JPH0269490A - Novel platinum-containing compound and remedy for malignant tumor - Google Patents
Novel platinum-containing compound and remedy for malignant tumorInfo
- Publication number
- JPH0269490A JPH0269490A JP63220616A JP22061688A JPH0269490A JP H0269490 A JPH0269490 A JP H0269490A JP 63220616 A JP63220616 A JP 63220616A JP 22061688 A JP22061688 A JP 22061688A JP H0269490 A JPH0269490 A JP H0269490A
- Authority
- JP
- Japan
- Prior art keywords
- platinum
- compound
- present
- containing compound
- formula
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 53
- 201000011510 cancer Diseases 0.000 title claims abstract description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims description 42
- 229910052697 platinum Inorganic materials 0.000 title claims description 17
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims abstract description 4
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims abstract 3
- 239000003814 drug Substances 0.000 claims description 15
- 229940124597 therapeutic agent Drugs 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 6
- -1 platinum (II) compound Chemical class 0.000 claims description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims 4
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910004679 ONO2 Inorganic materials 0.000 abstract description 4
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 abstract description 4
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 abstract description 4
- 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 abstract description 3
- 229910000272 alkali metal oxide Inorganic materials 0.000 abstract 1
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 231100000417 nephrotoxicity Toxicity 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 150000003058 platinum compounds Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010029155 Nephropathy toxic Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000007694 nephrotoxicity Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101100498160 Mus musculus Dach1 gene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- CCQPAEQGAVNNIA-UHFFFAOYSA-L cyclobutane-1,1-dicarboxylate(2-) Chemical compound [O-]C(=O)C1(C([O-])=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-L 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(I) nitrate Inorganic materials [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〈産業上の利用分野〉
本発明は、新規白金含有化合物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-containing compound 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
に著効を示したなめである。しかしながら、ＣＤＤＰに
は腎毒性や骨ｆｍ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). In other words, CDDP has been shown to be highly effective 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 fm toxicity, which poses problems in clinical use.
一方、特にＤ Ｌ Ｆ （ｄｏｓｅ ｌｉｌｉｔｉｎｇ
ｆａｃｔｏｒ）となっている腎毒性を改善すべく、様
々な研究が重ねられ、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、ＣＢＤＣ
Ａ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（特開
昭５６−１５４４９３号公報など）。On the other hand, especially D L F (dose
In order to improve renal toxicity, which has become a factor of
Second-generation platinum complexes of cis-0,0-glycolate (diammine) platinum (abbreviated as A) and cis-0,0-glycolate (diammine) platinum have been developed (Japanese Patent Laid-Open Publication No. 154493/1983, etc.).
〈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、
抗腫瘍作用が強く、かつ毒性が弱い白金化合物の開発が
望まれている。<Problems to be Solved by the Invention> However, although these compounds have weak nephrotoxicity, their antitumor activity is not as high as that of CDDP. For this reason,
There is a desire to develop platinum compounds that have strong antitumor 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含有化合物を提供す
ることにあり、さらにかかる両条件を満足する悪性Ｊｌ
！！！瘍治療剤を提供することにある。An object of the present invention is to provide a novel platinum-containing compound that has both strong antitumor activity and low toxicity, and also to provide a novel platinum-containing compound that satisfies both conditions.
! ! ! The purpose of the present invention is to provide a therapeutic agent for cancer.
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−最大（Ａ）で示される新規
白金含有化合物（以下、本発明化合物と略す）および上
記式（Ａ）で示される新規白金含有化合物を有効成分と
する悪性腫瘍治療剤である。That is, the present invention provides a malignant tumor therapeutic agent containing as active ingredients a novel platinum-containing compound represented by the following maximum (A) (hereinafter abbreviated as the compound of the present invention) and a novel platinum-containing compound represented by the above formula (A). It is.
また、本発明は（イ）下記式（Ｂ）
（式中、（Ｒ’ ） Ｌｔ （ＯＮＯ２） ｔ、ｆｓ
ハ（０５Ｏ３）を示す。）
で示される白金■化合物およびアルカリ金属水酸化物も
しくはアルカリ土類金属水酸化物または
（ロ）下記式（Ｃ）
で示される白金■化合物と
（ハ）下記式ＦＤ）
で示される化合物とを反応させて得られる白金含有化合
物を有効成分とする悪性腫瘍治療剤である。Further, the present invention provides (a) the following formula (B) (wherein (R') Lt (ONO2) t, fs
(05O3) is shown. ) A platinum ■ compound and an alkali metal hydroxide or an alkaline earth metal hydroxide, or (b) a platinum compound represented by the following formula (C) and (c) a compound represented by the following formula FD). This is a malignant tumor therapeutic agent whose active ingredient is a platinum-containing compound obtained by the reaction.
本発明化合物はジニトラト（１，２−ジアミノシクロヘ
キサン）白金■（化合物（Ｂｌ））あるいはジスルファ
ト（１，２−ジアミノシクロヘキサン）白金■く化合物
（Ｂ２））をアルカリ金属水酸化物もしくはアルカリ土
類金属水酸化物の存在下で、上記式＋Ｄ）で示される化
合物（化合物（Ｄ））と反応させることによって、また
は、ジヒドロキソ（１，２−ジアミノシクロヘキサン）
白金■（化合物（Ｃ））と化合物（Ｄ）とを反応させる
ことにより合成することができる。The compounds of the present invention are dinitrato(1,2-diaminocyclohexane)platinum (compound (Bl)) or disulfato(1,2-diaminocyclohexane)platinum (compound (B2))) in an alkali metal hydroxide or alkaline earth metal. By reacting with a compound represented by the above formula +D (compound (D)) in the presence of hydroxide, or dihydroxo(1,2-diaminocyclohexane)
It can be synthesized by reacting platinum (compound (C)) and compound (D).
ここで、アルカリ金属水酸化物もしくはアルカリ土類金
属水酸化物としては、水酸化ナトリウム、水酸化カリウ
ム、水酸化バリウムなどが好ましく用いられ、化合物（
Ｂ）に対して通常１〜２，５倍モル、化合物（０）に対
して１〜２．５倍モル用いる。Here, as the alkali metal hydroxide or alkaline earth metal hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. are preferably used, and the compound (
It is usually used in an amount of 1 to 2.5 times mole relative to B), and 1 to 2.5 times mole relative to compound (0).
化合物（Ｃ）は、通常、化合物（Ｂ１）または（Ｂ２）
の水溶液を“アンバーライトＩ ＲＡ−４００”″ダイ
ヤイオン５Ａ−１０Ａ″などの陰イオン交換樹脂（ＯＨ
型）を充填したカラムに通して得られる。Compound (C) is usually compound (B1) or (B2)
Anion exchange resin (OH
It is obtained by passing it through a column packed with
（Ｂ） （Ｄ）（Ａ）
コ錯体も本発明化合物の範囲に含まれる。ここでアコ錯
体として含まれる水の量は反応条件によって異なるが、
いずれのものも本発明化合物の範囲に含まれることは勿
論である。(B) (D) (A) Co-complexes are also included within the scope of the compounds of the present invention. The amount of water contained in the aco complex here varies depending on the reaction conditions, but
Of course, any of these compounds is included within the scope of the compounds of the present invention.
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■（化合物（Ｂｌ））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 (compound (Bl)), which is a raw material for the compound of the present invention, can be synthesized, for example, by the following method.
（Ｃ）
（Ｅ）
（Ａ）
反応は通常、常温、常圧下に化合物（Ｂ１）、（Ｂ２）
または化合物（Ｃ）に対して化合物（０）を２〜２．５
倍モル１モル用い水溶液中あるいは水−エタノール溶液
中で混和することにより実施できる。このようにして得
られた本発明化合物はＴコｉ′ａ体として水そ古む場合
がめるが、Ｔ（Ｂ１）
化合物（Ｂ２）は上記反応式におへ）てＡｇＮｏ３の代
りにＡ ｇ ２ Ｓ Ｏ４を用〜することＧこよって合
成することができる。(C) (E) (A) The reaction is usually carried out by adding compounds (B1) and (B2) at room temperature and pressure.
or 2 to 2.5 of compound (0) to compound (C)
This can be carried out by mixing in an aqueous solution or a water-ethanol solution using 1 mole. The compound of the present invention obtained in this manner may deteriorate in water as a T coi'a form, but T (B1) compound (B2) is converted into A g 2 instead of AgNo3 in the above reaction formula. It can be synthesized by using SO4.
上記反応式で得られる化合物（Ｂ１）、（Ｂ２）、（Ｃ
）には、原料として用（Ｘる１、２−ジアミノシクロヘ
キサン（以下、ｄａｃｈと略す）の立体配置によりＰｔ
（トランス−１−ｄａｃｈ）（ＯＮＯ２）２、Ｐｔ （
トランス−ｄ−ｄａｃ ｈＨＯＮＯ２）２ 、Ｐｔ （
シス−ｄａｃｈ）（ＯＮＯ２）２の三種の異性体１、Ｐ
ｔ（トランス−ｆｔ−ｄａｃｈ）（０８０３） 、Ｐｔ
（トランス−ｄ−ｄａｃｈ）（Ｏ３Ｏ３） 、Ｐｔ
（シス−ｄａｃｈ）（Ｏ３Ｏ３）の三種の異性体、〔Ｐ
ｔ（トランス−ｊ！−ｄａｃｈ）（ＯＨ）２）、：Ｐｔ
（トランス−ｄ−ｄａｃｈ）（ＯＨ）２ ）および（ｐ
ｔ ＜シス−ｄａｃｈＨＯＨ）２ ）の三種の異性体が
それぞれ存在する。Compounds (B1), (B2), (C
) has Pt as a raw material due to the configuration of 1,2-diaminocyclohexane (hereinafter abbreviated as dach).
(trans-1-dach)(ONO2)2,Pt (
trans-d-dac hHONO2)2, Pt (
Three isomers of cis-dach) (ONO2) 1, P
t(trans-ft-dach)(0803), Pt
(trans-d-dach)(O3O3), Pt
Three isomers of (cis-dach)(O3O3), [P
t(trans-j!-dach)(OH)2), :Pt
(trans-d-dach)(OH)2) and (p
There are three isomers of t<cis-dachHOH)2).
かくして得られる本発明化合物は抗腫瘍剤、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 can be used as an active ingredient of an antitumor agent, that is, a tumor therapeutic 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、串刺、注射剤などを包含し、これらは
、医薬上許容される賦形剤（ｅｘｃｉｐｉｅｎｔ）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（たと
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、等張剤、榎
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, lozenges, liquids, skewers, injections, etc., which are manufactured by incorporating pharmaceutically acceptable excipients. be done. 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, and thickening agents. , stabilizers, isotonic agents, thickeners, etc., and other pharmaceutically acceptable excipients.
本発明の治療剤は、本発明化合物を０．００１〜８５ｆ
！量％、好ましくは０．００５〜６０重量％含有するこ
とができる。The therapeutic agent of the present invention contains the compound of the present invention at 0.001 to 85f.
! %, 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０．００５〜２００■、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 0.005 to 200 cm, preferably 0.01 to 50 cm per 10 adult body weights.
〈実施例〉
以下、実施例を挙げて本発明をさらに具体的に説明する
。<Example> Hereinafter, the present invention will be explained in more detail by giving examples.
実施例１
（Ｐｔ （）−ランス−１−ｄａｃｈ）３０４）水溶液
３０ｍ１（５ミリモル）に０ｕｉｎｔｃＡｃｉｄ１．９
６ｇと水酸化バリウム・８８２０１．５８ｇの水溶液３
０ｍ１を滴下した。室温上暗所で４日間撹拌後、反応液
を十分に水冷し、析出物を濾過した。枦液を全：ａ縮後
、水−エタノール系で精製することにより薄黄色粉末状
のビス（Ｉ Ｒ１３Ｒ１４Ｒ１５Ｒ−テトラヒドロへシ
シクロヘキサン力ルポキシラト）（トランス−１！−ｄ
ａｃｈ）白金■含有化合物の４水和物く以下、本発明化
合物（Ａ１）と略す）を２．１７ｇ得た０本発明化合物
〈Ａ１）の赤外吸収スペクトル（ＩＲ）を第１図に示す
、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）。Example 1 (Pt()-Lance-1-dach)304) 0 uintcAcid 1.9 in 30 ml (5 mmol) of aqueous solution
6g and barium hydroxide・88201.58g aqueous solution 3
0ml was added dropwise. After stirring for 4 days at room temperature in the dark, the reaction solution was sufficiently cooled with water, and the precipitate was filtered. After condensing the citrus liquid, it was purified in a water-ethanol system to obtain a pale yellow powder of bis(I
ach) 2.17 g of tetrahydrate of a platinum-containing compound (hereinafter abbreviated as the compound of the present invention (A1)) was obtained. The infrared absorption spectrum (IR) of the compound of the present invention (A1) is shown in Figure 1. In addition, the melting point and elemental analysis values are shown below (Pt was determined by atomic absorption spectrometry).
融 点 １７４〜１７９℃ （ｄｅｃン元素分
析値（％） Ｃ２ｏＨ３６Ｎ ２０＋ｚ −Ｐ ｔ −
４Ｒ２０として
実施例２
ＣＤＦ＋マウス（雄性、６週齢、１群６〜］Ｏ匹使用）
腹腔内にＤＢＡ／２マウスで継代したマウス白血病細胞
Ｌ１２１０ １０Ｓ個を移植した。移植日を０日として
、１日目、５日目、９日目の計３回本発明化合￥ＩＪ（
ＡＩ）を被検薬として腹腔内投与した８本実験の比較薬
としてはＣＤＤＰを用いた。各薬剤は０．０５％”Ｔｗ
ｅｅｎ８０”溶液に溶解または懸濁して使用した。Ｌ１
２１０移植マウスに対する白金化合物の抗腫瘍作用の効
果判定は、以下の式により求められるＴ／Ｃ値ならびに
３００日目おける生存マウス数によって行った。Melting point 174-179℃ (dec elemental analysis value (%) C2oH36N 20+z -P t -
Example 2 CDF+ mice (male, 6 weeks old, 6 to 1 group) O mice were used as 4R20.
10S mouse leukemia cells L1210 passaged in DBA/2 mice were intraperitoneally transplanted. The compound of the present invention ￥IJ (
CDDP was used as a comparison drug in eight experiments in which AI) was administered intraperitoneally as a test drug. Each drug is 0.05%”Tw
It was used by dissolving or suspending it in een80” solution. L1
The antitumor effect of the platinum compound on 210-implanted mice was evaluated based on the T/C value determined by the following formula and the number of surviving mice on the 300th day.
表 結果を表１に示す。table The results are shown in Table 1.
表１に示す結果より、本発明化合物（Ａ１）は、ｉｏｏ
■／ ｋｇ投与群において、２４１％のＴ／ＣＭを示し
、３０日Ｉｃおける生存マウスも１１６であった。これ
は、ＣＤＤＰおよびＣＢＤＣＡよりも強い抗腫瘍作用を
示したといえる。From the results shown in Table 1, the compound (A1) of the present invention has ioo
■/kg administration group showed T/CM of 241%, and the number of surviving mice after 30 days Ic was also 116. It can be said that this showed a stronger antitumor effect than 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。ＳＩ Ｃ： ＩＣＲ７
ウス（ａ性：５週齢）ノ腹腔内に本発明化合物（Ａ１）
を被検薬として投与した。被検薬は０．０５％” Ｔｗ
ｅｅｎ ８０”溶液に溶解または懸濁して用いた。投与
後１４日口の死亡率からＬ Ｄ ｓ ｏ値を算出した。Example 3 An acute toxicity test of the compound (A1) of the present invention in mice was conducted using CDDP as a control. SIC: ICR7
The compound of the present invention (A1) was intraperitoneally administered to a mouse (a sex: 5 weeks old).
was administered as the test drug. Test drug is 0.05%” Tw
The L Dso value was calculated from the mortality rate 14 days after administration.
その結果を表２に示す。The results are shown in Table 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。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＠瘍活性を有し、かつ毒性も弱
く、悪性Ｉｌｌｌｌ療治療剤て有用である。<Effects of the Invention> The compound of the present invention has strong anti-cancer activity and low toxicity, and is useful as a therapeutic agent for malignant disease.
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 an infrared absorption spectrum of the compound (A1) of the present invention obtained in Example 1.
Claims (3)
する悪性腫瘍治療剤。(2) A therapeutic agent for malignant tumor comprising the novel platinum-containing compound according to claim 1 as an active ingredient.
Ｏ＿３）を示す。） で示される白金（II）化合物およびアルカリ金属水酸化
物もしくはアルカリ土類金属水酸化物または （ロ）下記式（Ｃ） ▲数式、化学式、表等があります▼・・・・・・（Ｃ） で示される白金（II）化合物と （ハ）下記式（Ｄ） ▲数式、化学式、表等があります▼・・・・・・（Ｄ） で示される化合物を反応させて得られる白金含有化合物
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). ) Platinum (II) compounds and alkali metal hydroxides or alkaline earth metal hydroxides, or (b) the following formula (C) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(C ) A platinum-containing compound obtained by reacting a platinum (II) compound represented by (c) the following formula (D) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(D) A malignant tumor treatment agent containing as an active ingredient.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63220616A JPH0269490A (en) | 1988-09-02 | 1988-09-02 | Novel platinum-containing compound and remedy for malignant tumor |
| PCT/JP1988/001137 WO1989004318A1 (en) | 1987-11-11 | 1988-11-11 | Platinum complex and therapeutic agent for malignant tumor |
| EP19880909832 EP0345356A4 (en) | 1987-11-11 | 1988-11-11 | Platinum complex and therapeutic agent for malignant tumor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63220616A JPH0269490A (en) | 1988-09-02 | 1988-09-02 | Novel platinum-containing compound and remedy for malignant tumor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0269490A true JPH0269490A (en) | 1990-03-08 |
Family
ID=16753765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63220616A Pending JPH0269490A (en) | 1987-11-11 | 1988-09-02 | Novel platinum-containing compound and remedy for malignant tumor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0269490A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10663331B2 (en) | 2013-09-26 | 2020-05-26 | Rosemount Inc. | Magnetic flowmeter with power limit and over-current detection |
-
1988
- 1988-09-02 JP JP63220616A patent/JPH0269490A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10663331B2 (en) | 2013-09-26 | 2020-05-26 | Rosemount Inc. | Magnetic flowmeter with power limit and over-current detection |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0228298B1 (en) | Stable soluble 1,2-diamino-cyclohexane platinum complexes | |
| JPH02795A (en) | 1,2-bis(aminomethyl)cyclobutane-platinum complex compound, its manufacture, drug containing it and having antitumor action, and manufacture of said drug | |
| ITMI940610A1 (en) | PLATINUM TRINUCLEAR CATIONIC COMPLEXES FOR ANTI-CANCER ACTIVITIES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
| EP0163316B1 (en) | Platinum-intercalative complexes for the treatment of cancer | |
| CN101456881A (en) | Luteolin and platinum complexes of derivatives thereof, preparation method and use thereof | |
| CN101475596A (en) | Platinum complexes of quercetin and derivatives thereof, as well as preparation and use thereof | |
| JPH0269490A (en) | Novel platinum-containing compound and remedy for malignant tumor | |
| JPH10509159A (en) | Trinuclear cationic platinum complex having antitumor activity and pharmaceutical composition containing them | |
| JPH0311091A (en) | Novel platinum (ii) complex and remedy for malignant tumor | |
| JPH02311489A (en) | New platinum-containing compound and treating agent for malignant tumor | |
| JPH01157993A (en) | Novel platinum (ii) complex and malignant tumor remedy | |
| JPH0232086A (en) | Novel platinum-containing compound and malignant tumor remedy | |
| JPH02286694A (en) | New platinum (ii) complex and malignant tumor remedy | |
| JPH01165594A (en) | Novel platinum(ii)complex and remedy for malignant tumor | |
| JPH01132596A (en) | Novel pt(ii) complex and remedy for malignant tumor | |
| JPH0236144A (en) | Novel platinum (ii) complex and remedy for malignant tumor | |
| JPH01128991A (en) | Novel platinum (ii) complex and remedy for malignant tumor | |
| JPH0311090A (en) | Novel platinum-containing compound and remedy for malignant tumor | |
| JPH0245494A (en) | Novel platinum-containing compound and remedy for malignant tumor | |
| JPH01143884A (en) | Novel platinum (ii) complex and remedy for malignant tumor | |
| JP2778043B2 (en) | New platinum-containing compounds and therapeutic agents for malignant tumors | |
| JPH01163192A (en) | Novel platinum(ii) complex and remedy for malignant tumor | |
| JPS63303987A (en) | Novel platinum (ii) complex and remedy for therioma | |
| JPS61249993A (en) | Novel organoplatinum complex and production thereof | |
| JPH02295993A (en) | Novel platinum (ii) complex and malignant tumor therapeutic agent therefrom |