JPS61286396A - Novel platinum complex and use thereof - Google Patents
Novel platinum complex and use thereofInfo
- Publication number
- JPS61286396A JPS61286396A JP12755185A JP12755185A JPS61286396A JP S61286396 A JPS61286396 A JP S61286396A JP 12755185 A JP12755185 A JP 12755185A JP 12755185 A JP12755185 A JP 12755185A JP S61286396 A JPS61286396 A JP S61286396A
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- JP
- Japan
- Prior art keywords
- tables
- formulas
- platinum
- chemical formulas
- mathematical
- 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.)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、水溶性の新規シス−ジアミノシクロヘキサノ
ール白金錯体および該化合物を有効成分として含有する
抗腫瘍剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new water-soluble cis-diaminocyclohexanol platinum complex and an antitumor agent containing the compound as an active ingredient.
従来の技術
シスプラチン(シス−ジクロロジアミン白金(■))に
すぐれた抗腫瘍性が見い出されて以来(ネイチャー (
Nature) +第222巻、385頁、 1969
年参照。)、その抗腫瘍剤としての幅広い研究がなされ
、現在では米国、英国、仏画において臨床に用いられる
に至っている。しかし、シスプラチンには腎毒性、吐き
気、嘔吐、難聴などの強い副作用があることから、各国
の研究者によシスプラチンより抗腫瘍性が強く、副作用
の少ない第二世代の白金錯体の合成、開発が進められて
いる。中でもシス−ジクロロ−1,2−ジアミノシクロ
ヘキサン白金(■)(ケミカルバイオロジカルインター
ラクションズ(Chsm、 Blol、 Intera
ctions) 、第5巻、415頁、 1972年参
照。)が有効とされているが、水溶性の点で問題点があ
る。この点に着目して、マロネー) (1,2−ジアミ
ノシクロヘキサン)白金(■)(特開昭53−3164
8号明細書参照。)、4−カルがキシフタレート(1,
2−ジアミノシクロヘキサン)白金(■)(特開昭54
−46752号明細書参照。)などの水溶性に優れた化
合物が開発されている。Conventional technology Ever since cisplatin (cis-dichlorodiamine platinum (■)) was discovered to have excellent antitumor properties (Nature (
Nature) +Volume 222, Page 385, 1969
See year. ), its use as an antitumor agent has been extensively studied, and it is now being used clinically in the United States, Britain, and France. However, because cisplatin has strong side effects such as nephrotoxicity, nausea, vomiting, and hearing loss, researchers in various countries are trying to synthesize and develop a second-generation platinum complex that has stronger antitumor properties and fewer side effects than cisplatin. It is progressing. Among them, cis-dichloro-1,2-diaminocyclohexane platinum (■) (Chemical Biological Interactions (Chsm, Blol, Intera
ctions), Vol. 5, p. 415, 1972. ) is said to be effective, but there are problems with water solubility. Focusing on this point, we have developed a method using JP-A-53-3164
See specification No. 8. ), 4-cal is xyphthalate (1,
2-diaminocyclohexane) platinum (■) (Unexamined Japanese Patent Publication No. 1983
See specification No.-46752. ) and other compounds with excellent water solubility have been developed.
優れた抗腫瘍剤として使用できる低毒性で抗腫瘍活性が
強い水溶性のシスプラチン類縁化合物の開発が望まれて
いる。It is desired to develop water-soluble cisplatin analogues with low toxicity and strong antitumor activity that can be used as excellent antitumor agents.
本発明者は、上記目的を達成すべく鋭意研究を行なった
結果、アミン成分としてジアミノシクロヘキサノール類
を用いることにより、新規白金錯体を合成することに成
功し、さらにとの錯体が特にマウス白血病L−1210
、8−180に対して生育障害作用を有していることが
確認され、優れた抗腫瘍剤として使用できることを見出
し、本発明を完成させるに到った。即ち、本発明の白金
錯化合物は下記一般式
%式%()
のいずれかで示される、シス−ジアミノシクロヘキサノ
ール白金錯体および、これを有効成分として含有する抗
腫瘍剤である。式中R−Rは水素原子または水酸基を、
しかしシクロヘキサン環を構成する炭素原子において一
つの炭素原子に水酸基が二個同時に置換しないように、
それぞれ表わす。As a result of intensive research to achieve the above object, the present inventors succeeded in synthesizing a new platinum complex by using diaminocyclohexanols as the amine component, and furthermore, the complex with -1210
, 8-180, and found that it can be used as an excellent antitumor agent, leading to the completion of the present invention. That is, the platinum complex compound of the present invention is a cis-diaminocyclohexanol platinum complex represented by any of the following general formulas (%) and an antitumor agent containing this as an active ingredient. In the formula, R-R represents a hydrogen atom or a hydroxyl group,
However, in order to prevent two hydroxyl groups from substituting one carbon atom at the same time in the carbon atoms constituting the cyclohexane ring,
Represent each.
本発明の白金(II)錯化合物は、塩化白金酸カリウム
(If)水溶液に、ジアミノシクロヘキサノール塩酸塩
または臭素酸塩水溶液を加え、これに炭酸水素ナトリウ
ムを加え冷蔵庫に放置し析出した結晶を集め、洗浄する
ことにより容易に製造することができる。また、先のジ
アミノシクロヘキサノール類は発明J部が先に報告した
方法〔プーテ。The platinum (II) complex compound of the present invention is produced by adding diaminocyclohexanol hydrochloride or bromate aqueous solution to an aqueous solution of potassium chloroplatinate (If), adding sodium bicarbonate to the solution, and collecting the precipitated crystals by adding sodium bicarbonate and leaving the mixture in a refrigerator. , can be easily manufactured by washing. In addition, the aforementioned diaminocyclohexanols were prepared by the method previously reported by Invention J [Poutet.
ンケミカルソサイアティージャパン(Bull、Che
m。Chemical Society Japan (Bull, Che
m.
Soc、 Jpn、)第37巻、733頁、 1964
年;同第38巻、758頁、 1965年−同第38巻
、 2026頁、 1965年;同第39巻、170頁
、 1966年;同第40巻、1295頁、 1967
年参照。〕または文献記載の方法〔ジャーナルアメリカ
ンケミカルソサイアティー(J、 Amer、 Che
m、 Soc、)第80巻。Soc, Jpn,) Volume 37, Page 733, 1964
Year; Vol. 38, p. 758, 1965 - Vol. 38, p. 2026, 1965; Vol. 39, p. 170, 1966; Vol. 40, p. 1295, 1967
See year. ] or the method described in the literature [Journal American Chemical Society (J, Amer, Che
m, Soc,) Volume 80.
752頁、 1958年参照。〕により合成できる。See page 752, 1958. ] can be synthesized.
本発明の化合物はシスプラチンと同等もしくはそれ以上
の抗腫瘍性を有し、かつ水溶性が高いため投与が容易で
ある。本発明の化合物は適当な注射用溶剤に溶解し、静
注、筋注、若しくは皮下注射あるいは点滴などによって
投与し得る。The compound of the present invention has antitumor properties equivalent to or better than cisplatin, and is highly water-soluble and therefore easy to administer. The compound of the present invention can be dissolved in a suitable injection solvent and administered by intravenous, intramuscular, subcutaneous injection, or infusion.
実施例 本発明を実施例により具体的に説明する。Example The present invention will be specifically explained with reference to Examples.
実施例1
塩化白金酸カリウム(II) 1711%’(0,41
mmol)を水1.4 mlに浴解し、これにDL−2
、3−ノアミノ−(1、2/3 )−シクロヘキサノー
ルジノ1イドロクロライ ド(プルティンケミストリー
ソサイアティージャノ9ン(Bull、 Chem、
Soc、 Jpn、)、第37巻、733頁、 196
4年参照。)IoolW(0,49mmol)k水0.
6 tyreに溶かした溶液を加え、次に炭酸水素ナト
リウム689ルで洗浄し減圧乾燥して、ジクロロ[DL
−2,3−ジアミノ−(1、273)−シクロヘキサノ
ール〕白金(ID118■(収率72%)を得た。Example 1 Potassium chloroplatinate (II) 1711%' (0,41
mmol) in 1.4 ml of water, and add DL-2 to this.
, 3-noamino-(1,2/3)-cyclohexanol dinohydrochloride (Bull, Chem.
Soc, Jpn, ), Volume 37, Page 733, 196
See Year 4. ) IoolW (0,49 mmol) k water 0.
Add the solution dissolved in 6 tires, then wash with 689 liters of sodium bicarbonate, dry under reduced pressure, and dichloro[DL
-2,3-diamino-(1,273)-cyclohexanol]platinum (ID 118) (yield 72%) was obtained.
融点 301〜302℃
元素分析値 C16H44N2Ct2PtOとして実施
例2
DL−ミオ−イノサジアミン−1,2−ジハイドロクロ
ライド441’l&(0,17mmol)を実施例1と
同様に反応させ黄色結晶のジクロロ(DL−ミオ−イノ
サジアミン−162)白金(II) 45■(収率70
%)を得た。Melting point: 301-302°C Elemental analysis value: C16H44N2Ct2PtO Example 2 DL-myo-inosadiamine-1,2-dihydrochloride 441'l & (0.17 mmol) was reacted in the same manner as in Example 1 to give yellow crystals of dichloro(DL- myo-inosadiamine-162) platinum(II) 45■ (yield 70
%) was obtained.
融点 240〜242℃
元素分析値 C6H44N2Ct204Ptとし【実施
例3
2−デオキシストレゾタミンジハイドロクロラナ
イド(ジャーiルアメリカンケミカルソサイアティー(
J、 Aynsr、 Chem、 Soc、) 、第8
0巻、752頁。Melting point 240-242°C Elemental analysis value C6H44N2Ct204Pt [Example 3 2-Deoxystrezotamine dihydrochloranide (Jar American Chemical Society)
J, Aynsr, Chem, Soc, ), No. 8
Volume 0, page 752.
1958年参照。) 80m? (0,19mmol)
を実施例1と同様に反応させ黄色結晶のジクロロ(2−
デオキシストレプタミン)白金(II) 57■(収率
69チ)を得た。See 1958. ) 80m? (0.19 mmol)
was reacted in the same manner as in Example 1 to give yellow crystals of dichloro(2-
Deoxystreptamine) platinum(II) 57cm (yield: 69cm) was obtained.
融点 219〜221℃
元素分析値 C6H14N2C620,Ptとして計算
値 C:16.83 、H: 3.30 、N :
6.54チ測定値 C: 16.85.H: 3.4
9.N : 6.25チ実施例4 抗腫瘍試験1
(1)供与動物
IC1%/CRJC1ウ/CRJを用い、一群7匹(7
週令)を使用した。Melting point 219-221°C Elemental analysis value C6H14N2C620, calculated value as Pt C: 16.83, H: 3.30, N:
6.54 measured value C: 16.85. H: 3.4
9. N: 6.25cm Example 4 Antitumor Test 1 (1) Using donor animals IC1%/CRJC1c/CRJ, 7 animals per group (7
Weekly) was used.
(2)試験方法
上記マウスの腹腔内にサルコーマ−180゜I X 1
0’個を移植した日を第0日として延命率を調べた。実
施例1〜3で調整した各種Pt(n)錯化合物を第18
目に腹腔内投与した。注射の溶剤には生理食塩水を用い
、また対照には生理食塩水を用いた。(2) Test method Inject Sarcoma-180°I x 1 into the abdominal cavity of the above mouse.
The survival rate was examined with the day when 0' cells were transplanted as day 0. The various Pt(n) complex compounds prepared in Examples 1 to 3 were
It was administered intraperitoneally to the eye. Physiological saline was used as the injection solvent, and physiological saline was used as a control.
その結果は表−1の示す如く、本発明のpt(II)錯
化合物は優れた抗腫瘍活性を示すことが判明した。As shown in Table 1, the results showed that the pt(II) complex of the present invention exhibited excellent antitumor activity.
表 −1
実施例5 抗腫瘍試験2
(1)供与動物
Br)F1マウス(雌)を用い、一群5匹(7週令)を
使用した。Table 1 Example 5 Antitumor Test 2 (1) Donor Animals Br) F1 mice (female) were used in a group of 5 mice (7 weeks old).
(2)試験方法
上記マウスの腹腔内にマウス白血病L1210肺瘍細胞
1×105個を移植した日を第01として延命率を調べ
た。実施例1〜3で調整した各種PL(II)錯化合物
を第1日月に腹腔内投与した。注射の溶剤には生理食塩
水を用い、また対照には生理食塩水を用いた。(2) Test method The survival rate was determined from the day 01 when 1×10 5 murine leukemia L1210 lung tumor cells were intraperitoneally transplanted into the mouse. The various PL(II) complex compounds prepared in Examples 1 to 3 were intraperitoneally administered on the first day of the month. Physiological saline was used as the injection solvent, and physiological saline was used as a control.
その結果は表−2の示す如く、本発明のPt(II)錯
化合物は優れた抗腫瘍活性を示すことが判明した。As shown in Table 2, the results showed that the Pt(II) complex of the present invention exhibited excellent antitumor activity.
表 −2
発明の効果
以上から明らかな如く、本発明の新規白金錯体は、優れ
た抗腫瘍活性を示し、抗)jΦ瘍剤としての使用が期待
できる。故に、本発明は医薬産業上極めて有用である。Table 2 Effects of the Invention As is clear from the above, the novel platinum complex of the present invention exhibits excellent antitumor activity and can be expected to be used as an anti-)jΦ tumor agent. Therefore, the present invention is extremely useful in the pharmaceutical industry.
手続補正書
昭和60年7月201
待訂庁艮官殿
!ン
V夕
1、事イ′1の表示
昭和60年特許願第127551号
2、発明の名称
新規白金11体おJ:びぞの用途
3、補正をする者
事イ′1どの関係 特許出願人
イ1所 東京都中央区京橋−1目5番8号5、補j
[により増hnリ−る発明の数 なし7、補正の内
容
明細書を以下の通り訂正する。Procedural amendment document July 1985 201 Official of the Office of Corrections! 1, Indication of 1985 Patent Application No. 127551, 2, Name of the invention, 11 new platinum bodies, J: Purpose of use, 3, Person making the amendment, A'1, Relationship, Patent applicant, I 1st place Kyobashi, Chuo-ku, Tokyo-1, 5-8, 5, supplementary j
[Number of inventions increased due to n/a 7. The statement of contents of the amendment is amended as follows.
(1)第8頁2行目[融点301〜302℃lを[融点
301〜302℃(分解)]と訂正する。(1) On page 8, line 2, [melting point 301-302°C] is corrected to [melting point 301-302°C (decomposition)].
(2)第8頁13行目[融点240〜242℃]を[融
点240〜242℃(分解)]と訂正する。(2) On page 8, line 13, [melting point 240-242°C] is corrected to [melting point 240-242°C (decomposition)].
(3)第9頁5行目「融点219〜221℃」を[融点
219〜221℃(分解)」と訂正する。(3) On page 9, line 5, "melting point 219-221°C" is corrected to "melting point 219-221°C (decomposition)".
(4)第9頁8行目rN:6.25%1ど9行目「実施
例4」の間に下記の記載を挿入する。(4) Page 9, line 8, rN: 6.25% The following statement is inserted between “Example 4” on line 1 and 9.
[実施例4
ミオ−イノサジアミン−1,3−ジハイドロクロライド
(J、 OrL Chem、、 33 .2831(1
968))152mg(0,60mmol)を実施例1
と同様に反応させ19られた結晶を、1、規定塩酸より
再結晶することにより、声色結晶のジクロロ(ミオ−イ
ノサジアミン−1,3)白金(IT)93mg(収率3
4%)を得た。[Example 4 Myo-inosadiamine-1,3-dihydrochloride (J, OrL Chem, 33.2831 (1
968)) 152 mg (0.60 mmol) in Example 1
By recrystallizing the crystals reacted in the same manner as above from 1,N hydrochloric acid, 93 mg of dichloro(myo-inosadiamine-1,3)platinum (IT) (yield: 3
4%).
融点 253〜260℃(分解)
元素分析値 Cs l−114N2 CI 20a P
t として計算値 C: 16,22 、l−1:
3.18 、N : 6,31測定値 C:16.1
5 、H: 3.19 、N : 6,05 +(
5)第9頁9行目「実施例4」を「実施例5」と訂正す
る。Melting point 253-260℃ (decomposition) Elemental analysis value Cs l-114N2 CI 20a P
Calculated value as t C: 16,22, l-1:
3.18, N: 6,31 Measured value C: 16.1
5, H: 3.19, N: 6,05 +(
5) On page 9, line 9, "Example 4" is corrected to "Example 5."
(6)第11頁1行目「実施例5」を「実施例6」と訂
正する。(6) On page 11, line 1, "Example 5" is corrected to "Example 6."
以−トBelow
Claims (2)
学式、表等があります▼(II) ▲数式、化学式、表等があります▼(III)▲数式、化
学式、表等があります▼(IV) のいずれかで示される、シス−ジアミノシクロヘキサノ
ール白金錯体。式中R^1〜R^8は水素原子または水
酸基を、しかしシクロヘキサン環を構成する炭素原子に
おいて一つの炭素原子に水酸基が二個置換しないように
、それぞれ表わす。(1) The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼ (IV) Cis-diaminocyclohexanol platinum complexes shown in any of the following. In the formula, R^1 to R^8 each represent a hydrogen atom or a hydroxyl group, but so as not to substitute two hydroxyl groups on one carbon atom in the carbon atoms constituting the cyclohexane ring.
学式、表等があります▼(II) ▲数式、化学式、表等があります▼(III)▲数式、化
学式、表等があります▼(IV) のいずれかで示される、シス−ジアミノシクロヘキサノ
ール白金錯体を有効成分として含有する抗腫瘍剤。式中
R^1〜R^8は水素原子または水酸基を、しかしシク
ロヘキサン環を構成する炭素原子において一つの炭素原
子に水酸基が二個置換しないように、それぞれ表わす。(2) The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) ▲ Mathematical formulas, chemical formulas, An antitumor agent containing a cis-diaminocyclohexanol platinum complex as an active ingredient, shown in any of the following tables. In the formula, R^1 to R^8 each represent a hydrogen atom or a hydroxyl group, but so as not to substitute two hydroxyl groups on one carbon atom in the carbon atoms constituting the cyclohexane ring.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12755185A JPS61286396A (en) | 1985-06-12 | 1985-06-12 | Novel platinum complex and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12755185A JPS61286396A (en) | 1985-06-12 | 1985-06-12 | Novel platinum complex and use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS61286396A true JPS61286396A (en) | 1986-12-16 |
Family
ID=14962802
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP12755185A Pending JPS61286396A (en) | 1985-06-12 | 1985-06-12 | Novel platinum complex and use thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61286396A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0310260A2 (en) * | 1987-09-26 | 1989-04-05 | Ajinomoto Co., Inc. | Platinum complexes and their use as anti-tumor agents |
-
1985
- 1985-06-12 JP JP12755185A patent/JPS61286396A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0310260A2 (en) * | 1987-09-26 | 1989-04-05 | Ajinomoto Co., Inc. | Platinum complexes and their use as anti-tumor agents |
US5041579A (en) * | 1987-09-26 | 1991-08-20 | Ajinomoto Co., Inc. | Platinum complexes and uses therewith |
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