JPS63218620A - Normalizing agent for cancerated cell - Google Patents
Normalizing agent for cancerated cellInfo
- Publication number
- JPS63218620A JPS63218620A JP5347887A JP5347887A JPS63218620A JP S63218620 A JPS63218620 A JP S63218620A JP 5347887 A JP5347887 A JP 5347887A JP 5347887 A JP5347887 A JP 5347887A JP S63218620 A JPS63218620 A JP S63218620A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- herbimycin
- compound
- formulas
- tables
- 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
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical class N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 claims abstract description 18
- 239000000126 substance Substances 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 18
- MCAHMSDENAOJFZ-UHFFFAOYSA-N Herbimycin A Natural products N1C(=O)C(C)=CC=CC(OC)C(OC(N)=O)C(C)=CC(C)C(OC)C(OC)CC(C)C(OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-UHFFFAOYSA-N 0.000 abstract description 12
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 150000001412 amines Chemical class 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 125000003700 epoxy group Chemical group 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- MAUMSNABMVEOGP-UHFFFAOYSA-N (methyl-$l^{2}-azanyl)methane Chemical compound C[N]C MAUMSNABMVEOGP-UHFFFAOYSA-N 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 12
- 239000000843 powder Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- -1 Herbimycin A Compound Chemical class 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 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
- 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
- 229920000084 Gum arabic Polymers 0.000 description 1
- 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 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000700605 Viruses Species 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
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 229930193320 herbimycin Natural products 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940080526 mannitol injection Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000006464 oxidative addition reaction Methods 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 description 1
- 229960000885 rifabutin Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明はハービマイシン誘導体を有効成分として含有す
る癌化細胞の正常化剤に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a cancerous cell normalizing agent containing a herbimycin derivative as an active ingredient.
従来技術
ハービマイシンはアンサマイシン系抗生物質に分類され
る抗生物質で除草活性、抗タバコモザイクビールス活性
およびＰ３８８０イケミア、８１６メラノーマ、 Ｌ１
２１０ 口イケミア、ルイス・ラング・カルシノーマ、
エーリッヒ・アサイテス・カルシノーマ等を用いたマウ
ス実験動物系において抗腫瘍活性を示すことが知られて
いる。ある種のハービマイシンの誘導体がエーリッヒ・
アサイテス・カルシノーマを用いたマウス実験動物系に
おいて抗腫瘍活性を有することが知られている。Prior Art Herbimycin is an antibiotic classified as ansamycin antibiotics and has herbicidal activity, anti-tobacco mosaic virus activity, P3880 Ikemia, 816 Melanoma, L1
210 Mouth ikemia, Lewis Lang Carcinoma,
It is known to exhibit antitumor activity in mouse experimental animal systems such as Ehrlich acytes carcinoma. Certain derivatives of herbimycin have been
It is known to have antitumor activity in a mouse experimental animal system using Acytes carcinoma.
〔Ｊ、＾ｎｔｉｂｉｏｔｉｃｓ、 ３７．１２６４（１
９８４） ；３９．４１５（１９８６） ）それらの誘
導体の中には治療効果が量化合物であるハービマイシン
Ａと比較して優れているものも見出せるが、その効果を
顕わすのに必要な投与量はハービマイシンＡの２０〜１
００倍となっている。ハービマイシンＡの場合、最適投
与量以上マウスに投与すると毒性列することを考えると
これらの誘導体では毒性が１／２０〜１／１００に減じ
ているものと思われる。[J, ^ntibiotics, 37.1264 (1
984); 39.415 (1986)) Some of these derivatives have superior therapeutic effects compared to the compound herbimycin A, but the dosage required to manifest their effects is limited. is 20-1 of herbimycin A
00 times. Considering that herbimycin A is toxic when administered to mice in doses exceeding the optimum dose, it is thought that the toxicity of these derivatives is reduced to 1/20 to 1/100.
温度感受性癌遺伝子Ｖ−８ｒＣを含むラット腎細胞（ｓ
ｒｃ”／ＮＲＫ）は許容温度の３３℃では癌の形態を
とって増殖するが、非許容温度の３９℃では正常の形態
で増殖する。そしてハービマイシンＡが３３℃において
癌から正常への形態変化を起こす。すなわち癌化した細
胞を正常の細胞に直すことが知られている。（Ｍｏｌ、
Ｃｅ１ｌ、 Ｂｉｏｌ、。Rat kidney cells (s) containing the temperature-sensitive oncogene V-8rC
rc''/NRK) proliferates in a cancerous form at the permissive temperature of 33°C, but proliferates in a normal form at the non-permissive temperature of 39°C. It is known to cause changes, that is, to transform cancerous cells into normal cells. (Mol,
Ce1l, Biol.
６、２１９８（１９８６））
発明が解決しようとする問題点
癌化した細胞を正常な細胞に直す優れた化合物が求めら
れている。6, 2198 (1986)) Problems to be Solved by the Invention There is a need for an excellent compound that can transform cancerous cells into normal cells.
問題点を解決するための手段
本発明によれば一般式（Ｉ）
テ表されるハービマイシン誘導体〔以下化合物（１）と
いう〕が癌癌細胞を正常化する優れた活性を有すること
が見出された。Means for Solving the Problems According to the present invention, it has been found that a herbimycin derivative represented by the general formula (I) [hereinafter referred to as compound (1)] has an excellent activity of normalizing cancer cells. It was done.
次に化合物（Ｉ）の製造方法について説明する。Next, a method for producing compound (I) will be explained.
化合物（Ｉ）はハービマイシンＡあるいはその８位の二
重結合がエポキシ基に変換された誘導体〔化合物（■）
〕に置換アミンを酸化的に付加することによって製造す
ることができる。Compound (I) is herbimycin A or a derivative in which the double bond at position 8 is converted to an epoxy group [Compound (■)
] by oxidative addition of a substituted amine.
ハービマイシンＡ 化合物（ＩＩ）（式中、
ＭｅはＣＨｓを示し、Ｒ，、Ｒ２は前記と同義である。Herbimycin A Compound (II) (wherein,
Me represents CHs, and R,, R2 have the same meanings as above.
）
化合物（ｎ）はハービマイシンＡを有機溶媒中で１〜３
等量のｍ−クロロ過安息香酸と０〜５０℃で３〜１２時
間反応させることによって製造できる。有機溶媒として
はクロロホルム、ジクロロメタン、四塩化炭素、ジクロ
ロエタン、トリクロロエタン、ベンゼン、トルエン、酢
酸エチル、アセトン、エタノール、メタノール、２−メ
トキシエタノール、エチレングリコール、エチレングリ
コールジメチルエーテル、テトラヒドロフラン、ジオキ
サン等を挙げることができる。クロロホルム中で１．２
倍モルのｍ−クロロ過安息香酸を用い、２５℃、６時間
反応させることが好ましい。反応混合物はシリカゲルカ
ラムクロマトグラフィーを用いて精製することができる
。) Compound (n) is a mixture of herbimycin A in an organic solvent of 1 to 3
It can be produced by reacting with an equal amount of m-chloroperbenzoic acid at 0 to 50°C for 3 to 12 hours. Examples of organic solvents include chloroform, dichloromethane, carbon tetrachloride, dichloroethane, trichloroethane, benzene, toluene, ethyl acetate, acetone, ethanol, methanol, 2-methoxyethanol, ethylene glycol, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, and the like. . 1.2 in chloroform
It is preferable to use twice the molar amount of m-chloroperbenzoic acid and to react at 25° C. for 6 hours. The reaction mixture can be purified using silica gel column chromatography.
化合物（１）はハービマイシンＡあるいは化合物（ｎ）
を有機溶媒中で置換アミンと０〜５０℃で１２〜９６時
間反応させることによって製造することができる。有機
溶媒としては前記したものと同一のものを使用できる。Compound (1) is herbimycin A or compound (n)
can be produced by reacting with a substituted amine in an organic solvent at 0 to 50°C for 12 to 96 hours. As the organic solvent, the same ones mentioned above can be used.
置換アミンとしてはジメチルアミン、メチルビペラジン
、シクロプロピルアミン、アリルアミンを使用すること
ができる。ベンゼン中２７℃で４８時間反応させること
が好ましい。Dimethylamine, methylbiperazine, cyclopropylamine, and allylamine can be used as substituted amines. Preferably, the reaction is carried out in benzene at 27° C. for 48 hours.
急性毒性試験
６週齢、雄のＤＤＹマウス（２５±１ｇ、１群３匹）に
、２％のアラビアゴムを含む生理食塩水に懸濁した薬剤
をｉｐで投与し、２４時間後の生存率から５０％生存投
与量（ＬＤ、。）を上げ下げ法で算出した結果、化合物
（１）はＬＤｓ。；〉２００■／ ｋｇであった。Acute toxicity test A drug suspended in physiological saline containing 2% gum arabic was administered ip to 6-week-old male DDY mice (25 ± 1 g, 3 mice per group), and the survival rate after 24 hours was determined. As a result of calculating the 50% survival dose (LD, .) using the up-down method, compound (1) showed LDs. ;〉200■/kg.
化合物（Ｉ）は生理食塩水、ブドウ糖、ラクトース、マ
ンニット注射液に適当な界面活性剤例えばＴｗｅｅｎ８
０を助剤として加え化合物（Ｉ）を懸濁させ、これを１
〜１０００■／ｋｇ、 １日１〜３回で静脈内あるいは
局所に投与される。Compound (I) is mixed with physiological saline, glucose, lactose, and a surfactant suitable for mannitol injection, such as Tween 8.
0 as an auxiliary agent to suspend compound (I), and
~1000 μ/kg, administered intravenously or locally 1 to 3 times a day.
実施例
化合物（１）のｓ ｒｃ”ＮＲＫ細胞に対する作用をハ
ービマイシンＡと比較して表に示す。The effect of Example Compound (1) on src''NRK cells is shown in the table in comparison with Herbimycin A.
細胞：Ｒｏｕｓ ｓａｒｃｏｍａ ｖｉｒｕｓ Ｐｒａ
ｇｕｅ ５ｔｒａｉｎＳｔｓ２５で感染したラットの腎
細胞（ｓｒｃ” ＮＲに細胞）
培地：５％ｈｅａｔ−ｉｎａｃｔｉｖａｔｅｄ ｃａｌ
ｆ ｓｅｒｕｍ （ＧＩＢＣＯＬａｂｏｒａｔｏｒｉｅ
ｓ、 Ｇｒａｎｄ ｌ５ｌａｎｄ、 Ｎ、Ｙ、製）を含
むＤｕｌｂｅｃｃｏ ｍｏｄｉｆｉｅｄ Ｅａｇｌｅｍ
ｅｄｉｕｍ（ＧＩＢＣＯＬａｂｏｒａｔｏｒｉｅｓ製）
を含むＤｕｌｂｅｃｃ。Cell: Rous sarcoma virus Pra
Rat kidney cells infected with 5trainSts25 (cells in src”NR) Medium: 5% heat-inactivated cal
f serum (GIBCO Laboratory
Dulbecco modified Eagle including
edium (manufactured by GIBCO Laboratories)
Dulbecc, including.
ｍｏｄｉｆｉｅｄ Ｅａｇｌｅ ｍｅｄｉｕｍ （ＧＩ
ＢＣＯＬａｂｏｒａｔｏｒｉｅｓ製）
培養条件：直径３５ｍｍのシャーレ中に２ｒＱｌの培地
を取り３Ｘ１０’個の細胞を接種した。modified Eagle medium (GI
(manufactured by BCOL Laboratories) Culture conditions: A 2rQl medium was taken in a Petri dish with a diameter of 35 mm, and 3×10' cells were inoculated.
次いで薬剤を加え５％の炭酸ガスを含 む加湿空気中で、３３℃で１日間培養 した後、細胞数および細胞形態を顕微 鏡で観察した。Next, add the drug and add 5% carbon dioxide. Cultured for 1 day at 33℃ in humidified air. After that, cell number and cell morphology were examined using a microscope. I observed it in the mirror.
参考例１゜
１９−アリルアミツノ１−ビマイシンへの製造ハービマ
イシンＡ（３，０ｇ＞とアリルアミン（５，０ｍ１）を
ベンゼン（１０Ｑｍｌ）に溶解し、室温に２４時間放置
する。反応液を減圧濃縮すると紫色の粉末物質が得られ
る。粉末物質をベンゼン：酢酸エチル＝１：１を展開溶
媒とするシリカゲルカラムクロマトグラフィーを用いて
精製すると標題化合物が赤紫色粉末として得られる。１
．０６ｇ（３２，３％）
ＴＬＣＲｆ値：０，４５（ベンゼン：酢酸エチル＝Ｃ１
）（１３，１００）、 ３３５（９００）マススペクト
ル： ｍ／ ｚ６２９ （Ｍ” 、 Ｃ１ＪａＪｓＯｓ
）核磁気共鳴スペクトル（ＣＤＣｊ！３中）：δ（ｐ＋
）’ｍ） ４．４６（ｂｒｓ、 Ｈ−１５）、 ６．４
８（ｄ、 Ｊ＝１．８Ｈｚ。Reference Example 1 Production of 19-allylamino-1-bimycin Herbimycin A (3.0 g) and allylamine (5.0 ml) were dissolved in benzene (10 Q ml) and left at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure. A purple powder substance is obtained.The powder substance is purified using silica gel column chromatography using benzene:ethyl acetate=1:1 as a developing solvent to obtain the title compound as a reddish-purple powder.1
．． 06g (32,3%) TLCRf value: 0,45 (benzene: ethyl acetate = C1
) (13,100), 335 (900) mass spectrum: m/z629 (M”, C1JaJsOs
) Nuclear magnetic resonance spectrum (in CDCj!3): δ(p+
)'m) 4.46 (brs, H-15), 6.4
8(d, J=1.8Hz.
Ｈ−１７）、 ７．４５（ｍ、 ＮＨ）参考例２゜
１７−シクロプロピルアミノハービマイシンＡの製造
ハービマイシンＡ（３，０ｇ）とシクロプロピルアミン
（５，０ｍ１）をベンゼン（１０Ｑｍｌ）に溶解し、室
温に４８時間放置する。反応液を減圧濃縮すると、赤紫
色の粉末物質が得られる。粉末物質をベンゼン：酢酸エ
チル＝１：１を展開溶媒とするシリカゲルカラムクロマ
トグラフィーを用いて精製すると、標題化合物が赤紫色
粉末として得られる。■、６３ｇ（４９，６％）
ＴＬＣＲｆ値：０．６０（ベンゼン：酢酸エチル＝１：
１）
旋光度： 〔α）” −１３８，０°（ＣＯ，２，Ｃ
Ｈ（： ｆ ３）δ（ｐｐｍ） ４．４８（ｂｒｓ、
Ｈ−１５）、 ６．９５（ｓ、 Ｈ−１９）。H-17), 7.45 (m, NH) Reference Example 2 Production of 17-cyclopropylaminoherbimycin A Herbimycin A (3.0 g) and cyclopropylamine (5.0 ml) were dissolved in benzene (10 Qml). Dissolve and leave at room temperature for 48 hours. The reaction solution is concentrated under reduced pressure to obtain a reddish-purple powder. The powdered substance is purified using silica gel column chromatography using benzene:ethyl acetate=1:1 as a developing solvent to obtain the title compound as a reddish-purple powder. ■, 63g (49.6%) TLCRf value: 0.60 (benzene: ethyl acetate = 1:
1) Optical rotation: [α)” -138,0° (CO,2,C
H (: f 3) δ (ppm) 4.48 (brs,
H-15), 6.95 (s, H-19).
７、５９ （ｂｒｄ、 ＮＨ）
参考例３゜
８．９−エポキシ−１９−シクロプロピルアミノハービ
マイシンＡの製造
ハービマイシンＡ（７，０ｇ）とｍ−クロロ過安息香酸
（２，１ｇ）をりｏｏホルム（３００ｍ１）に溶解し、
室温で２４時間放置する。反応液を氷冷しながら飽和炭
酸水素す） ＩＪウム水溶液で中和し、クロロホルム層
を抽出する。抽出液を飽和食塩水で洗浄後、無水硫酸ナ
トリウムで脱水し、減圧濃縮すると、黄色粉末が得られ
る。粉末物質をベンゼン：酢酸エチル＝１：１を展開溶
媒とするシリカゲルカラムクロマトグラフィーを用いて
精製すると、８，９−エポキシハービマイシン八が淡黄
色粉末として得られる。４．７０ｇ（６５，３％）ＴＬ
ＣＲｆ値：０．５４（ベンゼン：酢酸エチル＝１：１）
８．９−エポキシハービマイシンＡ（１，０ｇ）とシク
ロプロピルアミン（６，０＋ｎｌ）をベンゼン（１００
ｍｌ）に溶解し、室温に７０時間放置する。7,59 (brd, NH) Reference Example 3 8. Production of 9-epoxy-19-cyclopropylaminoherbimycin A Separate herbimycin A (7.0 g) and m-chloroperbenzoic acid (2.1 g). Dissolved in oo form (300ml),
Leave at room temperature for 24 hours. The reaction solution is neutralized with an aqueous solution of saturated hydrogen carbonate while cooling on ice, and the chloroform layer is extracted. The extract is washed with saturated brine, dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow powder. The powder substance is purified using silica gel column chromatography using benzene:ethyl acetate=1:1 as a developing solvent to obtain 8,9-epoxyherbimycin 8 as a pale yellow powder. 4.70g (65.3%) TL
CRf value: 0.54 (benzene: ethyl acetate = 1:1)
8.9-Epoxyherbimycin A (1,0g) and cyclopropylamine (6,0+nl) were dissolved in benzene (100g).
ml) and left at room temperature for 70 hours.
Claims (1)
、表等があります▼、▲数式、化学式、表等があります
▼、▲数式、化学式、表等があります▼、▲数式、化学
式、表等があります▼ であり、Ｘ−Ｙは▲数式、化学式、表等があります▼ま
たは▲数式、化学式、表等があります▼である）で表さ
れるハービマイシン誘導体を有効成分として含有する癌
化細胞の正常化剤[Claims] Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 are H or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and X-Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ) A normalizing agent for cancerous cells containing a herbimycin derivative represented by () as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5347887A JPS63218620A (en) | 1987-03-09 | 1987-03-09 | Normalizing agent for cancerated cell |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5347887A JPS63218620A (en) | 1987-03-09 | 1987-03-09 | Normalizing agent for cancerated cell |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63218620A true JPS63218620A (en) | 1988-09-12 |
Family
ID=12943955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5347887A Pending JPS63218620A (en) | 1987-03-09 | 1987-03-09 | Normalizing agent for cancerated cell |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63218620A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6855705B1 (en) | 2003-11-12 | 2005-02-15 | Kosan Biosciences, Inc. | 11-O-methylgeldanamycin compounds |
| US6870049B1 (en) | 2003-11-12 | 2005-03-22 | Kosan Biosciences, Inc. | 11-O-methylgeldanamycin compounds |
| US6872715B2 (en) | 2001-08-06 | 2005-03-29 | Kosan Biosciences, Inc. | Benzoquinone ansamycins |
| US6875863B1 (en) | 2003-11-12 | 2005-04-05 | Kosan Biosciences, Inc. | 11-O-methylgeldanamycin compounds |
| US6887993B1 (en) | 2003-11-12 | 2005-05-03 | Kosan Biosciences, Inc. | 11-O-methylgeldanamycin compounds |
| US7241754B2 (en) | 2003-06-13 | 2007-07-10 | Kosan Biosciences, Inc. | 2-Desmethyl ansamycin compounds |
| US7259156B2 (en) | 2004-05-20 | 2007-08-21 | Kosan Biosciences Incorporated | Geldanamycin compounds and method of use |
| US8466140B2 (en) | 2007-09-10 | 2013-06-18 | University Of Massachusetts | Mitochondria-targeted anti-tumor agents |
-
1987
- 1987-03-09 JP JP5347887A patent/JPS63218620A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6872715B2 (en) | 2001-08-06 | 2005-03-29 | Kosan Biosciences, Inc. | Benzoquinone ansamycins |
| US7405208B2 (en) | 2001-08-06 | 2008-07-29 | Kosan Biosciences, Inc. | Benzoquinone ansamycins |
| US7241754B2 (en) | 2003-06-13 | 2007-07-10 | Kosan Biosciences, Inc. | 2-Desmethyl ansamycin compounds |
| US6855705B1 (en) | 2003-11-12 | 2005-02-15 | Kosan Biosciences, Inc. | 11-O-methylgeldanamycin compounds |
| US6870049B1 (en) | 2003-11-12 | 2005-03-22 | Kosan Biosciences, Inc. | 11-O-methylgeldanamycin compounds |
| US6875863B1 (en) | 2003-11-12 | 2005-04-05 | Kosan Biosciences, Inc. | 11-O-methylgeldanamycin compounds |
| US6887993B1 (en) | 2003-11-12 | 2005-05-03 | Kosan Biosciences, Inc. | 11-O-methylgeldanamycin compounds |
| US7259156B2 (en) | 2004-05-20 | 2007-08-21 | Kosan Biosciences Incorporated | Geldanamycin compounds and method of use |
| US7378407B2 (en) | 2004-05-20 | 2008-05-27 | Kosan Biosciences Incorporated | Geldanamycin compounds and method of use |
| US8466140B2 (en) | 2007-09-10 | 2013-06-18 | University Of Massachusetts | Mitochondria-targeted anti-tumor agents |
| US9987294B2 (en) | 2007-09-10 | 2018-06-05 | University Of Massachusetts | Mitochondria-targeted anti-tumor agents |
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