JPH01246246A - Novel platinum(ii) complex and remedy of malignant tumor - Google Patents
Novel platinum(ii) complex and remedy of malignant tumorInfo
- Publication number
- JPH01246246A JPH01246246A JP63072983A JP7298388A JPH01246246A JP H01246246 A JPH01246246 A JP H01246246A JP 63072983 A JP63072983 A JP 63072983A JP 7298388 A JP7298388 A JP 7298388A JP H01246246 A JPH01246246 A JP H01246246A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- platinum
- complex
- compound
- present
- 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
- 201000011510 cancer Diseases 0.000 title claims abstract description 8
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- -1 platinum(II) compound Chemical class 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims abstract description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 15
- 229940124597 therapeutic agent Drugs 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 40
- 229910052697 platinum Inorganic materials 0.000 abstract description 16
- 229910004679 ONO2 Inorganic materials 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 abstract description 4
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 3
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- 230000015572 biosynthetic process Effects 0.000 description 3
- UQKCTBFPACVZSU-UHFFFAOYSA-N cyclohexane-1,2-diamine;platinum(2+);dinitrate Chemical compound [Pt+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O.NC1CCCCC1N UQKCTBFPACVZSU-UHFFFAOYSA-N 0.000 description 3
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Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明は新規白金■錯体およびそれを有効成分とする悪
性腫瘍治療剤に関する。DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel platinum complex and a therapeutic agent for malignant tumors containing the same as an active ingredient.
〈従来の技術〉
悪性腫瘍の化学療法は、近年シス−ジクロロ（ジアンミ
ン）白金■（以下、ＣＤＤＰと略す）の適用で飛躍的な
進歩をとげた。すなわち、ＣＤＤＰは、それまで化学療
法剤での治療が難しかった卵巣癌や精巣癌などの性器癌
に著効を示したためである。しかしながら、ＣＤＤＰに
は腎毒性や骨髄毒性などの重篤な副作用があり、臨床使
用上の問題点となっている。<Prior Art> Chemotherapy for malignant tumors has made dramatic progress in recent years with the application of cis-dichloro(diammine)platinum (hereinafter abbreviated as CDDP). That is, this is because CDDP has shown remarkable efficacy against genital cancers such as ovarian cancer and testicular cancer, which were previously difficult to treat with chemotherapeutic agents. However, CDDP has serious side effects such as nephrotoxicity and bone marrow toxicity, which poses problems in clinical use.
一方、特にＤ Ｌ Ｆ （ｄｏｓｅ ｌｉｎｉｔｉｎｇ
ｆａｃｔｏｒ）と、なっている腎毒性を改善すべく、
さまざまな研究が重ねられ、シス−１，１−シクロブタ
ンジカルボキシレイト（ジアンミン）白金■（以下、Ｃ
ＢＤＣＡと略す）、シス−０，０−−グリコレイト（ジ
アンミン）白金■なとの第二世代白金錯体が開発された
。On the other hand, especially D L F (dose lining
factor) and to improve the nephrotoxicity that has become
Various studies have been carried out, and cis-1,1-cyclobutanedicarboxylate (diammine) platinum ■ (hereinafter referred to as C
A second generation platinum complex with cis-0,0-glycolate (diammine) platinum (abbreviated as BDCA) has been developed.
〈発明が解決しようとする課題〉
しかしながら、これらの化合物は、腎毒性こそ弱いもの
の、抗腫瘍活性がＣＤＤＰはど高くはない、このため、
抗ｒｗ瘍作用が強く、かつ毒性が弱い白金錯体の開発が
望まれている。<Problem to be solved by the invention> However, although these compounds have weak nephrotoxicity, their antitumor activity is not as high as that of CDDP.
It is desired to develop platinum complexes that have strong anti-RW tumor effects and low toxicity.
本発明の目的は、強い抗腫瘍活性を有し、かつ毒性が弱
いという両条件を満足する新規白金■錯体を提供するこ
とにあり、さらにかかる両条件を満足する悪性Ｉｌｌｌ
ｌ療治療剤供することにある。An object of the present invention is to provide a novel platinum complex that satisfies both the requirements of having strong antitumor activity and having low toxicity.
The purpose is to provide therapeutic agents.
く課題を解決するための手段〉 上記目的は、以下の本発明により達成される。Means to solve problems〉 The above object is achieved by the present invention as described below.
すなわち、本発明は、下記一般式（八）（式中、Ｒは炭
素原子数１〜１５のアルキル基を示す。）
で示される新規白金■錯体（以下、本発明化合物と略す
）および上記式（＾）で示される新規白金■錯体を有効
成分とする悪性Ｍ療治療剤である。また、本発明は
（イ）下記式（Ｂ）
（式中、（Ｒ１）は（ＯＮＯ２）２または（Ｏ３Ｏ３）
を示す。）
で示される白金■化合物と（ロ）下記式（Ｃ）（式中、
Ｒは炭素原子数１〜１５のアルキル基を示す。）
で示される化合物および（ハ）水酸化アルカリを反応さ
せて得られる白金■錯体を有効成分とする悪性Ｗ１瘍泊
療剤であり、さらに、本発明は
（イ）下記式（０）
で示される白金■化合物および（ロ）下記式（Ｃ）（式
中、Ｒは炭素原子数１〜１５のアルキル基を示す。）
で示される化合物を反応させて得られる白金■錯体を有
効成分とする悪性腫瘍治療剤である。That is, the present invention provides a novel platinum complex (hereinafter abbreviated as the compound of the present invention) represented by the following general formula (8) (wherein R represents an alkyl group having 1 to 15 carbon atoms) and the above formula This is a therapeutic agent for malignant M that contains a novel platinum complex indicated by (^) as an active ingredient. Further, the present invention provides (a) the following formula (B) (wherein (R1) is (ONO2)2 or (O3O3)
shows. ) A platinum compound represented by (b) the following formula (C) (in the formula,
R represents an alkyl group having 1 to 15 carbon atoms. ) and (iii) a platinum complex obtained by reacting an alkali hydroxide as an active ingredient. A malignant compound containing as an active ingredient a platinum complex obtained by reacting a platinum compound and (b) a compound represented by the following formula (C) (in the formula, R represents an alkyl group having 1 to 15 carbon atoms). It is a tumor therapeutic agent.
上記式（＾）においてＲは炭素原子数１〜１５のアルキ
ル基を示す、Ｒの具体例としては、たとえばメチル基、
エチル基、プロピル基、ブチル基、ペンチル基、ヘキシ
ル基、ヘプチル基、オクチル基、ノニル基、デシル基、
ウンデシル基、ドデシル基、トリデシル基、テトラデシ
ル基、ペンタデシル基などが挙げられる。好ましくはＲ
はメチル基、エチル基、プロピル基、ブチル基などの炭
素原子数１−４の低級アルキル基を示し、特に好ましく
はメチル基を示す。In the above formula (^), R represents an alkyl group having 1 to 15 carbon atoms. Specific examples of R include, for example, a methyl group,
Ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group,
Examples include undecyl group, dodecyl group, tridecyl group, tetradecyl group, and pentadecyl group. Preferably R
represents a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, and particularly preferably a methyl group.
本発明化合物の配位子 は下記式 で示される共役系を意味する。Ligand of the compound of the present invention is the following formula means a conjugated system shown by
本発明化合物（Ａ）はたとえば、以下に示す反応式にし
たがって合成することができる。The compound (A) of the present invention can be synthesized, for example, according to the reaction formula shown below.
（Ｂｌ） （Ｄ
）（Ｃ）
（Ａ）
すなわち、本発明化合物（八）はジニトラト（１，２−
ジアミノシクロヘキサン）白金■（化合物（Ｂｌ））ま
たはジスルファト（１，２−ジアミノシクロヘキサン）
白金■（化合物（Ｂ ２ ））の水溶液を２′アンバー
ライトＩＲＡ−４００”Ｌ１ダイヤイオン５Ａ−１０Ａ
”などの陰イオン交換樹脂（Ｏｌ−Ｉ型）を充填したカ
ラムに通して得られなジヒドロキソ（１，２−ジアミノ
シクロヘキサン）白金■（Ｄ）と３−アセチル−６−ア
ルキルピペリジン−２，４−ジオン（Ｃ）とを反応させ
ることにより合成することができる０反応は通常、常温
下ジヒドロキソ（１，２−ジアミノシクロヘキサン）白
金■（Ｄ）の水溶液に１当量の３−アセチル−６−アル
キルピペリジン−２゜４−ジオン（Ｃ）を混合すること
により実施できる。(Bl) (D
)(C) (A) That is, the compound (8) of the present invention is dinitrato(1,2-
diaminocyclohexane) platinum (compound (Bl)) or disulfato (1,2-diaminocyclohexane)
An aqueous solution of platinum (compound (B 2 )) was added to 2' Amberlite IRA-400''L1 Diamondion 5A-10A.
dihydroxo(1,2-diaminocyclohexane)platinum (D) and 3-acetyl-6-alkylpiperidine-2,4 obtained by passing it through a column packed with anion exchange resin (Ol-I type) such as 0 reaction, which can be synthesized by reacting dione (C), is usually performed by adding 1 equivalent of 3-acetyl-6-alkyl to an aqueous solution of dihydroxo(1,2-diaminocyclohexane)platinum (D) at room temperature. This can be carried out by mixing piperidine-2°4-dione (C).
また、本発明化合物（Ａ）はジニトラト（１，２−ジア
ミノシクロヘキサン）白金■（化合物（Ｂ １ ））、
ｔたはジスルファト（１，２−ジアミノシクロヘキサン
）白金■（化合物（Ｂ ２ ））と水酸化アルカリを反
応させることによって合成することができる。ここで水
酸化アルカリとしては、水酸化ナトリウム、水酸化カリ
ウムなどが好ましく用いられ、化合物ＩＣ＞に対して通
常１゜５〜２．５倍モル、好ましくは２倍モル用いる。In addition, the compound (A) of the present invention is dinitrato(1,2-diaminocyclohexane)platinum (compound (B 1 )),
It can be synthesized by reacting disulfato(1,2-diaminocyclohexane)platinum (compound (B 2 )) with an alkali hydroxide. Here, as the alkali hydroxide, sodium hydroxide, potassium hydroxide, etc. are preferably used, and the amount is usually 1.5 to 2.5 times, preferably 2 times, the mole of compound IC>.
本発明化合物の原料であるジニトラト（１，２−ジアミ
ノシクロヘキサン）白金■（Ｂ１）はたとえば次の方法
により合成することができる。Dinitrato(1,2-diaminocyclohexane)platinum (B1), which is a raw material for the compound of the present invention, can be synthesized, for example, by the following method.
（Ｅ）
（Ｂ）
化合物（Ｂ２）は−Ｆ記反応式においてＡｇＮＯ３の代
りにＡｇｐＳＯ４を用いることによって合成することが
できる。(E) (B) Compound (B2) can be synthesized by using AgpSO4 in place of AgNO3 in the reaction formula -F.
上記反応式で得られる化合物（Ｂｌ）、（Ｂ２）には、
原料として用いる１、２−ジアミノシクロヘキサン（以
下、ｄａｃｈと略′１四の立体配置によりＰｔ （）ラ
ンス−１−ｄ ａ ｃ ｈ ）［０ＮＯ２）２、Ｐｔ
（トランス−ｄ−ｄａｃｈＨＯＮＯ２）２、Ｐｔ （シ
ス−ｄａｃｈ）（ＯＮＯ２）２の三種、Ｐｔ （）ラン
ス−ｊ！−ｄａｃｈ）（Ｏ３Ｏ３） 、Ｐｔ （トラン
ス−ｄ −ｄ’ａ ｃ ｈ ）（０３０３）、ｐｔ （
シス−ｄａｃｈ）（Ｏ３Ｏ３）の三種の異性体がそれぞ
れ存在する。Compounds (Bl) and (B2) obtained by the above reaction formula include:
1,2-diaminocyclohexane (hereinafter referred to as dach and abbreviated as Pt ()lance-1-d ach ) [0NO2)2, Pt as a raw material due to the configuration of '14'
(trans-d-dachHONO2)2, Pt(cis-dach)(ONO2)2, Pt()lance-j! -dach) (O3O3), Pt (trans-d -d'ach) (0303), pt (
There are three isomers of cis-dach) (O3O3).
本発明化合物のもう一つの原料である３−アセチル−６
−アルキルピペリジン−２，４−ジオン（０）は、３−
アミノカルボン酸エステルとジゲテンとを反応させて３
− （Ｎ−３−オキソブタノイル）アミノカルボン酸エ
ステルとしたのち、環化縮合することにより得ることが
できる。3-acetyl-6, another raw material for the compound of the present invention
-Alkylpiperidine-2,4-dione (0) is 3-
By reacting aminocarboxylic acid ester and digetene, 3
- It can be obtained by forming an (N-3-oxobutanoyl)aminocarboxylic acid ester and then subjecting it to cyclization condensation.
３−アミノカルボン酸エステルはＢｕｌｌ、 ｃｈａＩ
ｌ。3-aminocarboxylic acid ester is Bull, chaI
l.
Ｓｏｃ、 Ｊｐｎ、、５５−１２１８６〜２１８９ （
１９８２）に記載の方法に準じて２．２−ジメチル−１
゜３−ジオキサン−４，６−ジオンと酸塩化物とを反応
させたのち脱炭酸して得られる３−オキソカルボン酸エ
ステルにヒドロキシルアミンを反応させてオキシムとし
、これを還元することにより容易に得られる。Soc, Jpn, 55-12186~2189 (
2,2-dimethyl-1 according to the method described in (1982)
゜The 3-oxocarboxylic acid ester obtained by reacting 3-dioxane-4,6-dione with an acid chloride and then decarboxylating it is reacted with hydroxylamine to form an oxime, which can be easily converted into an oxime by reducing it. can get.
かくして得られる本発明化合物は抗ＩＩ！ｉ！瘍刑、す
なわち腫瘍治療剤の有効成分として使用することができ
る。The compound of the present invention thus obtained is anti-II! i! It can be used as an active ingredient in a tumor treatment agent.
本発明化合物の有効量を含む治療剤を臨床において投与
する場合、経口または非経口経路により投与される。そ
の剤形は、錠剤、糖衣錠、火剤、カプセル剤、散剤、ト
ローチ剤、液剤、坐剤、注射剤などを包含し、これらは
、医薬上許容される賦形剤（ｅｘｃ；ｐ；ｅｎｔ）を配
合して製造される。賦形剤としては次のようなものを例
示することができる。乳糖、ショ糖、ブドウ糖、ソルビ
トール、マンニトール、ばれいしょでんぷん、アミロペ
クチン、その他各種でんぷん、セルローズ誘導体（例え
ば、カルボキシメチルセルローズ、ハイドロキシエチル
セルローズなど）、ゼラチン、ステアリン酸マグネシウ
ム、ポリビニルアルコール、ステアリン酸カルシウム、
ポリエチレングリコールワックス、アラビアゴム、タル
ク、二酸化チタン、オリーブ油、ピーナツ油、ゴマ油な
どの植物油、パラフィン油、中性脂肪基剤、エタノール
、プロピレングリコール、生理食塩水、滅菌水、グリセ
リン、着色剤、調味剤、濃厚剤、安定剤、等銀剤、緩衝
剤などおよびその他医薬上許容される賦形剤。When administering a therapeutic agent containing an effective amount of the compound of the present invention in a clinical setting, it is administered by oral or parenteral routes. The dosage forms include tablets, sugar-coated tablets, gunpowders, capsules, powders, troches, solutions, suppositories, injections, etc. Manufactured by blending. Examples of excipients include the following. Lactose, sucrose, glucose, sorbitol, mannitol, potato starch, amylopectin, various other starches, cellulose derivatives (e.g. carboxymethyl cellulose, hydroxyethyl cellulose, etc.), gelatin, magnesium stearate, polyvinyl alcohol, calcium stearate,
Polyethylene glycol wax, gum arabic, talc, titanium dioxide, vegetable oils such as olive oil, peanut oil, and sesame oil, paraffin oil, neutral fat base, ethanol, propylene glycol, physiological saline, sterile water, glycerin, coloring agents, seasonings. , thickeners, stabilizers, silvering agents, buffering agents, etc. and other pharmaceutically acceptable excipients.
本発明の治療剤は、本発明化合物を０．００１〜８５重
量％、好ましくは０．００５〜６０重景％含有すること
ができる。The therapeutic agent of the present invention may contain the compound of the present invention in an amount of 0.001 to 85% by weight, preferably 0.005 to 60% by weight.
本発明の治療剤の投与量は、主として症状により左右さ
れるが、１０成人体重あたり０．０５〜２００■、好ま
しくは０．０１〜５０■である。The dosage of the therapeutic agent of the present invention mainly depends on the symptoms, but is 0.05 to 200 cm, preferably 0.01 to 50 cm per 10 adult body weights.
く実施例〉 以下、実施例により本発明を具体的に説明する。Example Hereinafter, the present invention will be specifically explained with reference to Examples.
実施例１
ａ、３−（Ｎ−３−オキツブタイノル）アミノクロトン
酸メチルの合成
３−アミノクロトン酸メチル２５ｇ（０，２１７モル）
、トリエチルアミン０．４ｍｌをベンゼン６０ｍ１に溶
かした溶液を６０〜６５℃に加熱し、ジゲテン１９．７
ｇ（０，２３４モル）を滴下した。滴下後、６０〜６５
℃で４５分撹拌した０反応溶液を４０ｇに濃縮後、冷却
晶析した。結晶を沢取後、冷トルエンで洗浄し、３−
（Ｎ−３−オキソブタノイル）アミノクロトン酸メチル
１３．２ｇを得た（収率３１％）。Example 1 a, Synthesis of methyl 3-(N-3-oxbutynol)aminocrotonate 25 g (0,217 mol) of methyl 3-aminocrotonate
, a solution of 0.4 ml of triethylamine dissolved in 60 ml of benzene was heated to 60-65°C, digetene 19.7
g (0,234 mol) was added dropwise. After dropping, 60-65
The O reaction solution was stirred at ℃ for 45 minutes, concentrated to 40 g, and then cooled and crystallized. After collecting a lot of crystals, they were washed with cold toluene, and 3-
13.2 g of methyl (N-3-oxobutanoyl)aminocrotonate was obtained (yield 31%).
得られた化合物の分析結果は次のとおりであった。The analysis results of the obtained compound were as follows.
融点 ５２〜５３℃
ｂ、３−アセチル−６−メチルピペリジン−２゜４−ジ
オンの合成
ａで得られた３−（Ｎ−３−オキソブタノイル）アミノ
クロトン酸メチル５．０５ｇ＜０゜０２０モル）、エタ
ノール１００ ｆｉｌｌ、５％パラジウム／カーボン０
．２５３ｇを５００ｍ１のオートクレーブに仕込んだ。Melting point 52-53°C b, 3-acetyl-6-methylpiperidine-2° Synthesis of 4-dione Methyl 3-(N-3-oxobutanoyl)aminocrotonate obtained in step a 5.05g <0°020 mole), ethanol 100 fill, 5% palladium/carbon 0
．． 253g was charged into a 500ml autoclave.
常温４気圧で１０時間水添した０反応液から触媒を除去
し、炉液を濃縮乾固して５．０２ｓｒの３− （Ｎ−３
−オキソブタノイル）アミノ醋酸メチルを得た。The catalyst was removed from the 0 reaction solution which was hydrogenated for 10 hours at room temperature and 4 atm, and the furnace solution was concentrated to dryness to give 5.02sr of 3-(N-3
-oxobutanoyl)aminomethyl acetate was obtained.
この３−（Ｎ−３−オキソブタノイル）アミノ醋酸メチ
ル５．０２ ｇと無水メタノール１５ｍ１および無水ベ
ンゼン２５１＋１１の混合溶液に２８％のナトリウムメ
チラート４．８７ｇを加えて６時間加熱還流した。反応
液に水６０ｍ１を添加して、水層とベンゼン層とを分離
してベンセン層を水洗した。この水洗液と分離した水層
を合わせて濃硫酸０．７ ｍｌで酸性とした。4.87 g of 28% sodium methylate was added to a mixed solution of 5.02 g of this methyl 3-(N-3-oxobutanoyl)aminoacetate, 15 ml of anhydrous methanol, and 251+11 anhydrous benzene, and the mixture was heated under reflux for 6 hours. 60 ml of water was added to the reaction solution to separate the aqueous layer and the benzene layer, and the benzene layer was washed with water. This washing solution and the separated aqueous layer were combined and acidified with 0.7 ml of concentrated sulfuric acid.
酸析された結晶１．３３ｇをｌ’ｉｌ＝酸エチル：ｎ−
ヘキサン−１：１の混合溶媒を用いて再結晶して、１．
０９＋ｒの３−アセチル−６−メチルピベリジンー２．
４− ジオンを得た（収率２５％）。1.33 g of the acid-precipitated crystals were added to l'il = ethyl acid: n-
1. Recrystallize using a hexane-1:1 mixed solvent.
09+r 3-acetyl-6-methylpiveridine-2.
4-dione was obtained (yield 25%).
得られた化合物の分析結果は次のとおりであった。The analysis results of the obtained compound were as follows.
融 点 １３０〜１３１℃
１ トＩＮＭＲ（ＣＤＣＪ！ ３ ）
δ （１１１１１１） 、 １ ７．４（Ｓ
、 ＩＨ） 、 ６．１０（ｂｒ 、
ＩＨ） 、 ３．７０（ｍ、 ＩＨ）、２．５６
（ｄ、 ２Ｈ）、２．５２（ｓ、３Ｈ） 、１．２７
（ｄ、３Ｈ）Ｃ１錯体の合成
Ｐｔ （トランス−Ｊ！−ｄａｃ ｈ）（ＯＮＯ２）２
水溶液を陰イオン交ｔ＊ｍ脂１゛ダイヤイオンＳＡ−１
０Ａ” （Ｏ）［型）を充填したカラムに通して得られ
たＰｔ （Ｆ−ランス−１−ｄａｃｈＨＯＨ）２水溶液
１００ｍ１（４，２ミリモル）に３−アセチル−６−メ
チルピベリジンー２．４−ジオンを０．７１ｇ（４，２
ミリモル）加え、室温で２０時間撹拌した０反応溶液を
乾固したのち、酢酸エチルで洗浄、減圧乾燥して３−ア
セチル−６−メチルピペリジン−２，４−ジオン−ヒト
０キソ（トランス−１−１，２−ジアミノシクロヘキサ
ン）白金■・１水和物（以下、本発明化合物（ＡＩ）と
略す）を１．８０ｇ得た（収率８４％）。Melting point 130-131℃ 1 INMR (CDCJ! 3)
δ (111111), 1 7.4(S
, IH), 6.10(br,
IH), 3.70 (m, IH), 2.56
(d, 2H), 2.52 (s, 3H), 1.27
(d,3H) Synthesis of C1 complex Pt (trans-J!-dach) (ONO2)2
Exchange the aqueous solution with anions t*m fat 1゛Diaion SA-1
3-acetyl-6-methylpiberidine-2 was added to 100 ml (4.2 mmol) of a Pt (F-lance-1-dachHOH)2 aqueous solution obtained by passing through a column packed with 0A'' (O) [type]. 0.71 g of 4-dione (4,2
After stirring at room temperature for 20 hours, the reaction solution was dried, washed with ethyl acetate, and dried under reduced pressure to give 3-acetyl-6-methylpiperidine-2,4-dione-human xo(trans-1 1.80 g of platinum (1,2-diaminocyclohexane) monohydrate (hereinafter abbreviated as the compound of the present invention (AI)) was obtained (yield: 84%).
本発明化合物（Ａ１）のＩＲを第１図、また、融点と元
素分析値を以下に示す（ｐｔは原子吸光分析により求め
た）。The IR of the compound (A1) of the present invention is shown in FIG. 1, and the melting point and elemental analysis values are shown below (pt was determined by atomic absorption spectrometry).
融 点 ２３１〜２３４℃（分解）元素分析値
（％）ＣＩ４Ｈ２７Ｎ３０Ｓ Ｐｔと実施例２
ＣＤＦ、マウス（雄性、６退勤、１群６〜１０匹使用）
腹腔内にＤＢＡ／２マウスで継代したマウス白血病４１
胞Ｌ１２１０ １０５個を移植した。移植日を０日とし
て、１日日、５日日、９日日の計３回本発明化合物（Ａ
１）を被検薬として腹腔内投与した０本実験の比較薬と
してはＣＢＤＣＡ、ＣＤＤＰを用いた。各薬剤は０゜０
５％” Ｔｗｃｅｎ ８０”溶液に溶解または懸濁して
使用した。Ｌ１２１０移植マウスに対する白金１１１体
の抗腫瘍作用の効果判定は、以下の式により求められる
Ｔ ／ Ｃ値ならびに３０日１における生存マウス数に
よって行った。Melting point 231-234°C (decomposition) Elemental analysis value (%) CI4H27N30S Pt and Example 2 CDF, mice (male, 6 retired, 6-10 mice per group used)
Mouse leukemia 41 passaged intraperitoneally in DBA/2 mice
105 L1210 cells were transplanted. The compound of the present invention (A
CBDCA and CDDP were used as comparative drugs in this experiment in which 1) was administered intraperitoneally as a test drug. Each drug is 0゜0
It was used by dissolving or suspending it in a 5% "Twcen 80" solution. The antitumor effect of platinum 111 bodies on mice transplanted with L1210 was evaluated based on the T/C value determined by the following formula and the number of surviving mice on day 30.
結果を表１に示す。The results are shown in Table 1.
表 １
表１に示す結果から明らかなように、本発明化合物（Ａ
１）は、１０■／ ｋｇで２４４％のＴＺＣ値を示した
。これは、ＣＤＤＰおよびＣＢＤＣＡ以上の抗ＩＩ瘍作
用であるといえる。Table 1 As is clear from the results shown in Table 1, the compound of the present invention (A
1) showed a TZC value of 244% at 10 μ/kg. This can be said to have an anti-II tumor effect greater than that of CDDP and CBDCA.
実施例３
本発明化合物（Ａ１）のマウスにおける急性毒性試験を
ＣＤＤＰを対照として行った。Ｓｌｃ：ＩｃＲマウス（
雄性：５退勤）の腹腔内に本発明化合物（Ａ１）を被検
薬として投与した。Example 3 An acute toxicity test of the compound (A1) of the present invention in mice was conducted using CDDP as a control. Slc:IcR mouse (
The compound (A1) of the present invention was intraperitoneally administered to a male (5 days old) as a test drug.
被検薬は０．０５％” Ｔｗｃｅｎ ８Ｇ”溶液に溶解
または懸濁して用いた。投与後１４日０の死亡率からＬ
Ｄ ｓｏ値を算出した。The test drug was dissolved or suspended in a 0.05% "Twcen 8G" solution. L from the mortality rate 14 days after administration
The Dso value was calculated.
その結果を表２に示す。The results are shown in Table 2.
表 ２
表２に示す結果から明らかなように、本発明化合物（Ａ
１）はＣＤＤＰに比べ低毒性である。Table 2 As is clear from the results shown in Table 2, the compound of the present invention (A
1) has lower toxicity than CDDP.
〈発明の効果〉
本発明の化合物は強い抗ｊＮｉ 瘍活性を有し、かつ毒
性も弱く、悪性腫瘍治療剤として有用である。<Effects of the Invention> The compounds of the present invention have strong anti-Ni tumor activity and low toxicity, and are useful as therapeutic agents for malignant tumors.
第１図は実施例１で得られた本発明化合物（Ａ１）の赤
外吸収スペクトルを示す。FIG. 1 shows the infrared absorption spectrum of the compound (A1) of the present invention obtained in Example 1.
Claims (4)
瘍治療剤。(2) A novel platinum (II) complex represented by the following general formula (A) ▲Mathematical formulas, chemical formulas, tables, etc.▼(A) (In the formula, R represents an alkyl group having 1 to 15 carbon atoms.) A malignant tumor treatment agent containing as an active ingredient.
Ｏ＿３）を示す。） で示される白金（II）化合物と（ロ）下記式（Ｃ）▲数
式、化学式、表等があります▼（Ｃ） （式中、Ｒは炭素原子数１〜１５のアルキル基を示す。 ） で示される化合物および（ハ）水酸化アルカリを反応さ
せて得られる白金（II）錯体を有効成分とする悪性腫瘍
治療剤。(3) (A) The following formula (B) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (B) (In the formula, (R^1) is (ONO_2)_2 or (OS
O_3). ) A platinum (II) compound represented by (b) the following formula (C) ▲ Numerical formula, chemical formula, table, etc. ▼ (C) (In the formula, R represents an alkyl group having 1 to 15 carbon atoms.) A malignant tumor therapeutic agent containing as an active ingredient a platinum (II) complex obtained by reacting the compound represented by (3) and an alkali hydroxide.
▲数式、化学式、表等があります▼（Ｃ） （式中、Ｒは炭素原子数１〜１５のアルキル基を示す。 ） で示される化合物を反応させて得られる白金（II）錯体
を有効成分とする悪性腫瘍治療剤。(4) (A) The following formula (D) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (D) A platinum (II) compound represented by the following formula (C) and (B) The following formula (C)
▲There are mathematical formulas, chemical formulas, tables, etc.▼(C) (In the formula, R represents an alkyl group having 1 to 15 carbon atoms.) The active ingredient is a platinum (II) complex obtained by reacting the compound shown by A therapeutic agent for malignant tumors.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63072983A JPH01246246A (en) | 1988-03-25 | 1988-03-25 | Novel platinum(ii) complex and remedy of malignant tumor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63072983A JPH01246246A (en) | 1988-03-25 | 1988-03-25 | Novel platinum(ii) complex and remedy of malignant tumor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01246246A true JPH01246246A (en) | 1989-10-02 |
Family
ID=13505134
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63072983A Pending JPH01246246A (en) | 1988-03-25 | 1988-03-25 | Novel platinum(ii) complex and remedy of malignant tumor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01246246A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991009041A1 (en) * | 1989-12-12 | 1991-06-27 | Toray Industries, Inc. | Novel platinum (ii) complex and drug for treating malignant tumor |
-
1988
- 1988-03-25 JP JP63072983A patent/JPH01246246A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991009041A1 (en) * | 1989-12-12 | 1991-06-27 | Toray Industries, Inc. | Novel platinum (ii) complex and drug for treating malignant tumor |
| US5302587A (en) * | 1989-12-12 | 1994-04-12 | Toray Industries, Inc. | Platinum (II) complex and agent for treating malignant tumor |
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