JPS6360949A - Triterpene compound and carcinostatic agent - Google Patents
Triterpene compound and carcinostatic agentInfo
- Publication number
- JPS6360949A JPS6360949A JP20289786A JP20289786A JPS6360949A JP S6360949 A JPS6360949 A JP S6360949A JP 20289786 A JP20289786 A JP 20289786A JP 20289786 A JP20289786 A JP 20289786A JP S6360949 A JPS6360949 A JP S6360949A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- ethyl acetate
- fraction
- separated
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Triterpene compound Chemical class 0.000 title claims description 18
- 230000003327 cancerostatic effect Effects 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 239000000126 substance Substances 0.000 claims abstract description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 13
- 239000013078 crystal Substances 0.000 abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002253 acid Substances 0.000 abstract description 8
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 239000000287 crude extract Substances 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 208000009916 Yoshida Sarcoma Diseases 0.000 abstract description 2
- BLAKAEFIFWAFGH-UHFFFAOYSA-N acetyl acetate;pyridine Chemical compound C1=CC=NC=C1.CC(=O)OC(C)=O BLAKAEFIFWAFGH-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005377 adsorption chromatography Methods 0.000 abstract description 2
- 239000000284 extract Substances 0.000 abstract description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 abstract description 2
- 210000004748 cultured cell Anatomy 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000000203 mixture Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 230000037396 body weight Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000001093 anti-cancer Effects 0.000 description 7
- 238000000576 coating method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
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- 239000011248 coating agent Substances 0.000 description 6
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- 238000010253 intravenous injection Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- MDZKJHQSJHYOHJ-UHFFFAOYSA-N crataegolic acid Natural products C1C(O)C(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MDZKJHQSJHYOHJ-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
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- 231100000053 low toxicity Toxicity 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- 238000010998 test method Methods 0.000 description 2
- XUARCIYIVXVTAE-ZAPOICBTSA-N uvaol Chemical compound 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@H](C)[C@H]5C4=CC[C@@H]3[C@]21C XUARCIYIVXVTAE-ZAPOICBTSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- ILFPCMXTASDZKM-YFKPBYRVSA-N (1s)-2-methylidene-3-oxocyclopentane-1-carboxylic acid Chemical compound OC(=O)[C@H]1CCC(=O)C1=C ILFPCMXTASDZKM-YFKPBYRVSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- MDZKJHQSJHYOHJ-RMUAHEEJSA-N 2alpha,3beta-Dihydroxyolean-12-en-28-oic acid Natural products C1[C@@H](O)[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@@H]5C4=CC[C@@H]3[C@]21C MDZKJHQSJHYOHJ-RMUAHEEJSA-N 0.000 description 1
- RPGMVOVTCDJHJS-UHFFFAOYSA-N 4-(aminomethyl)-1-[2-(diethylamino)ethylamino]thioxanthen-9-one Chemical compound S1C2=CC=CC=C2C(=O)C2=C1C(CN)=CC=C2NCCN(CC)CC RPGMVOVTCDJHJS-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 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
- WQBCAASPALGAKX-UHFFFAOYSA-N Benzenemethanol, 4-(dimethylamino)- Chemical compound CN(C)C1=CC=C(CO)C=C1 WQBCAASPALGAKX-UHFFFAOYSA-N 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
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- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- 206010013883 Dwarfism Diseases 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
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- 239000002202 Polyethylene glycol Substances 0.000 description 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
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- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 229940096998 ursolic acid Drugs 0.000 description 1
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 description 1
- SYFNOXYZEIYOSE-UHFFFAOYSA-N uvaol Natural products CC1CCC2(O)CCC3(C)C(=CCC4(C)C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C SYFNOXYZEIYOSE-UHFFFAOYSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
(技術分野)
本発明は、新規なトリテルペン化合物及び該化合物を有
効成分として含有する制癌剤に関する。DETAILED DESCRIPTION OF THE INVENTION (Technical Field) The present invention relates to a novel triterpene compound and an anticancer agent containing the compound as an active ingredient.
(発明の背景)
従来、癌化学療法剤として、アルキル化剤(ナイトロジ
エンマスタード順、エチレンイミン類、スルホン酸エス
テル類)、代謝拮抗物質(葉酸拮抗剤、プリン拮抗剤、
ピリミジン拮抗剤)、植物性核分裂前(コルセミド、ビ
ンブラスチン等)、抗生物質(ザルコマイシン、カルチ
ノフイリン、マイトマイシン等)、ホルモン頚(副腎ス
テロイド、男性ホルモン、女性ホルモン)及びポルフィ
リン錯塩(マーフィリン、C0PP)等が用いられてい
る。しかしながら、その殆んどは、細胞毒型の物質であ
り、重大な副作用を呈するため、低毒性で優れた制癌活
性を有する制癌剤の開発が強く望まれている。(Background of the Invention) Conventionally, cancer chemotherapy agents include alkylating agents (nitrogien mustard, ethyleneimines, sulfonic acid esters), antimetabolites (folate antagonists, purine antagonists,
pyrimidine antagonists), plant pre-fission (colcemid, vinblastine, etc.), antibiotics (sarcomycin, carcinophylline, mitomycin, etc.), hormones (adrenal steroids, male hormones, female hormones), and porphyrin complex salts (marphyrin, C0PP) etc. are used. However, most of them are cytotoxic substances and exhibit serious side effects, so the development of anticancer agents with low toxicity and excellent anticancer activity is strongly desired.
本発明者らは、上記趣旨に鑑み、低毒性で制癌性を有す
る物質を動・植物、微生物界の広い生物範囲から探索を
行ってきたが、プルメリア・アクティフォリ7−ボイル
(Plumeriaacutifolia Pa1r)
(インドネシア名: Kembodja Putin
)より抽出された新規なトリテルペン化合物が、優れた
制癌活性を有することを見出し、本発明を完成したもの
である。In view of the above purpose, the present inventors have been searching for a substance with low toxicity and anticancer properties from a wide range of organisms in the animal, plant, and microbial worlds.
(Indonesian name: Kembodja Putin
The present invention has been completed based on the discovery that a novel triterpene compound extracted from A. ) has excellent anticancer activity.
プルメリア・アクティフォリア・ボイルは、インドネシ
ア産植物であり、古来より歯痛、皮ふ病等の治療に用い
られているといわれる。今回、本発明者らは、上記プル
メリア・アクティフォリア・ボイルの葉の成分について
、その生理活性を探索したところ、本発明の新規なトリ
テルペン化合物を単離・精製し、該化合物が優れた制癌
活性を示すことを見出した。Plumeria actifolia Boil is a plant from Indonesia, and is said to have been used to treat toothaches, skin diseases, etc. since ancient times. This time, the present inventors investigated the physiological activity of the above-mentioned components of the leaves of Plumeria actifolia Boil, and found that the novel triterpene compound of the present invention was isolated and purified. It was found that it showed activity.
(発明の目的)
本発明の目的は、よりすぐれた制癌活性を有する新規な
化合物を提供することにある。又、本発明の目的は、上
記新規な化合物を有効成分とする制癌剤を提供すること
にある。(Objective of the Invention) An object of the present invention is to provide a novel compound having better anticancer activity. Another object of the present invention is to provide an anticancer agent containing the above-mentioned novel compound as an active ingredient.
(発明の構成)
本発明の新規なトリテルペン化合物は、後述の理化学的
性質を示し、プルメリア・アクティフォリア・ボイルよ
り抽出・単離される。以下、その抽出・単離方法の一例
を示す。(Structure of the Invention) The novel triterpene compound of the present invention exhibits the physical and chemical properties described below, and is extracted and isolated from Plumeria actifolia Boil. An example of the extraction/isolation method will be shown below.
プルメリア・アクティフォリア・ボイルの乾燥葉を粉末
化した後、90%エタノール溶液にて抽出し、減圧a縮
して粗抽出物を得る。次いで、得られた粗抽出物を吸着
クロマトグラフィーに付し、水−メタノール系溶媒にて
順次溶出する。得られた各分画について吉田肉腫培養細
胞に対して生育阻害活性の強い分画から得られた粗結晶
を酢酸エチルにて処理し、酢酸エチル可溶部と難溶性粗
結晶に分離する。得られた酢酸エチル可溶部を、無水酢
酸−ピリジンにてアセチル化処理後、高速液体クロマト
グラフィーにて分離・精製し、596!JeOH−KO
Hにより脱アセチル化し、元の化合物に戻し3種の化合
物を単離する。これらの化合物のウチ、2 ffiはマ
ススペクトル、NMRスペクトルデータから公知物質で
あると同定されたが、他の1種は、そのスペクトルデー
タより新規物質と同定された。The dried leaves of Plumeria actifolia Boil are powdered, extracted with a 90% ethanol solution, and compressed under reduced pressure to obtain a crude extract. Next, the obtained crude extract is subjected to adsorption chromatography and sequentially eluted with water-methanol solvent. For each of the obtained fractions, the crude crystals obtained from the fraction with strong growth inhibiting activity against cultured Yoshida sarcoma cells are treated with ethyl acetate to separate into ethyl acetate soluble portion and sparingly soluble crude crystals. The obtained ethyl acetate soluble portion was acetylated with acetic anhydride-pyridine, and then separated and purified using high performance liquid chromatography. JeOH-KO
Deacetylation is performed with H to restore the original compound and isolate three types of compounds. One of these compounds, 2ffi, was identified as a known substance based on mass spectrum and NMR spectrum data, while the other one was identified as a new substance based on its spectrum data.
かくして単離された本発明のトリテルペン化合物は、下
記の構造式及び物理的性質を有する。The triterpene compound of the present invention thus isolated has the following structural formula and physical properties.
Cl−1゜
化合、物〔1〕 (R=H)(ブルメル酸(Plume
ricacid)と命名した。)
化合物CUE (R=CH,) (ブルメル酸メチル
(!、1ethyl Plumerate )と命名し
た。)
〔物理的性質〕
化合物CI)(R=H)
m、p、 : 209.5〜212.5℃(エタノール
より再結晶、微細結晶)
マス・スペクトル:m/Z; 456(M−) C29
H4404゜248(ベースピーク)、207 (8%
)、203(33%)、189(10%)
’ H−N!、IR(400MHz、δ、 C[lCf
3) :5、28 (LH,bs、 ビニル) 、
5.13 (LH,bs 、エキソメチレン) 、4.
75(18,bs、 エキソメチル0、97 (3H
,d、 −CD5) 、0.88 (3H,d、−CH
,)、0、84(3H,S、 −CL) 、0.79(
3H,S、 CH,)化合物[II] (R=CII
、)
m、p、 : 130.5〜132.5℃(メタノール
より再結晶、柱状晶)
マス・スペクトル+m/z; 470(M” ) C3
0)14604.262(ベースビーク)、207 (
4%)、203(87%)、189(2896)’H−
NMR(400MHz、δ、 CDCl 3) ’5、
27 (t、 J=3.5)1z、ビール)、5.14
.4.75(2H,bs、 エキソメチレン)、1、
10 (3H,s、 CH,)、0.94 (3H,d
、−C)13)、0.87(3H,d、−CD5) 、
0.79(3H,s、−CH*)、0、78 (3H,
s、 (L)
いずれの化合物も、マウスに対し50mg/kg連続投
与しても何ら毒性を認めない。Cl-1° compound, substance [1] (R=H) (Blumeric acid (Plume
ricacid). ) Compound CUE (R=CH,) (Named methyl plumerate (!, 1ethyl Plumerate).) [Physical properties] Compound CI) (R=H) m, p, : 209.5-212.5°C (Recrystallized from ethanol, fine crystals) Mass spectrum: m/Z; 456 (M-) C29
H4404°248 (base peak), 207 (8%
), 203 (33%), 189 (10%) 'H-N! , IR (400MHz, δ, C[lCf
3): 5, 28 (LH, bs, vinyl),
5.13 (LH, bs, exomethylene), 4.
75 (18, bs, exomethyl 0,97 (3H
,d, -CD5) ,0.88 (3H,d, -CH
,), 0,84(3H,S, -CL), 0.79(
3H,S, CH,) Compound [II] (R=CII
, ) m, p, : 130.5-132.5°C (recrystallized from methanol, columnar crystal) Mass spectrum + m/z; 470 (M”) C3
0) 14604.262 (base beak), 207 (
4%), 203 (87%), 189 (2896)'H-
NMR (400MHz, δ, CDCl3) '5,
27 (t, J=3.5)1z, beer), 5.14
.. 4.75 (2H, bs, exomethylene), 1,
10 (3H,s, CH,), 0.94 (3H,d
, -C)13), 0.87 (3H, d, -CD5),
0.79 (3H, s, -CH*), 0,78 (3H,
(L) No toxicity was observed for any of the compounds even when 50 mg/kg was continuously administered to mice.
本発明の制癌剤は、経口及び非経口投与のいずれも使用
可能であり、経口投与する場合は、軟・硬カプセル剤又
は錠剤、顆粒剤、細粒剤、散剤として投与され、非経口
投与する場合は、水溶性懸濁液、油性製剤などの皮下或
いは静脈注射剤、点滴剤及び固体状又は懸濁粘稠液状と
して持続的な粘膜吸収が維持できるように生薬のような
剤型で投与され得る。The anticancer agent of the present invention can be administered either orally or parenterally; when administered orally, it is administered as a soft/hard capsule, tablet, granule, fine granule, or powder; when administered parenterally, can be administered in the form of herbal medicines, such as subcutaneous or intravenous injections such as aqueous suspensions and oil-based preparations, infusions, and solid or suspended viscous liquids to maintain sustained mucosal absorption. .
本発明の有効成分の製剤化は、界面活性剤、賦形剤、滑
沢剤、佐剤、及び必要に応じて腸溶性製剤とするために
医薬的に許容し得る被膜形成物質、コーティング助剤等
を用いて適宜行うことができ、その具体例を挙げれば、
次のとおりである。The active ingredients of the present invention are formulated using surfactants, excipients, lubricants, adjuvants, and, if necessary, pharmaceutically acceptable film-forming substances and coating aids to form enteric-coated formulations. This can be done as appropriate using, for example,
It is as follows.
本発明の組成物の崩壊、溶出を良好ならしめるために、
界面活性剤、例えばアルコール、エステル類、ポリエチ
レングリコール誘導体、ソルビタンの脂肪酸エステル類
、硫酸化脂肪アルコール類等の1種又は2種以上を添加
することができる。In order to improve the disintegration and elution of the composition of the present invention,
One or more surfactants such as alcohols, esters, polyethylene glycol derivatives, fatty acid esters of sorbitan, sulfated fatty alcohols, etc. can be added.
また、賦形剤として、例えば蔗糖、乳糖、デンプン、結
晶セルロース、マンニラ)、[[水珪酸、アルミン酸マ
グネシウム、メタ珪酸アルミン酸マグネシウム、合成珪
酸アルミニウム、炭酸カルシウム、炭酸水素ナトリウム
、リン酸水素カルシウム、カルボキシメチルセルロース
カルシウム等の1種又は2種以上を組合せて添加するこ
とができる。In addition, as excipients, for example, sucrose, lactose, starch, crystalline cellulose, mannilla), [[hydrosilicic acid, magnesium aluminate, magnesium metasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium hydrogen carbonate, calcium hydrogen phosphate] , carboxymethylcellulose calcium, etc., or a combination of two or more thereof can be added.
滑沢剤としては、例えばステアリン酸マグネシウム、タ
ルク、硬化油等を1種又は2種以上添加することができ
、また矯味剤及び矯臭剤として、食塩、サッカリン、糖
、マンニット、オレンジ油カンゾウエキス、クエン酸、
ブドウ糖、メントール、ユーカリ油、リンゴ酸等の甘味
剤、香料、着色料、保存料等を含有させてもよい。As a lubricant, for example, one or more types of magnesium stearate, talc, hydrogenated oil, etc. can be added, and as a flavoring agent and a flavoring agent, salt, saccharin, sugar, mannitol, orange oil licorice extract, etc. can be added. ,citric acid,
Sweeteners such as glucose, menthol, eucalyptus oil, and malic acid, fragrances, coloring agents, preservatives, and the like may be included.
懸濁剤、潤滑剤の如き佐剤としては、例えばココナツト
油、オリーブ油、ゴマ油、落花生油、乳酸カルシウム、
ベニバナ油、大豆リン脂質等を含有させることができる
。Examples of adjuvants such as suspending agents and lubricants include coconut oil, olive oil, sesame oil, peanut oil, calcium lactate,
Safflower oil, soybean phospholipids, etc. can be contained.
また被膜形成物質としては、セルロース、糖類等の炭水
化物誘導体として酢酸フタル酸セルロース(CPA)、
またアクリル酸系共重合体、二塩基酸モノエステル類等
のポリビニル誘導体としてアクリル酸メチル・メタアク
リル酸共重合体、メタアクリル酸メチル・メタアクリル
酸共重合体が挙げられる。Film-forming substances include cellulose, cellulose acetate phthalate (CPA) as carbohydrate derivatives such as sugars,
Examples of polyvinyl derivatives such as acrylic acid copolymers and dibasic acid monoesters include methyl acrylate/methacrylic acid copolymers and methyl methacrylate/methacrylic acid copolymers.
また、上記皮膜形成物質をコーティングするに際し、通
常使用されるコーティング助剤、例えば可塑剤の池、コ
ーティング操作時の薬剤相互の付着防止のための各種添
加剤を添加することによって皮膜形成剤の性質を改良し
たり、コーティング操作をより容易ならしめることがで
きる。なお、有効成分を皮膜形成物質を用いてマイクロ
カプセル化してから賦形剤等を混合した剤型としても良
次に代表的な剤型における配合比は下記の通りである。In addition, when coating the above-mentioned film-forming substances, the properties of the film-forming agent can be improved by adding commonly used coating aids, such as plasticizers, and various additives to prevent mutual adhesion of chemicals during coating operations. This can improve the coating process and make coating operations easier. In addition, the compounding ratio in a typical dosage form, which is a dosage form in which the active ingredient is microencapsulated using a film-forming substance and then mixed with excipients, etc., is as follows.
有効成分 0.1〜90 重量%0.3〜15 重
量%賦 形 剤 10〜99.8 〃8
5〜99.4 〃滑 沢 剤 0〜50
〃0〜20〃界面活性剤 0〜50〃0〜20〃
皮膜形成物質 0.1〜50 〃0.3〜20
〃特に好ましい賦形剤は、乳糖、結晶セルローズ、カル
ボキシメチルセルロースカルシウムである。Active ingredient 0.1-90 Weight% 0.3-15 Weight% Excipient 10-99.8 〃8
5~99.4 Lubricating agent 0~50
〃0~20〃Surfactant 0~50〃0~20〃 Film forming substance 0.1~50 〃0.3~20
Particularly preferred excipients are lactose, crystalline cellulose, and calcium carboxymethylcellulose.
また、投与量は、対象腫瘍を有効に治療するに十分な量
であり、腫瘍の症状、投与経路、剤型などによって左右
されるが、一般に、経口投与の場合、大人では1日当り
、薬0.01〜100mg/kg体重(小人では0.0
1〜60mg/kg体重)の範囲で、その上限は好まし
くは約50mg/kg体重、更に好ましくは約10mg
/kg体重程度であり、非経口投与の場合、その上限は
約10mg/kg体重程度であり、好ましくは5 mg
/ kg体重、更に好ましくは2 mg / kg体
重が適当である。In addition, the dosage is sufficient to effectively treat the target tumor, and depends on the symptoms of the tumor, administration route, dosage form, etc., but in general, in the case of oral administration, adults should receive 0 drug per day. .01-100mg/kg body weight (0.0 for dwarfs)
1 to 60 mg/kg body weight), and the upper limit is preferably about 50 mg/kg body weight, more preferably about 10 mg
/kg body weight, and in the case of parenteral administration, the upper limit is about 10 mg/kg body weight, preferably 5 mg/kg body weight.
/kg body weight, more preferably 2 mg/kg body weight.
次に、本発明化合物の制癌活性を確認した制癌性試験法
について述べる。Next, the anticancer activity test method for confirming the anticancer activity of the compound of the present invention will be described.
15%の子牛血清を含有するMEM培地にッスイ製)に
、ラットの復水から取り出した書出肉腫細胞(Yosh
ida sarcoma cells)を接種して培養
し、細胞数が約10XI 05cells /−になっ
た時点で上記培地で5倍に希釈(20X 10’cel
ls/−) L、imI!づつバイアルビンに分注する
。次いで、各濃度の本発明化合物のメタノール又はアセ
トン溶液を加え、ゴム栓をして37℃で培養し約3日後
にトリパンブルーにて染色後、生細抱数を計測する。供
試細胞増殖の抑制率は、次式により求めた。Written sarcoma cells (Yosh) taken from rat condensate were placed in MEM medium containing 15% calf serum (Ssui).
ida sarcoma cells) and cultured, and when the cell number reached approximately 10XI 05 cells/-, diluted 5 times with the above medium (20X 10' cells/-).
ls/-) L,imI! Dispense into vials. Next, a methanol or acetone solution of the compound of the present invention at each concentration is added, a rubber stopper is placed, and the cells are cultured at 37°C. About 3 days later, after staining with trypan blue, the number of viable cells is counted. The inhibition rate of test cell proliferation was determined by the following formula.
以下に本発明を実施例、製剤例及び試験例によって具体
的に説明する。The present invention will be specifically explained below using Examples, Formulation Examples, and Test Examples.
実施例1
インドネシアにて採集したプルメリア・アクティフォリ
ア・ボイルの葉を、自然乾燥させたちの500gを、ミ
キサーにて粉末状にし、90%EtOHに一晩浸漬した
後濾別し、抽出液を減圧下にて1縮し黒褐色の油状物質
18.5 gを得た。Example 1 500g of naturally dried leaves of Plumeria actifolia Boil collected in Indonesia were ground into powder using a mixer, immersed in 90% EtOH overnight, filtered, and the extract was decompressed. The mixture was condensed at the bottom to obtain 18.5 g of a dark brown oily substance.
これを、EtOAc 、 H2Oそれぞれ600m1!
、200m1に分配し両層を減圧S縮して、EtOAc
層かみ黒色油状物質17.3g、水層から茶色油状物質
1.22 gを1等だ。Add this to 600ml each of EtOAc and H2O!
, 200ml, both layers were compressed under reduced pressure, and EtOAc
17.3g of black oily substance in the layer and 1.22g of brown oily substance in the water layer.
EtOAc層を、逆相カラムクロマトグラフィー(ダイ
ヤイオンHP−2040φ×470の1にてa −gの
7つの分画に分離した。展開溶媒は、H2OS)1.0
: MeOtl= 80 : 20.60:40.4
0:60各21.20 : 80 2.342、!、I
eOH7j2、アセトン41を順次使用した。The EtOAc layer was separated into seven fractions a to g using reverse phase column chromatography (Diaion HP-2040φ x 470. The developing solvent was H2OS) 1.0
:MeOtl=80:20.60:40.4
0:60 each 21.20: 80 2.342,! , I
eOH7j2 and acetone 41 were used in this order.
各分画を、減圧濃縮した後、書出肉腫培養細胞に対する
生育阻害活性試験を行なった結果、H2O:MeOH=
60:40,40:60及び!Jest(100%の分
画に強い活性が認められた。After concentrating each fraction under reduced pressure, we conducted a growth inhibitory activity test on cultured written sarcoma cells. As a result, H2O:MeOH=
60:40, 40:60 and! Jest (strong activity was observed in the 100% fraction.
MeO)1100%の分画にεtOAc30+++j!
を加え、吸引濾過し、EtOAc難溶性の結晶を濾別し
、さらに結晶をEtOAc 5 mj!で4回洗い、黄
白色の粗結晶(α)3.60gとEtOAc層から5.
98 gの粗結晶を得た。MeO) εtOAc30+++j for the 1100% fraction!
was added, filtered with suction, and filtered off crystals that were poorly soluble in EtOAc. Washed 4 times with
98 g of crude crystals were obtained.
EtOAc層(5,98g)をカラムクロマトグラフィ
ー’ (Sin、、40φX250+n+n)にて7分
画(h〜m)に分離した。展開溶媒は、ヘキサン:Et
OAc = 20 : 1.10:1各400m1.7
:3500−11:1 600me、ヘキサン:巳tO
Ac= 3・: 7 、EtOAc 、及び!、1 e
OH各500mアセトン200m1を順次使用した。The EtOAc layer (5.98 g) was separated into 7 fractions (hm) by column chromatography (Sin, 40φX250+n+n). The developing solvent is hexane:Et
OAc = 20: 1.10:1 each 400m 1.7
:3500-11:1 600me, hexane:mitO
Ac= 3.: 7, EtOAc, and! , 1 e
500ml each of OH and 200ml of acetone were used sequentially.
各分画について細胞活性試験を行なった結果、ヘキサン
:EtOAc = 1 :1及び3ニアの分画に強い活
性が認められた。As a result of carrying out a cell activity test on each fraction, strong activity was observed in the hexane:EtOAc=1:1 and 3Nia fractions.
活性の強かった八本サン:EtOAc = 3 : 7
の分画をIIPLC(ヌクレオシル50−5 20φX
300uヘキサン:EtOAc = 1 : 1 )
テ1分画に分け、各分画について細胞活性試験を行い、
活性の強い分画(Rf値0.38〜0.32 )をさら
に高速液体クロマトグラフィー(HPLC) (ヌク
レオシル50−58φX300nm ヘキサン: E
tOAc=1:1)で分離したところ、C)Ic Il
s難溶性(EtOAcも、同様)の結晶F(66mg)
、G(22mg)を得た。Hachimotosan with strong activity: EtOAc = 3: 7
The fraction was analyzed by IIPLC (Nucleosil 50-5 20φX
300u hexane:EtOAc = 1:1)
Divide into 1 fraction, perform cell activity test on each fraction,
The highly active fraction (Rf value 0.38-0.32) was further subjected to high performance liquid chromatography (HPLC) (Nucleosil 50-58φX300nm Hexane: E
When separated with tOAc=1:1), C) Ic Il
s Poorly soluble (same as EtOAc) crystal F (66 mg)
, G (22 mg) was obtained.
F 、 Gの書出肉腫培養細胞に対する活性は、それぞ
れ100.25μg/m1で、100%生育阻害を示し
た。The activity of F and G against cultured written sarcoma cells was 100.25 μg/ml, respectively, showing 100% growth inhibition.
G(22mg)をHPLC(ODS−1t−21516
φ×150mm Meol(:820 =4 : 1
)にて分離した後、主成分である無色微細結晶M(18
mg)を得た。G (22 mg) by HPLC (ODS-1t-21516
φ×150mm Meol (:820 =4:1
), the main component, colorless fine crystals M (18
mg) was obtained.
この結晶M (8,3mg)にピリジン1,5ml、A
C20150μ!を加え室温で14時間攪拌し、さらに
ベンゼンを加え減圧下で共沸し、濃縮した後HPLC(
ヌクレオシル5o−58φX300mmへキサ7:Et
O^c=8:1にて分離・精!!(4−デメチル−4,
23−fヒドロ−2α−ヒドロキシウルソル酸ジアセテ
ート(4−demethyl −4、23−dehyd
ro −2a−hydroxyursolic aCi
d diacetate)(A〕6.0mgを得た。To this crystal M (8.3 mg), 1.5 ml of pyridine, A
C20150μ! was added and stirred at room temperature for 14 hours, further benzene was added, azeotropically distilled under reduced pressure, concentrated, and HPLC (
Nucleosil 5o-58φX300mm Hexa7:Et
Separation and separation at O^c=8:1! ! (4-demethyl-4,
23-f hydro-2α-hydroxyursolic acid diacetate (4-demethyl-4,23-dehyd
ro-2a-hydroxyursolic aCi
d diacetate) (A) 6.0 mg was obtained.
(〔A〕の物理的性質)
m、I]、 : L 67.3〜169.0℃(’、t
i e OHより再結晶、微細結晶)
MS:m/Z ; 540(M” ) CsJ<sos
、494(M−HCO21110%、248(ベースピ
ーク)、203 (40%)、189(15%)、
5.26 (LH,t、ビニル) 、4.99(LH,
t −d −J=2、01 (3H,C)l、[:0□
) 、1.10(311,S、CH,)、0、95 (
3H,d、 CH3)、0.85 (3H,d、 CH
3)、0、84 (3)1. S、 CH3)、0.8
2 (3H,S、 C)l、)。(Physical properties of [A]) m, I], : L 67.3-169.0°C (', t
i e Recrystallized from OH, fine crystal) MS: m/Z; 540 (M”) CsJ<sos
, 494 (M-HCO21110%, 248 (base peak), 203 (40%), 189 (15%), 5.26 (LH, t, vinyl), 4.99 (LH,
t −d −J=2,01 (3H,C)l,[:0□
), 1.10(311,S,CH,),0,95(
3H, d, CH3), 0.85 (3H, d, CH
3), 0, 84 (3)1. S, CH3), 0.8
2 (3H,S,C)l,).
実施例2
?4られた化合物[A]l、5mgに5%KOH−Me
O)11m7!を加え、室温で90分間攪拌し、蒸留水
を加え希11Cj2でpH3にした後、EtOAcで抽
出、Na2SO4で乾燥後、減圧a縮し、IIPLC(
ヌクレオシル5〇−5,8φ×300胴、ヘキサン:E
tOAc = 2 :1)で精製し、ブルメル酸(4−
demethyl −4,23−dehydro −2
a −hydroxy ursolic acid)〔
121,3111gを得た。Example 2? 5% KOH-Me to 5 mg of compound [A]
O) 11m7! was added, stirred at room temperature for 90 minutes, added distilled water, adjusted to pH 3 with diluted 11Cj2, extracted with EtOAc, dried over Na2SO4, concentrated under reduced pressure, and analyzed by IIPLC (
Nucleosil 50-5, 8φ x 300 body, hexane: E
tOAc = 2:1) and purified with brumeric acid (4-
demethyl-4,23-dehydro-2
a-hydroxy ursolic acid) [
121,3111 g was obtained.
実施例3
結晶M(3,0mg)にCH2N2 /Et、0を加え
、常法によりメチルエステル化し、HPLC(ヌクレオ
シル50−5.8φX300mm、ヘキサン:EtOA
C=1:1)にて分離・精製し、ブルメル酸メチル(m
ethyl −4−demethyl −4,23−d
ehydro −2a −hydroxy ursol
ate) (II) 2.4mgを得た。Example 3 CH2N2/Et, 0 was added to crystal M (3.0 mg), methyl esterified by a conventional method, and HPLC (Nucleosil 50-5.8φ x 300 mm, hexane:EtOA
Methyl brumerate (m
ethyl-4-demethyl-4,23-d
ehydro-2a-hydroxy ursol
ate) (II) 2.4 mg was obtained.
製剤例1(注射・点滴剤)
本発明化合物〔I〕又はCII〕10mgを含有するよ
うに粉末ぶどうP5gを加えてバイアルに無菌的に分配
し、密封した上、窒累、ヘリウム等の不活性ガスを封入
して冷暗所に保存したc使用前にエタノールに溶解し、
0.85%生理的食塩水100rITlを添加して静脈
内注射剤とし、1日、10〜100dを症状に応じて静
脈内注射又は点滴で投与する。Formulation Example 1 (Injection/Drop) 5 g of powdered grape P was added to contain 10 mg of the compound of the present invention [I] or CII, and the vials were aseptically dispensed, sealed, and inert with nitrogen, helium, etc. Filled with gas and stored in a cool dark place.C Dissolved in ethanol before use.
Add 100 rITl of 0.85% physiological saline to make an intravenous injection, and administer 10 to 100 d per day by intravenous injection or drip depending on the symptoms.
製剤例2(注射・点滴剤)
本発明化合物〔I〕又はCIIE 2mgを用いて、製
剤例1と同様の方法により軽症用静脈内注射剤とし、1
日、10〜100−を症状に応じて静脈内注射又は点滴
で投与する。Formulation Example 2 (Injection/Drop) Using 2 mg of the compound [I] of the present invention or CIIE, an intravenous injection for mild symptoms was prepared in the same manner as in Formulation Example 1.
Administer 10 to 100 doses per day by intravenous injection or infusion depending on the symptoms.
製剤例3(腸溶性カプセル剤)
本発明化合物〔■〕又は〔II)5g、乳糖2.46g
及びヒドロキシプロピルセルロース0、04 gを各々
とり、よく混合した後、常法に従って粒状に成形し、こ
れをよく乾燥して篩別してビン、ヒートシール包装など
に適したマ頁粒剤を製造した。次に、酢酸フタル酸セル
ロース0.5g及びヒドロキシプロピルセルロースフタ
レート0.5gを溶解して被覆基材となし、前記顆粒を
浮遊流動させつつこの基材を被覆して腸溶性の頚粒材と
した。この組成物をカプセルに充填して腸溶性カプセル
製剤100個を製造する。Formulation example 3 (enteric-coated capsule) 5 g of the compound of the present invention [■] or [II], 2.46 g of lactose
After thoroughly mixing 0.04 g of hydroxypropyl cellulose and 0.04 g of hydroxypropyl cellulose, the mixture was formed into granules according to a conventional method, thoroughly dried, and sieved to produce mapage granules suitable for bottles, heat-seal packaging, etc. Next, 0.5 g of cellulose acetate phthalate and 0.5 g of hydroxypropyl cellulose phthalate were dissolved to form a coating base material, and the granules were coated with this base material while floating and flowing to obtain an enteric neck granule material. . This composition is filled into capsules to produce 100 enteric-coated capsule preparations.
試験例(制癌活性試験)
本発明化合物を用い、前記試験法により書出肉腫細胞の
増殖抑制率(%)を算出したところ、第1表に示す結果
が得られた。Test Example (Anticancer Activity Test) When the growth inhibition rate (%) of written sarcoma cells was calculated using the compound of the present invention according to the test method described above, the results shown in Table 1 were obtained.
なお、比較例として、プルメリア・アクティフォリア・
ボイルより抽出された他のトリテルペン化合m(公知化
合物)である下記の化合物を用いた。In addition, as a comparative example, Plumeria actifolia
The following compound, which is another triterpene compound m (known compound) extracted from Boil, was used.
0化合物〔■〕 ニオレアノール酸(oleanoli
c acid)(参考文献:“The Merck I
ndex N1neth ed、p887)0化合物
〔■〕 :ウルソール酸(ursolic acid)
(参考文献:“Theλ1erck Index″N1
neth ed、、 p1269)0化合物〔■〕 :
ラバオール(uvaol)(参考文献:W、H,Hui
and !J、!、1.Li、 Phytochem
istry0化合物〔■〕 :クラテゴール酸(cra
taegolic acid)(参考文献:A、Yag
i、 N、Okamura、 Y、Haraguchi
。0 compound [■] Nioleanolic acid (oleanoli
c acid) (Reference: “The Merck I
ndex N1neth ed, p887) 0 Compound [■]: Ursolic acid
(Reference: “Theλ1erck Index”N1
neth ed,, p1269) 0 compound [■]:
uvaol (References: W, H, Hui
and! J,! , 1. Li, Phytochem
istry0 compound [■]: Crategolic acid (cra
taegolic acid) (References: A, Yag
i, N, Okamura, Y, Haraguchi
.
K、Noda and N15hioka、 Chem
、 Pharm、Bull、、260化合物〔■]2α
−ヒドロウルソル酸(2α−hydroxyursol
ic acid)(参考文献:A、F、Thomas
and B、Willhalm。K, Noda and N15hioka, Chem
, Pharm, Bull, , 260 compounds [■] 2α
-Hydroursolic acid (2α-hydroxyursol)
ic acid) (References: A, F, Thomas
and B, Willhalm.
Tetrohedron Letters、 3177
(1964) )手続補正書
特許庁長官 黒 1)明 雄 殿
り事件の表示 昭和61年特許願第202897号
2、発明の名称 トリテルペン化合物及び制癌剤3
、補正をする者
事件との関係 出願人
名称 (679)理化学研究所
4、代理人
f、油止の円谷
■、 特許請求の範囲を別紙のとおり訂正する。Tetrohedron Letters, 3177
(1964) ) Procedural amendment Commissioner of the Patent Office Black 1) Indication of Yu Akira Tonori case 1985 Patent Application No. 202897 2, Title of invention Triterpene compound and anticancer agent 3
, Relationship with the case of the person making the amendment Applicant name (679) RIKEN 4, Agent F, Tsuburaya of Yutome ■ The scope of the claims is amended as shown in the attached sheet.
2. 明細書第6頁の構造式を、以下の如く訂正する。2. The structural formula on page 6 of the specification is corrected as follows.
「
ql+・
赴
3、 同第4頁第2行の“Plume・・・Pa1r”
をrPIumeria actifo’lia Po1
r Jと訂正する。"ql+・Go3, "Plume...Pa1r" on page 4, line 2
rPIumeria actifo'lia Po1
r Correct as J.
4、 同第4頁第3行の”Kembod、ia Put
in“をrKembodja Putih Jと訂正す
る。4. "Kembod, ia Put" on page 4, line 3.
in" is corrected as rKembodja Putih J.
5、 同第15頁第19行の“ヌクレオシル5O−5”
を「ヌクレオシル5O−5jと訂正する。5. “Nucleosil 5O-5” on page 15, line 19
is corrected to ``Nucleosil 5O-5j.''
特許請求の範囲
(1)構造式:
(但し、式中Rは水素原子又はメチル基を示す。)で示
されるトリテルペン化合物。Claims (1) A triterpene compound represented by the structural formula: (wherein R represents a hydrogen atom or a methyl group.)
(2)Rが水素原子である特許請求の範囲第(1)項記
載の化合物。(2) The compound according to claim (1), wherein R is a hydrogen atom.
(3)Rがメチル基である特許請求の範囲第(1〕項記
載の化合物。(3) The compound according to claim (1), wherein R is a methyl group.
(4)構造式:
(但し、式中、Rは水素原子又はメチル基を示す。)
で示されるトリテルペン化合物を有効成分とする制癌剤
。(4) An anticancer agent containing a triterpene compound represented by the following structural formula: (wherein, R represents a hydrogen atom or a methyl group) as an active ingredient.
Claims (4)
されるトリテルペン化合物。(1) Structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, R represents a hydrogen atom or a methyl group.) A triterpene compound represented by the following.
載の化合物。(2) The compound according to claim (1), wherein R is a hydrogen atom.
載の化合物。(3) The compound according to claim (1), wherein R is a methyl group.
。(4) Structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, R represents a hydrogen atom or a methyl group.) An anticancer agent containing a triterpene compound as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP20289786A JPH064563B2 (en) | 1986-08-29 | 1986-08-29 | Triterpene compound and anticancer agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP20289786A JPH064563B2 (en) | 1986-08-29 | 1986-08-29 | Triterpene compound and anticancer agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS6360949A true JPS6360949A (en) | 1988-03-17 |
JPH064563B2 JPH064563B2 (en) | 1994-01-19 |
Family
ID=16465009
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP20289786A Expired - Lifetime JPH064563B2 (en) | 1986-08-29 | 1986-08-29 | Triterpene compound and anticancer agent |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH064563B2 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001064709A1 (en) * | 2000-02-29 | 2001-09-07 | Dabur Research Foundation | A novel process for manufacturing betulinic acid from ziziphus jujuba |
WO2002009719A1 (en) * | 2000-07-31 | 2002-02-07 | The Nisshin Oillio, Ltd. | Antitumor agents |
JP2002097151A (en) * | 2000-07-21 | 2002-04-02 | Maruzen Pharmaceut Co Ltd | Skin care preparation |
WO2005087246A1 (en) * | 2004-03-12 | 2005-09-22 | Kuniaki Nerome | Antitumor agent |
WO2022135331A1 (en) * | 2020-12-21 | 2022-06-30 | 上海凯屹医药科技有限公司 | Stable liquid pharmaceutical composition containing kuding saponin compound |
-
1986
- 1986-08-29 JP JP20289786A patent/JPH064563B2/en not_active Expired - Lifetime
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001064709A1 (en) * | 2000-02-29 | 2001-09-07 | Dabur Research Foundation | A novel process for manufacturing betulinic acid from ziziphus jujuba |
JP2002097151A (en) * | 2000-07-21 | 2002-04-02 | Maruzen Pharmaceut Co Ltd | Skin care preparation |
WO2002009719A1 (en) * | 2000-07-31 | 2002-02-07 | The Nisshin Oillio, Ltd. | Antitumor agents |
WO2005087246A1 (en) * | 2004-03-12 | 2005-09-22 | Kuniaki Nerome | Antitumor agent |
WO2022135331A1 (en) * | 2020-12-21 | 2022-06-30 | 上海凯屹医药科技有限公司 | Stable liquid pharmaceutical composition containing kuding saponin compound |
Also Published As
Publication number | Publication date |
---|---|
JPH064563B2 (en) | 1994-01-19 |
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