JPS6317894A - Novel platinum complex and use thereof - Google Patents
Novel platinum complex and use thereofInfo
- Publication number
- JPS6317894A JPS6317894A JP16152986A JP16152986A JPS6317894A JP S6317894 A JPS6317894 A JP S6317894A JP 16152986 A JP16152986 A JP 16152986A JP 16152986 A JP16152986 A JP 16152986A JP S6317894 A JPS6317894 A JP S6317894A
- Authority
- JP
- Japan
- Prior art keywords
- formulas
- tables
- platinum
- mathematical
- chemical formulas
- 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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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 22
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims description 17
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims 1
- 239000013078 crystal Substances 0.000 abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 8
- 125000003963 dichloro group Chemical group Cl* 0.000 abstract description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 6
- 229960004316 cisplatin Drugs 0.000 abstract description 6
- 239000007864 aqueous solution Substances 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 abstract description 3
- -1 diaminocyclohexanol hydrochloride Chemical compound 0.000 abstract description 3
- 229910052700 potassium Inorganic materials 0.000 abstract description 3
- 239000011591 potassium Substances 0.000 abstract description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 3
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical group C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 244000309464 bull Species 0.000 description 4
- 239000012155 injection solvent Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- CUEFMMVRXYVLBS-UHFFFAOYSA-N 4,4-diaminocyclohexan-1-ol Chemical class NC1(N)CCC(O)CC1 CUEFMMVRXYVLBS-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000003200 peritoneal cavity Anatomy 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- WZUWEVKVBYKREW-UHFFFAOYSA-N 1,2-diaminocyclohexan-1-ol Chemical compound NC1CCCCC1(N)O WZUWEVKVBYKREW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 235000015111 chews Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 1
- PNNCIXRVXCLADM-UHFFFAOYSA-L cyclohexane-1,2-diamine;dichloroplatinum Chemical compound Cl[Pt]Cl.NC1CCCCC1N PNNCIXRVXCLADM-UHFFFAOYSA-L 0.000 description 1
- POQBJIOLWPDPJE-UHFFFAOYSA-N cyclohexane-1,2-diamine;platinum Chemical compound [Pt].NC1CCCCC1N POQBJIOLWPDPJE-UHFFFAOYSA-N 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ARCGXLSVLAOJQL-UHFFFAOYSA-N trimellitic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1 ARCGXLSVLAOJQL-UHFFFAOYSA-N 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (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値））にす
ぐれた抗腫瘍性が見い出されて以来（ネイチャー （Ｎ
ａｔｕｒｅ）、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シ抗腫瘍性が強く、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（ＩＩ） （ケミカルバイオロジカルインター
ラクシ、ンズ（Ｃｈｅｍ、 Ｂｉｏｌ、 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Ｃｎ） （特開昭５３−３１６４
８号明細書参照。）、４−カルホキシフタレ−） （１
，２−ジアミノシクロヘキサン）白金（■）（特開昭５
４−４６７５２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 value)) was discovered to have excellent antitumor properties (Nature (N
ture), Vol. 222, p. 385, 1969. ), 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, cisplatin has nephrotoxicity, nausea,
Because cisplatin has strong side effects such as vomiting and hearing loss, researchers around the world are working to synthesize and develop second-generation platinum complexes that have stronger antitumor properties and fewer side effects than cisplatin. Among them, cis-dichloro-1,2-diaminocyclohexane platinum(II) (Chem, Biol, Intera
cations) + vol. 5, p. 415, 1972. ) is said to be effective, but there are problems with water solubility. Focusing on this point, Maroney) (1,2-diaminocyclohexane)platinum Cn) (JP-A-53-3164
See specification No. 8. ), 4-carboxyphthalate) (1
, 2-diaminocyclohexane) platinum (■) (Unexamined Japanese Patent Publication No. 1973
See specification No. 4-46752. ) 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
を用いることによシ、新規白金錯体を合成することに成
功し、さらにこ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
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Ｒ１〜Ｒ８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 aimed at achieving the above object, the present inventors succeeded in synthesizing a new platinum complex by using diaminocyclohexanols as the amine component, and furthermore, this complex was found to be particularly effective against murine leukemia. L-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, R1 to R8 each represent a hydrogen atom or a hydroxyl group such that one carbon atom constituting the cyclohexane ring is not substituted by two hydroxyl groups at the same time.
本発明の白金（ｎ）錯化合物は、塩化白金酸カリウム（
ｎ）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
によシ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者の一部が先に報告した
方法〔プルティンケミカルソサイアティージャパン（Ｂ
ｕｌｌ、Ｃｈｅｍ。The platinum (n) complex compound of the present invention is potassium chloroplatinate (
n) It can be easily produced by adding an aqueous solution of diaminocyclohexanol hydrochloride or bromate to an aqueous solution, adding sodium bicarbonate thereto, leaving it in a refrigerator, collecting the precipitated crystals, and washing them. In addition, the aforementioned diaminocyclohexanols were obtained by a method previously reported by some of the inventors [Plutin Chemical Society Japan (B
ull, Chem.
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ンサイア
ティ−（Ｊ、 Ａｍｅｒ 、 Ｃｈｅｍ、 Ｓｏｃ、
）第８０巻。Page, 1965: Volume 39, page 170, 1966:
See vol. 40, p. 1295, 1967. ] or the method described in the literature [Journal American Chemical Science (J, Amer, Chem, Soc,
) Volume 80.
７５２頁、１９５８年参照。〕により合成できる。See p. 752, 1958. ] can be synthesized.
本発明の化合物はシスグ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
投与でき、抗腫瘍剤として使用し得る。The compound of the present invention has antitumor properties equivalent to or better than cisgratin, and is highly water-soluble, so it is 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 drip, and can be used as an antitumor agent.
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（ｎ） １７１■（０，４１ｍｍｏ
ｌ）を水１．４ｄに溶解し、これにＤＬ−２＄３−ジア
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（プルティンケミカルソサイアティーゾ
ヤノ４ン（Ｂｕｌｌ、 Ｃｈｅｗｓ ５ｏｃｅ Ｊｐｎ
、 ） を第３７巻。Example 1 Potassium chloroplatinate (n) 171■ (0.41 mmo
l) in 1.4 d of water, and to this was added DL-2$3-diamino-(1,2/3)-cyclohexanol dino-hydrochloride (Plutin Chemical Societies 5occe Jpn
, ) Volume 37.
７３３頁、１９６４年参照。） １００ Ｗ （０，４
９ｍｍｏｌ）を水０．６ ｄに溶かした溶液を加え、次
に炭酸水素ナトリウム６８■（０，８１・ｍｍｏｌ）を
加え、冷蔵庫に放置した。４８後析出した黄色結晶を濾
過し、冷水、アセトン、エーテルで洗浄し減圧乾燥して
、ジクロロ（ＤＬ−２，３−ジアミノ−（Ｌ２／３ ）
−シクロヘキサノール〕白金Ｑｌ） １１８ ｍ９ （
収率７２％）を得た。See p. 733, 1964. ) 100 W (0,4
A solution of 9 mmol) dissolved in 0.6 d of water was added, followed by 68 μm (0.81 mmol) of sodium hydrogen carbonate, and the mixture was left in the refrigerator. After 48 days, the precipitated yellow crystals were filtered, washed with cold water, acetone, and ether, and dried under reduced pressure to give dichloro(DL-2,3-diamino-(L2/3)).
-cyclohexanol] platinum Ql) 118 m9 (
A yield of 72% was obtained.
融点 ３０１〜３０２℃（分解）。Melting point: 301-302°C (decomposed).
元素分析値 Ｃ６Ｈ１４Ｎ２ｃｔ２ｏｐｔとして計算値
Ｃ１８，１９，Ｈ３，５６，Ｎ ７．０７゜ＣＬ
１７．９０％
測定値 Ｃ１７゜９１．Ｈ３，５４，Ｎ ６．８８゜
ＣＬ １７．６０％
実施例２
ＤＬ−ミオ−イノサジアミン−１，２−ヅハイドロクロ
ライド４４ｑ （０，１７ｍｍｏｌ ）を実施例１と同
様に反応させ処理を行ない黄色結晶のジクロロ（ＤＬ−
ミオ−イノサシアミン−１，２）白金（Ｉｌ） ４５
Ｈ？（収率７０％）を得た。Elemental analysis value Calculated value as C6H14N2ct2opt C18,19,H3,56,N 7.07゜CL
17.90% Measured value C17°91. H3,54,N 6.88゜CL 17.60% Example 2 DL-myo-inosadiamine-1,2-dihydrochloride 44q (0.17 mmol) was reacted and treated in the same manner as in Example 1 to give yellow crystals. dichloro(DL-
myo-inosacyamine-1,2) platinum (Il) 45
H? (yield 70%).
融点 ２４０〜２４２℃（分解）。Melting point: 240-242°C (decomposed).
元素分析値 Ｃ６Ｈ１４Ｎ２ｃｚ２ｏ４ｐｔとして計算
値 ＣＩ６．２２．Ｈ３，１８，Ｎ ６．３１゜Ｃ２
１５，９６％
測定値 Ｃ１５，９６ｐＨ３，２０，Ｎ ６．１０゜
Ｃ１１６，１２チ
実施例３
２−デオキシストレグタミンジハイドロクロライド（ジ
ャーナルアメリカンケミカルンサイアテ４− （Ｊ、
Ａｍｅｒ、 Ｃｈｅｗｓ Ｓｏｃ、）＠第８０巻、７５
２１ｊ、１９５８年参照。） ８０１９ （０，１９ｍ
ｍｏｌ ）を実施例１と同様に反応させ処理を行ない
黄色結晶のジクロロ（２−デオキシストレグタミン）白
金（Ｉｔ）５７Ｎｉ（収率６９％ ）ｔ−４７’ｃ。Elemental analysis value Calculated value as C6H14N2cz2o4pt CI6.22. H3, 18, N 6.31°C2
15,96% Measured value C15,96pH3,20,N 6.10゜C116,12CH Example 3 2-deoxystrectamine dihydrochloride (Journal American Chemical Society 4-(J,
Amer, Chews Soc, ) @ Volume 80, 75
21j, 1958. ) 8019 (0,19m
mol) was reacted and treated in the same manner as in Example 1 to obtain yellow crystals of dichloro(2-deoxystregtamine)platinum (It) 57Ni (yield 69%) t-47'c.
融点 ２１９〜２２１℃（分解）。Melting point: 219-221°C (decomposed).
元素分析値 Ｃ６Ｈ１４Ｎ２ｃｚ２ｏ３ｐｔとして計算
値 Ｃ１６，８３，１（３，３０，Ｎ ６．５４チ測
定値 Ｃ１６，８５，Ｈ３，４９，Ｎ ６．２５％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、 Ｏｒｇ、 Ｃｈｅｍ、ｓ ３３ 、２８３１
（１９６８）ン１５２Ｎ９（０，６０ｍｍｏｌ ）を実
施例１と同様に反応させ得られた結晶を、１規定塩酸よ
り再結晶することにより、黄色結晶のジクロロ（ミオ−
イノサジアミン−１，３）白金（ＩＩ）９３ダ（収率３
４％）を得た。Elemental analysis value Calculated value as C6H14N2cz2o3pt C16,83,1(3,30,N 6.54CH Measured value C16,85,H3,49,N 6.25%Example 4 Myo-inosadiamine-1,3-dihydro Chloride (J, Org, Chem, s 33, 2831
Dichloro(myo-
Inosadiamine-1,3) platinum(II) 93 da (yield 3
4%).
融点 ２５３〜２６０℃（分解）。Melting point: 253-260°C (decomposed).
元素分析値 Ｃ６Ｈ１４Ｎ２Ｃｔ２０４Ｐｔとして計算
値 Ｃ１６，２２，Ｈ３，１８，Ｎ ６．３１％測定
値 Ｃ１６，１５，Ｈ３，１９，Ｎ ６．０５％実施
例５
ＤＬ−２，３−ジアミノ（１，３／２）−１−シクロヘ
キサノールソハイドロクロライド（Ｂｕｌｌ・Ｃｈ ｅ
ｍφＳｏｃ・Ｊｐｎ、第３８巻、７５８負１９６５年参
照）１５０■（０，７４ｍｍｏｌ ）を実施例１と同様
に反応させ、処理を行ない目的とする白金錯体、ジクロ
ロＣＤＬ−２，３−ジアミノ−（１，３／２）−１−シ
クロヘキサノール〕白金（Ｉｔ） １８４〜（収率６３
チ）を得た。Elemental analysis value Calculated value as C6H14N2Ct204Pt C16,22,H3,18,N 6.31% Measured value C16,15,H3,19,N 6.05%Example 5 DL-2,3-diamino (1,3/ 2)-1-Cyclohexanol sohydrochloride (Bull・Che
mφSoc・Jpn, Vol. 38, 758-1965) was reacted in the same manner as in Example 1 and treated to obtain the desired platinum complex, dichloroCDL-2,3-diamino-( 1,3/2)-1-cyclohexanol] platinum (It) 184~(yield 63
h) was obtained.
元素分析値 ｃ６Ｈ，４Ｎ２Ｃ１２０Ｐｔ （！： Ｌ
テ計算値 Ｃ１８，１９，Ｈ３，５６，Ｎ ７．０
７饅測定値 Ｃ１８，０９，Ｈ３，８５，Ｎ ７．２
３％ＩＲ（ＫＢｒ）ｙ ３３６０，３２５０，１５
７５，１１８０゜１０５０ｃｍ−１
実施例６
（１，３／２）−２−アミノ−１，３−シクロヘキサン
ジオ−、Ｑ／ （Ｂｕｌｌ、 Ｃｈｅｍ、 Ｓｏｃ、
Ｊｐｎ、第３７巻１９４頁１９６４年参照）３．０＆の
メタノール溶液（９Ｃａｌ）に２．４−ノニトロフルオ
ロベンゼン（３，５ゴ） ト） ！ｊエチルアミン（６
，５−）を加え、−時間攪拌した。Elemental analysis value c6H,4N2C120Pt (!: L
Calculated value C18, 19, H3, 56, N 7.0
7 steamed rice measurement value C18, 09, H3, 85, N 7.2
3%IR(KBr)y 3360,3250,15
75,1180°1050cm-1 Example 6 (1,3/2)-2-amino-1,3-cyclohexanedio-,Q/ (Bull, Chem, Soc,
Jpn, Vol. 37, p. 194, 1964) 2.4-nonitrofluorobenzene (3,5)! j ethylamine (6
, 5-) was added and stirred for - hours.
反応混合物を減圧下に約１／３容になるまで濃縮し、析
出した黄色結晶を濾過し、６．２ｇの２−（２，４−ジ
ニトロフェニル）アミノ−（１，３／２）−Ｌ３−シク
ロヘキサンジオール（ｍ、ｐ、２６７−２６９℃（ｄｅ
ｃ、））を得た。収率９１チ。The reaction mixture was concentrated under reduced pressure to about 1/3 volume, and the precipitated yellow crystals were filtered to give 6.2 g of 2-(2,4-dinitrophenyl)amino-(1,3/2)-L3. -Cyclohexanediol (m, p, 267-269°C (de
c, )) was obtained. Yield: 91 cm.
得られた結晶６．Ｏｌをピリジン（６０ゴ）に溶解し、
水浴にて冷却しながらメタンスルホニルクロライド（２
，２１！ｊ）を滴下した。１時間後、冷水（６ｄ）を加
え、反応混合物を減圧濃縮し、残渣を酢酸エチルに溶解
した。その溶液を冷水で洗い、無水硫酸ナトリウムで乾
燥した後、減圧下に？ｌ！！縮□した。残渣を温めた酢
酸エチルに懸濁させ、室温で放置後濾過してＰ液を減圧
濃縮した。その残渣を熱エタノールに溶解し、不溶物を
熱時デ過によって取シ除いた。テ液を室温で放置すると
４．１９の２− （２，４−ジニトロフェニル）アミノ
−１−０−メシル−（１，３７２） −１，３−シクロ
ヘキサンジオールを黄色結晶として得た。融点：１８５
−１８６℃（分解）収率５５チ。Obtained crystal 6. Dissolve Ol in pyridine (60g),
While cooling in a water bath, methanesulfonyl chloride (2
,21! j) was added dropwise. After 1 hour, cold water (6d) was added, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with cold water, dried over anhydrous sodium sulfate, and then placed under reduced pressure. l! ! It shrunk □. The residue was suspended in warmed ethyl acetate, allowed to stand at room temperature, filtered, and the P solution was concentrated under reduced pressure. The residue was dissolved in hot ethanol, and insoluble matter was removed by hot filtration. When the solution was allowed to stand at room temperature, 4.19 of 2-(2,4-dinitrophenyl)amino-1-0-mesyl-(1,372)-1,3-cyclohexanediol was obtained as yellow crystals. Melting point: 185
-186°C (decomposition) Yield: 55 cm.
次いで、そのメシレー）（３，０ｇ）とナトリウムアジ
ド（ｏ、ｓｙ）の混合物をＤＭＦ （３０ゴ）中で１０
０℃９０分間加熱攪拌した。反応混合物全減圧濃縮し、
残渣を酢酸エチルで抽出した。酢酸エチル溶液を水で洗
浄後、無水硫酸す） ＩＪウムで乾燥し減圧下に濃縮す
ると２．８ｇの結晶性の残渣が得られた。その残渣を９
Ｑｍ／のアセトン−水（２／１：Ｖ／Ｖ）に溶解し、そ
こに東京有機化学工業（株）製イオン交換樹脂「アンバ
ーライ） ＩＲＡ−４００」（ＯＨ−型）（６０ｆｆＬ
／）を加えた。−晩攪拌後樹脂を濾過によって除去し、
デ液を減圧濃縮して０．５１３の無色の結晶を得た。そ
れをエーテル−メタノールから再結晶して純粋な２−ア
ミノ−３−アジド−（１／２，３）−シクロヘキサノー
ルを得た。融点１１３−１１４℃。Then, a mixture of the methane) (3,0 g) and sodium azide (o, sy) was dissolved in DMF (30 g) for 10 min.
The mixture was heated and stirred at 0°C for 90 minutes. The reaction mixture was concentrated under reduced pressure,
The residue was extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to obtain 2.8 g of crystalline residue. The residue is 9
Dissolved in acetone-water (2/1: V/V) of Qm/, and added ion exchange resin "Amberly" IRA-400 (OH-type) (60ffL) manufactured by Tokyo Organic Chemical Industry Co., Ltd.
/) was added. - After stirring overnight, the resin is removed by filtration;
The deliquon was concentrated under reduced pressure to obtain colorless crystals of 0.513. It was recrystallized from ether-methanol to obtain pure 2-amino-3-azido-(1/2,3)-cyclohexanol. Melting point 113-114°C.
得られたアジド体２．０５’を１０チ、Ｐｄ／Ｃ（０，
２１り存在下メタノール中（５０ｍ）で接触還元（）ぞ
−ル中圧還元装置、Ｈ２＝３．４に９／α２）を行なり
た。１２時間後、触媒を濾過し、テ液を濃縮して残渣を
エタノールに溶解し、濃塩酸を用いて−を２に調整した
。その溶液を濃縮し、残渣を冷エタノールで洗浄して２
．１１１の（１／２，３ ） −２，３−ジ７ミｙ−１
−シクロヘキ茗ノールの二塩酸塩を無色の結晶として得
た。融点２１３−２１５℃（分解）。10 pieces of the obtained azide body 2.05' were mixed with Pd/C (0,
Catalytic reduction (9/α2) was carried out in methanol (50 m) in the presence of 21 ml (H2 = 3.4 using a medium pressure reduction apparatus). After 12 hours, the catalyst was filtered, the solution was concentrated, the residue was dissolved in ethanol, and - was adjusted to 2 using concentrated hydrochloric acid. The solution was concentrated and the residue was washed with cold ethanol for 2
．． 111 (1/2,3) -2,3-di7miy-1
-Dihydrochloride of cyclohexylnol was obtained as colorless crystals. Melting point 213-215°C (decomposed).
得られたジアミノシクロヘキサノールを実施例１と同様
に反応させ、処理を行ない目的とする白金錯体ジクロロ
（ＤＬ −２，３−ジアミノ−（１／２，３）−１−シ
クロヘキサノール〕白金（Ｉｆ） １．２７ Ｎ （収
率６５チ）。融点２５７−２５９℃（分解）を得た。The obtained diaminocyclohexanol was reacted and treated in the same manner as in Example 1 to obtain the desired platinum complex dichloro(DL-2,3-diamino-(1/2,3)-1-cyclohexanol)platinum (If ) 1.27 N (yield: 65 cm), melting point 257-259°C (decomposed).
元素分析値 Ｃ６Ｈ１４Ｎ２Ｃｔ２０Ｐｔとして計算値
Ｃ１８，１９，Ｈ３，５６，Ｎ ７．０７％測定値
Ｃ１７，９８，Ｈ３，５６，Ｎ ７．０９チＩＲ（ＫＢ
ｒ） ｙ ３４６０． ３２６０． ３２００． １
５８０゜１５６０、１０６０ｚ−’
実施例７
ＤＬ −ムコ−イノサジアミン−１，５ジハイドロク
ロライド（Ｂｕｌｌ、 Ｃｈｅｗ、 Ｓｏｃ、 Ｊｐｎ
、第３９巻１７０頁１９６６年参照。） ２７０”Ｓ’
（１，０７ｍｍｏ！ ）を実施例１と同様に反応させ、
処理を行ない目的とする白金錯体ジクロロ（ＤＬ−ムコ
−イノサジアミン−１，５〕白金（ｎＨ３９■（収率２
９％）を淡黄色結晶として得た。融点２２５−２２６℃
（分解）。Elemental analysis value Calculated value as C6H14N2Ct20Pt C18,19,H3,56,N 7.07% measured value
C17, 98, H3, 56, N 7.09chi IR (KB
r) y 3460. 3260. 3200. 1
580°1560, 1060z-' Example 7 DL-muco-inosadiamine-1,5 dihydrochloride (Bull, Chew, Soc, Jpn
, Vol. 39, p. 170, 1966. ) 270"S'
(1,07 mmo!) was reacted in the same manner as in Example 1,
After treatment, the desired platinum complex dichloro(DL-muco-inosadiamine-1,5)platinum (nH39■ (yield 2
9%) was obtained as pale yellow crystals. Melting point 225-226℃
(Disassembly).
元素分析値 Ｃ６Ｈ１４Ｎ２Ｃｔ２０４Ｐｔ・２．５
Ｈ２Ｏとして計算値 Ｃ１４，７５，Ｈ３，９１，Ｎ
５．７３％測定値 Ｃ１４，７１，Ｈ３，６６、Ｎ
５．７６％ＩＲ（ＫＢｒ）ｙ ３４１０，３２００，
１５８０ｍ−’実施例８
ＤＬ−ムコ−イノサジアミン−３，６−ソハイドロクロ
ライド（Ｂｕｌｌ、 Ｃｈｅｍ、 Ｓｏｃ、 Ｊｐｎ、
第４０巻、１４８８頁１９６７年参照。） ９３”ｆＦ
（０，３７ｍｍｏｌ）を実施例１と同様に反応させ、
処理を行ない目的とする白金錯体ジクロロ〔ＤＬ−ムコ
−イノサジアミン−３，６”ｌ白金（Ｉｔ）８０■（収
率３０％）を淡黄色結晶として得た。融点２１２−２１
４℃（分解）元素分析値 Ｃ６Ｈ１４Ｎ２Ｃｔ２０４Ｐ
ｔとして計算値 Ｃ１６，２２，Ｈ３，１８，Ｎ ６
．３１％測定値 Ｃ１６，３５，Ｈ３，０８，Ｎ ６
．０２％ＩＣＲ／ＣＲＪ系マウス（雌）を用い、−群５
あるいは７匹（５〜７週令）を使用した。Elemental analysis value C6H14N2Ct204Pt・2.5
Calculated value as H2O C14,75,H3,91,N
5.73% measurement value C14,71,H3,66,N
5.76%IR(KBr)y 3410,3200,
1580m-'Example 8 DL-muco-inosadiamine-3,6-sohydrochloride (Bull, Chem, Soc, Jpn,
See Vol. 40, p. 1488, 1967. ) 93”fF
(0.37 mmol) was reacted in the same manner as in Example 1,
After treatment, the desired platinum complex dichloro[DL-muco-inosadiamine-3,6''l platinum (It)] 80 μm (yield 30%) was obtained as light yellow crystals. Melting point 212-21
4℃ (decomposition) elemental analysis value C6H14N2Ct204P
Calculated value as t C16, 22, H3, 18, N 6
．． 31% measurement value C16, 35, H3, 08, N 6
．． -Group 5 using 02% ICR/CRJ mouse (female)
Alternatively, 7 mice (5 to 7 weeks old) were used.
（２ン試験方法
上記マウスの腹腔内にサルコーマ−１８０細胞、１刈０
６個を移植した日を第０日として延命率を調ぺた。実施
例１〜３，５〜７で調製した各種Ｐ仰）錯化合物を第１
日月に腹腔内に投与した。注射の溶剤には生理食塩水を
用いた。(2-in test method Sarcoma-180 cells were injected into the peritoneal cavity of the above mouse.
The survival rate was measured with the day 6 transplanted as day 0. The various P complex compounds prepared in Examples 1 to 3 and 5 to 7 were
It was administered intraperitoneally on the day of the month. Physiological saline was used as the injection solvent.
その結果は表−１〜３に示す如く、太発明のＰ ｔ（Ｉ
Ｉ）錯化合物は優れた抗腫瘍効果を示すことが判明した
。As shown in Tables 1 to 3, the results are as follows:
I) The complex compound was found to exhibit excellent antitumor effects.
表−１
（１群７匹）
表 −２（１群５匹）
表−３
（１群７匹）
実施例１０ 抗腫瘍試験２
（１）供与動物
ＢＤＦ １マウス（雌）マウスを用い、−群３あるいは
５匹（５週令）を使用した。Table-1 (7 mice per group) Table-2 (5 mice per group) Table-3 (7 mice per group) Example 10 Anti-tumor test 2 (1) Donor animal BDF 1 mouse (female) using - Groups 3 or 5 animals (5 weeks old) were used.
（２）試験方法
上記マウスの腹腔内にマウス白血病Ｌ１２１０腫瘍、ｌ
Ｘ１０５個を移植した日を第０日として延命率を調べた
。実施例１〜３．５〜８で調製した各種Ｐ ｔ（１）錯
化合物を第１．５．９日月に腹腔内投与し九。(2) Test method Mouse leukemia L1210 tumor was placed in the peritoneal cavity of the above mouse.
The survival rate was examined with the day when 105 X cells were transplanted as day 0. The various Pt(1) complex compounds prepared in Examples 1-3.5-8 were intraperitoneally administered on the 1.5.9th day of the month.
注射の溶媒には生理食塩水を用いた。Physiological saline was used as the injection solvent.
その結果は表−４〜６に示す如く、本発明のＰ ｔ（Ｉ
Ｉ）錯化合物は優れた抗腫瘍効果を示すことが判明した
。The results are shown in Tables 4 to 6, and the Pt(I
I) The complex compound was found to exhibit excellent antitumor effects.
表 −“ （１群３匹）
表 −５（１群５匹）
実施例１１′ｍ性試験
（１ン 供与動物
ＩＣＲ／ＣＲＪ系マウス（雌）を用い、−群５匹（５週
令）を使用した、７
（２）試験方法
上記マウスの腹腔内に、実施例１〜３，５〜７で調製し
た各種Ｐｔ（［）錯化合物を投与した。Table -" (3 mice per group) Table -5 (5 mice per group) Example 11'm sex test (1 donor animal ICR/CRJ mouse (female) was used, 5 mice (5 weeks old) in group - (2) Test method Various Pt([) complex compounds prepared in Examples 1 to 3 and 5 to 7 were administered intraperitoneally to the above mice.
投与後第７日月まで観察し、ＬＤ５０値を求めた。Observations were made until the 7th day after administration, and the LD50 value was determined.
注射の溶剤には生理食塩水を用いた。Physiological saline was used as the injection solvent.
その結果は表−７に示す如く、本発明のＰｔ（ｎ）錯化
合物は、シスグラチンよシ弱い毒性を示すことが判明し
た。The results are shown in Table 7, and it was found that the Pt(n) complex compound of the present invention exhibits weaker toxicity than cisgratin.
表−７
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、抗腫瘍剤としての使用が期待でき
る。故Ｋ、本発明は医薬産業上極めて有用である。Table 7 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 antitumor agent. The present invention is extremely useful in the pharmaceutical industry.
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） ▲数式、化学式、表等があります▼（Ｖ）▲数式、化学
式、表等があります▼（VI） 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) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) A cis-diaminocyclohexanol platinum complex shown by either 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） ▲数式、化学式、表等があります▼（Ｖ）▲数式、化学
式、表等があります▼（VI） 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, There are tables, etc. ▼ (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) Validate the cis-diaminocyclohexanol platinum complex shown in either Antitumor agent contained as an ingredient. 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 |
|---|---|---|---|
| JP16152986A JPS6317894A (en) | 1986-07-09 | 1986-07-09 | Novel platinum complex and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16152986A JPS6317894A (en) | 1986-07-09 | 1986-07-09 | Novel platinum complex and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6317894A true JPS6317894A (en) | 1988-01-25 |
Family
ID=15736821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16152986A Pending JPS6317894A (en) | 1986-07-09 | 1986-07-09 | Novel platinum complex and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6317894A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4999444A (en) * | 1989-03-10 | 1991-03-12 | Warner-Lambert Co. | Novel neutral mixed ligand platinum(II) and platinum(IV) complexes |
| US9220705B2 (en) | 2013-03-07 | 2015-12-29 | James David Hoeschele | Method of treating colorectal cancer |
-
1986
- 1986-07-09 JP JP16152986A patent/JPS6317894A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4999444A (en) * | 1989-03-10 | 1991-03-12 | Warner-Lambert Co. | Novel neutral mixed ligand platinum(II) and platinum(IV) complexes |
| US9220705B2 (en) | 2013-03-07 | 2015-12-29 | James David Hoeschele | Method of treating colorectal cancer |
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