JPS61148187A - Novel platinum complex - Google Patents
Novel platinum complexInfo
- Publication number
- JPS61148187A JPS61148187A JP59271411A JP27141184A JPS61148187A JP S61148187 A JPS61148187 A JP S61148187A JP 59271411 A JP59271411 A JP 59271411A JP 27141184 A JP27141184 A JP 27141184A JP S61148187 A JPS61148187 A JP S61148187A
- Authority
- JP
- Japan
- Prior art keywords
- platinum
- dichloro
- cis
- dihydroxy
- trans
- 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
Abstract
Description
【発明の詳細な説明】 ！ の１ 本発明の新規白金錯体は、制癌剤として有用である。[Detailed description of the invention] ! No. 1 The novel platinum complex of the present invention is useful as an anticancer agent.
支釆立且五
ローゼンベルグらによるシスプラチン（ＣＤＤＰ）の抗
腫瘍活性の発見 ［Ｎａｔｕｒｅ、ツユ、 ３８５ （
１９８９）］以来、抗腫瘍活性を有する白金錯体の研究
が盛んに行われるようになってきた（特公昭５９−５５
９９．特開昭５７−７７６９４等）。Discovery of antitumor activity of cisplatin (CDDP) by Rosenberg et al. [Nature, Tsuyu, 385 (
1989)], research on platinum complexes with antitumor activity has been actively conducted since then (Special Publication No. 1989-1989).
99. JP-A-57-77694, etc.).
Ｂ イ ° 。B.
シスプラチン（ＣＤＤＰ）をはじめとする従来の白金錯
体は、幅広い抗腫瘍スペクトラムを有しながら、その致
命的な腎毒性を有しており、そのため、投与総量、適応
症例が制限されている。Although conventional platinum complexes such as cisplatin (CDDP) have a wide antitumor spectrum, they have fatal nephrotoxicity, which limits the total amount of administration and applicable cases.
また、一般に白金錯体は血漿蛋白と結合し、不活性体に
なると言われている。Furthermore, it is generally said that platinum complexes bind to plasma proteins and become inactive.
本発明者らはより優れた抗腫瘍活性を有し、しかも毒性
の少ない白金錯体を見い出すべく種々検討を重ね１次の
ような手段により本発明化合物を合成し、問題点を解決
した。The present inventors conducted various studies in order to find a platinum complex having superior antitumor activity and less toxicity, and synthesized the compound of the present invention by the following method to solve the problems.
。 ° −の
本発明者らはプラチナム（ＩＩ）ポタシウムクロライド
と２−アミノメチルピロリジン誘導体とを反応させ、シ
ス−ジクロロ（２−アミノメチルピロリジン）プラチナ
ム（ＩＦ）誘導体とし、次いで、これを過酸化水素と反
応させることにより、シス−ジクロロ−トランス−ジヒ
ドロキシ（２−アミノメチルピロリジン）プラチナム（
ＩＶ）誘導体を合成し、前記の問題点を解決した。. ° - The present inventors reacted platinum (II) potassium chloride with a 2-aminomethylpyrrolidine derivative to form a cis-dichloro(2-aminomethylpyrrolidine)platinum (IF) derivative, which was then converted into a hydrogen peroxide By reacting with cis-dichloro-trans-dihydroxy(2-aminomethylpyrrolidine)platinum (
IV) A derivative was synthesized to solve the above problems.
本発明の白金錯体として具体的には、例えばシス−ジク
ロロ−トランス−ジヒドロキシ［２−（１−アミノエチ
ル）ピロリジン］プラチナム（■）。Specifically, the platinum complex of the present invention is, for example, cis-dichloro-trans-dihydroxy[2-(1-aminoethyl)pyrrolidine]platinum (■).
シス−ジクロロ−トランス−ジヒドロキシ（２−アミノ
メチル−１−メチルピロリジン）プラチナム（ＩＶ）
、 シス−ジクロロ−トランス−ジヒドロキシ（２−ア
ミノメチル−１−エチルピロリジン）プラチナム（ＩＶ
） 、 シス−ジクロロ−トランス−ジヒドロキシ（２
−アミノメチル−１，５−ジメチルピロリジン）プラチ
ナム（ｆＶ）等である。cis-dichloro-trans-dihydroxy(2-aminomethyl-1-methylpyrrolidine)platinum(IV)
, cis-dichloro-trans-dihydroxy(2-aminomethyl-1-ethylpyrrolidine)platinum(IV
), cis-dichloro-trans-dihydroxy (2
-aminomethyl-1,5-dimethylpyrrolidine) platinum (fV), and the like.
１月
このようにして得られた本発明化合物は、優れた抗腫瘍
活性を有し、しかも毒性が低く、水溶性が高いため医薬
としてきわめて有用である。The compound of the present invention thus obtained has excellent antitumor activity, low toxicity, and high water solubility, making it extremely useful as a medicine.
Ｌ１旦
（イ） プラチナム（ＩＩ）ポタシウムクロライド ４
゜１５ｇ（０，０１モル）を水１００１に溶解し、若干
の不溶物をろ過により除いた後、２−（１−アミノエチ
ル）ピロリジン １．１４ｇ（０，０ｆモル）を水１０
１に溶解した溶液を加え、室温で１日撹拌する。L1 Dan (A) Platinum (II) Potassium Chloride 4
゜15 g (0.01 mol) was dissolved in 100 ml of water, some insoluble matter was removed by filtration, and 1.14 g (0.0 f mol) of 2-(1-aminoethyl)pyrrolidine was dissolved in 10 ml of water.
Add a solution dissolved in 1 and stir at room temperature for 1 day.
生成した固体をろ取し、水洗後、６０℃で３時間域圧下
乾燥し、灰白色のシス−ジクロロ［２−（１−アミノエ
チル）ピロリジンコプラチナム（Ｉｆ）２゜７６ｇ（収
率７３％）を得た。融点２８０〜３１０℃（分解）。The generated solid was collected by filtration, washed with water, and dried under pressure at 60°C for 3 hours to obtain 2°76 g of off-white cis-dichloro[2-(1-aminoethyl)pyrrolidine coplatinum (If) (yield 73%). I got it. Melting point 280-310°C (decomposition).
この１．９０ｇ（０，０５モル）を水３１に懸濁し、同
温度で３０分、次いで８０℃で１時間反応させる。冷機
、生成した固体をろ取し水洗した後、６０℃で３時間域
圧下乾燥し、白色のシス−ジクロロ−トランス−ジヒド
ロキシ［２−（１−アミノエチル）ピロリジン］プラチ
ナム（■）（化合物Ｎｏ。This 1.90 g (0.05 mol) is suspended in water 31 and reacted at the same temperature for 30 minutes and then at 80° C. for 1 hour. After filtering the generated solid in a cold machine and washing it with water, it was dried under pressure at 60°C for 3 hours to obtain white cis-dichloro-trans-dihydroxy[2-(1-aminoethyl)pyrrolidine]platinum (■) (compound No. .
１）０．８５ｇ（収率３１％）を得た。融点３００℃以
上。1) 0.85g (yield 31%) was obtained. Melting point 300℃ or higher.
元素分析値 分子式ＣＢＨ１６Ｃ１２Ｎ２０□Ｐｔとし
てＣＨＮ
理論値（％） １７，３９ ３，８９６．７６実測
値（％） １７．２７ ３．７８ Ｂ、６８Ｉ
ＲｖＫＢ’ｃｍ、−” ：５４５ （Ｐｔ −０）ｉ
＋ａｘ
上記と同様にして以下の化合物を得た。Elemental analysis value CHN as molecular formula CBH16C12N20□Pt Theoretical value (%) 17,39 3,896.76 Actual value (%) 17.27 3.78 B, 68I
RvKB'cm, -" :545 (Pt -0)i
+ax The following compounds were obtained in the same manner as above.
（ロ）シス−ジクロロ−トランス−ジヒドロキシ（２−
アミノメチル−１−メチルピロリジン）プラチナム（■
）（化合物Ｎｏ、２）（収率６７％）白色粉末。融点２
２５〜２３２℃（分解）。(b) cis-dichloro-trans-dihydroxy (2-
Aminomethyl-1-methylpyrrolidine) platinum (■
) (Compound No. 2) (Yield 67%) White powder. Melting point 2
25-232°C (decomposition).
元素分析値 分子式Ｃ３Ｈ１６Ｃ１２Ｎ２０２Ｐｔとし
てＣＨＮ
理論値（％） １７，３９ ３，８９ ６．７６
実測値（％） １７，０９ ３．８１ Ｂ、５
９ＩＲｖＫＢ’ｃｗｓ−” ：５４０ （Ｐｔ −０
）腸ａｒ
（ハ）シス−ジクロロ−トランス−ジヒドロキシ（２−
アミノメチル−１−エチルピロリジン）プラチナム（■
）（化合物Ｎｏ、３）（収率７５％）黄色粉末。融点１
８３〜１８５℃（分解）。Elemental analysis value CHN as molecular formula C3H16C12N202Pt Theoretical value (%) 17,39 3,89 6.76
Actual value (%) 17.09 3.81 B, 5
9IRvKB'cws-" :540 (Pt-0
) intestinal ar (c) cis-dichloro-trans-dihydroxy (2-
Aminomethyl-1-ethylpyrrolidine) platinum (■
) (Compound No. 3) (Yield 75%) Yellow powder. Melting point 1
83-185°C (decomposition).
元素分析値 分子式Ｃ７Ｈｉｓ Ｃ１□Ｎ２０□ｐｔと
してＣＨＮ
理論値（％） １９．６３ ４，２４ ６．５４
実測値（％） １９．７０ ４．１Ｂ ６．５
１１ＲｖＫＢ’ｃｔａ−’ ：５３０（Ｐｔ −０）
ａｘ
（ニ）シス−ジクロロ−トランス−ジヒドロキシ（２−
アミノメチル−１，５−ジメチルピロリジン）プラチナ
ム（■）（化合物Ｎｏ、４）（収率５３％）淡黄色粉末
。融点１９９〜２０１’Ｃ（分解）。Elemental analysis value Molecular formula C7His CHN as C1□N20□pt Theoretical value (%) 19.63 4,24 6.54
Actual value (%) 19.70 4.1B 6.5
11RvKB'cta-': 530 (Pt-0)
ax (d)cis-dichloro-trans-dihydroxy(2-
Aminomethyl-1,5-dimethylpyrrolidine) platinum (■) (Compound No. 4) (Yield 53%) Pale yellow powder. Melting point 199-201'C (decomposed).
元素分析値 分子式 Ｃ７ＨｔｓＣｌ□Ｎ２０２Ｐｔと
してＣＨＮ
理論値（％） １９．６３ ４．２４ ６．５４
実／ＩＩＩ値（％） １９．８０ ４．１７
Ｅ３．２５ＩＲシＫＢ’ｃ＋ｇ−’ ：５３５（Ｐ
ｔ −０）ａＸ
災」Ｌ伝
Ｃｏ１ｏｎ ２６ ｃａｒｃｌｎｏｉ＋ａに対するＩｎ
ｖｊｖｏ抗腫瘍試験腫瘍片を移植し、その４日日、６
日目、８日目に４０ ｍｇ／ ｋｇの薬物を腹腔内に投
与し、腫瘍移植後１４日目間腫瘍重量を測定して、増殖
阻止率（ＧＩＲ％）を求めた。Elemental analysis value Molecular formula CHN as C7HtsCl□N202Pt Theoretical value (%) 19.63 4.24 6.54
Actual/III value (%) 19.80 4.17
E3.25IR KB'c+g-':535(P
t -0)a
vjvo anti-tumor test Tumor pieces were transplanted, and on the 4th day, 6
On day 8, 40 mg/kg of the drug was administered intraperitoneally, and the tumor weight was measured for 14 days after tumor implantation to determine the growth inhibition rate (GIR%).
ＧＩＲ（％）＝＋×１００（％）
ここで、ＣおよびＴは、各々対照群および薬物投与群の
平均腫瘍重量を表わす。GIR (%) = + x 100 (%) Here, C and T represent the average tumor weights of the control group and drug administration group, respectively.
結果を表１に示した。The results are shown in Table 1.
表１ 、 ｑｏｌｏｎ ２６ ｃａｒｃｉｎｏｉｅａ
に対する抗腫瘍活性本発明化合物は、優れた抗腫瘍
活性をイ１°し、毒性が低く、水溶性が高いため制癌剤
として宵月である。Table 1, qolon 26 carcinoiea
The compound of the present invention has excellent antitumor activity, low toxicity, and high water solubility, making it a promising candidate as an anticancer agent.
Claims (1)
って水素原子、メチル基又はエチル基を示す。ただし、
Ｒ＿１、Ｒ＿２、Ｒ＿３は同時に水素原子となることは
ない。）で表わされる新規白金錯体。[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, and R_3 are the same or different and represent a hydrogen atom, a methyl group, or an ethyl group. However,
R_1, R_2, and R_3 never become hydrogen atoms at the same time. ) A novel platinum complex represented by
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59271411A JPS61148187A (en) | 1984-12-22 | 1984-12-22 | Novel platinum complex |
| CA000489925A CA1256115A (en) | 1984-09-12 | 1985-09-03 | Platinum complexes |
| HU853419A HU193809B (en) | 1984-09-12 | 1985-09-10 | Process for producing new platinum complexes |
| EP85111497A EP0176005B1 (en) | 1984-09-12 | 1985-09-11 | Novel platinum complexes |
| DE8585111497T DE3581346D1 (en) | 1984-09-12 | 1985-09-11 | PLATINUM COMPLEXES. |
| AT85111497T ATE60059T1 (en) | 1984-09-12 | 1985-09-11 | PLATINUM COMPLEXES. |
| KR1019850006653A KR930005261B1 (en) | 1984-09-12 | 1985-09-11 | Process for producing new platinium complexes |
| CN85107559.2A CN1005337B (en) | 1984-12-22 | 1985-10-15 | Preparation of novel platinum complexes |
| US07/165,404 US4822892A (en) | 1984-09-12 | 1988-02-24 | N-heterocyclic platinum complexes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59271411A JPS61148187A (en) | 1984-12-22 | 1984-12-22 | Novel platinum complex |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS61148187A true JPS61148187A (en) | 1986-07-05 |
Family
ID=17499668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59271411A Pending JPS61148187A (en) | 1984-09-12 | 1984-12-22 | Novel platinum complex |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61148187A (en) |
-
1984
- 1984-12-22 JP JP59271411A patent/JPS61148187A/en active Pending
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