JPH0569113B2 - - Google Patents
Info
- Publication number
- JPH0569113B2 JPH0569113B2 JP1146186A JP1146186A JPH0569113B2 JP H0569113 B2 JPH0569113 B2 JP H0569113B2 JP 1146186 A JP1146186 A JP 1146186A JP 1146186 A JP1146186 A JP 1146186A JP H0569113 B2 JPH0569113 B2 JP H0569113B2
- Authority
- JP
- Japan
- Prior art keywords
- tumor
- platinum
- aminomethylaziridine
- water
- dichloro
- 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.)
- Expired - Lifetime
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 17
- 229910052697 platinum Inorganic materials 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- AEXCVBXGIHNPIK-UHFFFAOYSA-N aziridin-2-ylmethanamine Chemical compound NCC1CN1 AEXCVBXGIHNPIK-UHFFFAOYSA-N 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
産業上の利用分野
本発明の新規白金錯体は、制癌剤として有用で
ある。
従来の技術
ローゼンベルグらによるシスプラチン
（CDDP）の坑腫瘍活性の発見［Nature.222．385
（1969）］以来、坑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つてきた（特公昭59
−5589、特公昭57−77694等）。
発明が解決しようとする問題点
シスプランチ（CDDP）をはじめとする従来の
白金錯体は、幅広い坑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。
本発明者らはより優れた坑腫瘍活性を有し、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、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。
問題点を解決するための手段
本発明者らはプラチナム（）ポタシウムクロ
ライドと２−アミノメチルアジリジンとを反応さ
せ、シス−ジクロロ（２−アミノメチルアジリジ
ン）プラチナム（）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−アミノメチルア
ジリジン）プラチナム（）合成し、前記の問題
点を解決した。
作 用
このようにして得られた本発明化合物は、優れ
た坑腫瘍活性を有し、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。
実施例
プラムナム（）ポタシウムクロライド4.15ｇ
（0.01モル）を水100mlに溶解し、若干の不溶物を
ろ過により除いた後、２−アミノメチルアジリジ
ン072ｇ（0.01モル）を水20mlに溶解した溶液を
加え、室温で４時間撹拌する。生成した固体をろ
取し、水洗後、60℃で３時間減圧下乾燥し、淡褐
色のシス−ジクロロ（２−アミノメチルアジリジ
ン）プラチナム（）2.82ｇ（収率83％）を得
た。融点260〜280℃（分解）。
この1.69ｇ（0.005モル）を水３mlに懸濁し、
室温撹拌下、31％過酸化水素水10mlを加え、同温
度で30分、次いで80℃で１時間反応させる。冷
後、生成した固体をろ取し水洗したのち、60℃で
３時間減圧下乾燥し、淡褐色のシス−ジクロロ−
トランス−ジヒドロキシ（２−アミノメチルアジ
リジン）プラチナム（）0.56ｇ（収率30％）を
得た。融点220〜240℃（分解）。
元素分析値 分子式C3H10Cl2N2O2Ptとして
Ｃ Ｈ Ｎ
理論値（％） 9.68 2.71 7.53
実測値（％） 9.63 2.71 7.42
IRνKBr naxcm-1：540（Pt−Ｏ）
実験例 ２
Colon 26 carcinomaに対するin vivo坑腫瘍試
験６週令のCDF1／Crj雄性マウスの側腹部皮下
に、１〜２mm3角のColon 26 carcinoma腫瘍片を
移植し、その４日後にほぼ同サイズの腫瘍を担癌
するマウス（１群、５〜６匹）に、所定量の薬物
を腹腔内に投与し、その10日後（腫瘍移植後14日
目）に腫瘍重量を測定して、増殖阻止率（GIR
％）を求めた。
GIR（％）＝Ｃ−Ｔ／Ｃ×100（％）
ここで、ＣおよびＴは、各々対照群および薬物
投与群の平均腫瘍量を表わす。
結果を表１に示した。なお公知化合物CDDP
（シスプラチン）を比較薬物として用いた。
Industrial Application Field The novel platinum complex of the present invention is useful as an anticancer agent. Prior Art Discovery of antitumor activity of cisplatin (CDDP) by Rosenberg et al. [Nature. 222 . 385
(1969)], research on platinum complexes with anti-tumor activity has been actively conducted since
-5589, Special Publication Showa 57-77694, etc.) Problems to be Solved by the Invention Conventional platinum complexes such as cisplanch (CDDP) have a wide anti-tumor spectrum, but they also have fatal nephrotoxicity. is restricted. The present inventors conducted various studies in order to find a platinum complex having superior anti-tumor activity and less toxicity, and synthesized the compound of the present invention by the following means to solve the problems. Means for Solving the Problems The present inventors reacted platinum()potassium chloride and 2-aminomethylaziridine to form cis-dichloro(2-aminomethylaziridine)platinum(), and then peroxidized this. By reacting with hydrogen, cis-dichloro-trans-dihydroxy(2-aminomethylaziridine)platinum () was synthesized to solve the above problems. Effects 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. Example: Pramnum () Potassium Chloride 4.15g
(0.01 mol) was dissolved in 100 ml of water, some insoluble matter was removed by filtration, and a solution of 072 g (0.01 mol) of 2-aminomethylaziridine dissolved in 20 ml of water was added and stirred at room temperature for 4 hours. The generated solid was collected by filtration, washed with water, and then dried under reduced pressure at 60°C for 3 hours to obtain 2.82 g (yield: 83%) of light brown cis-dichloro(2-aminomethylaziridine)platinum (). Melting point 260-280℃ (decomposition). Suspend this 1.69g (0.005mol) in 3ml of water,
While stirring at room temperature, add 10 ml of 31% hydrogen peroxide solution, and react at the same temperature for 30 minutes, then at 80°C for 1 hour. After cooling, the produced solid was collected by filtration, washed with water, and dried under reduced pressure at 60°C for 3 hours to obtain a light brown cis-dichloro-
0.56 g (yield 30%) of trans-dihydroxy(2-aminomethylaziridine)platinum () was obtained. Melting point 220-240℃ (decomposition). Elemental analysis value Molecular formula C 3 H 10 Cl 2 N 2 O 2 As Pt C H N Theoretical value (%) 9.68 2.71 7.53 Actual value (%) 9.63 2.71 7.42 IRν KBr nax cm -1 :540 (Pt-O) Experimental example 2. In vivo antitumor test against Colon 26 carcinoma A 1-2 mm triangular piece of Colon 26 carcinoma tumor was implanted subcutaneously into the flank of a 6-week-old CDF 1 /Crj male mouse, and 4 days later, a tumor of approximately the same size was implanted. A predetermined amount of the drug was intraperitoneally administered to tumor-bearing mice (group 1, 5 to 6 mice), and 10 days later (14 days after tumor implantation), the tumor weight was measured and the growth inhibition rate ( GIR
%) was calculated. GIR (%) = CT/C x 100 (%) Here, C and T represent the average tumor burden of the control group and drug administration group, respectively. The results are shown in Table 1. Furthermore, the known compound CDDP
(cisplatin) was used as a comparison drug.
【表】
発明の効果
本発明化合物は、優れた坑腫瘍活性を有し、毒
性が低く、水溶性が高いため制癌剤として有用で
ある。[Table] Effects of the Invention The compound of the present invention has excellent antitumor activity, low toxicity, and high water solubility, and is therefore useful as an anticancer agent.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP838385 | 1985-01-22 | ||
| JP60-8383 | 1985-01-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61267595A JPS61267595A (en) | 1986-11-27 |
| JPH0569113B2 true JPH0569113B2 (en) | 1993-09-30 |
Family
ID=11691693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61011461A Granted JPS61267595A (en) | 1985-01-22 | 1986-01-22 | Novel platinum complex |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61267595A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH093711A (en) * | 1995-06-16 | 1997-01-07 | Nagai Emiko | Long sleeve part, shoulder part and neck part-opening and shutting clothing |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6310724A (en) * | 1986-03-11 | 1988-01-18 | Chugai Pharmaceut Co Ltd | Carcinostatic agent containing novel platinum complex as active component |
| JPS6310725A (en) * | 1986-03-11 | 1988-01-18 | Chugai Pharmaceut Co Ltd | Carcinostatic agent containing novel platinum complex as active component |
-
1986
- 1986-01-22 JP JP61011461A patent/JPS61267595A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH093711A (en) * | 1995-06-16 | 1997-01-07 | Nagai Emiko | Long sleeve part, shoulder part and neck part-opening and shutting clothing |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61267595A (en) | 1986-11-27 |
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