cell Volume）
を測定し、対照群の癌細胞の容積に対する対照群
と投与群の癌細胞の容積の差のパーセンテージを
もつて、癌細胞成長抑制率とし、用量−作用曲線
を描き、それにより、癌細胞成長50％抑制率を導
いた。
なお、対照群には整理食塩水を腹腔内投与し
た。
その結果を表１に示す。
The present invention is based on the formula () [Wherein, R is α-L-rhamnopyranosyl-(1
→2)-[α-L-arabinofuranosyl (1 → 4)]
-β-D-glucopyranosyl group, or α-L
-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranosyl group] It is an anticancer agent containing glycosides as an active ingredient. As a result of screening tests for the anti-tumor effects of various herbal medicines, the present inventors found that Kusahesha, the dried rhizome of Paris polyphylla Sm., a member of the Liliaceae family, has excellent anti-cancer effects. While focusing on this fact and separating and researching its active ingredients, we discovered that diosgenin glycosides contained in Kusakawasha exhibit strong anticancer effects, and based on this new knowledge, we We have now completed the present invention. In order to obtain the diosgenin glycoside which is the active ingredient of the drug of the present invention, for example, Paris polyphylla
Sm. rhizomes are extracted with methanol, the extract is dried, the resulting extract is defatted by adding n-hexane, and then the extract is distributed between water and n-butanol. After concentrating the n-butanol layer under reduced pressure to form a syrup, methanol was added to collect the methanol-insoluble material (crude material containing diosgenin glycosides). -methanol-
A purified product can be obtained by elution with water (8:2:1.1). Methanol extraction of the raw material herbal medicine, Kuahesha, can be carried out at room temperature or with heating;
It is desirable to heat it to 30-80°C. A specific example of the production of diosgenin glycoside, which is the active ingredient of the drug of the present invention, is as follows. Specific example 1 After crushing Kusakawaguruma into powder, take 100g,
The mixture was placed in a flask equipped with a reflux condenser, 500 ml of methanol was added, and the mixture was heated and extracted on a 75°C water bath for 1 hour. After filtering the extract, 500 ml of methanol was added to the residue again, and the mixture was heated and extracted on a 75°C water bath for 1 hour. Strain the extract and combine with the previous extract.
The mixture was concentrated to dryness under reduced pressure to obtain 18 g of methanol extract. After extracting this methanol extract with 150 ml of n-hexane, the extract was partitioned between water and n-butanol. The n-butanol layer was taken and concentrated under reduced pressure to form a syrup, to which 200 ml of methanol was added, methanol-insoluble material was collected, and concentrated to dryness under reduced pressure to obtain 7.0 g of powder. The powder obtained in the above specific example 1 contains diosgenin glycoside, which is an active ingredient of the drug of the present invention,
Although it can be used as an anticancer drug as it is, it contains impurities, so it is desirable to further purify it. Specific Example 2 After dissolving the powder obtained in Specific Example 1 in 20 ml of n-butanol, it was subjected to silica gel column chromatography using silica gel 40, and eluted with chloroform-methanol-water (8:2:1.1). Then, divide into three fractions (Fr~) in order of elution. After concentrating Fr to 10 ml under reduced pressure, it was further subjected to silica gel column chromatography.
It was eluted with chloroform-n-butanol-methanol-water (40:10:5:1), and divided into two fractions (Fr-1 and Fr-2) in the order of elution. Fr-1
By concentrating and recrystallizing by adding methanol, R represented by the formula (), which is the active ingredient of the drug of the present invention, is converted to α-L-rhamnopyranosyl-(1→
2) -[α-L-arabinofuranosyl-(1→4)]
-β-D-glucopyranosyl group, white needle-shaped diosgenin 3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-arabinofuranosyl-
(1→4)]-β-D-glucopyranoside (hereinafter referred to as
800 mg of diosgenin glycoside A) was obtained. Specific example 3 Fraction Fr obtained in specific example 2
After concentrating and drying, methanol is added to remove insoluble matter, dissolved in n-butanol, and then recrystallized with methanol. is α−L−
Rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranosyl group, white needle-like diosgenin 3- O-α-L-
Rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranoside (hereinafter referred to as diosgenin glycoside B) 750 mg was obtained. Specific example 4 Fraction Fr obtained in specific example 2
The methanol-soluble fraction of Fr obtained in Example 3 were combined, concentrated under reduced pressure, and subjected to silica gel column chromatography using silica gel 40 to obtain chloroform-methanol-water ((8:2: 0.15), separated into two fractions (Fr-1 and Fr-2) in the order of elution, concentrated Fr-2 under reduced pressure to 5 ml, and recrystallized by adding methanol to obtain white needles. 230 mg of diosgenin glycoside B was obtained in the form of crystals. The properties of diosgenin glycoside A and diosgenin glycoside B obtained in Specific Example 2, Specific Example 3, and Specific Example 4 were as follows. Glycoside A Color/Property White needle-like crystals Melting point 278℃ (measured value) 276-278℃ (literature value) Specific optical rotation [α] 20 D = -132.5° (c = 0.56, MeOH)
(Measured value) [α] 20 D = -133.0° (c = 0.56, MeOH)
(Literature value) Diosgenin glycoside B Color/Property White needle-like crystals Melting point 206℃ (measured value) 203-206℃ (literature value) Specific optical rotation [α] 20 D = -113.8° (c = 0.57, MeOH )
(Measured value) [α] 20 D = -113.4° (c = 0.57, MeOH)
(Literature value) [Literature name: Chem.Pharm.Bull.21(6)1240−
1247 (1973)] Next, the anticancer effect of the drug of the present invention and its safety will be explained using experimental examples. Experimental Example 1 Ehritzch ascites carcinoma was transplanted into an ICR albino mouse, and one week later, ascites was collected, and 1×10 7 Ehritzch ascites carcinoma cells per mouse were transplanted into the peritoneal cavity of another mouse. There were 5 animals in each group, and each test drug (diosgenin glycoside A and diosgenin glycoside B) was intraperitoneally administered once a day for 5 days starting the day after cancer transplantation. Seven days after transplantation, the abdomen was opened to remove ascites fluid, which was centrifuged at 2000G for 5 minutes to separate cancer cells. Volume of this cancer cell (Packed Cell Volume)
The ratio of the difference in the volume of cancer cells between the control group and the administration group to the volume of cancer cells in the control group is taken as the cancer cell growth inhibition rate, and a dose-effect curve is drawn. Led a 50% suppression rate. In addition, regulated saline was administered intraperitoneally to the control group. The results are shown in Table 1.
【表】
実験例 ２
Hela培養細胞に対する本発明の薬剤の効果
MEM培地（イーグル社製）に５％ウシ血清を
添加したものをメインテナンス−メデイウムとし
て使用した。
Hela細胞１×104個及びメインテナンス−メデ
イウムを35mmプラスチツク製ペトリ皿に入れ、37
℃、５％CO2インキユベーター中にて培養した。
24時間後にペトリ皿底の約50％にHela細胞の着
床を認めた段階で、種々の濃度に調整した被験薬
（ジオスゲニン配糖体Ａおよびジオスゲニン配糖
体Ｂ）を入れ、15分間接触させた後にメインテナ
ンス−メデイウムを去り、Hanks溶液にて２回
洗浄した。これに再びメインテナンス−メデイウ
ムを加え、37℃、５％CO2インキユベーター中で
４日間培養した後、クリスタルバイオレツトで染
色し、顕微鏡下で８〜10個の細胞集団を１コロニ
ーとして計数した。
なお、対照群は生理食塩水のみを接触させたも
のとし、Hela細胞コロニー形成阻害率は、対照
群と被験薬群のコロニー数の差に対する対照群の
コロニー数の割合を％で示し、50％阻害濃度
（IC50）値を算出した。
その結果を表２に示す。[Table] Experimental Example 2 Effect of the drug of the present invention on Hela cultured cells MEM medium (manufactured by Eagle) supplemented with 5% bovine serum was used as a maintenance medium. Place 4 Hela cells (1 x 10) and maintenance medium in a 35 mm plastic Petri dish,
The cells were cultured at 5% CO2 in an incubator.
After 24 hours, when HeLa cells were observed to have implanted in approximately 50% of the bottom of the Petri dish, test drugs (diosgenin glycoside A and diosgenin glycoside B) adjusted to various concentrations were added and left in contact for 15 minutes. After cleaning, the maintenance medium was removed and washed twice with Hanks solution. Maintenance medium was added again to this, and after culturing for 4 days at 37°C in a 5% CO 2 incubator, the cells were stained with crystal violet, and 8 to 10 cell populations were counted as one colony under a microscope. . The control group was contacted only with physiological saline, and the HeLa cell colony formation inhibition rate is expressed as a percentage of the number of colonies in the control group relative to the difference in the number of colonies between the control group and the test drug group, and is 50%. Inhibitory concentration (IC 50 ) values were calculated. The results are shown in Table 2.
【表】
表１および表２に示す結果から明らかなごと
く、本発明の薬剤はin vivo，in vitroにおいて
も優れた抗腫瘍活性を示した。
実験例 ３
本発明の薬剤の急性毒性試験
ddY系マウスを１群10匹として用い、これに本
発明の薬剤を経口投与、腹腔内投与および静脈内
投与した場合のLD50値は、経口投与の場合3000
mg／Kg以上、腹腔内投与および静脈内投与した場
合は、いずれも100mg／Kgであつた。
以上の実験例の結果から考えて、本発明の薬剤
の抗腫瘍剤としての有効投与量は、患者の年令、
体重および疾患の程度により異なるが、通常成人
で１回500〜700mg、１日２〜３回までの内服ある
いは１日700mgまでの点滴静注、筋肉内注射が適
当と思われ、この投与量の範囲では本発明の薬剤
は高い安全性を示すものと思われる。
本発明の薬剤の有効成分であるジオスゲニン配
糖体は、そのままでも制癌剤として使用すること
がでるが、これに通常の製剤に用いられる賦形
剤、補助剤などを加えて、製剤製法の常法にした
がつて散剤、顆粒剤、錠剤、カプセル剤、シロツ
プ剤、坐剤、腸溶剤および注射剤などの製剤とし
て用いることもできる。
経口投与のために少くとも一種の賦形剤、例え
ばデンプン、乳糖、白糖、マンニツト、カルボキ
シメチルセルロース等を用いて錠剤、丸剤、カプ
セル剤、散剤、顆粒剤等に処方できる。
この種の製剤には、適宜前記賦形剤の他に、例
えばステアリン酸マグネシウム、ラウリル硫酸ナ
トリウム、タルク等の滑沢剤、デキストリン、結
晶セルロース、ポリビニルピロリドン、アラビア
ゴム、トウモロコシデンプン、ゼラチン等の結合
剤、バレイシヨデンプン、カルボキシメチルセル
ロース等の崩壊剤を使用することができる。また
懸濁液、エマルジヨン剤、シロツプ剤、エリキシ
ル剤として投与することができ、これら剤型に
は、矯味矯臭剤、着色剤を含有してもよい。
非経口用製剤として、適当な基剤と混和してク
リーム、軟膏剤、パツプ剤、または坐剤とするこ
とができる。
希釈剤として一般に注射用蒸留水、生理食塩
水、デキストロース水溶液、注射用植物油、プロ
ピレングリコール、ポリエチレングリコール等を
用いることができる。さらに必要に応じて、適宜
等張化剤、溶解補助剤、安定剤、防腐剤、無痛化
剤等を加えてもよい。また、この種の剤型の場
合、滅菌された注射用媒体に溶解することが望ま
しい。
次に実施例を示して本発明を具体的に説明する
が、本発明はこれによりなんら制限されるもので
はない。
実施例 １
具体例３において得られたジオスゲニン配糖体
B200gを微結晶セルロース95gおよびステアリン
酸マグネシウム5gと混合し、この混合物を単発
式打錠機にて打錠して直径７mm、重量300mgの錠
剤を製造した。
本錠剤一錠中には具体例３において得られたジ
オスゲニン配糖体Ｂを300mg含有する。本錠剤は
症状にあわせて１回１〜２錠を１日３回服用す
る。
実施例 ２
具体例２において得られたジオスゲニン配糖体
A100gをトウモロコシデンプン400gと混合し水を
加えて練合し、１mm×１mmの網目を有するスクリ
ーンにて造粒して乾燥し顆粒剤とした。
本顆粒剤1g中には具体例２において得られた
ジオスゲニン配糖体Ａを200mg含有する。本顆粒
剤は症状にあわせて１回２〜3gを１日３回服用
する。
実施例 ３
具体例２において得られたジオスゲニン配糖体
A100gを乳糖90gおよびステアリン酸マグネシウ
ム10gと混合し、500mgづづ硬カプセルに充填し
た。
本カプセル剤１カプセル中には具体例２におい
て得られたジオスゲニン配糖体Ａを250mg含有す
る。本カプセル剤は症状にあわせて１回３カプセ
ルを１日２回服用する。
実施例 ４
具体例３において得られたジオスゲニン配糖体
B70gを水250mlに溶解し、オレンジエツセンス３
mlおよび単シロツプを加えて全量1000mlのシロツ
プ剤とした。
本シロツプ剤１ml中には具体例３において得ら
れたジオスゲニン配糖体Ｂを70mg含有する。本シ
ロツプ剤は症状にあわせて１回７〜10mlを１日３
回服用する。
実施例 ５
実施例１において得られた錠剤をセルロースア
セテートフタレート（CAP）でフイルムコーテ
ングし腸溶剤とした。
本錠剤一錠中には具体例３において得られたジ
オスゲニン配糖体Ｂを300mg含有する。本錠剤は
症状にあわせて１回１〜２錠を１日２〜３回服用
する。
実施例 ６
具体例３において得られたジオスゲニン配糖体
B100gを乳糖90gおよびステアリン酸マグネシウ
ム10gと混合し、400mgづつ腸溶カプセルに充填
した。
本腸溶カプセル剤１カプセル中には具体例３に
おいて得られたジオスゲニン配糖体Ｂを200mg含
有する。本カプセル剤は症状にあわせて１回３カ
プセルを１日３回服用する。
実施例 ７
具体例３において得られたジオスゲニン配糖体
B50gを注射剤製造の常法に従つて、60℃に加温
した注射用蒸留水１に溶解し、塩化ナトリウム
にて等張化した後、アンプルに封入した。
本注射剤１mlには具体例３において得られたジ
オスゲニン配糖体B50mgを含有する。本注射剤は
症状にあわせて１日14mlまでを筋肉中注射する
か、200mlのリンゲル液等の輸液と同時に点滴静
注する。[Table] As is clear from the results shown in Tables 1 and 2, the drug of the present invention exhibited excellent antitumor activity both in vivo and in vitro. Experimental Example 3 Acute toxicity test of the drug of the present invention Using ddY mice (10 mice per group), the drug of the present invention was administered orally, intraperitoneally, and intravenously.The LD50 value was the same as that of oral administration. case 3000
mg/Kg or more, and when administered intraperitoneally or intravenously, the dose was 100 mg/Kg in both cases. Considering the results of the above experimental examples, the effective dosage of the drug of the present invention as an antitumor agent is determined by the patient's age,
Although it varies depending on the body weight and severity of the disease, it is usually appropriate for adults to take 500 to 700 mg at a time, up to 2 to 3 times a day, or up to 700 mg a day by intravenous drip or intramuscular injection. Within this range, the drug of the present invention appears to exhibit high safety. The diosgenin glycoside, which is the active ingredient of the drug of the present invention, can be used as an anticancer agent as it is, but it can be used as an anticancer drug by adding excipients, adjuvants, etc. used in normal preparations, and then using the usual method of manufacturing the drug. Accordingly, it can also be used in preparations such as powders, granules, tablets, capsules, syrups, suppositories, enteric-coated preparations and injections. For oral administration, they can be formulated into tablets, pills, capsules, powders, granules, etc. using at least one excipient such as starch, lactose, sucrose, mannitrate, carboxymethyl cellulose, etc. In addition to the above-mentioned excipients, this type of preparation may contain, for example, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc, binders such as dextrin, crystalline cellulose, polyvinylpyrrolidone, gum arabic, corn starch, and gelatin. A disintegrating agent such as an agent, potato starch, carboxymethyl cellulose, etc. can be used. It can also be administered as a suspension, emulsion, syrup, or elixir, and these dosage forms may contain flavoring agents and coloring agents. As a parenteral preparation, it can be mixed with a suitable base to form a cream, ointment, poultice, or suppository. As a diluent, distilled water for injection, physiological saline, aqueous dextrose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, etc. can generally be used. Furthermore, if necessary, an isotonizing agent, a solubilizing agent, a stabilizer, a preservative, a soothing agent, etc. may be added as appropriate. Moreover, in the case of this type of dosage form, it is desirable to dissolve it in a sterile injection medium. EXAMPLES Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto in any way. Example 1 Diosgenin glycoside obtained in Specific Example 3
200 g of B was mixed with 95 g of microcrystalline cellulose and 5 g of magnesium stearate, and this mixture was compressed using a single-shot tablet machine to produce tablets with a diameter of 7 mm and a weight of 300 mg. One tablet of the present invention contains 300 mg of diosgenin glycoside B obtained in Specific Example 3. Take 1 to 2 tablets three times a day depending on your symptoms. Example 2 Diosgenin glycoside obtained in specific example 2
100 g of A was mixed with 400 g of corn starch, kneaded with water, and granulated using a screen having a mesh size of 1 mm x 1 mm and dried to obtain granules. 1 g of this granule contains 200 mg of diosgenin glycoside A obtained in Specific Example 2. This granule is administered at a dose of 2 to 3 g three times a day, depending on the symptoms. Example 3 Diosgenin glycoside obtained in specific example 2
100 g of A was mixed with 90 g of lactose and 10 g of magnesium stearate and filled into 500 mg hard capsules. One capsule of the present invention contains 250 mg of diosgenin glycoside A obtained in Specific Example 2. This capsule formulation is taken at a time of 3 capsules twice a day depending on the symptoms. Example 4 Diosgenin glycoside obtained in specific example 3
Dissolve 70g of B in 250ml of water and add Orange Essence 3.
ml and single syrup were added to make a syrup with a total volume of 1000 ml. 1 ml of this syrup contains 70 mg of diosgenin glycoside B obtained in Example 3. This syrup is 7 to 10 ml at a time, 3 times a day, depending on the symptoms.
Take multiple doses. Example 5 The tablet obtained in Example 1 was film-coated with cellulose acetate phthalate (CAP) to form an enteric agent. One tablet of the present invention contains 300 mg of diosgenin glycoside B obtained in Specific Example 3. Take 1 to 2 tablets at a time, 2 to 3 times a day, depending on your symptoms. Example 6 Diosgenin glycoside obtained in specific example 3
100 g of B was mixed with 90 g of lactose and 10 g of magnesium stearate, and 400 mg each was filled into enteric-coated capsules. One capsule of the present enteric-coated capsule contains 200 mg of diosgenin glycoside B obtained in Specific Example 3. This capsule is taken at a time, 3 capsules, 3 times a day, depending on the symptoms. Example 7 Diosgenin glycoside obtained in specific example 3
50 g of B was dissolved in distilled water for injection heated to 60° C. 1 according to a conventional method for manufacturing injections, made isotonic with sodium chloride, and then sealed in an ampoule. 1 ml of this injection contains 50 mg of diosgenin glycoside B obtained in Specific Example 3. Depending on the symptoms, up to 14ml of this injection can be injected intramuscularly per day, or intravenously administered at the same time as 200ml of Ringer's solution or other infusion.
Claims (1)
→２）−〔α−Ｌ−アラビノフラノシル−（１→４）
−β−Ｄ−グルコピラノシル基、あるいはα−Ｌ
−ラムノピラノシル−（１→４）−α−Ｌ−ラムノ
ピラノシル−（１→４）−〔α−Ｌ−ラムノピラノ
シル−（１→２）−β−Ｄ−グルコピラノシル基を
示す〕 で表されるジオスゲニン配糖体を有効成分として
含有する制癌剤。[Claims] 1 Formula () [Wherein, R is α-L-rhamnopyranosyl-(1
→2)-[α-L-arabinofuranosyl-(1→4)
-β-D-glucopyranosyl group, or α-L
-Rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-[represents α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl group] Diosgenin glycoside represented by An anticancer drug containing body fat as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10782783A JPS601130A (en) | 1983-06-17 | 1983-06-17 | Carcinostatic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10782783A JPS601130A (en) | 1983-06-17 | 1983-06-17 | Carcinostatic agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS601130A JPS601130A (en) | 1985-01-07 |
| JPH052650B2 true JPH052650B2 (en) | 1993-01-13 |
Family
ID=14469039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10782783A Granted JPS601130A (en) | 1983-06-17 | 1983-06-17 | Carcinostatic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS601130A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56154500A (en) * | 1979-05-02 | 1981-11-30 | Aruba Kiyuu Eru Deii Pty Ltd | Drug composition containing alkaloid and extraction thereof |
-
1983
- 1983-06-17 JP JP10782783A patent/JPS601130A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56154500A (en) * | 1979-05-02 | 1981-11-30 | Aruba Kiyuu Eru Deii Pty Ltd | Drug composition containing alkaloid and extraction thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS601130A (en) | 1985-01-07 |
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