JPH01143832A - Carcinostatic agent - Google Patents
Carcinostatic agentInfo
- Publication number
- JPH01143832A JPH01143832A JP30158087A JP30158087A JPH01143832A JP H01143832 A JPH01143832 A JP H01143832A JP 30158087 A JP30158087 A JP 30158087A JP 30158087 A JP30158087 A JP 30158087A JP H01143832 A JPH01143832 A JP H01143832A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- formula
- betulin
- anticancer agent
- 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
- 230000003327 cancerostatic effect Effects 0.000 title abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- -1 p-toluenesulfonyloxy Chemical group 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- 125000004970 halomethyl group Chemical group 0.000 claims abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 13
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 4
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000005997 bromomethyl group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- FVWJYYTZTCVBKE-ROUWMTJPSA-N betulin Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(CO)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C FVWJYYTZTCVBKE-ROUWMTJPSA-N 0.000 abstract description 25
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 241000124008 Mammalia Species 0.000 abstract description 2
- 238000007911 parenteral administration Methods 0.000 abstract description 2
- 210000000683 abdominal cavity Anatomy 0.000 abstract 1
- 230000002459 sustained effect Effects 0.000 abstract 1
- JYDNKGUBLIKNAM-UHFFFAOYSA-N Oxyallobutulin Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(CO)CCC(C(=C)C)C5C4CCC3C21C JYDNKGUBLIKNAM-UHFFFAOYSA-N 0.000 description 22
- MVIRREHRVZLANQ-UHFFFAOYSA-N betulin Natural products CC(=O)OC1CCC2(C)C(CCC3(C)C2CC=C4C5C(CCC5(CO)CCC34C)C(=C)C)C1(C)C MVIRREHRVZLANQ-UHFFFAOYSA-N 0.000 description 22
- 238000002474 experimental method Methods 0.000 description 14
- 230000001093 anti-cancer Effects 0.000 description 11
- 239000002504 physiological saline solution Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000002100 tumorsuppressive effect Effects 0.000 description 2
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000505924 Ougeinia Species 0.000 description 1
- 241000667922 Ougeinia dalbergioides Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は植物由来の５環系化合物ベツリンの誘導体を有
効成分とする制癌剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an anticancer agent containing a derivative of the plant-derived pentacyclic compound betulin as an active ingredient.
ベツリン（ｂｅｔｕｌｉｎ）はシラカバの樹皮に比較的
多量に含有される５環系化合物であり、北欧で多量に生
産されている。ベツリンは、抗炎症作用及びある種の抗
ウィルス作用を有することが報告されており （Ａｎｔ
ｉｖｉａｌ Ｒｅ５ｅａｒｃｈ↓（１９８４） 、 ２
３１−２４３）、さらに抗腫瘍作用を有することが知ら
れている（Ｊ、 Ｐｈａｒｍａｃｅｕｔｉｃａｌ
５ｃｉｅｎｃｅ ６２（１Σ−（１９７３）、１３９
−１４０ ；日本薬学会第１０７年会、１９８７年４月
）。Betulin is a pentacyclic compound contained in relatively large amounts in birch bark, and is produced in large quantities in Northern Europe. Betulin has been reported to have anti-inflammatory and certain antiviral effects (Ant
ivial Re5earch↓(1984), 2
31-243), which is also known to have antitumor effects (J, Pharmaceutical
5science 62 (1Σ-(1973), 139
-140; 107th Annual Meeting of the Pharmaceutical Society of Japan, April 1987).
ベツリンは極めて毒性が低く、多量投与が可能であるが
、抗腫瘍効果は必ずしも十分ではなく、現在では化粧品
の基剤などに実用化されているに過ぎない。Although betulin has extremely low toxicity and can be administered in large doses, its antitumor effects are not necessarily sufficient, and it is currently only being put into practical use as a base for cosmetics.
従って、本発明はベツリンが有する毒性が極めて低いと
いう利点と、−層高い抗腫瘍性とを併せ持つベツリンの
誘導体を含んで成る制−剤を提供使用とするものである
。Accordingly, the present invention provides and uses an inhibitor comprising a derivative of betulin, which has both the advantage of extremely low toxicity of betulin and high antitumor properties.
前記の目的は、次の一般式：
（式中、Ｒ，及びＲ２はそれぞれ独立にヒドロキシル基
、炭素原子数１８個以下のアシル基、又はｐ−）ルエン
スルホニルオキシ基であり、そしてＲ１はメチル基又は
ハローメチル基であるが、Ｒ１及びＲ８は同時にヒドロ
キシル基ではない）で表わされる化合物を有効成分とし
て含有する制癌剤を提供することにより達成される。This purpose is achieved by the following general formula: where R and R2 are each independently a hydroxyl group, an acyl group having up to 18 carbon atoms, or a p-)luenesulfonyloxy group, and R1 is a methyl or a halomethyl group, but R1 and R8 are not hydroxyl groups at the same time).
ベツリン（ｂｅｔｕｌｉｎ）は前記一般式においてＲ３
及びＲ１がヒドロキシル基であり、Ｒ３がメチル基であ
る天然５環系化合物である０本発明者等は、ベツリンの
種々の誘導体を合成し、それらの化合物と制癌効果との
関連を検討した結果、前記一般式においてＲ３（３位）
のヒドロキシル基又はＲｔ（２８位）のヒドロキシル基
、あるいはこの両者を炭素原子数１８個以下の脂肪酸の
アシル基、ベンゾイルオキシ基、又はｐ−）ルエンスル
ホニルオキシ基により置換した化合物、及びＲｊ（２９
位）の炭素原子がハロゲン原子を有する化合物がベツリ
ンより高い制癌活性を示し、さらにＲ２がｐ−トルエン
スルホニルオキシ基である化合物及び２９位の炭素がハ
ロゲン原子を有する化合物がベツリンより長い制癌作用
の持続性を有するという全く新しい知見を得た。Betulin is R3 in the above general formula.
and a natural pentacyclic compound in which R1 is a hydroxyl group and R3 is a methyl group. The present inventors synthesized various derivatives of betulin and examined the relationship between these compounds and their anticancer effects. As a result, R3 (3rd position) in the general formula
or a hydroxyl group at Rt (position 28), or both thereof, are substituted with an acyl group, benzoyloxy group, or p-)luenesulfonyloxy group of a fatty acid having 18 or less carbon atoms, and Rj (29
Compounds having a halogen atom in the carbon atom at position 2) exhibit higher anticancer activity than betulin, and compounds in which R2 is a p-toluenesulfonyloxy group and compounds having a halogen atom at carbon position 29 have a longer anticancer activity than betulin. We obtained a completely new finding that the drug has a long-lasting effect.
Ｒｔ及びＲｔの脂肪酸のアシルオキシ基としては、例え
ばセチトキシ基、ｎ−プロパノイルオキシ基、イソプロ
パノイルオキシ基、ｎ−ブチロイルオキシ基、イソブチ
ロイルオキシ基、ペンタノイルオキシ基類、ヘキサノイ
ルオキシ基類ヘプタノイルオキシ基類、ラウロイルオキ
シ基、ミリストイルオキシ基、パルミトイルオキシ基、
ステアロイルオキシ基等が挙げられる。Examples of the acyloxy group of Rt and Rt fatty acid include cetitoxy group, n-propanoyloxy group, isopropanoyloxy group, n-butyroyloxy group, isobutyroyloxy group, pentanoyloxy group, and hexanoyloxy group. heptanoyloxy groups, lauroyloxy groups, myristoyloxy groups, palmitoyloxy groups,
Examples include stearoyloxy group.
具体的な化合物として例えば次のものが挙げられる。Examples of specific compounds include the following.
Ｒ８及びＲｔがアセトキシ基であり、そしてＲ１がメチ
ル基である化合物（３，２８−ジ−アセトキシルブー２
０ （２９）−エン）または（化合物Ｌ−２２０と称す
る）：
Ｒ−を及びＲ２がｎ−ブチルオキシ基であり、そしてＲ
３がメチル基゛である化合物（３，２８−ジ−ｎ−ブチ
リルオキシルブー２０ （２９）エン〕または（化合物
Ｌ−３３０と称する）；
Ｒ１及びＲ２がステアロイルオキシ基であり、モしてＲ
３がメチル基である化合物（３，２８−ジステアロイル
オキシルブー２０ （２９）−エン〕または（化合物Ｌ
−４４０と称する）；
Ｒ，及びＲｚがベンゾイルオキシ基であり、そしてＲ５
がメチル基である化合物（３，２８−ジベンゾイルオキ
シルプ−２０（２９）−エン〕またはく化合物Ｌ−５５
０と称する）；
Ｒ１及びＲｔがアセトキシ基であり、そしてＲ５がブロ
ムメチル基である化合物（３，２８−ジアセトキシ−２
９−プロモルブー２０ （２９）−エン〕または（化合
物２２ＢＲと称する）；
Ｒ１がヒドロキシル基であり、Ｒ１がｐ−トルエンスル
ホニルオキシ基であり、そしてＲ１がメチル基である化
合物〔３−ヒドロキシ−２８−ｐ−トルエンスルホニル
オキシルブー２０ （２９）−エン〕または（化合物Ｌ
−ＩＴＳＯと称する）。Compounds in which R8 and Rt are acetoxy groups, and R1 is a methyl group (3,28-di-acetoxylbu 2
0 (29)-ene) or (referred to as compound L-220): R- and R2 are n-butyloxy groups, and R
A compound in which 3 is a methyl group (3,28-di-n-butyryloxylb-20(29)ene) or (referred to as compound L-330); R1 and R2 are a stearoyloxy group, and R
A compound in which 3 is a methyl group (3,28-distearoyloxylbut-20(29)-ene) or (compound L
-440); R and Rz are benzoyloxy groups, and R5
is a methyl group (3,28-dibenzoyloxylp-20(29)-ene) or compound L-55
0); a compound in which R1 and Rt are acetoxy groups and R5 is a bromomethyl group (referred to as 3,28-diacetoxy-2
9-promorbu-20 (29)-ene] or (referred to as compound 22BR); a compound [3-hydroxy-28 -p-toluenesulfonyloxylbut20 (29)-ene] or (compound L
- ITSO).
上記の化合物は既知化合物であり下記の文献に記載され
ている。The above compound is a known compound and is described in the following literature.
〔化合物Ｌ−２２０）
Ｃｈｅｍｉｃａｌ Ｉｎｖｅｓｔｉｇａｔｉｏｎ ｏｆ
Ｏｕｇｅｉｎｉａ Ｄａｌｂｅｒｇｉ−ｏｉｄｅｓ
Ｂｅｎｔｈ、”＋ Ａ、Ｃ，Ｇｈｏｓｈ ａｎｄ Ｎ、
Ｌ、Ｄｕｔｔａ、 Ｊ、Ｉｎ−ｄｉａｎ Ｃｈｅｍ、
Ｓｏｃ、、 ４２．８３１〜８３５（１９６５）・〔
化合物Ｌ−３３０）
１！１ｓｅｖｉｅｒｓ Ｅｎｃｙｃｌｏｐａｅｄｉａ
ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅ閣１ｓｔｒｙ。[Compound L-220] Chemical Investigation of
Ougeinia Dalbergi-oides
Benth, ”+ A, C, Ghosh and N,
L, Dutta, J, In-dian Chem,
Soc,, 42.831-835 (1965)・[
Compound L-330) 1!1seviers Encyclopaedia
of Organic Chekaku 1st try.
５ｅｒｉｅｓ ＴＬ Ｖｏｌ、１４＋ ５ｕｐｐ１．、
Ｅｌｓｅｖｉｅｒｓ Ｐｕｂｌｉ−ｓｈｉｎｇ Ｃｏ
ｍｐａｎｙ、 Ｌｏｎｄｏｎ １９５２＋ １１３３
Ｓ〔化合物Ｌ−４４０３
”Ｆａｔｔｙ ａｃｉｄ ｅｓｔｅｒｓ ｆｒｏｍ ｂ
ｅｔｕｌｉｎｏｌ’、 Ｖ、Ｅｒｅａ＋Ｐ、Ｊａｅａｅ
ｓｋｅｌａｅｉｎｅｎｅ ａｎｄ Ｋ、ＬＩｋｋｏ
ｎｅｎ＋ Ｊ、＾−ｅｒ、ＯｉｌＣｈｅｗ、Ｓｏｃ、
、 ５８． ２０ ２３（１９８１）（化合物Ｌ−５
５０）
“Ｃｈｅｓ＋１ｃａｌ Ｉｎｖｅｓｔｉｇａｔｉｏｎ
ｏｆ Ｏｕｇｅｉｎｉａ Ｄａｌｂｅｒｇｉ−ｏｉｄ
ｅｓ Ｂｅｎｔｈ、”、 Ａ、Ｃ，Ｇｈｏｓｈ ａｎｄ
Ｎ、Ｌ、Ｄｕｔｔａ、 Ｊ、Ｉｎ−ｄｉａｎ Ｃｈｅ
ｓ、Ｓｏｃ、、 ４２．８３１〜８３５（１９６５）
〔化合物２２ＢＲ）
“２α、３β −Ｄｉｈｙｄｒｏｘｙ Ｔｒｉｔｅｒ
ｐｅｎｅｓ、Ｉｆ 、Ａｔｔｅｍｐｔｅｄｐａｒｔｉａ
ｌ ５ｙｎｔｈｅｓｉｓ 、ｏｆ ５ｅｔｈｙｌ ｄｉ
ｈｙｄｒｏａｌｐｈｉｔｏｌａｔｅ、’Ｌ、Ｒ，Ｒｏｅ
ｅ、Ｃ，Ｓ、Ｒａｏ ａｎｄ Ｔ、Ｓ、Ｒａｍａｉａｈ
、Ｉｎｄｉａｎ Ｊ。5eries TL Vol, 14+ 5upp1. ,
Elseviers Publishing Co
mpany, London 1952+ 1133
S [Compound L-4403 “Fatty acid esters from b
etulinol', V, Erea+P, Jaeae
skelaeinene and K, LIkko
nen+ J, ^-er, OilChew, Soc,
, 58. 20 23 (1981) (Compound L-5
50) “Ches+1cal Investigation
of Ougeinia Dalbergi-oid
es Benth,” A, C, Ghosh and
N., L., Dutta, J., In-dian Che.
s, Soc, 42.831-835 (1965)
[Compound 22BR] “2α,3β-Dihydroxy Triter
penes, If, Attemptedpartia
l 5ynthesis, of 5ethyl di
hydroalphytolate,'L,R,Roe
e, C, S, Rao and T, S, Ramaiah.
, Indian J.
Ｃｈｅｍ、＋ ６． １６−１９（１９６８）〔化合
物Ｌ−ＩＴＳＯ）
”５ｔｕｄｉｅｓ ｏｎ ｔｈｅ Ｃｏｎ５ｔｉｔｕ
ｅｎｔｓ ｏｆ Ａｒｔｅ＋ｍｉｓｉａａｒｇｙｉ
ＬＨＶＬ、ｅｔ ＶＡＮＴ、’ Ａ、Ｌａｏ、 Ｙ、Ｆ
ｕｊｉｍｏｔｏ ａｎｄ Ｔ。Chem, +6. 16-19 (1968) [Compound L-ITSO] “5 studies on the Con5titu
ents of Arte+misiaargyi
LHVL, et VANT,' A, Lao, Y, F
ujimoto and T.
Ｔａｔｓｕｎｏ、 Ｃｈｅｍ、Ｐｈａｒｍ、Ｂｕｌｌ
、、 ３２，７２３−７２７（１９８４）本発明の
制癌剤の制癌作用を次の様にして確認した。Tatsuno, Chem, Pharm, Bull
, 32, 723-727 (1984) The anticancer effect of the anticancer agent of the present invention was confirmed as follows.
裏腹上
６週令の雌性ＩＣＲマウスの腋下皮下に１０”個／マウ
スの５ａｒｃｏ＋ｍａ１８０細胞を移植し、７匹を１群
として移植後１〜５日目と７〜１１日目に１日１回（合
計１０回） １．０〜０．１ｑｒ／ｋｇ／回の被検化合
物を、生理食塩水にて０．２ｍ１ｒ／マウスの容量とな
るように調製して、腹腔内投与した。マウスのガンのサ
イズを計測し、その長径×短径（鶴８）を求め、７匹の
平均値をガンのサイズとした。被検化合物としてベツリ
ン、Ｌ−２２０を用い、生理食塩水投与群を対照とした
結果を第１図に示す、ベツリンの−３，−２８位側鎖を
アセチル基で置換したＬ−２２０がベツリンに比べ高い
制ガン効果をもっていることがわかる。10"/mouse of 5arco+ma180 cells were transplanted subcutaneously in the axilla of 6-week-old female ICR mice on the upper abdomen, and once a day on days 1 to 5 and days 7 to 11 after transplantation, 7 mice were grouped into one group. (10 times in total) 1.0 to 0.1 qr/kg/time of the test compound was prepared in physiological saline to a volume of 0.2 ml/mouse and administered intraperitoneally. The size of the cancer was measured, and its long axis x short axis (Tsuru 8) was determined, and the average value of the seven animals was taken as the cancer size. Betulin and L-220 were used as test compounds, and the physiological saline administration group was used as a control. The results are shown in FIG. 1, and it can be seen that L-220, in which the -3 and -28 side chains of betulin are substituted with acetyl groups, has a higher anticancer effect than betulin.
実験ｌ
実験１．と同じ手法で、被検化合物として、前記一般式
中Ｒ１及びＲ２が水素原子でＲ１がメチル基であるルペ
ン、ベツリン及びＬ−２２０を用いた結果を、第１表に
示す。ルペンのガンサイズを１００％としたときの７．
１１．２３日後のガンの比がルペン、ベツリン、Ｌ−２
２０の順に小さくなっていることから、−３および一２
８位のアセチル化が制ガン効果を増強するといえる。こ
の結果を第１表に示す。Experiment 1 Experiment 1. Table 1 shows the results of using lupene, betulin, and L-220, in which R1 and R2 are hydrogen atoms and R1 is a methyl group, as test compounds in the same manner as above. 7. When Le Pen's gun size is taken as 100%.
11.The ratio of cancer after 23 days was lupen, betulin, L-2
Since they are decreasing in the order of 20, -3 and -2
It can be said that acetylation at position 8 enhances the anticancer effect. The results are shown in Table 1.
第一」−一表
実験１．の場合と同様に、Ｌ−２２０化合物はベツリン
に比べて高い腫瘍抑制効果を示した。1” - Table 1 Experiment 1. Similar to the case, L-220 compound showed higher tumor suppressive effect compared to betulin.
実験１
実験１．と同じ手法で被検化合物として、ベツリン、Ｌ
−３３０、Ｌ−４４０、Ｌ−５５０、Ｌ−２２ＢＲを用
いて実験を行、なった結果を第２表に示す、このことか
ら−３，−２８位の同族置換体さらにその一２９位を臭
素化した化合物がＬ−２２０と同様、制ガン効果増強に
有効であることがわかった。Experiment 1 Experiment 1. Using the same method as test compound, betulin, L
Experiments were conducted using -330, L-440, L-550, and L-22BR, and the results are shown in Table 2. From this, it can be concluded that homologous substitutions at the -3 and -28 positions, as well as the -29 position. It was found that the brominated compound is effective in enhancing the anticancer effect, similar to L-220.
裏−」Ｌ−表
６週令の雌性ＩＣＲマウス（１グル一プ３匹、対照グル
ープは４匹）に、１０’個／ｍｌの５ａｒｃｏｎ＋ａ１
８０の懸濁液と生理食塩水中被検化合物の懸濁液との等
置部合物０．２ ｍ Ａ ／マウスを皮下移植し腫瘍に
対する増殖抑制効果をしらべた。Back - L - Front 6-week-old female ICR mice (3 mice per group, 4 mice in the control group) were treated with 5arcon + a1 at 10'/ml.
A suspension of test compound No. 80 and a suspension of the test compound in physiological saline were subcutaneously implanted in equidistant portions at 0.2 mA/mouse to examine the growth-inhibiting effect on tumors.
被検化合物として、ベツリン、Ｌ−２２０、Ｌ−ＩＴＳ
Ｏを用い、対照に生理食塩水をおいて実験を行った結果
を第３表に示す。Test compounds include betulin, L-220, L-ITS
Table 3 shows the results of an experiment using O and physiological saline as a control.
第一」Ｌ−表
Ｌ−２２０及びＬ−ＩＴＳＯはいずれも７日百において
ベツリンより高い腫瘍増殖抑制作用を示し、Ｌ−ＩＴＳ
Ｏは１１日目においてもなお高い腫瘍増殖抑制作用を示
した。Daiichi's L-Table L-220 and L-ITSO both showed a higher tumor growth inhibitory effect than betulin at 7 days, and L-ITS
O still showed a high tumor growth inhibitory effect even on the 11th day.
実験１〜４の結果より、Ｌ−２２０、Ｌ−３３０、Ｌ−
４４０、Ｌ−５５０、Ｌ−２２ＢＲおよびＬ−ＩＴＳＯ
などのベツリンへの置換基導入が制ガン効果増強に有効
であることがわかった。From the results of experiments 1 to 4, L-220, L-330, L-
440, L-550, L-22BR and L-ITSO
It was found that introducing substituents into betulin, such as , is effective in enhancing the anticancer effect.
裏腹ｉ
実験１．と同様の実験を、投与終了（１１日後）以後の
腫瘍サイズを、ベツリン、Ｌ−２２０、Ｌ−ＩＴＳＯｏ
、 １ Ｘ １０■／ ｋｇ投与について行なった結果
を第４表に示す。Urahara i Experiment 1. A similar experiment was conducted to determine the tumor size after the end of administration (11 days later) using betulin, L-220, and L-ITSOo.
Table 4 shows the results for administration of 1×10 μg/kg.
化合物Ｌ−ＩＴＳＯは、ベツリンに比べて高い腫瘍抑制
活性を示すのみならず、長い持続側を有する。Compound L-ITSO not only exhibits higher tumor suppressive activity compared to betulin, but also has a longer duration.
実用基
実験４．と同様な実験を行った。但し、腫瘍細胞の移植
及び被検化合物の接種後１６日目、２２日目及び３２日
目に化合物Ｌ−２２ＢＲの腫瘍増殖抑制効果を対照（生
理食塩水）及びベツリンのそれと比較した。この結果を
次の第５表に示す。Practical experiment 4. A similar experiment was conducted. However, on the 16th, 22nd, and 32nd days after transplantation of tumor cells and inoculation of the test compound, the tumor growth inhibitory effect of compound L-22BR was compared with that of a control (physiological saline) and betulin. The results are shown in Table 5 below.
遍−」■−表
第５表から明らかなごとく、化合物Ｌ−２２ＢＲはベツ
リンに比べて高い腫瘍増殖抑制作用を示すのみならず、
その作用を長期間にわたって維持した。As is clear from Table 5, compound L-22BR not only exhibits a higher tumor growth inhibitory effect than betulin, but also
The effect was maintained for a long period of time.
実験５．および６．からＬ−ＩＴＳＯｌＬ−２２ＢＲに
は投与終了後の制ガン作用を持続させる効果があるとい
える。Experiment 5. and 6. Therefore, it can be said that L-ITSOLL-22BR has the effect of sustaining the anticancer effect after the end of administration.
以上の結果から明らかなごとく、本発明の化合物はイン
ビボ試験において制癌効果を有する。本発明の化合物は
、制癌剤としてヒトを包含する哺乳類に投与することが
できる。経口投与又は非経口投与により投与され、非経
口投与の場合には、静脈内投与、腹腔内投与、皮下投与
等により行われる。As is clear from the above results, the compounds of the present invention have anticancer effects in in vivo tests. The compounds of the present invention can be administered to mammals, including humans, as anticancer agents. It is administered orally or parenterally, and in the case of parenteral administration, it is administered intravenously, intraperitoneally, subcutaneously, etc.
本発明の制癌剤は、活性成分として１０■〜１１００ａ
／回をおよそ１−日ごとに投与するか、あるいは約３０
■／回を３〜７日ごとに投与するのか好ましい。投与方
法は点滴又は静脈注射が好ましいが、油脂基剤と混合し
て皮膚に塗布し、経皮的に投与することもできる。The anticancer agent of the present invention contains 10~1100a as an active ingredient.
/dose approximately every 1-day, or about 30
It is preferable to administer the drug once every 3 to 7 days. The preferred method of administration is drip or intravenous injection, but it can also be administered transdermally by mixing it with an oil base and applying it to the skin.
本発明の制癌剤の有効成分は極めて毒性が低く、１日に
５００■／ ｋｇ経口投与した場合でも、はとんど毒性
を示さない。The active ingredient of the anticancer agent of the present invention has extremely low toxicity, and shows almost no toxicity even when administered orally at 500 μ/kg per day.
本発明の制癌剤は、前記の活性成分のいずれかを用いて
、常用の製剤法に従って製造することができる６例えば
生理的食塩水、リン酸緩衝液等に単位投与量の活性成分
を懸濁してアンプルに充填することができる。また、本
発明の活性成分を油性基剤と混合することにより、塗布
剤や生薬とすることもできる。また、常用の賦型剤と共
に錠剤、カプセル剤等の経口投与剤とすることもできる
。The anticancer agent of the present invention can be manufactured using any of the active ingredients described above according to conventional formulation methods.6 For example, by suspending a unit dose of the active ingredient in physiological saline, phosphate buffer, etc. Can be filled into ampoules. Moreover, by mixing the active ingredient of the present invention with an oily base, it can also be made into a liniment or a crude drug. It can also be made into oral preparations such as tablets and capsules together with commonly used excipients.
本発明の活性成分は活性成分として単独で投与すること
もでき、また他の活性成分、例えば他の抗癌剤、抗菌剤
、感冒薬等と組合わせて使用することができる。The active ingredient of the present invention can be administered alone as an active ingredient, or can be used in combination with other active ingredients, such as other anticancer agents, antibacterial agents, cold medicines, etc.
第１図は実験１．における化合物Ｌ−２２０の制癌効果
を示すグラフである。Figure 1 shows Experiment 1. 2 is a graph showing the anticancer effect of compound L-220 in FIG.
Claims (1)
ル基、炭素原子数１８個以下のアシル基、又はｐ−トル
エンスルホニルオキシ基であり、そしてＲ＿３はメチル
基又はハロ−メチル基であるが、Ｒ＿１及びＲ＿２は同
時にヒドロキシル基ではない）で表わされる化合物を有
効成分として含有する制癌剤。 ２、Ｒ＿１及びＲ＿２がアセトキシ基であり、そしてＲ
＿３がメチル基である化合物を含有する特許請求の範囲
第１項に記載の制癌剤。 ３、Ｒ＿１及びＲ＿２がｎ−ブチリルオキシ基であり、
そしてＲ＿３がメチル基である化合物を含有する特許請
求の範囲第１項に記載の制癌剤。 ４、Ｒ＿１及びＲ＿２がステアロイルオキシ基であり、
そしてＲ＿３がメチル基である化合物を含有する特許請
求の範囲第１項に記載の制癌剤。 ５、Ｒ＿１及びＲ＿２がベンゾイルオキシ基であり、そ
してＲ＿３がメチル基である化合物を含有する特許請求
の範囲第１項に記載の制癌剤。 ６、Ｒ＿１及びＲ＿２がアセトキシ基であり、そしてＲ
＿３がブロムメチル基である化合物を含有する特許請求
の範囲第１項に記載の制癌剤。 ７、Ｒ＿１がヒドロキシル基であり、Ｒ＿２がｐ−トル
エンスルホニルオキシ基であり、そしてＲ＿３がメチル
基である化合物を含有する特許請求の範囲第１項に記載
の制癌剤。[Claims] 1. The following general formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 and R_2 each independently represent a hydroxyl group, an acyl group having 18 or less carbon atoms, or p- An anticancer agent containing as an active ingredient a compound represented by the following formula: toluenesulfonyloxy group, R_3 is a methyl group or halo-methyl group, but R_1 and R_2 are not hydroxyl groups at the same time. 2, R_1 and R_2 are acetoxy groups, and R
The anticancer agent according to claim 1, which contains a compound in which _3 is a methyl group. 3, R_1 and R_2 are n-butyryloxy groups,
The anticancer agent according to claim 1, which contains a compound in which R_3 is a methyl group. 4, R_1 and R_2 are stearoyloxy groups,
The anticancer agent according to claim 1, which contains a compound in which R_3 is a methyl group. 5. The anticancer agent according to claim 1, which contains a compound in which R_1 and R_2 are benzoyloxy groups, and R_3 is a methyl group. 6, R_1 and R_2 are acetoxy groups, and R
The anticancer agent according to claim 1, which contains a compound in which _3 is a bromomethyl group. 7. The anticancer agent according to claim 1, which contains a compound in which R_1 is a hydroxyl group, R_2 is a p-toluenesulfonyloxy group, and R_3 is a methyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30158087A JPH01143832A (en) | 1987-12-01 | 1987-12-01 | Carcinostatic agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30158087A JPH01143832A (en) | 1987-12-01 | 1987-12-01 | Carcinostatic agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01143832A true JPH01143832A (en) | 1989-06-06 |
Family
ID=17898658
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP30158087A Pending JPH01143832A (en) | 1987-12-01 | 1987-12-01 | Carcinostatic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01143832A (en) |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2705097A1 (en) * | 1993-05-11 | 1994-11-18 | Rhone Poulenc Rorer Sa | New lupane derivatives, their preparation and pharmaceutical compositions containing them. |
| FR2705094A1 (en) * | 1993-05-11 | 1994-11-18 | Rhone Poulenc Rorer Sa | New lupane derivatives, their preparation and pharmaceutical compositions containing them. |
| WO1996029068A3 (en) * | 1995-03-21 | 1997-02-06 | Univ Illinois | Use of betulinic acid and its derivatives for inhibiting malignant melanoma growth and a method of monitoring this |
| WO1998051293A1 (en) * | 1997-05-16 | 1998-11-19 | The Board Of Trustees Of The University Of Illinois | Use of betulinic acid derivatives for the treatment and prevention of melanoma |
| WO1999009043A1 (en) * | 1997-08-19 | 1999-02-25 | Song Bae Kim | Novel triterpene glycoside compound, process for preparation thereof and anti-cancer composition containing the same |
| US6048847A (en) * | 1997-09-30 | 2000-04-11 | Dabur Research Foundation | Use of betulinic acid and its derivatives for inhibiting cancer growth and a method of monitoring this |
| US6124362A (en) * | 1998-07-17 | 2000-09-26 | The Procter & Gamble Company | Method for regulating hair growth |
| US6172110B1 (en) * | 1998-03-02 | 2001-01-09 | The University Of North Carolina At Chapel Hill | Acylated betulin and dihydrobetulin derivatives, preparation thereof and use thereof |
| WO2002009719A1 (en) * | 2000-07-31 | 2002-02-07 | The Nisshin Oillio, Ltd. | Antitumor agents |
| US6482857B1 (en) | 1998-07-17 | 2002-11-19 | The University Of Texas Southwestern Medical Center | Compositions which contain triterpenes for regulating hair growth |
| US6670345B1 (en) | 1997-09-30 | 2003-12-30 | Dabur Research Foundation | Betulinic acid derivatives for inhabiting cancer growth and process for the manufacture of betulinic acid |
| EP1473301A2 (en) * | 1997-06-04 | 2004-11-03 | Cornell Research Foundation, Inc. | Betulinol derivatives |
| US7537765B2 (en) | 2003-01-29 | 2009-05-26 | Panacos Pharmaceuticals, Inc. | Inhibition of HIV-1 replication by disruption of the processing of the viral capsid-spacer peptide 1 protein |
| US7799768B2 (en) | 2005-04-12 | 2010-09-21 | Myrexis, Inc. | Polymorphs of 3-O-(3′,3′-dimethylsuccinyl)betulinic acid di-N-methyl-D-glucamine |
| JP2011225538A (en) * | 2010-03-31 | 2011-11-10 | Toyama Prefecture | Weaning agent for cancer immunosuppression, composition for cancer immuno-therapy and cancer immuno-therapy |
-
1987
- 1987-12-01 JP JP30158087A patent/JPH01143832A/en active Pending
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2705094A1 (en) * | 1993-05-11 | 1994-11-18 | Rhone Poulenc Rorer Sa | New lupane derivatives, their preparation and pharmaceutical compositions containing them. |
| WO1994026695A1 (en) * | 1993-05-11 | 1994-11-24 | Rhone-Poulenc Rorer S.A. | Novel lupane derivatives, their preparation and pharmaceutical compositions containing same |
| WO1994026725A1 (en) * | 1993-05-11 | 1994-11-24 | Rhone-Poulenc Rorer S.A. | Novel lupane derivatives, their preparation and pharmaceutical compositions containing same |
| EP0698016A1 (en) * | 1993-05-11 | 1996-02-28 | Aventis Pharma S.A. | Novel lupane derivatives, their preparation and pharmaceutical compositions containing same |
| FR2705097A1 (en) * | 1993-05-11 | 1994-11-18 | Rhone Poulenc Rorer Sa | New lupane derivatives, their preparation and pharmaceutical compositions containing them. |
| WO1996029068A3 (en) * | 1995-03-21 | 1997-02-06 | Univ Illinois | Use of betulinic acid and its derivatives for inhibiting malignant melanoma growth and a method of monitoring this |
| EP1266658A2 (en) * | 1997-05-16 | 2002-12-18 | The Board Of Trustees Of The University Of Illinois | Use of betulinic acid derivatives for the treatment and prevention of melanoma |
| WO1998051293A1 (en) * | 1997-05-16 | 1998-11-19 | The Board Of Trustees Of The University Of Illinois | Use of betulinic acid derivatives for the treatment and prevention of melanoma |
| EP1266658A3 (en) * | 1997-05-16 | 2004-05-26 | The Board Of Trustees Of The University Of Illinois | Use of betulinic acid derivatives for the treatment and prevention of melanoma |
| EP1473301A3 (en) * | 1997-06-04 | 2005-01-26 | Cornell Research Foundation, Inc. | Betulinol derivatives |
| EP1473301A2 (en) * | 1997-06-04 | 2004-11-03 | Cornell Research Foundation, Inc. | Betulinol derivatives |
| WO1999009043A1 (en) * | 1997-08-19 | 1999-02-25 | Song Bae Kim | Novel triterpene glycoside compound, process for preparation thereof and anti-cancer composition containing the same |
| US6670345B1 (en) | 1997-09-30 | 2003-12-30 | Dabur Research Foundation | Betulinic acid derivatives for inhabiting cancer growth and process for the manufacture of betulinic acid |
| US6048847A (en) * | 1997-09-30 | 2000-04-11 | Dabur Research Foundation | Use of betulinic acid and its derivatives for inhibiting cancer growth and a method of monitoring this |
| US6172110B1 (en) * | 1998-03-02 | 2001-01-09 | The University Of North Carolina At Chapel Hill | Acylated betulin and dihydrobetulin derivatives, preparation thereof and use thereof |
| US6482857B1 (en) | 1998-07-17 | 2002-11-19 | The University Of Texas Southwestern Medical Center | Compositions which contain triterpenes for regulating hair growth |
| US6451777B1 (en) | 1998-07-17 | 2002-09-17 | The University Of Texas Southwestern Medical Center | Method for regulating hair growth |
| US6124362A (en) * | 1998-07-17 | 2000-09-26 | The Procter & Gamble Company | Method for regulating hair growth |
| WO2002009719A1 (en) * | 2000-07-31 | 2002-02-07 | The Nisshin Oillio, Ltd. | Antitumor agents |
| US7537765B2 (en) | 2003-01-29 | 2009-05-26 | Panacos Pharmaceuticals, Inc. | Inhibition of HIV-1 replication by disruption of the processing of the viral capsid-spacer peptide 1 protein |
| US7799768B2 (en) | 2005-04-12 | 2010-09-21 | Myrexis, Inc. | Polymorphs of 3-O-(3′,3′-dimethylsuccinyl)betulinic acid di-N-methyl-D-glucamine |
| JP2011225538A (en) * | 2010-03-31 | 2011-11-10 | Toyama Prefecture | Weaning agent for cancer immunosuppression, composition for cancer immuno-therapy and cancer immuno-therapy |
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