JPH1121284A - Furanonaphthoquinone derivative and medicine containing the same - Google Patents
Furanonaphthoquinone derivative and medicine containing the sameInfo
- Publication number
- JPH1121284A JPH1121284A JP17384897A JP17384897A JPH1121284A JP H1121284 A JPH1121284 A JP H1121284A JP 17384897 A JP17384897 A JP 17384897A JP 17384897 A JP17384897 A JP 17384897A JP H1121284 A JPH1121284 A JP H1121284A
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明はがん細胞に対して選
択的に作用し、安全性の高い抗腫瘍剤として有用な新規
フラノナフトキノン誘導体及びこれを含有する医薬に関
する。TECHNICAL FIELD The present invention relates to a novel furanonaphthoquinone derivative which acts selectively on cancer cells and is useful as a highly safe antitumor agent, and a medicament containing the same.
【０００２】[0002]
【従来の技術】がんによる死亡者数は年々増加し、がん
は今や我国における死亡原因のトップとなっている。か
かるがん治療の手段としては、抗腫瘍剤、手術、放射線
療法等が行われているが、このうち、抗腫瘍剤による治
療は内科的治療手段として最も重要である。2. Description of the Related Art The number of deaths from cancer is increasing year by year, and cancer is now the leading cause of death in Japan. Anticancer drugs, surgery, radiation therapy, and the like have been used as such cancer treatment means. Of these, treatment with an antitumor agent is the most important as a medical treatment means.
【０００３】がんは、放射能、紫外線、発がん物質、ウ
ィルス等の作用により遺伝子に異常がおこることにより
発生するものであり、従来の抗腫瘍剤としては、核酸前
駆物質の代謝、ＤＮＡ合成、ＲＮＡ合成又はタンパク合
成のいずれかに作用するものがほとんどである（阿部達
生、谷脇雅史、津田昌一郎：進行がんの化学療法、金芳
堂（１９９０））。ところが、このような代謝過程は、
がん細胞だけでなく正常細胞においてもおこっているこ
とである。従って、多くの抗腫瘍剤は、がん細胞だけで
なく正常細胞に対しても作用してしまい、種々の副作用
が発現することとなる。[0003] Cancer is caused by abnormalities in genes caused by the action of radioactivity, ultraviolet rays, carcinogens, viruses and the like. Conventional antitumor agents include metabolism of nucleic acid precursors, DNA synthesis, Most act on either RNA synthesis or protein synthesis (Abe Tatsuo, Taniwaki Masashi, Tsuda Shoichiro: Chemotherapy for advanced cancer, Kinyoshido (1990)). However, such metabolic processes
This occurs not only in cancer cells but also in normal cells. Therefore, many antitumor agents act not only on cancer cells but also on normal cells, resulting in various side effects.
【０００４】例えば、キノン誘導体には強い抗腫瘍活性
を有するものがいくつか知られており、その中でもマイ
トマイシンＣ、アドリアマイシン、アクラシノマイシン
Ａ、塩酸ダウノルビシン、塩酸ドキソルビシン等は広く
臨床において使用されている。また、フラノナフトキノ
ン類の中にも下記のように抗腫瘍活性を有するものが知
られている（Rhytochemistry, 20(9), 2271(1981) 、J.
of Natural Products,45(5), 600(1982))。For example, several quinone derivatives having strong antitumor activity are known. Among them, mitomycin C, adriamycin, acracinomycin A, daunorubicin hydrochloride, doxorubicin hydrochloride and the like are widely used in clinical practice. . Further, among furanonaphthoquinones, those having antitumor activity are known as follows (Rhytochemistry, 20 (9), 2271 (1981), J. Am.
of Natural Products, 45 (5), 600 (1982)).
【０００５】[0005]
【化２】 Embedded image
【０００６】しかしながら、これらの化合物はいずれ
も、腫瘍治療作用を有するものの、多くの副作用（嘔
吐、脱毛、皮膚炎、血球減少、胃腸障害、疼痛、腎障
害、心筋障害、精神神経障害等）を生じ、がん治療の大
きな妨げとなっている。[0006] However, although these compounds all have a tumor therapeutic effect, they have many side effects (vomiting, alopecia, dermatitis, cytopenia, gastrointestinal disorders, pain, renal disorders, myocardial disorders, psychiatric disorders, etc.). It is a major obstacle to cancer treatment.
【０００７】[0007]
【発明が解決しようとする課題】従って、本発明の目的
はがん細胞に選択的に作用し、正常細胞に対して毒性が
低く、安全性の高い抗腫瘍剤を提供することにある。Accordingly, an object of the present invention is to provide an antitumor agent which acts selectively on cancer cells, has low toxicity to normal cells, and is highly safe.
【０００８】[0008]
【課題を解決するための手段】そこで本発明者は、植物
由来の物質に着目し、その抗腫瘍活性を正常細胞に対す
る作用を検討してきた結果、ノウゼンカズラ科に属する
テコマ・イペ（Tecomaipe Mart. ex K.Shum.）に含まれ
る下記式（１）で表される新規化合物が優れた抗腫瘍活
性を有し、かつ正常細胞に対する作用が弱く、上記のキ
ノン系化合物に比べてがん細胞に対する選択性が高く、
安全性の高い抗腫瘍剤として有用であることを見出し、
本発明を完成するに至った。The present inventors have focused on plant-derived substances and examined their antitumor activity against normal cells. As a result, the present inventors have found that Tecomaipe Mart. K. Shum.) Has excellent antitumor activity and has a weak effect on normal cells, and is more selective against cancer cells than the above quinone compounds. Nature,
Found to be useful as a highly safe antitumor agent,
The present invention has been completed.
【０００９】すなわち、本発明は、次式（１）：That is, the present invention provides the following formula (1):
【００１０】[0010]
【化３】 Embedded image
【００１１】〔式中、Ｒ1 及びＲ2 は水素原子又はヒド
ロキシル基を示し、Ｒ1 がヒドロキシル基のときＲ2 は
水素原子であり、Ｒ1 が水素原子のときＲ2 はヒドロキ
シル基である〕で表されるフラノナフトキノン誘導体又
はその塩を提供するものである。また、本発明は、この
フラノナフトキノン誘導体（１）又はその塩を有効成分
とする医薬を提供するものである。[In the formula, R 1 and R 2 represent a hydrogen atom or a hydroxyl group. When R 1 is a hydroxyl group, R 2 is a hydrogen atom. When R 1 is a hydrogen atom, R 2 is a hydroxyl group. And a salt thereof. The present invention also provides a medicine containing the furanonaphthoquinone derivative (1) or a salt thereof as an active ingredient.
【００１２】[0012]
【発明の実施の形態】本発明のフラノナフトキノン誘導
体（１）は、より具体的には次の式（１Ａ）又は式（１
Ｂ）で表される化合物又はその塩である。DETAILED DESCRIPTION OF THE INVENTION The furanonaphthoquinone derivative (1) of the present invention is more specifically represented by the following formula (1A) or (1)
The compound represented by B) or a salt thereof.
【００１３】[0013]
【化４】 Embedded image
【００１４】また、フラノナフトキノン誘導体（１）の
塩としては、ナトリウム塩、カリウム塩等のアルカリ金
属塩、カルシウム塩、マグネシウム塩等のアルカリ土類
金属塩、アミン塩等が挙げられる。また、本発明におい
ては、水和物に代表される溶媒和物も含まれる。Examples of the salt of the furanonaphthoquinone derivative (1) include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and amine salts. In the present invention, a solvate represented by a hydrate is also included.
【００１５】本発明のフラノナフトキノン誘導体（１）
は、例えば前記の如く、ノウゼンカズラ科に属する樹木
であるテコマ・イぺ（Tecoma ipe Mart. ex K.Shum.＝T
abebuia avellanedae Lor. ex Griseb.）の樹皮から抽
出することにより得られる。具体的には、テコマ・イペ
の樹皮をメタノールで抽出し、メタノールを留去して得
られる残渣から更にクロロホルム可溶成分を取得し、こ
の成分をクロマトグラフィーに付すことにより分離する
ことができる。なお、このクロロホルム可溶成分中には
本発明化合物に構造の類似する化合物が多数存在する
が、薄層クロマトグラフィー、カラムクロマトグラフィ
ー等により分離することができる。The furanonaphthoquinone derivative of the present invention (1)
For example, as described above, Tecoma ipe Mart. Ex K. Shum.
abebuia avellanedae Lor. ex Griseb.). Specifically, the bark of Tecoma Ipe can be extracted with methanol, and a chloroform-soluble component can be further obtained from the residue obtained by distilling off methanol, and this component can be separated by chromatography. Although a large number of compounds having a structure similar to the compound of the present invention exist in the chloroform-soluble component, they can be separated by thin-layer chromatography, column chromatography, or the like.
【００１６】かくして得られる本発明化合物（１）は、
正常細胞に対する作用が弱く、かつ優れた抗腫瘍活性を
有し、抗腫瘍剤として有用である。すなわち、ヒト肺腺
がんＡ５４９細胞、結腸腺がんWiDr細胞、肺扁平上皮が
んCalu−１細胞を標的（Ｔ）とし、正常線維芽細胞Ｎ６
ＫＡ細胞を正常コントロール（Ｃ）としたときの５０％
細胞増殖阻害濃度の比（Ｃ／Ｔ）は、他のキノン系抗腫
瘍剤が２程度であり、他のフラノナフトキノン誘導体が
１〜４程度であるのに対し、本発明化合物（１）が６．
８であった。従って、本発明は、がん細胞に対して選択
的に作用する安全性の高い抗腫瘍剤である。The compound (1) of the present invention thus obtained is
It has a weak effect on normal cells and has excellent antitumor activity and is useful as an antitumor agent. Specifically, human lung adenocarcinoma A549 cells, colon adenocarcinoma WiDr cells, and lung squamous cell carcinoma Calu-1 cells were targeted (T), and normal fibroblasts N6
50% of KA cells as normal control (C)
The ratio (C / T) of the cell growth inhibitory concentration was about 2 for the other quinone-based antitumor agent and about 1 to 4 for the other furanonaphthoquinone derivatives, whereas the compound (1) of the present invention was 6 or less. .
It was 8. Therefore, the present invention is a highly safe antitumor agent that acts selectively on cancer cells.
【００１７】なお、最近の研究により、がん細胞の大多
数で、ＮＡＤ（Ｐ）Ｈ：キノンオキシドリダクターゼ
（ＮＱＯ）活性が正常細胞に比べて数十倍〜数百倍高く
発現していることが分かってきた（Cancer and Metasta
sis Reviews, 12:103-117(1993))。本発明化合物（１）
も、がん細胞内でＮＱＯと特異的に反応し、その結果フ
リーラジカルを生成してがん細胞を破壊するものと考え
られる。According to recent studies, the majority of cancer cells express NAD (P) H: quinone oxidoreductase (NQO) activity tens to hundreds of times higher than normal cells. (Cancer and Metasta
sis Reviews, 12: 103-117 (1993)). Compound of the present invention (1)
It is also thought that these also specifically react with NQO in cancer cells, thereby generating free radicals and destroying the cancer cells.
【００１８】従って、本発明化合物（１）は、各種臓器
における固形がん、血液がん、肉腫等種々の悪性腫瘍治
療用の医薬として使用できる。Therefore, the compound (1) of the present invention can be used as a medicament for treating various malignant tumors such as solid tumors, blood cancers, sarcomas and the like in various organs.
【００１９】本発明化合物（１）は、経口、非経口いず
れの方法によっても投与することが可能であり、本発明
の医薬は、各種の剤型、例えば散剤、顆粒剤、錠剤、糖
衣錠、カプセル剤、アンプル剤等の経口投与剤；皮下、
筋肉若しくは静脈注射剤；坐剤等とすることができる。The compound (1) of the present invention can be administered by any of oral and parenteral methods. The medicament of the present invention can be administered in various dosage forms, such as powders, granules, tablets, dragees and capsules. Preparations, ampoules, etc. for oral administration; subcutaneous,
Intramuscular or intravenous injections; suppositories and the like.
【００２０】上記製剤化は、本発明化合物（１）単独又
は本発明化合物（１）と賦形剤、増量剤、結合剤、湿潤
化剤、崩壊剤、界面活性剤、滑沢剤、分散剤、緩衝剤、
保存剤、矯味剤、香料、被覆剤等を適宜組み合わせて処
方することにより製造することができる。The above-mentioned preparation is carried out by compound (1) of the present invention alone or compound (1) of the present invention and excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants , Buffer,
It can be manufactured by formulating a preservative, a flavoring agent, a fragrance, a coating agent and the like in an appropriate combination.
【００２１】斯くして得られた本発明医薬の投与量は、
症状、投与ルート等によっても異なるが、一般的に成人
において、本発明化合物（１）として２０〜１０００mg
／日であり、これを通常１日３〜４回に分けて投与する
のが好適である。かかる投与量は、小児では約半量、乳
幼児では１／６量とするのが好ましい。The dosage of the medicament of the present invention thus obtained is as follows:
Although it varies depending on symptoms, administration route and the like, generally 20 to 1000 mg of the compound of the present invention (1) is used in adults.
/ Day, which is usually preferably administered in 3 to 4 divided doses per day. Such a dose is preferably about half the amount for children and 1/6 for infants.
【００２２】[0022]
【実施例】次に実施例を挙げて本発明を詳細に説明する
が、本発明はこれに何ら限定されるものではない。Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
【００２３】実施例１ ２−アセチル−５−ヒドロキシナフト〔２，３−ｂ〕フ
ラン−４，９−ジオン（化合物（１Ａ））及び２−アセ
チル−８−ヒドロキシナフト〔２，３−ｂ〕フラン−
４，９−ジオン（化合物（１Ｂ））の製造：テコマ・イ
ペの乾燥樹皮（ブラジル産）１０kgを純メタノール１０
Ｌあてで３０分間３回加温還流下に抽出し、溶媒を減圧
留去した。抽出物（１．４５kg）をクロロホルム４Ｌあ
てで３回冷浸し、クロロホルム層を水洗後、硫酸マグネ
シウムで乾燥し、溶媒を留去して抽出物１０ｇを得た。
これをクロロホルム・メタノール（２５０：１）を展開
溶媒として０．５mmシリカゲル６０Ｆ254プレートを用
いて分離薄層クロマトグラフィーを反復して行い、Ｒf
＝０．５４の黄色スポットをクロロホルム・トルエンで
抽出し、計１０mgの化合物を得た。これを０〜６０％ク
ロロホルムを含むクロロホルム・トルエン不連続密度勾
配カラムで精製し、ＨＰＬＣカラムを用いてシアン化メ
チル・水（３０〜６０％連続密度勾配）で溶出２４０nm
の吸収で検出しつつ化合物（１Ａ）を３mg、化合物（１
Ｂ）を３．５mg得た。Example 1 2-acetyl-5-hydroxynaphtho [2,3-b] furan-4,9-dione (compound (1A)) and 2-acetyl-8-hydroxynaphtho [2,3-b] Franc-
Production of 4,9-dione (compound (1B)): 10 kg of dry bark of Tecoma Ipe (from Brazil) is added to pure methanol 10
The mixture was extracted with heating to reflux three times for 30 minutes, and the solvent was distilled off under reduced pressure. The extract (1.45 kg) was cold-immersed three times in 4 L of chloroform, the chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain 10 g of the extract.
This was performed by repeating separation thin-layer chromatography using 0.5 mm silica gel 60F 254 plate using chloroform / methanol (250: 1) as a developing solvent to obtain R f
The yellow spot of 0.54 was extracted with chloroform / toluene to obtain a total of 10 mg of the compound. This was purified on a discontinuous density gradient column of chloroform / toluene containing 0-60% chloroform, and eluted with methyl cyanide / water (30-60% continuous density gradient) using an HPLC column.
3 mg of compound (1A) was detected by the absorption of
3.5 mg of B) were obtained.
【００２４】化合物（１Ａ）： Ｃ13Ｈ8Ｏ3＝２１２．２ ｍｐ：２１８〜２２１℃ ＩＲ：１６９５，１６７３，１６４６，１５７２，１４
４９ ＮＭＲ（ＣＤＣｌ3）δ：12.13(1H,s,OH), 7.82(1H,dd,
J=7.5,1.0Hz,8-H),7.67(1H,dd,J=8.2,7.5Hz,7-H), 7.60
(1H,s,3-H),7.33(1H,J=8.5,1.0Hz,6-H), 2.67(3H,s,C
H3)Compound (1A): C 13 H 8 O 3 = 212.2 mp: 218-221 ° C. IR: 1695, 1673, 1646, 1572, 14
49 NMR (CDCl 3 ) δ: 12.13 (1H, s, OH), 7.82 (1H, dd,
J = 7.5,1.0Hz, 8-H), 7.67 (1H, dd, J = 8.2,7.5Hz, 7-H), 7.60
(1H, s, 3-H), 7.33 (1H, J = 8.5,1.0Hz, 6-H), 2.67 (3H, s, C
H 3 )
【００２５】化合物（１Ｂ）： Ｃ13Ｈ8Ｏ3＝２１２．２ ｍｐ：２１２〜２１５℃ ＩＲ：１６８３，１６４６，１５９８，１５８２，１４
５３ ＮＭＲ（ＣＤＣｌ3）δ：11.95(1H,s,OH), 7.79(1H,dd,
J=7.5,1.2Hz,5-H),7.68(1H,dd,J=8.5,7.5Hz,6-H), 7.60
(1H,s,3-H),7.33(1H,J=8.5,1.2Hz,7-H), 2.67(3H,s,C
H3)Compound (1B): C 13 H 8 O 3 = 212.2 mp: 212-215 ° C. IR: 1683,1646,1598,1582,14
53 NMR (CDCl 3 ) δ: 11.95 (1H, s, OH), 7.79 (1H, dd,
J = 7.5,1.2Hz, 5-H), 7.68 (1H, dd, J = 8.5,7.5Hz, 6-H), 7.60
(1H, s, 3-H), 7.33 (1H, J = 8.5,1.2Hz, 7-H), 2.67 (3H, s, C
H 3 )
【００２６】実施例２ １）試験材料培養ヒト悪性腫瘍細胞 ：継代維持された肺腺がんＡ５４
９細胞、肺扁平上皮がんCalu−１細胞、結腸腺がんWiDr
細胞を用いた。これらの細胞は系統が樹立されており、
がん研究所振興財団の細胞バンク（国立衛生試験所、東
京都世田谷区）から入手し、１０％牛胎仔血清を含むＤ
ＭＥＭ培地を用い３７℃、５％ＣＯ2存在下に培養し
た。Example 2 1) Test Material Cultured Human Malignant Tumor Cell : Lung Adenocarcinoma A54 Maintained in Passage
9 cells, lung squamous cell carcinoma Calu-1 cells, colon adenocarcinoma WiDr
Cells were used. These cells have established lineages,
D obtained from the Cell Bank of the Cancer Research Foundation (National Institute of Health, Setagaya-ku, Tokyo) containing 10% fetal bovine serum
The cells were cultured in an MEM medium at 37 ° C. in the presence of 5% CO 2 .
【００２７】培養ヒト正常細胞：継代維持された線維芽
細胞Ｎ６ＫＡ細胞を用いた。気管上皮細胞は、金沢医科
大学病院病理剖検材料からトリプシン−ＥＤＴＡ処理で
採取した。Ｎ６ＫＡ細胞は、１０％牛胎仔血清を含むＤ
ＭＥＭ培地を用い培養し、気管上皮細胞は、同培養液に
更に１０ng／mlのＥＧＦ、５μg／mlのインスリン、
０．５μg／mlのハイドロコルチゾン、１００μg／mlス
トレプトマイシン、１００ＩＵのペニシリン及び０．２
５μg／mlのファンギーゾンを添加した培養液を用い培
養した。 Cultured human normal cells : Fibroblast N6KA cells maintained for a period of time were used. Tracheal epithelial cells were collected by trypsin-EDTA treatment from Kanazawa Medical University Hospital autopsy material. N6KA cells are D-containing 10% fetal calf serum.
After culturing using MEM medium, tracheal epithelial cells were further added to the culture solution with 10 ng / ml EGF, 5 μg / ml insulin,
0.5 μg / ml hydrocortisone, 100 μg / ml streptomycin, 100 IU penicillin and 0.2
Culture was performed using a culture solution supplemented with 5 μg / ml of fungizone.
【００２８】２）試験方法抗腫瘍活性試験（細胞増殖阻害毒性試験） ：９６穴マイ
クロプレート上のマイクロウエルで各細胞を培養し、細
胞が落着く２４時間後にＤＭＳＯ溶媒に適宜溶解した化
合物を添加し、７２時間後の細胞増殖度を調べた。陽性
対照として既知抗がん剤のアドリアマイシン（ＡＤＭ）
とマイトマイシンＣ（ＭＭＣ）を用い、同様にＤＭＳＯ
溶媒に適宜溶解して添加した。2) Test method Antitumor activity test (cell growth inhibition toxicity test) : Each cell is cultured in a microwell on a 96-well microplate, and a compound appropriately dissolved in a DMSO solvent is added 24 hours after the cells settle. After 72 hours, the degree of cell proliferation was examined. Adriamycin (ADM), a known anticancer drug, as a positive control
And mitomycin C (MMC) using DMSO
It was appropriately dissolved in a solvent and added.
【００２９】細胞増殖測定：各マイクロウエル内の細胞
をグルタルアルデヒトにて固定し、クリスタルバイオレ
ット染色した。細胞増殖は、タイターテックユニスキャ
ンII（大日本製薬株式会社、大阪市）を用いて５９０nm
の吸光度で測定した。 Measurement of cell proliferation : Cells in each microwell were fixed with glutaraldehyde and stained with crystal violet. Cell proliferation was performed at 590 nm using Titertec Uniscan II (Dainippon Pharmaceutical Co., Ltd., Osaka).
The absorbance was measured.
【００３０】抗腫瘍性効果の判定：抗腫瘍性（細胞増殖
阻害毒性）効果は、７２時間後細胞増殖を５０％阻害
（ＩＣ50）する化合物の量で表した。 Determination of antitumor effect : The antitumor effect (toxicity for inhibiting cell growth) was expressed by the amount of the compound which inhibited cell growth by 50% (IC 50 ) after 72 hours.
【００３１】がん細胞選択毒性倍率の判定：従来の抗腫
瘍剤は同時に正常細胞に対する毒性が強く、重篤な副作
用の原因となっていた。そこで化合物による正常細胞に
対する５０％細胞増殖阻害濃度（ＩＣ50）をがん細胞に
対するＩＣ50で除することによってがん細胞選択毒性倍
率を計算した。すなわち、倍率１．０では両細胞に同様
な毒性を与えることになり、抗腫瘍剤として不適当であ
り、倍率が大きい程正常細胞への毒性が低い優れた抗腫
瘍剤となる。 Determination of Selective Toxicity of Cancer Cell Toxicity : Conventional antitumor agents are also highly toxic to normal cells, causing serious side effects. Therefore, the selective toxicity of cancer cells was calculated by dividing the 50% cell growth inhibitory concentration (IC 50 ) of the compound against normal cells by the IC 50 against cancer cells. That is, at a magnification of 1.0, the same toxicity is given to both cells, which is unsuitable as an antitumor agent. As the magnification increases, an excellent antitumor agent has lower toxicity to normal cells.
【００３２】３）試験結果 抗腫瘍活性及びがん細胞選択毒性倍率は、表１及び表２
に示すとおりであった。また、比較のため前記公知の類
似化合物についても活性を測定し表３に示した。3) Test results Table 1 and Table 2 show the antitumor activity and the selective toxicity of cancer cells.
Was as shown in FIG. For comparison, the activity of the above-mentioned known analogous compounds was also measured and the results are shown in Table 3.
【００３３】[0033]
【表１】 [Table 1]
【００３４】[0034]
【表２】 [Table 2]
【００３５】[0035]
【表３】 [Table 3]
【００３６】その結果、本発明化合物（１Ａ）の悪性腫
瘍細胞に対するＩＣ50は、０．３６〜０．４０μg／ml
（平均０．３８μg／ml）の範囲にあり、正常細胞に対
する２．６μg／mlと比較して６．８倍がん細胞選択毒
性が強く、公知の類似化合物より優れていた。また化合
物（１Ａ）は、がん細胞選択毒性倍率が約２倍と計算さ
れたアドリアマイシンとマイトマイシンＣに比べてもは
るかに優れていた。As a result, the IC 50 of the compound (1A) of the present invention against malignant tumor cells was 0.36 to 0.40 μg / ml.
(Average: 0.38 μg / ml), 6.8 times stronger in selective toxicity of cancer cells than 2.6 μg / ml for normal cells, and superior to known analogous compounds. In addition, compound (1A) was far superior to adriamycin and mitomycin C, which were calculated to have a cancer cell selective toxicity of about twice.
【００３７】また本発明化合物（１Ｂ）の悪性腫瘍細胞
に対するＩＣ50は、０．３５〜０．４０μg／ml（平均
０．３７μg／ml）の範囲にあり、正常細胞に対する
２．５１μg／mlと比較して６．８倍がん細胞選択毒性
が強く公知の類似化合物より優れていた。化合物（１
Ｂ）も化合物（１Ａ）と同様アドリアマイシン、マイト
マイシンＣに比べはるかに優れていた。The IC 50 of the compound (1B) of the present invention for malignant tumor cells is in the range of 0.35 to 0.40 μg / ml (average 0.37 μg / ml), which is 2.51 μg / ml for normal cells. Compared to known analogous compounds, the toxicity was 6.8 times stronger than that of known analogous compounds. Compound (1
B) was much superior to adriamycin and mitomycin C as in compound (1A).
【００３８】実施例３ ＩＣＲマウス又はＢＡＬＢ／ｃヌードマウスに経口投与
したとき、化合物（１Ａ）又は化合物（１Ｂ）は２００
mg／kg体重において死亡例はなく、１０％死亡するＬＤ
10値は約３２０mg／kg体重であった。この値から推定さ
れるＬＤ50値はおよそ５００mg／kg体重である。化合物
（Ｃ）の経口投与によるＬＤ50値は８．４mg／kg体重と
されており（特開平６−１４５１６２号公報）、この化
合物（Ｃ）に比べて、本発明化合物は、極めて安全性が
高いことがわかる。Example 3 When orally administered to an ICR mouse or a BALB / c nude mouse, Compound (1A) or Compound (1B)
No deaths at 10 mg / kg body weight LD with 10% death
The 10 values were approximately 320 mg / kg body weight. The LD 50 value estimated from this value is approximately 500 mg / kg body weight. The LD 50 value by oral administration of compound (C) is 8.4 mg / kg body weight (JP-A-6-145162). Compared with this compound (C), the compound of the present invention is extremely safe. It turns out that it is high.
【００３９】実施例４ 化合物（１Ａ）又は化合物（１Ｂ）２０mgに対し賦形剤
として乳糖１１６mg、結合剤としてデンプンのり２０m
g、崩壊剤としてデンプン４０mg、滑沢剤としてステア
リン酸マグネシウム４mgを加えよく混合して打錠するこ
とにより、化合物（１Ａ）又は化合物（１Ｂ）２０mgを
含有する２００mgの錠剤を得る。Example 4 Lactose (116 mg) as an excipient and starch paste (20 m) as a binder per 20 mg of the compound (1A) or the compound (1B)
g, 40 mg of starch as a disintegrant and 4 mg of magnesium stearate as a lubricant are mixed well and tableted to give 200 mg tablets containing 20 mg of compound (1A) or compound (1B).
【００４０】[0040]
【発明の効果】本発明化合物（１）は、がん細胞に対し
て選択的に作用し、副作用の少ない抗腫瘍剤として有用
である。The compound (1) of the present invention acts selectively on cancer cells and is useful as an antitumor agent with few side effects.
Claims (3)
示し、Ｒ1 がヒドロキシル基のときＲ2 は水素原子であ
り、Ｒ1 が水素原子のときＲ2 はヒドロキシル基であ
る〕で表されるフラノナフトキノン誘導体又はその塩。1. The following formula (1) [Wherein, R 1 and R 2 represent a hydrogen atom or a hydroxyl group; when R 1 is a hydroxyl group, R 2 is a hydrogen atom; and when R 1 is a hydrogen atom, R 2 is a hydroxyl group]. Or a salt thereof.
体又はその塩を有効成分とする医薬。2. A medicament comprising the furanonaphthoquinone derivative according to claim 1 or a salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17384897A JPH1121284A (en) | 1997-06-30 | 1997-06-30 | Furanonaphthoquinone derivative and medicine containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17384897A JPH1121284A (en) | 1997-06-30 | 1997-06-30 | Furanonaphthoquinone derivative and medicine containing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH1121284A true JPH1121284A (en) | 1999-01-26 |
Family
ID=15968287
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17384897A Pending JPH1121284A (en) | 1997-06-30 | 1997-06-30 | Furanonaphthoquinone derivative and medicine containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH1121284A (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1551392A2 (en) * | 2002-09-17 | 2005-07-13 | Arqule, Inc. | Novel lapacho compounds and methods of use thereof |
| US7538234B2 (en) | 2007-05-31 | 2009-05-26 | Taheebo Japan Co., Ltd. | Preparation of Optically active 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4, 9-diones having anticancer activities |
| US7910752B2 (en) | 2005-03-16 | 2011-03-22 | Taheebo Japan Co., Ltd. | Anticancer compound, intermediate therefor, and processes for producing these |
| US9084766B2 (en) | 2010-03-19 | 2015-07-21 | Boston Biomedical, Inc. | Compounds and compositions for targeting cancer stem cells |
| US9730909B2 (en) | 2010-03-19 | 2017-08-15 | Boston Biomedical, Inc | Methods for targeting cancer stem cells |
| US9732055B2 (en) | 2007-09-10 | 2017-08-15 | Boston Biomedical, Inc. | Compositions and methods for cancer treatment |
| US10017488B2 (en) | 2014-02-07 | 2018-07-10 | Boston Biomedical, Inc. | 3-substituted carbonyl-naphtho[2,3-B]furane derivative or pharmaceutically acceptable salt thereof |
| CN109627253A (en) * | 2018-11-21 | 2019-04-16 | 中节能万润股份有限公司 | A kind of dicarboxylic anhydride containing butterfly structure and its synthetic method and polyimides based on dicarboxylic anhydride synthesis |
| US10543189B2 (en) | 2013-04-09 | 2020-01-28 | Boston Biomedical, Inc. | 2-acetylnaphtho[2,3-b]furan -4,9-dione for use on treating cancer |
| US10646464B2 (en) | 2017-05-17 | 2020-05-12 | Boston Biomedical, Inc. | Methods for treating cancer |
| US11299469B2 (en) | 2016-11-29 | 2022-04-12 | Sumitomo Dainippon Pharma Oncology, Inc. | Naphthofuran derivatives, preparation, and methods of use thereof |
-
1997
- 1997-06-30 JP JP17384897A patent/JPH1121284A/en active Pending
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1551392A2 (en) * | 2002-09-17 | 2005-07-13 | Arqule, Inc. | Novel lapacho compounds and methods of use thereof |
| EP1551392A4 (en) * | 2002-09-17 | 2006-09-20 | Arqule Inc | Novel lapacho compounds and methods of use thereof |
| US7910752B2 (en) | 2005-03-16 | 2011-03-22 | Taheebo Japan Co., Ltd. | Anticancer compound, intermediate therefor, and processes for producing these |
| US7538234B2 (en) | 2007-05-31 | 2009-05-26 | Taheebo Japan Co., Ltd. | Preparation of Optically active 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4, 9-diones having anticancer activities |
| US9732055B2 (en) | 2007-09-10 | 2017-08-15 | Boston Biomedical, Inc. | Compositions and methods for cancer treatment |
| US9745278B2 (en) | 2007-09-10 | 2017-08-29 | Boston Biomedical, Inc. | Group of STAT3 pathway inhibitors and cancer stem cell pathway inhibitors |
| US10377731B2 (en) | 2007-09-10 | 2019-08-13 | Boston Biomedical, Inc. | Compositions and methods for cancer treatment |
| US10851075B2 (en) | 2007-09-10 | 2020-12-01 | Sumitomo Dainippon Pharma Oncology, Inc. | Stat3 pathway inhibitors and cancer stem cell inhibitors |
| US9730909B2 (en) | 2010-03-19 | 2017-08-15 | Boston Biomedical, Inc | Methods for targeting cancer stem cells |
| US9084766B2 (en) | 2010-03-19 | 2015-07-21 | Boston Biomedical, Inc. | Compounds and compositions for targeting cancer stem cells |
| US10543189B2 (en) | 2013-04-09 | 2020-01-28 | Boston Biomedical, Inc. | 2-acetylnaphtho[2,3-b]furan -4,9-dione for use on treating cancer |
| US10017488B2 (en) | 2014-02-07 | 2018-07-10 | Boston Biomedical, Inc. | 3-substituted carbonyl-naphtho[2,3-B]furane derivative or pharmaceutically acceptable salt thereof |
| US11299469B2 (en) | 2016-11-29 | 2022-04-12 | Sumitomo Dainippon Pharma Oncology, Inc. | Naphthofuran derivatives, preparation, and methods of use thereof |
| US10646464B2 (en) | 2017-05-17 | 2020-05-12 | Boston Biomedical, Inc. | Methods for treating cancer |
| CN109627253A (en) * | 2018-11-21 | 2019-04-16 | 中节能万润股份有限公司 | A kind of dicarboxylic anhydride containing butterfly structure and its synthetic method and polyimides based on dicarboxylic anhydride synthesis |
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