JPH0689010B2 - Process for producing di-μ-hydroxoplatinum (II) binuclear complex nitrate - Google Patents
Process for producing di-μ-hydroxoplatinum (II) binuclear complex nitrateInfo
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- JPH0689010B2 JPH0689010B2 JP3353183A JP35318391A JPH0689010B2 JP H0689010 B2 JPH0689010 B2 JP H0689010B2 JP 3353183 A JP3353183 A JP 3353183A JP 35318391 A JP35318391 A JP 35318391A JP H0689010 B2 JPH0689010 B2 JP H0689010B2
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- compound
- hydroxoplatinum
- platinum
- nitrate
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Description
【０００１】[0001]
【産業上の利用分野】本発明は、ジ−μ−ヒドロキソ白
金（II）二核錯体硝酸塩の新規な製造方法に関する。FIELD OF THE INVENTION The present invention relates to a novel process for producing di-μ-hydroxoplatinum (II) binuclear complex nitrate.
【０００２】[0002]
【従来の技術】シスジアンミンジクロロ白金（II）錯体
の抗腫瘍活性をローゼンバーグ（ B.Rosenberg）が報告
して以来、多くのジアミン白金（II）錯体の抗腫瘍活性
の検索が行なわれている。シスジアンミンジクロロ白金
（II）錯体は、現在、切れ味の鋭い抗腫瘍剤として、米
国、欧州、日本などで臨床に使用されている。BACKGROUND OF THE INVENTION Since B. Rosenberg reported the antitumor activity of cis-diamminedichloroplatinum (II) complexes, many diamineplatinum (II) complexes have been searched for their antitumor activity. . The cis diammine dichloroplatinum (II) complex is currently clinically used as a sharp antitumor agent in the United States, Europe, Japan and the like.
【０００３】しかし、シスジアンミンジクロロ白金（I
I）錯体は腎毒性が強く、これが投与量を制限する因子
（Dose limiting factor）となっている。このような腎
毒性が生ずる原因については、現在のところ不明である
が、白金（II）錯体の腎排泄を促進させることにより、
腎毒性が軽減できることから、新しい抗腫瘍剤として水
溶性の高い白金（II）錯体が注目されている。However, cis diammine dichloroplatinum (I
I) Complex has a strong nephrotoxicity, which is a dose limiting factor. The cause of such nephrotoxicity is unknown at present, but by promoting renal excretion of platinum (II) complex,
A highly water-soluble platinum (II) complex is attracting attention as a new antitumor agent because it can reduce renal toxicity.
【０００４】一方、ファギアニ（R.Faggiani）らは、On the other hand, R. Faggiani et al.
【化３】 で表されるジ−μ−ヒドロキソビス［ジアンミン白金
（II）］二硝酸塩を合成した。 この白金（II）錯体
は、白金錯体（II）の研究歴史上初めて合成されたもの
であり、その特異な構造が注目を浴びている。[Chemical 3] A di-μ-hydroxobis [diammineplatinum (II)] dinitrate represented by This platinum (II) complex was synthesized for the first time in the history of research on platinum complex (II), and its unique structure has attracted attention.
【０００５】ファギアニの見出した上記白金（II）錯体
は、水に難溶性であり、毒性も強いことからそれ以上の
詳しい研究は行なわれていないが、これと構造的に類似
する次の式（I）The above-mentioned platinum (II) complex found by Faguiani is sparingly soluble in water and highly toxic, and thus no further detailed studies have been conducted. I)
【０００６】[0006]
【化４】 （式中、Ｒ1およびＲ2はそれぞれアルキル基を示すか、
一緒になってアルキレン基を示す）[Chemical 4] (In the formula, R 1 and R 2 each represent an alkyl group,
Together they represent an alkylene group)
【０００７】で表される化合物には水溶性の高い化合物
も存在することを本発明者らは見出している。The present inventors have found that a compound represented by the formula (1) also has a high water solubility.
【０００８】[0008]
【発明が解決しようとする課題】しかしながら、フィギ
アニらのジ−μ−ヒドロキソ白金（II）二核錯体を製造
する方法は、シスジクロロジアンミン白金（II）に硝酸
銀を作用させた後、これに水酸化ナトリウムを作用させ
て二核化する方法（R. Faggiani et al., J. Amer. Che
m. Soc., 99 777(1977)）であるため、最終化合物が水
に易溶の場合、同時に生成する硝酸ナトリウム塩と最終
化合物との分離が難しく、収率が極めて低いという欠点
があり、白金（II）錯体の製造および研究の上での隘路
となっていた。However, the method for producing the di-μ-hydroxoplatinum (II) binuclear complex of Figiani et al. Is such that silver nitrate is allowed to act on cisdichlorodiammineplatinum (II) and then water is added thereto. A method of dinuclearization by the action of sodium oxide (R. Faggiani et al., J. Amer. Che
m. Soc., 99 777 (1977)), there is a drawback that when the final compound is easily soluble in water, it is difficult to separate the sodium nitrate salt simultaneously produced from the final compound, and the yield is extremely low. It has been a bottleneck in the production and research of platinum (II) complexes.
【０００９】したがって、ジ−μ−ヒドロキソ白金（I
I）二核錯体を効率良く製造する方法の開発が強く望ま
れていた。Therefore, di-μ-hydroxoplatinum (I
I) It was strongly desired to develop a method for efficiently producing a binuclear complex.
【００１０】[0010]
【課題を解決するための手段】本発明者らは、前記の式
（I）で表されるジ−μ−ヒドロキソ白金（II）二核錯
体の製造方法に関し、鋭意研究を行なった結果、一般式
（II）DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies on a method for producing a di-μ-hydroxoplatinum (II) binuclear complex represented by the above formula (I), and as a result, Formula (II)
【化５】 （式中、Ｒ1およびＲ2は前記した意味を有する）で表さ
れる白金（II）化合物硫酸塩にバリウム化合物を作用さ
せることによりこの白金（II）化合物は二核化し、更に
これをイオン交換に付せば容易にジ−μ−ヒドロキソ白
金（II）二核錯体硝酸塩（I）が得られることを見出
し、本発明を完成した。[Chemical 5] (In the formula, R 1 and R 2 have the above-mentioned meanings.) By reacting a barium compound with a platinum (II) compound sulfate represented by the formula ( 1 ), the platinum (II) compound is binuclearized, and then this is ionized. It was found that the di-μ-hydroxoplatinum (II) binuclear complex nitrate (I) can be easily obtained by exchange, and the present invention was completed.
【００１１】すなわち本発明は、白金（II）化合物硫酸
塩（II）にバリウム化合物を作用させ、次いで、硝酸イ
オン型強塩基性陰イオン交換樹脂でイオン交換すること
を特徴とするジ−μ−ヒドロキソ白金（II）二核錯体硝
酸塩（I）の製造方法である。That is, the present invention is characterized in that a barium compound is allowed to act on a platinum (II) compound sulfate (II), and then ion-exchanged with a nitrate ion type strongly basic anion exchange resin. A method for producing a hydroxoplatinum (II) binuclear complex nitrate (I).
【００１２】本発明方法は、次の式により示される。The method of the present invention is represented by the following equation.
【化６】 （式中、Ｒ1およびＲ2は前記した意味を有する）[Chemical 6] (In the formula, R 1 and R 2 have the meanings described above.)
【００１３】上記式中、基Ｒ1およびＲ2のアルキル基の
具体的な例としては、メチル基、エチル基、プロピル
基、ブチル基等が、またアルキレン基の具体例として
は、エチレン基、１,２−プロピレン基、１,２−ブチレ
ン基、２,３−ブチレン基等が挙げられる。In the above formula, specific examples of the alkyl group of the groups R 1 and R 2 are methyl group, ethyl group, propyl group, butyl group and the like, and specific examples of the alkylene group are ethylene group, Examples thereof include 1,2-propylene group, 1,2-butylene group and 2,3-butylene group.
【００１４】上記反応のうち、式（III）で表される化
合物は、水等の溶媒中で、化合物（II）にバリウム化合
物を徐々に加えて撹拌し、その後適当な時間放置沈澱せ
しめ、更に生成した硫酸バリウムを濾過、分離すること
により調製される。In the above reaction, the compound represented by the formula (III) is gradually added with a barium compound to the compound (II) in a solvent such as water and stirred, and then left to stand for a suitable period of time to precipitate. It is prepared by filtering and separating the produced barium sulfate.
【００１５】バリウム化合物としては、水酸化バリウム
が好ましく利用できる。 なお、本発明の出発原料であ
る白金（II）化合物硫酸塩（II）は、公知の化合物であ
るが、例えば、次式に従い白金（II）化合物ハロゲン塩
（IV）に硫酸銀を反応させることにより製造される。Barium hydroxide can be preferably used as the barium compound. The platinum (II) compound sulfate (II) which is the starting material of the present invention is a known compound. For example, the platinum (II) compound halogen salt (IV) is reacted with silver sulfate according to the following formula. Manufactured by.
【００１６】[0016]
【化７】 （式中、Ｘはハロゲン原子を示し、Ｒ1およびＲ2は前記
した意味を有する）[Chemical 7] (In the formula, X represents a halogen atom, and R 1 and R 2 have the above-mentioned meanings)
【００１７】次いで、得られた化合物（III）は硝酸イ
オン型強塩基性陰イオン交換樹脂に付され、目的物であ
る化合物（I）が得られる。用いることのできる硝酸イ
オン型強塩基性陰イオン交換樹脂としては、例えばアン
バーライトＩＲＡ、ダウエックスＩ×８等の市販品が挙
げられる。Next, the obtained compound (III) is applied to a nitrate ion type strongly basic anion exchange resin to obtain the desired compound (I). Examples of nitrate ion-type strongly basic anion exchange resins that can be used include commercially available products such as Amberlite IRA and Dowex Ix8.
【００１８】以上のようにして得られた本発明のジ−μ
−ヒドロキソ白金（II）二核錯体硝酸塩（I）は、更に
必要により、公知の方法、例えば再結晶法、カラムクロ
マトグラフィー等の手段により生成することもできる。The di-μ of the present invention obtained as described above
The hydroxoplatinum (II) binuclear complex nitrate (I) can be produced, if necessary, by a known method such as a recrystallization method or column chromatography.
【００１９】斯くして得られるジ−μ−ヒドロキソ白金
（II）二核錯体硝酸塩（I）は、後記実施例に示すよう
にそれ自身抗腫瘍活性を有するので抗腫瘍剤として使用
することができる。また、これのみに留まらず、新規な
二核型白金錯体を製造するための中間原料としても使用
することができるものである。The di-μ-hydroxoplatinum (II) binuclear complex nitrate (I) thus obtained has antitumor activity by itself as shown in Examples below, and thus can be used as an antitumor agent. . Moreover, it is not limited to this, and can be used as an intermediate raw material for producing a novel binuclear platinum complex.
【００２０】[0020]
【発明の効果】本発明によれば、抗腫瘍活性が大きくか
つ水溶性の高いジ−μ−ヒドロキソ白金（II）二核錯体
硝酸塩（I）が収率および純度良く得られるので、工業
的に極めて有利なものである。INDUSTRIAL APPLICABILITY According to the present invention, a di-μ-hydroxoplatinum (II) binuclear complex nitrate (I) having a large antitumor activity and a high water solubility can be obtained in good yield and purity, and thus industrially. It is extremely advantageous.
【００２１】[0021]
【実施例】次に、実施例および試験例を挙げ本発明を更
に詳しく説明するが、本発明はこれら実施例等になんら
制約されるものではない。EXAMPLES Next, the present invention will be described in more detail with reference to examples and test examples, but the present invention is not limited to these examples.
【００２２】実 施 例 １ ジ−μ−ヒドロキソ［エチレンジアミン白金（II）］二
硝酸塩の製造：トハラ（S.C.Dhara）らの方法（Indian
J. Chem.,8,193(1970)）で合成したエチレンジアミンジ
ヨード白金（II）５.０９ｇを水２００ｍｌに懸濁し、
硫酸銀３.１１ｇを加え、遮光して１昼夜撹拌する。 生
成したヨウ化銀の沈澱を濾過して除き、濾液に水酸化バ
リウム（８水和物）の結晶２.５ｇを徐々に加えて２時
間撹拌する。 その後、水酸化バリウム（８水和物）の
結晶約０.５ｇを追加して１昼夜放置する。 生成した硫
酸バリウムの沈澱を濾過により除き、濾液を濃縮するこ
とにより白色結晶を得た。 この白色結晶を水１０ｍｌ
に溶解し、硝酸イオン型にした強塩基性陰イオン交換樹
脂１００ｇを充填したカラムに徐々に流し込み、通過し
てきた液を減圧下溶媒留去した。 残渣をメタノール−
水（５：１Ｖ／Ｖ）より再結晶して無色針状結晶とし
て、ジ−μ−ヒドロキソ［エチレンジアミン白金（I
I）］二硝酸塩 ３.８ｇを得た（収率 ５９％）。Example 1 Preparation of di-μ-hydroxo [ethylenediamineplatinum (II)] dinitrate: method of SCDhara et al.
J. Chem., 8,193 (1970)), ethylene diamine diiodo platinum (II) 5.09 g was suspended in 200 ml of water,
Add 3.11 g of silver sulphate and stir for 1 day under light shielding. The formed silver iodide precipitate was removed by filtration, and 2.5 g of crystals of barium hydroxide (octahydrate) were gradually added to the filtrate and the mixture was stirred for 2 hours. Then, about 0.5 g of crystals of barium hydroxide (octahydrate) is added and the mixture is left for one day. The formed barium sulfate precipitate was removed by filtration, and the filtrate was concentrated to give white crystals. 10 ml of this white crystal in water
Was slowly poured into a column filled with 100 g of a strongly basic anion exchange resin in the form of nitrate ion, and the liquid that had passed through was distilled off under reduced pressure. The residue is methanol
The crystals were recrystallized from water (5: 1 V / V) to give colorless needle crystals, and di-μ-hydroxo [ethylenediamine platinum (I
I)] dinitrate 3.8 g was obtained (yield 59%).
【００２３】融 点 ： １９０〜１９５℃ ＩＲ（ヌシ゛ョ-ル）maxｃｍ-1： ３２１６, ３１１６, １０
４８ 元素分析値： 計算値（％）； Ｃ ７.１９, Ｈ ２.７２, Ｎ １２.５
８ 実測値（％）； Ｃ ７.２６, Ｈ ２.８６, Ｎ １２.６
０Melting point: 190 to 195 ° C. IR (nuclear) max cm −1 : 3216, 3116, 10
48 Elemental analysis value: Calculated value (%); C 7.19, H 2.72, N 12.5
8 Found (%); C 7.26, H 2.86, N 12.6
0
【００２４】実 施 例 ２ 水２００ｍｌに対し、１,２−プロパンジアミン・ジヨー
ド白金（II）錯体 ６.９７ｇおよび硫酸銀 ３.１８ｇを
加え、遮光して１昼夜マグネチックスターラーで撹拌し
た。 生成したヨウ化銀の沈澱を濾過して除き、濾液に
水酸化バリウム（８水和物）の結晶２.５ｇを加えて２
時間撹拌した。 その後、溶液のｐＨを測定し、ｐＨが
約６になるまで水酸化バリウムの飽和溶液を追加し、１
昼夜３７℃で放置した。 生成した硫酸バリウムの沈澱
を濾過により除き、濾液を減圧下濃縮して約５ｍｌとし
た。 この濃縮液を硝酸イオン型強塩基性陰イオン交換
樹脂１００ｇを充填したカラムに通し、通過した液を減
圧下溶媒留去した。 残渣にエーテルを加えて結晶を析
出させることにより、ジ−μ−ヒドロキソ［（１,２−
プロパンジアミン）白金（II）］二硝酸塩 ３.１ｇを得
た（収率 ４５％）。Example 2 To 200 ml of water, 6.97 g of 1,2-propanediamine-diiodoplatinum (II) complex and 3.18 g of silver sulfate were added, and the mixture was stirred for one day with a magnetic stirrer while shielded from light. The formed silver iodide precipitate was filtered off, and 2.5 g of barium hydroxide (octahydrate) crystals were added to the filtrate to obtain 2
Stir for hours. After that, measure the pH of the solution, add a saturated solution of barium hydroxide until the pH reaches about 6, and add 1
It was left to stand at 37 ° C all day and night. The formed barium sulfate precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to about 5 ml. The concentrated solution was passed through a column packed with 100 g of a nitrate ion type strongly basic anion exchange resin, and the passing solution was evaporated under reduced pressure. Ether was added to the residue to precipitate crystals, whereby di-μ-hydroxo [(1,2-
3.1 g of propanediamine) platinum (II)] dinitrate was obtained (yield 45%).
【００２５】融 点 ： ２００〜２１０℃ ＩＲ（ヌシ゛ョ-ル）maxｃｍ-1： ３２００, ３０８０, １０
２６ 元素分析値： 計算値（％）； Ｃ １０.３５, Ｈ ３.１９, Ｎ １２.
０７ 実測値（％）； Ｃ ９.９５, Ｈ ３.５１, Ｎ １１.
８１Melting point: 200 to 210 ° C. IR (nuclear) max cm −1 : 3200, 3080, 10
26 Elemental analysis value: Calculated value (%); C 10.35, H 3.19, N 12.
07 Found (%); C 9.95, H 3.51, N 11.
81
【００２６】試 験 例 本発明方法により得られるジ−μ−ヒドロキソ白金（I
I）二核錯体硝酸塩について、その抗腫瘍活性および急
性毒性について以下の方法で試験した結果を表１に示
す。Test Example Di-μ-hydroxoplatinum (I
I) The results of the binuclear complex nitrate tested for its antitumor activity and acute toxicity by the following methods are shown in Table 1.
【００２７】（ 試験方法 ） 抗腫瘍活性：ヒト胃癌細胞をＲＰＭＩ−１６４０培地で
培養し、０.２５％トリプシンを添加して細胞を集め
る。 集めた細胞を１０5細胞／ｍｌに調整して、９６穴
プレートに１００μｌずつまき、３７℃、５％ＣＯ2イ
ンキュベーター内で培養する。２４時間後、１０μＭに
なるように被験化合物を添加し、更に４８時間培養後、
０.４％クリスタルバイオレット １００μｌを添加して
染色し、測定波長５９０ｎｍで吸光度を測定する。 急性毒性：急性毒性試験は、雄性マウスを用い、単回静
脈投与により行なった。(Test method) Antitumor activity: Human gastric cancer cells are cultured in RPMI-1640 medium, and 0.25% trypsin is added to collect the cells. Adjust collected cells to 105 cells / ml, seeded by 100μl in 96 well plates, 37 ° C., and cultured in a 5% CO 2 incubator. After 24 hours, the test compound was added to 10 μM, and after further culturing for 48 hours,
100 μl of 0.4% crystal violet is added for staining, and the absorbance is measured at a measurement wavelength of 590 nm. Acute toxicity: The acute toxicity test was performed by single intravenous administration using male mice.
【００２８】（ 試験結果 ） * 被験化合物は次のものである。 化合物１： シスジクロロジアンミン白金（II） 化合物２： ジ−μ−ヒドロキソ［エチレンジアミン白
金（II）］二硝酸塩（実施例２で合成したもの） 化合物３： ジ−μ−ヒドロキソ［（１,２−プロパン
ジアミン）白金（II）］二硝酸塩（実施例３で合成した
もの） ** 水のみを用いた時の腫瘍細胞の生存率を１００％と
した。(Test result) * Test compounds are as follows. Compound 1: cis-dichlorodiammine platinum (II) Compound 2: di-μ-hydroxo [ethylenediamine platinum (II)] dinitrate (synthesized in Example 2) Compound 3: di-μ-hydroxo [(1,2- Propanediamine) platinum (II)] dinitrate (synthesized in Example 3) ** The survival rate of tumor cells when only water was used was 100%.
Claims (1)
一緒になってアルキレン基を示し、Ｘはハロゲンイオン
を示す）で表される白金（II）化合物硫酸塩にバリウム
化合物を作用させ、次いで、硝酸イオン型強塩基性陰イ
オン交換樹脂でイオン交換することを特徴とする次の式
（I） 【化２】 （式中、Ｒ1およびＲ2は前記した意味を有する）ジ−μ
−ヒドロキソ白金（II）二核錯体硝酸塩の製造方法。1. The following formula (II): (In the formula, R 1 and R 2 each represent an alkyl group,
Together, they represent an alkylene group, and X represents a halogen ion), a barium compound is allowed to act on a platinum (II) compound sulfate represented by the formula (1), and then ion exchange is performed with a nitrate ion type strongly basic anion exchange resin. The following equation (I) is characterized by Where R 1 and R 2 have the meanings given above.
-Method for producing hydroxoplatinum (II) binuclear complex nitrate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3353183A JPH0689010B2 (en) | 1991-12-18 | 1991-12-18 | Process for producing di-μ-hydroxoplatinum (II) binuclear complex nitrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3353183A JPH0689010B2 (en) | 1991-12-18 | 1991-12-18 | Process for producing di-μ-hydroxoplatinum (II) binuclear complex nitrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05163152A JPH05163152A (en) | 1993-06-29 |
| JPH0689010B2 true JPH0689010B2 (en) | 1994-11-09 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3353183A Expired - Fee Related JPH0689010B2 (en) | 1991-12-18 | 1991-12-18 | Process for producing di-μ-hydroxoplatinum (II) binuclear complex nitrate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0689010B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100880804B1 (en) * | 2007-06-12 | 2009-01-30 | 주식회사 케이티앤지 | Health Functional Food Compositions Comprising Red Ginseng Acid Polysaccharide and Lycium Chinense Extract for Improving Hyperlipidemia |
| RU2417999C2 (en) | 2009-07-13 | 2011-05-10 | Закрытое Акционерное Общество "Ива Фарм" | BINUCLEAR COORDINATION COMPOUNDS OF BIOLOGICALLY ACTIVE d-ELEMENTS WITH ALIPHATIC THIOLS AS AGENTS FOR INCREASING EFFICIENCY OF MEDICINAL DRUGS |
-
1991
- 1991-12-18 JP JP3353183A patent/JPH0689010B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05163152A (en) | 1993-06-29 |
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