JP6154231B2 - Anticancer drug - Google Patents

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JP6154231B2
JP6154231B2 JP2013151507A JP2013151507A JP6154231B2 JP 6154231 B2 JP6154231 B2 JP 6154231B2 JP 2013151507 A JP2013151507 A JP 2013151507A JP 2013151507 A JP2013151507 A JP 2013151507A JP 6154231 B2 JP6154231 B2 JP 6154231B2
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anticancer agent
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JP2015020986A (en
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穣 人見
穣 人見
勇次 岩本
勇次 岩本
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Doshisha Co Ltd
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Description

この発明は、抗癌に関する。 This invention relates to an anti-cancer agent.

シスプラチン(cis‐ジクロロジアンミン白金(II))、カルボプラチン(cis‐1,1‐シクロブタンジカルボキシラートジアンミン白金(II)、特許文献1を参照。)、ネダプラチン(シス‐O,O′−グリコラートジアンミン白金(II)、特許文献2を参照。)等の白金製剤は強い抗癌活性を有し、現在、肺癌、悪性リンパ腫などの多くの癌に対し、主要な抗癌剤として使用されている。なお、これら白金製剤は、DNAを構成する塩基部分と強く結合してDNAの複製を防ぐことにより、癌細胞を死滅させることが分かっている。   Cisplatin (cis-dichlorodiammine platinum (II)), carboplatin (cis-1,1-cyclobutanedicarboxylate diammine platinum (II), see Patent Document 1), nedaplatin (cis-O, O′-glycolate diammine) Platinum preparations such as platinum (II) (see Patent Document 2) have strong anticancer activity, and are currently used as major anticancer agents against many cancers such as lung cancer and malignant lymphoma. These platinum preparations are known to kill cancer cells by strongly binding to the base portion constituting DNA and preventing DNA replication.

しかし、従来からある白金製剤には次に掲げるような問題点があった。まず、原材料に白金を使用しているため、薬剤の価格が高くなってしまうという問題点があった。また、癌細胞の中には、白金製剤を投与してもDNAと結合することなく細胞外に排出してしまう白金製剤耐性癌が存在するとの問題点もあった。   However, conventional platinum preparations have the following problems. First, since platinum is used as a raw material, there has been a problem that the price of the drug becomes high. In addition, some cancer cells have a platinum preparation-resistant cancer that is excreted out of the cell without binding to DNA even when a platinum preparation is administered.

一方、発明者らは、従来から、特定構造を有する複素環化合物、これを配位子とする金属錯体、及び前記金属錯体の酸化触媒として使用について研究し、既に特許出願している(特許文献3を参照。)。   On the other hand, the inventors have studied a heterocyclic compound having a specific structure, a metal complex having this as a ligand, and the use of the metal complex as an oxidation catalyst, and have already filed patent applications (Patent Documents). 3).

特開昭49−48621号公報JP 49-48621 特開昭59−222497号公報JP 59-222497 国際出願番号 PCT/JP2013/062176International application number PCT / JP2013 / 062176

そこで、この発明は、白金などの高価な貴金属を使用せず安価であるとともに、従来からある白金製剤とは作用機序が異なる抗癌剤を提供することを課題とする。   Thus, an object of the present invention is to provide an anticancer agent that is inexpensive without using expensive noble metals such as platinum and has a different mechanism of action from conventional platinum preparations.

発明者らは、前記金属錯体及びその類似化合物が水中で安定的に存在することができることから、抗癌剤として利用できるのではないかと推測し、鋭意研究を重ねた結果、前記金属錯体が癌細胞に対して優れた細胞毒性を有することを見出し、この発明を完成するに至った。   The inventors have speculated that the metal complex and its analogs can be stably present in water and can be used as an anticancer agent, and as a result of earnest research, the metal complex is found in cancer cells. The present inventors have found that it has excellent cytotoxicity, and have completed the present invention.

すなわち、この発明の抗癌剤は、下記一般式(1)で表される金属錯体を有効成分として含有する抗癌剤である。   That is, the anticancer agent of the present invention is an anticancer agent containing a metal complex represented by the following general formula (1) as an active ingredient.

Figure 0006154231
Figure 0006154231

(式中Mは鉄、マンガン又はコバルトの何れかを表す。Xは対イオンを表す、nは1又は2を表す。) (In the formula , M represents one of iron, manganese, and cobalt. X represents a counter ion, and n represents 1 or 2.)

中でもMがマンガン、XがClO4 -であるものが好ましい。 Among them, M is manganese, X is ClO 4 - in which is preferable.

この発明の抗癌剤は、貴金属であるプラチナを原料とせず、安価に製造することができる。また、この発明の抗癌剤の有効成分である金属錯体の配位は一般に置換活性であり、DNAを構成する塩基とは結合しない。そのため、白金製剤とは異なる作用機序によって、癌細胞を死滅させることができ、白金製剤が効力を発揮しない癌に対しても有効である。   The anticancer agent of the present invention can be produced at low cost without using platinum, which is a noble metal, as a raw material. In addition, the coordination of the metal complex which is an active ingredient of the anticancer agent of the present invention is generally substitution activity and does not bind to the base constituting DNA. Therefore, cancer cells can be killed by an action mechanism different from that of the platinum preparation, which is also effective for cancer in which the platinum preparation does not exert its effect.

図1は、この発明の抗癌剤を構成する複素環化合物あるH-dpaqH,esterの合成経路を示す図である。FIG. 1 is a diagram showing a synthesis route of H-dpaq H, ester , which is a heterocyclic compound constituting the anticancer agent of the present invention.

この発明は複素環化合物を配位子とする金属錯体有効成分とする抗癌剤に関する。そこで、これらについて以下に詳説する。なお、この発明は、以下の説明によって、如何なる意味においても限定されるものではなく、以下の例示以外についても、この発明の趣旨を損なわない範囲で適宜変更可能である。 The present invention, the heterocyclic compounds for anticancer agents as an active ingredient a metal complex having a ligand. Therefore, these will be described in detail below. In addition, this invention is not limited in any meaning by the following description, In the range which does not impair the meaning of this invention except the following illustrations, it can change suitably.

1.複素環化合物
(1)複素環化合物
この発明の抗癌剤を構成する複素環化合物は、下記一般式()で表される複素環化合物である。この複素環化合物を「H-dpaq H,ester 」と略記する。また、「H-dpaq H,ester 」の-OCH 2 CO 2 C 2 H 5 が水素原子に置換された化合物を「H-dpaq H,H 」、「H-dpaq H,H 」のキノリン部分の8位がニトロ基に置換された化合物を「H-dpaq NO2,H 」と略記する。
1. Heterocyclic Compound (1) Heterocyclic Compound The heterocyclic compound constituting the anticancer agent of the present invention is a heterocyclic compound represented by the following general formula ( 2 ). This heterocyclic compound is abbreviated as “H-dpaq H, ester ”. In addition, a compound in which —OCH 2 CO 2 C 2 H 5 of “H-dpaq H, ester is replaced with a hydrogen atom is replaced with “H-dpaq H, H ” or “H-dpaq H, H ” A compound in which the 8-position is substituted with a nitro group is abbreviated as “H-dpaq NO2, H ”.

Figure 0006154231
Figure 0006154231

(2)複素環化合物の製造方法
この発明の抗癌剤を構成する複素環化合物である「H-dpaqH,ester」を製造する方法を以下に説明する。なお、前記複素環化合物は、下記の製造方法で得られるものには限定されない。
(2) Method for producing heterocyclic compound A method for producing “H-dpaq H, ester, which is a heterocyclic compound constituting the anticancer agent of the present invention, will be described below. In addition, the said heterocyclic compound is not limited to what is obtained with the following manufacturing method.

この発明の抗癌剤を構成する複素環化合物は、下記一般式()で表される、6-ヒドロキシ-8-アミノキノリンのエーテル化物出発原料として用いる。 The heterocyclic compound constituting the anticancer agent of the present invention uses an etherified product of 6-hydroxy-8-aminoquinoline represented by the following general formula ( 3 ) as a starting material.

Figure 0006154231
Figure 0006154231

なお、上記6-ヒドロキシ-8-アミノキノリンのエーテル化は、例えば下記の化学式及び化学式に示すようにして容易に得られる。具体的には、まず4-アミノ-3-ニトロフェノーから、デーブナー・フォン=ミラー(DOEBNER-von MILLER)キノリン合成法やスクラウプ(SKRAUP)キノリン合成法などの公知のキノリン合成法により6-ヒドロキシ-8-ニトロキノリを合成したのち、その6位の水酸基を酢酸エチルのハロゲン化物でエーテル化する。次に、下記の化学式に示すように、その8位のニトロ基をアミノ基に還元する。 Incidentally, etherification products of the 6-hydroxy-8-aminoquinoline are readily obtained by example as shown in Chemical Formula 4 and Chemical Formula 5 below. Specifically, first, a 4-amino-3-nitrophenol, by Debuna von-Miller (DOEBNER-von MILLER) quinoline Synthesis and Sukuraupu (SKRAUP) known quinoline synthesis of quinoline synthesis 6- hydroxy - 8 - After synthesizing Nitorokinori down, etherifying the 6-position hydroxyl group in the halide of ethyl acetate. Next, as shown in the following chemical formula 5 , the nitro group at the 8-position is reduced to an amino group.

Figure 0006154231
Figure 0006154231

Figure 0006154231
Figure 0006154231

このようにして得れた一般式()で表される化合物を使用して、例えば、下記反応()、()を行う。 Using the compound represented by the general formula ( 3 ) thus obtained, for example, the following reactions ( 6 ) and ( 7 ) are performed.

Figure 0006154231
Figure 0006154231

Figure 0006154231
Figure 0006154231

ここで、X1、X2はハロゲン原子であり、何れもが臭素原子であるのが好ましい。なお、 反応()はアミノ基のアミド化反応であり、反応()はハロゲン化アルキルによるアミンのN-アルキル化反応である。 Here, X 1 and X 2 are halogen atoms, and preferably both are bromine atoms. Reaction ( 6 ) is an amidation reaction of an amino group, and reaction ( 7 ) is an N-alkylation reaction of an amine with an alkyl halide.

ここで、反応()で使用するアミンは、2,2'-ジピコリルアミである Here, amine used in the reaction (7) is 2,2' Jipikoriruami down.

なお、前記「H-dpaqH,ester」以外の複素環化合物、例えば、「H-dpaqH,H」、「H-dpaqNO2,H」、「H-dpaqOMe,H」については特許文献3に記載に従って合成すればよい。 Regarding heterocyclic compounds other than the above-mentioned “H-dpaq H, ester ”, for example, “H-dpaq H, H ”, “H-dpaq NO2, H ”, “H-dpaq OMe, H ”, Patent Document 3 And may be synthesized according to the description.

2.金属錯体
(1)金属錯体
この発明の抗癌剤の有効成分である金属錯体は、下記一般式()表されるものである。
2. Metal complex (1) Metal complex The metal complex which is an active ingredient of the anticancer agent of this invention is represented by the following general formula ( 1 ).

Figure 0006154231
Figure 0006154231

ここで、Mは鉄、マンガン又はコバルトの何れかを表し、中でも高活性であることからマンガンが好ましい。また、Xは対イオンを表し、具体的にはClO4 -、Cl-、Br-、AcO-、TfO-、CF3CO2 -、BF4 -、ReO4 -、AsF6 -、SbF6 -などが挙げられるが、中でも高活性であることからClO4 -が好ましい。なお、n=1又は2である Here, M represents any one of iron, manganese, and cobalt, and manganese is preferable because of its high activity. X represents a counter ion. Specifically, ClO 4 , Cl , Br , AcO , TfO , CF 3 CO 2 , BF 4 , ReO 4 , AsF 6 , SbF 6 Among them, ClO 4 is preferable because of its high activity. Note that n = 1 or 2 .

(2)金属錯体の製造方法
この発明の抗癌剤の有効成分である金属錯体は、この発明の複素環化合物を金属に配位させることによって得られ、その方法は公知の方法であれば特に限定することなく使用できる。
(2) Method for producing metal complex The metal complex which is an active ingredient of the anticancer agent of the present invention is obtained by coordinating the heterocyclic compound of the present invention to a metal, and the method is particularly limited as long as it is a known method. Can be used without

例えば、溶剤中、錯体を形成し得る条件で前記複素環化合物と所定の金属イオンとを共存させればよく、具体的には、前記複素環化合物を、塩基性化合物とともに溶剤に溶解して、所定の金属イオン溶液を添加すれば、錯体の微結晶を形成できる。 For example, in a solvent, it is sufficient under the conditions capable of forming a complex coexist and said heterocyclic compound and a predetermined metal ions, specifically, the heterocyclic compound is dissolved in a solvent together with a basic compound, If a predetermined metal ion solution is added, complex microcrystals can be formed.

なお、前記溶剤としては、メタノール、アセトニトリルなどの極性有機溶剤が好適である。また、前記塩基性化合物としては、トリエチルアミン、N,N-ジイソプロピルエチルアミンなどが好ましい。さらに、錯体形成したあとに、メタノールなどの溶剤で洗浄することによっ高純度の金属錯体が得られる。 In addition, as said solvent, polar organic solvents, such as methanol and acetonitrile, are suitable. Further, as the basic compound, triethylamine, N, N-diisopropylethylamine and the like are preferable. Furthermore, after complexed, high purity of the metal complex is obtained by the washing with a solvent such as methanol.

3.抗癌剤
この発明の抗癌剤は、下記一般式(1)で表される金属錯体を有効成分として含むものであり、金属錯体単体又は公知の製剤用担体と組合せて、癌に罹ったヒト又はそれ以外の動物に投与するものである。なお、その構造、適用症例、投与形態等については以下に詳説する。
3. Anti-cancer agent The anti-cancer agent of the present invention contains a metal complex represented by the following general formula (1) as an active ingredient, and is used in combination with a metal complex alone or a known pharmaceutical carrier, or a human suffering from cancer or other It is to be administered to animals. The structure, application case, administration mode, etc. will be described in detail below.

Figure 0006154231
Figure 0006154231

ここでM、X、nについては、前記金属錯体と同じであるので説明を省略する。 Here, M, X, for n will be omitted because it is same as the metal complex.

(1)適用症例
この発明の抗癌剤が適用される癌の種類は特に限定されるものではない。適用可能な癌の種類として、悪性黒色腫、悪性リンパ腫、消化器癌、肺癌、食道癌、胃癌、大腸癌、直腸癌、結腸癌、尿管腫瘍、胆嚢癌、胆管癌、胆道癌、乳癌、肝臓癌、膵臓癌、睾丸腫瘍、上顎癌、舌癌、口唇癌、口腔癌、咽頭癌、喉頭癌、卵巣癌、子宮癌、前立腺癌、甲状腺癌、脳腫瘍、カポジ肉腫、血管腫、白血病、真性多血症、神経芽腫、網膜芽腫、骨髄腫、膀胱腫、肉腫、骨肉腫、筋肉腫、皮膚癌、基底細胞癌、皮膚付属器癌、皮膚転移癌、皮膚黒色腫などが例示でき、悪性腫瘍だけではなく良性腫瘍にも適用できる。また、この発明の抗癌剤は、癌転移を抑制するために使用でき、術後の癌転移抑制剤としても使用できる。
(1) Application case The kind of cancer to which the anticancer agent of this invention is applied is not particularly limited. Applicable cancer types include malignant melanoma, malignant lymphoma, digestive organ cancer, lung cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, colon cancer, ureteral tumor, gallbladder cancer, bile duct cancer, biliary tract cancer, breast cancer, Liver cancer, pancreatic cancer, testicular tumor, maxillary cancer, tongue cancer, lip cancer, oral cancer, pharyngeal cancer, laryngeal cancer, ovarian cancer, uterine cancer, prostate cancer, thyroid cancer, brain tumor, Kaposi's sarcoma, hemangioma, leukemia, true Examples include polycythemia, neuroblastoma, retinoblastoma, myeloma, cystoma, sarcoma, osteosarcoma, myoma, skin cancer, basal cell cancer, skin appendage cancer, skin metastasis cancer, skin melanoma, etc. It can be applied not only to malignant tumors but also to benign tumors. Further, the anticancer agent of the present invention can be used for suppressing cancer metastasis, and can also be used as a postoperative cancer metastasis inhibitor.

(2)投与形態等
この発明の抗癌剤は、種々の形態でヒト又は動物に投与することができ、その投与形態は特に限定されるものではない。具体的には、経口投与でもよいし、静脈内、筋肉内、皮下又は皮内等への注射、直腸内投与、経粘膜投与等の非経口投与でもよい。
(2) Administration form etc. The anticancer agent of this invention can be administered to humans or animals in various forms, and the administration form is not particularly limited. Specifically, it may be oral administration, or parenteral administration such as intravenous, intramuscular, subcutaneous or intradermal injection, rectal administration or transmucosal administration.

経口投与に適する製剤形態としては、錠剤、丸剤、顆粒剤、散剤、カプセル剤、液剤、懸濁剤、乳剤、シロップ剤などが例示でき、非経口投与に適する医薬組成物としては、注射剤、点滴剤、点鼻剤、噴霧剤、吸入剤、坐剤、又は軟膏、クリーム、粉状塗布剤、液状塗布剤、貼付剤等の経皮吸収剤等が例示できる。さらに、埋め込み用ペレットや公知の技術により持続性製剤としてもよい。なお、好ましい投与形態や製剤形態等は、患者の年齢、性別、体質、症状、処置時期等に応じて、医師が適宜選択すればよい。   Examples of the dosage form suitable for oral administration include tablets, pills, granules, powders, capsules, solutions, suspensions, emulsions, syrups and the like, and pharmaceutical compositions suitable for parenteral administration include injections. And transdermal agents such as drops, nasal drops, sprays, inhalants, suppositories, ointments, creams, powdery coatings, liquid coatings, patches and the like. Furthermore, it may be a sustained-release preparation by embedding pellets or a known technique. In addition, a preferable dosage form, formulation form, etc. may be appropriately selected by a doctor according to the age, sex, constitution, symptom, treatment timing, etc. of the patient.

この発明の抗癌剤を錠剤、丸剤、散剤、粉剤、顆粒剤等の固形製剤とする場合には、前記金属錯体を、常法に従って適当な添加剤、例えば、乳糖、ショ糖、D−マンニトール、トウモロコシデンプン、合成もしくは天然ガム、結晶セルロース等の賦形剤、デンプン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、アラビアゴム、ゼラチン、ポリビニルピロリドン等の結合剤、カルボシキメチルセルーロースカルシウム、カルボシキメチルセルーロースナトリウム、デンプン、コーンスターチ、アルギン酸ナトリウム等の崩壊剤、タルク、ステアリン酸マグネシウム、ステアリン酸ナトリウム等の滑沢剤、炭酸カルシウム、炭酸ナトリウム、リン酸カルシウム、リン酸ナトリウム等の充填剤又は希釈剤等と適宜混合して製造することができる。錠剤等は、必要に応じて、ヒドロキシプロピルメチルセルロース、白糖、ポリエチレングリコール、酸化チタン等のコーティング剤を用いて、糖衣、ゼラチン、腸溶被覆、フイルムコーティング等を施してもよい。   When the anticancer agent of the present invention is used as a solid preparation such as a tablet, pill, powder, powder, granule or the like, the metal complex is converted into an appropriate additive according to a conventional method such as lactose, sucrose, D-mannitol, Corn starch, synthetic or natural gum, excipients such as crystalline cellulose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, gelatin, polyvinylpyrrolidone and other binders, carboxymethylcellulose calcium, carboxymethylcellulose Mix appropriately with disintegrants such as sodium, starch, corn starch, sodium alginate, lubricants such as talc, magnesium stearate, sodium stearate, fillers or diluents such as calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate Shi It can be produced. Tablets and the like may be subjected to sugar coating, gelatin, enteric coating, film coating, and the like using a coating agent such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, titanium oxide or the like, if necessary.

この発明の抗癌剤を注射剤、点眼剤、点鼻剤、吸入剤、噴霧剤、ローション剤、シロップ剤、液剤、懸濁剤、乳剤等の液状製剤とする場合には、前記金属錯体を、精製水、リン酸緩衝液等の適当な緩衝液、生理的食塩水、リンゲル溶液、ロック溶液等の生理的塩類溶液、カカオバター、ゴマ油、オリーブ油等の植物油、鉱油、高級アルコール、高級脂肪酸、エタノール等の有機溶媒等に溶解して、必要に応じてコレステロール等の乳化剤、アラビアゴム等の懸濁剤、分散助剤、浸潤剤、ポリオキシエチレン硬化ヒマシ油系、ポリエチレングリコール系等の界面活性剤、リン酸ナトリウム等の溶解補助剤、糖、糖アルコール、アルブミン等の安定化剤、パラベン等の保存剤、塩化ナトリウム、ブドウ糖、グリセリン等の等張化剤、緩衝剤、無痛化剤、吸着防止剤、保湿剤、酸化防止剤、着色剤、甘味料、フレーバー、芳香物質等を適宜添加することにより、滅菌された水溶液、非水溶液、懸濁液、リポソーム又はエマルジョン等として調製できる。この際、注射剤は、生理学的なpH、具体的にはpH6〜8の範囲であることが好ましい。   When the anticancer agent of the present invention is a liquid preparation such as an injection, eye drop, nasal drop, inhalant, spray, lotion, syrup, solution, suspension, emulsion, etc., the metal complex is purified. Water, suitable buffer solution such as phosphate buffer, physiological saline solution, Ringer solution, physiological salt solution such as lock solution, vegetable oil such as cocoa butter, sesame oil, olive oil, mineral oil, higher alcohol, higher fatty acid, ethanol, etc. In an organic solvent or the like, if necessary, an emulsifier such as cholesterol, a suspension agent such as gum arabic, a dispersion aid, a wetting agent, a surfactant such as polyoxyethylene hydrogenated castor oil type, polyethylene glycol type, Solubilizers such as sodium phosphate, stabilizers such as sugar, sugar alcohol and albumin, preservatives such as parabens, isotonic agents such as sodium chloride, glucose and glycerin, buffers, painless It can be prepared as a sterilized aqueous solution, non-aqueous solution, suspension, liposome, emulsion, etc. by appropriately adding an agent, adsorption inhibitor, moisturizer, antioxidant, colorant, sweetener, flavor, fragrance, etc. . At this time, the injection preferably has a physiological pH, specifically a pH range of 6-8.

この発明の抗癌剤を、ローション剤、クリーム剤、軟膏等の半固形製剤とする場合には、前記金属錯体を脂肪、脂肪油、ラノリン、ワセリン、パラフィン、蝋、硬膏剤、樹脂、プラスチック、グリコール類、高級アルコール、グリセリン、水、乳化剤、懸濁化剤等と適宜混和することにより製造することができる。   When the anticancer agent of this invention is a semi-solid preparation such as a lotion, cream, ointment, the metal complex is a fat, fatty oil, lanolin, petrolatum, paraffin, wax, plaster, resin, plastic, glycols It can be produced by appropriately mixing with higher alcohol, glycerin, water, emulsifier, suspending agent and the like.

なお、この発明の抗癌剤は公知のDDS技術、例えば、この発明の抗癌剤をリポソームなどの運搬体に封入して、体内投与してもよい。この場合、標的部位の細胞を特異的に認識する運搬体などを利用すれば、この発明の造影剤を標的部位に効率よく運ぶことができる。   The anticancer agent of the present invention may be administered in the body by enclosing the anticancer agent of the present invention in a carrier such as a liposome, for example, a known DDS technique. In this case, if a carrier that specifically recognizes cells at the target site is used, the contrast agent of the present invention can be efficiently delivered to the target site.

(3)含有量、投与量等
の発明の抗癌剤に含まれる金属錯体の含有量は、投与形態、重篤度や目的とする投与量などによって任意に調整すればよい。また、この発明の抗癌剤の投与量は、例えば患者の年齢、性別、体重、症状、及び投与経路などの条件に応じて適宜医者が決定すればよい。
(3) Content, dosage, etc.
The content of the metal complex contained in the anticancer agent of this invention, the dosage form may be adjusted arbitrarily by such dosage to severity and purposes. In addition, the dose of the anticancer agent of the present invention may be appropriately determined by a doctor according to conditions such as the age, sex, weight, symptoms, and administration route of the patient.

なお、この発明の抗癌剤は、既知の化学療法、外科的治療法、放射線療法、温熱療法や免疫療法などと組合せてもよい。   The anticancer agent of the present invention may be combined with known chemotherapy, surgical treatment, radiation therapy, hyperthermia or immunotherapy.

以下、この発明について実施例に基づいてより詳細に説明する。なお、この発明の特許請求の範囲は、以下の実施例によって如何なる意味においても制限されない。   Hereinafter, the present invention will be described in more detail based on examples. The claims of the present invention are not limited in any way by the following examples.

1.複素環化合物の製造
この発明の抗癌剤を構成する複素化合物であるH-dpaqH,esterを図1の合成経路に沿って合成した。なお、理解しやすくするため、以下の説明では、同じ化合物については図1と同じ記号を使用した。
1. Production of heterocyclic compound H-dpaq H, ester , which is a heterocyclic compound constituting the anticancer agent of the present invention, was synthesized along the synthetic route of FIG. In addition, in order to make it easy to understand, in the following description, the same symbol as FIG. 1 was used about the same compound.

(1)6-hydroxy-8-nitroquinoline(以下、化合物bと省略する。)の合成
反応容器に4-amino-3-nitrophenol 5.0 g (化合物a、32 mmol) 、濃塩酸 40 mL及び濃リン酸 15 gを加えて80℃まで加熱したのち、acrolein 6.5 mL (97 mmol) をゆっくりと加えた。4時間反応させたのち、反応液を室温まで放冷して、蒸留水を加え、Celite(Celite Corporation)で濾過した。濾液をアンモニア水で中和して、赤色の沈殿物を得た。その沈殿物を濾取して、真空乾燥し、赤色固体を得た(収量:3.0 g、収率:49%)。
(1) Synthesis of 6-hydroxy-8-nitroquinoline (hereinafter abbreviated as compound b) 4-amino-3-nitrophenol 5.0 g (compound a, 32 mmol), concentrated hydrochloric acid 40 mL and concentrated phosphoric acid in a reaction vessel After adding 15 g and heating to 80 ° C., 6.5 mL (97 mmol) of acrolein was slowly added. After reacting for 4 hours, the reaction solution was allowed to cool to room temperature, distilled water was added, and the mixture was filtered through Celite (Celite Corporation). The filtrate was neutralized with aqueous ammonia to obtain a red precipitate. The precipitate was collected by filtration and dried in vacuo to give a red solid (yield: 3.0 g, yield: 49%).

(2)Ethyl[(8-nitroquino-6-yloxy)acetate] (以下、化合物cと省略する。)の合成
反応容器に化合物b 2.8 g (15 mmol)及びK2CO3 4.1 g (29 mmol) を加え、嫌気条件下にしたのち、脱水アセトン 100 mLを加えた。さらに、ethyl bromoacetate 3.7 g (22 mmol) を滴下し、室温で一晩撹拌した。反応液をCeliteで濾過して、濾液を濃縮してからアルミナカラムで精製し、淡黄色の固体を得た(収量: 1.0 g、収率:25%)。
(2) Synthesis of Ethyl [(8-nitroquino-6-yloxy) acetate] (hereinafter abbreviated as compound c) Compound b 2.8 g (15 mmol) and K 2 CO 3 4.1 g (29 mmol) in a reaction vessel Was added under anaerobic conditions, and 100 mL of dehydrated acetone was added. Further, 3.7 g (22 mmol) of ethyl bromoacetate was added dropwise and stirred overnight at room temperature. The reaction solution was filtered through Celite, and the filtrate was concentrated and then purified with an alumina column to obtain a pale yellow solid (yield: 1.0 g, yield: 25%).

(3)Ethyl[(8-aminoquino-6-yloxy)acetate] (以下、化合物dと省略する。)の合成
反応容器に化合物c 0.96 g (3.5mmol)及び10% Pd-C 0.096 gを加え、窒素雰囲気下にして、ジクロロメタン 40 mL及びエタノール 80 mLを加えて溶解したのち、水素雰囲気下で一晩撹拌した。反応液をCeliteで濾過して、濾液を濃縮し、淡黄色固体を得た(収量: 0.84 g 、収率: 98%)。
(3) Synthesis of Ethyl [(8-aminoquino-6-yloxy) acetate] (hereinafter abbreviated as Compound d) Compound c 0.96 g (3.5 mmol) and 10% Pd-C 0.096 g were added to a reaction vessel, Under a nitrogen atmosphere, 40 mL of dichloromethane and 80 mL of ethanol were added and dissolved, and then the mixture was stirred overnight under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain a pale yellow solid (yield: 0.84 g, yield: 98%).

(4)H-dpaqH,ester(化合物e)の合成
反応容器に化合物d 0.80 g (3.3 mmol) 及びNa2CO3 0.41 g (3.9 mmol) を加え、窒素雰囲気下にして、脱水アセトニトリル 50 mLに溶解した。反応容器を撹拌しながら氷浴により0℃にし、bromoacetyl bromide 0.34 mL (3.9 mmol) を滴下した。滴下を始めてから20分後、生じた淡黄色固体をジクロロメタンに溶解した。反応液をCeliteで濾過して、濾液を濃縮し、オレンジ色の固体を得た。
(4) Synthesis of H-dpaq H, ester (Compound e) Add 0.80 g (3.3 mmol) of compound d and 0.41 g (3.9 mmol) of Na 2 CO 3 to the reaction vessel, put under nitrogen atmosphere, and add 50 mL of dehydrated acetonitrile. Dissolved in. The reaction vessel was stirred at 0 ° C. with an ice bath, and 0.34 mL (3.9 mmol) of bromoacetyl bromide was added dropwise. Twenty minutes after the start of dropping, the resulting pale yellow solid was dissolved in dichloromethane. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give an orange solid.

反応容器に得られたN-acetylbromide-N-2-quinoline-2-carboxamide、 Na2CO3 0.41 g (3.9 mmol)及び2,2-dipicolylamine 0.78 g (3.9 mmol) を加え、窒素雰囲気下にして、脱水アセトニトリル 50 mLに溶解させたのち、一晩撹拌した。反応液をCeliteで濾過して、濾液を濃縮したのち、アルミナカラムで精製すると、淡黄色の固体を得た(収量: 0.95 g 、収率: 60%)。なお、この化合物は核磁気共鳴分光法(1H NMR及び13C NMR)、フーリエ変換赤外分光光度計(FT-IR) の測定結果から同定した。その結果を以下に示す。 Add the obtained N-acetylbromide-N-2-quinoline-2-carboxamide, 0.41 g (3.9 mmol) of Na 2 CO 3 and 0.78 g (3.9 mmol) of 2,2-dipicolylamine to the reaction vessel, and put under nitrogen atmosphere. After dissolving in 50 mL of dehydrated acetonitrile, the mixture was stirred overnight. The reaction solution was filtered through Celite, and the filtrate was concentrated and purified by an alumina column to obtain a pale yellow solid (yield: 0.95 g, yield: 60%). This compound was identified from the measurement results of nuclear magnetic resonance spectroscopy ( 1 H NMR and 13 C NMR) and Fourier transform infrared spectrophotometer (FT-IR). The results are shown below.

1H NMR (500 MHz, CDCl3): 1.30 (t, J = 7.2 Hz, CH2CH3, 3H), 2.84 (s, -CH3, 3H), 3.51 (s, CH2CO, 2H), 3.98 (s, CH2Py, 4H), 4.26 (q, J = 7.2 Hz, -CH2CH3, 2H), 4.73 (s, CH2, 2H), 6.78 (d, J = 2.6 Hz, Qu7, 1H), 7.15 (dd, J = 7.6, 5.2 Hz, Py5, 2H), 7.35 (d, J = 8.6 Hz, Qu3, 1H), 7.62 (dd, J = 7.6, 7.6 Hz, Py4, 2H), 7.96 (d, J = 8.6 Hz, Qu4, 1H), 7.97 (t, J = 7.6 Hz, Py3, 2H), 8.52 (d, J = 5.2 Hz, Py6, 2H), 8.59 (d, J = 2.6 Hz, Qu5, 1H), 11.66 (s, -NHCO-, 1H). 13C NMR (125 MHz, CDCl3): 14.4 (CH2CH3), 25.1 (CH3), 59.7 (-CH2CO-), 61.3 (-CH2Py), 61.6 (CH2CH3), 65.8 (-CH2-), 101.8 (Qu7), 108.5 (Qu5), 122.6 (Py5), 123.1 (Qu3), 123.3 (Py3), 127.0 (Qu9), 135.1 (Qu10), 135.2 (Qu8), 135.7 (Qu4), 136.8 (Py4), 149.3 (Py6), 155.0 (Qu2), 156.1 (Qu6), 158.5 (Py2), 169.0 (-CO-), 169.8 (-NHCO-). FT-IR (ATR): 3300 cm-1 (N-H (amido)), 1757 cm-1 (C=O (ester)), 1682 cm-1 (C=O (amido)). 1 H NMR (500 MHz, CDCl 3 ): 1.30 (t, J = 7.2 Hz, CH 2 CH 3 , 3H), 2.84 (s, -CH 3 , 3H), 3.51 (s, CH 2 CO, 2H), 3.98 (s, CH 2 Py, 4H), 4.26 (q, J = 7.2 Hz, -CH 2 CH 3 , 2H), 4.73 (s, CH 2 , 2H), 6.78 (d, J = 2.6 Hz, Qu7, 1H), 7.15 (dd, J = 7.6, 5.2 Hz, Py5, 2H), 7.35 (d, J = 8.6 Hz, Qu3, 1H), 7.62 (dd, J = 7.6, 7.6 Hz, Py4, 2H), 7.96 (d, J = 8.6 Hz, Qu4, 1H), 7.97 (t, J = 7.6 Hz, Py3, 2H), 8.52 (d, J = 5.2 Hz, Py6, 2H), 8.59 (d, J = 2.6 Hz, . Qu5, 1H), 11.66 ( s, -NHCO-, 1H) 13 C NMR (125 MHz, CDCl 3): 14.4 (CH 2 CH 3), 25.1 (CH 3), 59.7 (-CH 2 CO-), 61.3 (-CH 2 Py), 61.6 (CH 2 CH 3 ), 65.8 (-CH 2- ), 101.8 (Qu7), 108.5 (Qu5), 122.6 (Py5), 123.1 (Qu3), 123.3 (Py3), 127.0 (Qu9), 135.1 (Qu10), 135.2 (Qu8), 135.7 (Qu4), 136.8 (Py4), 149.3 (Py6), 155.0 (Qu2), 156.1 (Qu6), 158.5 (Py2), 169.0 (-CO-) FT-IR (ATR): 3300 cm -1 (NH (amido)), 1757 cm -1 (C = O (ester)), 1682 cm -1 (C = O (amido) ).

2.金属錯体の製造
実施例1で製造した「H-dpaqH,ester」及び特許文献3に記載の方法で製造した「H-dpaqH,H」、「H-dpaqNO2,H」、「H-dpaqOMe,H」を使用して、この発明の金属錯体を製造した。
2. Production of Metal Complex “H-dpaq H, ester ” produced in Example 1 and “H-dpaq H, H ”, “H-dpaq NO2, H ” produced by the method described in Patent Document 3, “ H-dpaq OMe, H "was used to produce the metal complexes of this invention.

(1)[Mn(dpaqH,H)]ClO4の合成
H-dpaqH,H 100 mg (0.26 mmol) 及びtriethyleamine 40 μL (0.29 mmol) を脱水アセトニトリル2 mLに溶解し、Mn(ClO4)2・6H2O 110 mg (0.31 mmol) を脱水アセトニトリル 0.5 mLに溶解した溶液に窒素雰囲気下で滴下して、一晩撹拌した。生じた沈殿物をメンブレンフィルターで濾取して、真空乾燥し、淡黄色固体を得た(収量: 126 mg 、収率:90%)。なお、この化合物は元素分析装置、フーリエ変換赤外分光光度計(FT-IR) 及び質量分析装置(エレクトロスプレー方式)の測定結果から同定した。その結果を以下に示す。
(1) Synthesis of [Mn (dpaq H, H )] ClO 4
H-dpaq H, H 100 mg (0.26 mmol) and triethyleamine 40 μL (0.29 mmol) are dissolved in 2 mL of dehydrated acetonitrile, and Mn (ClO 4 ) 2 · 6H 2 O 110 mg (0.31 mmol) is dehydrated in 0.5 mL of dehydrated acetonitrile. The solution dissolved in was added dropwise under a nitrogen atmosphere and stirred overnight. The resulting precipitate was collected with a membrane filter and dried in vacuo to give a pale yellow solid (yield: 126 mg, yield: 90%). This compound was identified from the measurement results of an elemental analyzer, a Fourier transform infrared spectrophotometer (FT-IR), and a mass spectrometer (electrospray method). The results are shown below.

Anal. Calcd for [Mn(dpaqH,H)](ClO4)(H2O)0.8: C, 50.11; H, 3.95; N, 12.70. Found: C, 50.19; H, 3.81; N, 12.74. Selected IR frequencies (cm-1, FT-ATR): 1541 (CO). Electronic absorption spectrum in CH3CN (nm (M-1 cm-1)): 375 (4500), 262 (37100). Electronic absorption spectrum in MES buffer (pH 7.2, 5% DMSO) (nm (M-1 cm-1)): 309 (5300), 241 (23800). ESI-MS, positive mode: m/z 437.08 [Mn(dpaqH,H)]+. Anal. Calcd for [Mn (dpaq H, H )] (ClO 4 ) (H 2 O) 0.8 : C, 50.11; H, 3.95; N, 12.70. Found: C, 50.19; H, 3.81; N, 12.74. Selected IR frequencies (cm -1 , FT-ATR): 1541 (CO). Electronic absorption spectrum in CH 3 CN (nm (M -1 cm -1 )): 375 (4500), 262 (37100). Electronic absorption spectrum in MES buffer (pH 7.2, 5% DMSO) (nm (M -1 cm -1 )): 309 (5300), 241 (23800). ESI-MS, positive mode: m / z 437.08 [Mn (dpaq H, H )] + .

(2)[Mn(dpaqNO2,H)]ClO4の合成
H-dpaqNO2,H 100 mg (0.23 mmol)及びtriethyleamine 34 μL (0.25 mmol) を脱水アセトニトリル3.5 mLに溶解し、Mn(ClO4)2・6H2O 99 mg (0.28 mmol) を脱水アセトニトリル 0.5 mLに溶解した溶液に窒素雰囲気下で滴下して、一晩撹拌した。生じた沈殿物をメンブレンフィルターで濾取して、真空乾燥し、オレンジ色の固体を得た (収量: 124 mg、収率:93%)。なお、この化合物は元素分析装置、フーリエ変換赤外分光光度計(FT-IR) 及び質量分析装置(エレクトロスプレー方式)の測定結果から同定した。その結果を以下に示す。
(2) Synthesis of [Mn (dpaq NO2, H )] ClO 4
H-dpaq NO2, H 100 mg (0.23 mmol) and triethyleamine 34 μL of (0.25 mmol) was dissolved in dehydrated acetonitrile 3.5 mL, Mn (ClO 4) 2 · 6H 2 O 99 mg (0.28 mmol) of dehydrated acetonitrile 0.5 mL The solution dissolved in was added dropwise under a nitrogen atmosphere and stirred overnight. The resulting precipitate was collected by filtration with a membrane filter and dried under vacuum to obtain an orange solid (yield: 124 mg, yield: 93%). This compound was identified from the measurement results of an elemental analyzer, a Fourier transform infrared spectrophotometer (FT-IR), and a mass spectrometer (electrospray method). The results are shown below.

Anal. Calcd for [Mn(dpaqNO2,H)](ClO4)(H2O)0.5: C, 46.76; H, 3.41; N, 14.22. Found: C, 47.03; H, 3.26; N, 13.92. Selected IR frequencies (cm-1, FT-ATR): 1533 (CO). Electronic absorption spectrum in CH3CN (nm (M-1 cm-1)): 428 (19100), 322 (3990), 262 (22900). Electronic absorption spectrum in MES buffer (pH 7.2, 5% DMSO) (nm (M-1 cm-1)): 380 (10100), 238 (12000). ESI-MS, positive mode: m/z 482.15 [Mn(dpaqNO2,H)]+. Anal. Calcd for [Mn (dpaq NO2, H )] (ClO 4 ) (H 2 O) 0.5 : C, 46.76; H, 3.41; N, 14.22. Found: C, 47.03; H, 3.26; N, 13.92. Selected IR frequencies (cm -1 , FT-ATR): 1533 (CO). Electronic absorption spectrum in CH 3 CN (nm (M -1 cm -1 )): 428 (19100), 322 (3990), 262 (22900 ). Electronic absorption spectrum in MES buffer (pH 7.2, 5% DMSO) (nm (M -1 cm -1 )): 380 (10100), 238 (12000). ESI-MS, positive mode: m / z 482.15 [ Mn (dpaq NO2, H )] + .

(3)[Mn(dpaqOMe,H)]ClO4の合成
H-dpaqOMe,H 100 mg (0.24 mmol) 及びtriethyleamine 36 μL (0.26 mmol) を脱水アセトニトリル2 mLに溶解し、これをMn(ClO4)2・6H2O 103 mg (0.29 mmol) を脱水アセトニトリル 0.5 mLに溶解した溶液に窒素雰囲気下で滴下して、一晩撹拌した。生じた沈殿物をメンブレンフィルターで濾取して、真空乾燥し、黄色固体を得た(収量: 75 mg、収率:55%)。なお、この化合物は元素分析装置、フーリエ変換赤外分光光度計(FT-IR) 及び質量分析装置(エレクトロスプレー方式)の測定結果から同定した。その結果を以下に示す。
(3) Synthesis of [Mn (dpaq OMe, H )] ClO 4
H-dpaq OMe, H 100 mg (0.24 mmol) and triethyleamine 36 μL (0.26 mmol) were dissolved in 2 mL of dehydrated acetonitrile, and this was dissolved in 103 mL (0.29 mmol) of dehydrated acetonitrile with Mn (ClO 4 ) 2 · 6H 2 O. The solution dissolved in 0.5 mL was added dropwise under a nitrogen atmosphere and stirred overnight. The resulting precipitate was collected with a membrane filter and dried under vacuum to obtain a yellow solid (yield: 75 mg, yield: 55%). This compound was identified from the measurement results of an elemental analyzer, a Fourier transform infrared spectrophotometer (FT-IR), and a mass spectrometer (electrospray method). The results are shown below.

Anal. Calcd for [Mn(dpaqOMe,H)](ClO4)(H2O)0.5: C, 50.06; H, 4.03; N, 12.16. Found: C, 50.22; H, 4.00; N, 12.35. Selected IR frequencies (cm-1, FT-ATR): 1549 (CO). Electronic absorption spectrum in CH3CN (nm (M-1 cm-1)): 405 (3320), 346 (2330), 264 (33200). Electronic absorption spectrum in MES buffer (pH 7.2, 5% DMSO) (nm (M-1 cm-1)): 334 (4270), 248 (29200). ESI-MS, positive mode: m/z 467.19 [Mn(dpaqOMe,H)]+. Anal.Calcd for [Mn (dpaq OMe, H )] (ClO 4 ) (H 2 O) 0.5 : C, 50.06; H, 4.03; N, 12.16.Found: C, 50.22; H, 4.00; N, 12.35. Selected IR frequencies (cm -1 , FT-ATR): 1549 (CO). Electronic absorption spectrum in CH 3 CN (nm (M -1 cm -1 )): 405 (3320), 346 (2330), 264 (33200 ). Electronic absorption spectrum in MES buffer (pH 7.2, 5% DMSO) (nm (M -1 cm -1 )): 334 (4270), 248 (29200). ESI-MS, positive mode: m / z 467.19 [ Mn (dpaq OMe, H )] + .

(4)[Mn(dpaqH,ester)]ClO4の合成
H-dpaqH,ester 100 mg (0.21 mmol) 及びtriethyleamine 32 μL (0.25 mmol) を脱水エタノール50 mLに溶解して、Mn(ClO4)2・6H2O 90 mg (0.25 mmol) を脱水エタノール1 mLに溶解した溶液に窒素雰囲気下で滴下し、一晩撹拌した。生じた沈殿物をメンブレンフィルターで濾取して、真空乾燥し、淡黄色固体を得た(収量: 86 mg 、収率: 65%)。なお、この化合物は元素分析装置、フーリエ変換赤外分光光度計(FT-IR) 及び質量分析装置(エレクトロスプレー方式)の測定結果から同定した。その結果を以下に示す。
(4) Synthesis of [Mn (dpaq H, ester )] ClO 4
H-dpaq H, was dissolved in ester 100 mg (0.21 mmol) and triethyleamine 32 μL (0.25 mmol) of dehydrated ethanol 50 mL, Mn (ClO 4) 2 · 6H 2 O 90 mg (0.25 mmol) of dehydrated ethanol 1 The solution dissolved in mL was added dropwise under a nitrogen atmosphere and stirred overnight. The resulting precipitate was collected by filtration with a membrane filter and vacuum dried to obtain a pale yellow solid (yield: 86 mg, yield: 65%). This compound was identified from the measurement results of an elemental analyzer, a Fourier transform infrared spectrophotometer (FT-IR), and a mass spectrometer (electrospray method). The results are shown below.

ESI-MS, positive mode: m/z 539.14 [Mn(dpaqH,ester)]+. Selected IR frequencies (cm-1, FT-ATR): 1733 (CO (ester)), 1626 (CO (amido)). ESI-MS, positive mode: m / z 539.14 [Mn (dpaq H, ester )] + . Selected IR frequencies (cm -1 , FT-ATR): 1733 (CO (ester)), 1626 (CO (amido)) .

3.細胞毒性評価
実施例2で得られた金属錯体の腫瘍細胞に対する活性(IC50)を、ヒト子宮頸癌由来の癌細胞であるHeLa細胞を使って測定した。なお、シスプラチン(cisplatin、和研薬製)を実験対照として使用した。具体的には以下のようにして測定した。
3. Cytotoxicity Evaluation The activity (IC 50 ) of the metal complex obtained in Example 2 against tumor cells was measured using HeLa cells, which are cancer cells derived from human cervical cancer. Note that cisplatin (manufactured by Wakken Pharmaceutical) was used as an experimental control. Specifically, it measured as follows.

まず、HeLa細胞を10%ウシ胎児血清及び1%抗生物質、抗真菌剤を補足したDulbecco's Modified Eagle培地(DMEM)を含むフラスコに接種し、5%二酸化炭素雰囲気下、湿潤インキュベーター中、37℃で培養した。フラスコ内で培養細胞が、80%コンフルエントに達したら、フラスコ内の細胞をトリプシン処理して、細胞をリン酸緩衝生理食塩水(PBS)で洗浄した。   First, HeLa cells are inoculated into a flask containing Dulbecco's Modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum, 1% antibiotics, and antifungal agents, in a humidified incubator at 37 ° C in a 5% carbon dioxide atmosphere. Cultured. When the cultured cells reached 80% confluence in the flask, the cells in the flask were trypsinized, and the cells were washed with phosphate buffered saline (PBS).

血球計算盤で緩衝液に含まれる細胞数を計数したのち、細胞培養に使用した培地を使用して、5×104細胞/mlの細胞懸濁液を調製した。滅菌96ウェルのマイクロプレートに前記の細胞懸濁液を100μL/ウェルとなるように加えて、37℃で24時間培養した。 After counting the number of cells contained in the buffer with a hemocytometer, a cell suspension of 5 × 10 4 cells / ml was prepared using the medium used for cell culture. The cell suspension was added to a sterile 96-well microplate at 100 μL / well and cultured at 37 ° C. for 24 hours.

次に、実施例2で得られた金属錯体及びシスプラチンの段階希釈水溶液(5%DMSOを含む。)を調製した。この段階希釈水溶液をマイクロプレートの各ウェルに20μLずつ添加し、24時間又は48時間前記の条件下で培養した。   Next, a serially diluted aqueous solution (containing 5% DMSO) of the metal complex and cisplatin obtained in Example 2 was prepared. 20 μL of this serially diluted aqueous solution was added to each well of the microplate, and cultured under the above conditions for 24 hours or 48 hours.

全てのウェル中の培養液を除去したのち、MTT水溶液 (5 mg/mL) を各ウェルに10 μLずつ加えて、マイクロプレートの蓋を閉め、37℃で4時間保温した。蓋をはずして、2N 塩酸水溶液を1%含む2-プロパノール溶液 を100 μL/ウェルとなるように加えて、ホルマザンを溶解させた。   After removing the culture medium in all wells, 10 μL of MTT aqueous solution (5 mg / mL) was added to each well, the microplate lid was closed, and the mixture was incubated at 37 ° C. for 4 hours. The lid was removed, and a 2-propanol solution containing 1% of 2N aqueous hydrochloric acid was added at 100 μL / well to dissolve formazan.

最後に、96 wellプレートリーダーで570 nmの吸光度を測定したのち、これを生存細胞数として評価し、50%細胞発育抑制濃度(IC50)を算出した。なお、IC50値の算出に当たっては、同様に実施した少なくとも5回以上の実験値の平均値を採用した。その結果を表に示す。 Finally, after measuring the absorbance at 570 nm with a 96-well plate reader, this was evaluated as the number of viable cells, and the 50% cell growth inhibitory concentration (IC 50 ) was calculated. In calculating the IC 50 value, an average value of at least five experimental values carried out in the same manner was adopted. The results are shown in Table 1 .

Figure 0006154231
Figure 0006154231

から、[Mn(dpaqH,ester)]ClO4はシスプラチン(cisplatin)よりも高い細胞毒性を有しており、優れた抗癌剤となる可能性が高いことが確認できた。また、シスプラチンには及ばないものの、[Mn(dpaqH,H)]ClO4 、[Mn(dpaqNO2,H)]ClO4及び[Mn(dpaqOMe,H)]ClO4も抗癌剤として使用できる可能性があることが確認できた。 From Table 1 , it was confirmed that [Mn (dpaq H, ester )] ClO 4 has higher cytotoxicity than cisplatin and is likely to be an excellent anticancer agent. [Mn (dpaq H, H )] ClO 4 , [Mn (dpaq NO2, H )] ClO 4 and [Mn (dpaq OMe, H )] ClO 4 can also be used as anticancer agents although they do not reach cisplatin. It was confirmed that there is sex.

Claims (2)

下記一般式(1)で表される金属錯体を有効成分として含有する抗癌剤。
Figure 0006154231
(式中Mは鉄、マンガン又はコバルトの何れかを表す。Xは対イオンを表す、nは1又は2を表す。)
The anticancer agent which contains the metal complex represented by following General formula (1) as an active ingredient.
Figure 0006154231
(In the formula , M represents one of iron, manganese, and cobalt. X represents a counter ion, and n represents 1 or 2.)
Mがマンガンであり、XがClO4 -である請求項1に記載の抗癌剤。 M is manganese, X is ClO 4 - anticancer agents according to the is claim 1.
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