JPH0232086A - Novel platinum-containing compound and malignant tumor remedy - Google Patents
Novel platinum-containing compound and malignant tumor remedyInfo
- Publication number
- JPH0232086A JPH0232086A JP63181221A JP18122188A JPH0232086A JP H0232086 A JPH0232086 A JP H0232086A JP 63181221 A JP63181221 A JP 63181221A JP 18122188 A JP18122188 A JP 18122188A JP H0232086 A JPH0232086 A JP H0232086A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- platinum
- compound
- alkyl group
- containing compound
- 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 49
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 201000011510 cancer Diseases 0.000 title claims abstract description 10
- 229910052697 platinum Inorganic materials 0.000 title claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims description 16
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- 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
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims 6
- 229910004679 ONO2 Inorganic materials 0.000 abstract description 6
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 150000003058 platinum compounds Chemical class 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 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
- 238000000921 elemental analysis Methods 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
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 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
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 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 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 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
- 238000000034 method Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 230000007694 nephrotoxicity Effects 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- UTOJPZBVJLHYGO-UHFFFAOYSA-N 1-(2,4-Dihydroxyquinolin-3-yl)ethan-1-one Chemical compound C1=CC=C2C(=O)C(C(=O)C)=C(O)NC2=C1 UTOJPZBVJLHYGO-UHFFFAOYSA-N 0.000 description 1
- 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
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 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
- 238000011765 DBA/2 mouse Methods 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
- 241001529936 Murinae Species 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
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 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
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 239000006172 buffering agent Substances 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
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose 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
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 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
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring 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
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000003721 gunpowder Substances 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
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 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
- 239000007788 liquid Substances 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
- 239000002609 medium Substances 0.000 description 1
- 239000000203 mixture Substances 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
- 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
- 239000000843 powder Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 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
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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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ｍ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 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 ｆｉｎｉｔｉｎｇ
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−ｏ、ｏ”−グリコレイト（ジアンミ
ン）白金■なとの第二世代白金１３体が開発されたく特
開昭５６−１５４４９３号公報など）。On the other hand, especially D L F (dose finishing
In order to improve renal toxicity, which has become a factor of
A), cis-o,o''-glycolate (diammine) platinum 13 second-generation platinum compounds have been developed (Japanese Patent Laid-Open Publication No. 154493/1984, 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。<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 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腫瘍
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 satisfies both the requirements of having strong antitumor activity and low toxicity, and further to provide a therapeutic agent for malignant tumors that satisfies both of these requirements. It is in.
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（＾）（ロ）下記式（
Ｃ）
（式中、Ｒ１は水素原子またはアルキル基を示れる基（
ここでＲ３，Ｒ４は同一もしくは興なり、アルキル基も
しくはフェニル基を示す、）を示す、）
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 the following - maximum (^) (b) the following formula (
C) (wherein R1 is a hydrogen atom or an alkyl group (
Here, R3 and R4 are the same or the same and represent an alkyl group or a phenyl group. This is a malignant tumor therapeutic agent that contains a platinum-containing compound as an active ingredient.
また、本発明は（イ）下記式（Ｂ）
（式中、（Ｒ５）は（ＯＮＯ２） または（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で示される白金■
化合物と
（拘下記式（Ｄ）
（式中、Ｒ１は水素原子またはアルキル基を示／Ｒ３
し、Ｒ２はアルキル基または−Ｎ８□で示される基（こ
こでＲ３、Ｒ４は同一もしくは異なり、アルキル基もし
くはフェニル基を示す、）を示す、）
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 (R5) is (ONO2) or (05O3
), platinum compounds represented by ) and platinum compounds represented by alkali metal hydroxides or alkaline earth metal hydroxides
A compound (with the following formula (D) (where R1 represents a hydrogen atom or an alkyl group/R3, and R2 represents an alkyl group or a group represented by -N8□) (where R3 and R4 are the same or different, and This is a malignant tumor therapeutic agent containing, as an active ingredient, a platinum-containing compound obtained by reacting with a compound represented by ( ) or phenyl group.
ここで、本発明化合物における は、下記式 で示される共役系を意味する。Here, in the compound of the present invention is the following formula means a conjugated system shown by
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（８１））あるいはスルファト
（１，２−ジアミノシクロヘキサン）白金■（化合物（
Ｂ ２ ））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（０）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（０）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 (81)) or sulfato(1,2-diaminocyclohexane)platinum (compound (81)).
B 2 )) in the presence of an alkali metal hydroxide or an alkaline earth metal hydroxide, or by reacting dihydroxo (1, It can be synthesized by reacting platinum (2-diaminocyclohexane) (compound (C)) with compound (0).
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２倍モル、化合物（Ｂ）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 (
Compound (B) is usually used in twice the molar amount as compared to B).
化合物（Ｃ）は、通常、化合物（Ｂ１）または（Ｂ２）
の水溶液を１１アンバーライトＩＲＡ−４００”１１ダ
イヤイオン５Ａ−１ＯＡ”などの陰イオン交換樹脂（Ｏ
Ｈ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)
An aqueous solution of anion exchange resin (O
It is obtained by passing it through a column packed with H type).
（Ｂ） ＜Ｄ）
（Ａ）
む場合があるが、７３８体も本発明化合物の範囲に含ま
れる。(B) <D) (A) However, 738 compounds are also included in 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〜１００℃、好ましくは１０〜５０℃
で、常圧下に化合物（Ｂ１）、（Ｂ２）または化合物（
Ｃ）に対して化合物（Ｄ）を０゜５〜１．１モル１モル
、好ましくは等モル１モル用い水溶液中あるいは水−エ
タノール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アコ錯体として水な含
（Ｂ１）
化合物（Ｂ２）は上記反応式においてＡｇＮＯ３の代り
にＡｇ２ Ｓｏ、を用いることによって合成することが
できる。(C) (E) (A) The reaction is usually carried out at room temperature to 100°C, preferably 10 to 50°C.
Then, compound (B1), (B2) or compound (
This can be carried out by mixing 0.5 to 1.1 mol of compound (D) to C), preferably 1 mol, preferably equimolar 1 mol, in an aqueous solution or a water-ethanol solution. The compound of the present invention thus obtained is an aco complex containing water (B1). The compound (B2) can be synthesized by using Ag2 So in place of AgNO3 in the above reaction formula.
上記反応式で得られる化合物（Ｂ１）、（Ｂ２ ） 、
（Ｃ）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と略す）の立体配置により（
ｌ・ランス−ぶ−ｄａｅｈ）（ＯＮＯ２）２、Ｐｔ （
１−ランス−ｄ−ａａｅｈ）（ＯＮＯ２）２ 、Ｐｔ
（シス−ｄ ａ ｃ ｈ ）（ＯＮＯ２）２の三種の異
性体５、Ｐｔ（トランス１−ｄａｃｈ）（０５０３）、
Ｐｔ （ｈランスｄ−ｄａｃｈ）（０３０３）、Ｐｔ
（シス−ｄａｃｈＨＯ８Ｏ３）の三種の異性体、（ｐｔ
（トランス−１−ｄａｅ ｈ）（ＯＨ）２ ）、〔Ｐｔ
（トランス−ｃｉ−ｄａｃｈ）（ＯＨ）２ ）およびｃ
ｐｔ ＜シス−ｄａｃｈ）（ＯＨ）２ ）の三種の異性
体がそれぞれ存在する。Compounds (B1), (B2) obtained by the above reaction formula,
(C) is (
l.lance-bu-daeh) (ONO2)2, Pt (
1-lance-d-aaeh)(ONO2)2, Pt
Three isomers of (cis-d ach ) (ONO2) 5, Pt (trans 1-dach) (0503),
Pt (h lance d-dach) (0303), Pt
Three isomers of (cis-dachHO8O3), (pt
(trans-1-dae h)(OH)2), [Pt
(trans-ci-dach)(OH)2) and c
There are three isomers of pt<cis-dach)(OH)2).
本発明化合物のもう一つの原料である化合物（Ｄ）は特
開昭５７−１７１９７５号公報、Ｊ、Ａｎ、 Ｃｈｅｌ
ｌ＋、 Ｓａｃ、、 ７５−１２０４４（１，９５３年
）またはＪ、 Ｃｈｅｎ、Ｓｏｅ、、８５０ （１９５
４年）に記載の方法に準じて容易に合成することができ
る。Compound (D), which is another raw material for the compound of the present invention, is disclosed in JP-A-57-171975, J. An. Chel
l+, Sac, 75-12044 (1,953) or J, Chen, Soe, 850 (195
It can be easily synthesized according to the method described in 4).
かくして得られる本発明化合物は抗Ｍ瘍剤、ずなわち腫
瘍治療剤の有効成分として使用することができるや
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
の射影は、Ｉｊｌ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（θｘｃｉｏｉｅｒＨ）
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ｈ−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、滅漏水、
グリセリン、着色剤、調味剤、濃厚剤、安定剤、等張剤
、緩衡剤なとおよびその他医薬上許容される賦形剤。The thus obtained compound of the present invention can be used as an active ingredient of an anti-M tumor agent, that is, a tumor therapeutic agent.When a therapeutic agent containing an effective amount of the compound of the present invention is administered clinically, it can be administered by oral or parenteral route. administered by. Its projections include Ijl agents, sugar-coated tablets, gunpowder, capsules, powders, lozenges, liquids, suppositories, injections, etc., which are formulated with pharmaceutically acceptable excipients (θxcioierH).
Manufactured by blending. Examples of excipients include the following: lactose, sucrose, glucose, sorbyl, 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, sesame oil, paraffin oil, medium Fat base, ethanol, propylene glycol, physiological saline, non-leakage water,
Glycerin, colorants, flavoring agents, thickeners, stabilizers, isotonic agents, buffering agents and other pharmaceutically acceptable excipients.
本発明の治療剤は、本発明化合物をｏ、ｏｏｉ〜８５！
１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 o, ooi~85!
It can be contained in an amount of 1% 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、１８成人体重あたり０．００５〜２００■、好
ましくは０．０１〜５０１１ｆである。The dosage of the therapeutic agent of the present invention mainly depends on the symptoms, but is 0.005 to 200 f/18 adult body weight, preferably 0.01 to 5011 f/18 adult body weight.
〈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
〔１−メチル−２，４（３Ｈ）−キノリンジオン−３−
（Ｎ−メチル−Ｎ−フェニル）カルボキシアミド−モノ
ヒドロキソ（トランス−１−１，２−ジアミノシクロヘ
キサン）白金■・１水和物〕
Ｐｔ（トランス−１−ｄａｃ ｈ）（ＯＮＯ２）２水溶
液を陰イオン交換樹脂“１ダイヤイオン５Ａ−１０’Ａ
″’（ＯＨ型）を充填したカラムに通して得られたＰｔ
（１−ランス−１−ｄ ａ、、 ｃ ｈ ）（ＯＨ）
２水溶液１００（＋）ｌ（４，２ミリモル）にＮ−メチ
ル−Ｎ−フェニル−１，２−ジしドロー４−ヒドロキシ
−１−メチル−２−オキソキノリン−３−カルボキシア
ミド１．２９ｇ（４，２ミリモル）を加え、室温で６時
間撹拌した８反応溶液を？！！４１ｉｌ、乾固したのち
、酢酸エチルで洗浄、減圧乾燥し、１−メチル−２，４
（３Ｈ）−キノリンジオン−３−（Ｎ−メチル−Ｎ−フ
ェニル）カルボキシアミドモノしドロキソ（トランス〜
Ｊ−１，２−ジアミノシクロヘキサン）白金■の１水和
物２．３０ ｇを得た。Example 1 [1-Methyl-2,4(3H)-quinolinedione-3-
(N-Methyl-N-phenyl)carboxamide-monohydroxo(trans-1-1,2-diaminocyclohexane)platinum monohydrate] Pt(trans-1-dach)(ONO2)2 aqueous solution was Ion exchange resin "1 Diamond Ion 5A-10'A
Pt obtained by passing through a column packed with ``'' (OH type)
(1-lance-1-d a,, ch) (OH)
Draw 1.29 g of N-methyl-N-phenyl-1,2-di-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide in 100 (+) l (4.2 mmol) of 2 aqueous solution ( 4.2 mmol) and stirred at room temperature for 6 hours. ! ! After drying, wash with ethyl acetate and dry under reduced pressure to obtain 1-methyl-2,4
(3H)-Quinolinedione-3-(N-methyl-N-phenyl)carboxamide mono-doloxo(trans-
2.30 g of platinum (J-1,2-diaminocyclohexane) monohydrate was obtained.
この化合物の赤外吸収スペクトル（ＩＲ）を第１図に、
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 infrared absorption spectrum (IR) of this compound is shown in Figure 1.
Further, the melting point and elemental analysis values are shown below (Pt was determined by atomic absorption spectrometry).
融 点 ２２２〜２２５℃（分解）実施例２
〔３−アセチル−２，４（ＩＨ１３Ｉ（）−キノリンジ
オン−モノヒドロキソ（トランス−！−１，２−ジアミ
ノシクロヘキサン）白金■・１水和物〕
実施例１と同様に処理して得られたＰｔ（トランス−ｊ
！−ｄａｃｈ）（ＯＨ）２水溶液１００［１１１１＜４
．２ミリモル）に１，２−ジヒドロ−３−アセチル−４
−ヒドロキシ−２−オキソキノリン０．８５ｇ（４，２
ミリモル）をエタノール８０ｍ１に溶かした溶液を加え
、室温で２４時間撹拌した。反応溶液を２６ｉｒに減圧
濃縮後、約１０℃に冷却し、晶析物をＰ去した。Ｐ液を
濃縮、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−２，４（ＩＨ１３Ｈ）−キノリンジオン
−モノヒドロキソ（トランス−１−１，２−ジアミノシ
クロヘキサン）白金■の１水和物１．５４ｉｒを得た（
収率６７％）。Melting point: 222-225°C (decomposed) Example 2 [3-acetyl-2,4(IH13I()-quinolinedione-monohydroxo(trans-!-1,2-diaminocyclohexane) platinum monohydrate] Pt (trans-j) obtained by the same treatment as in Example 1
! -dach)(OH)2 aqueous solution 100[1111<4
．． 2 mmol) to 1,2-dihydro-3-acetyl-4
-Hydroxy-2-oxoquinoline 0.85g (4,2
A solution of 1 mmol) dissolved in 80 ml of ethanol was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure at 26 ir, then cooled to about 10°C, and the crystallized product was removed. After concentrating and drying the P solution, it was washed with ethyl acetate and dried under reduced pressure to obtain 3-acetyl-2,4(IH13H)-quinolinedione-monohydroxo(trans-1-1,2-diaminocyclohexane)platinum. Monohydrate 1.54ir was obtained (
yield 67%).
この化合物のＩＲを第２図に、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 this compound is shown in FIG. 2, and the melting point and elemental analysis values are shown below (pt was determined by atomic absorption spectrometry).
融 点 ２５１〜２５２℃ （分解）元素分析値（
％）ＣＩ７Ｈ２５Ｎ３０Ｓ Ｐｔとして実施例３
ＣＤＦＴマウス（雄性、６週齢、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細胞
ｔ、１２ｘｏ １０５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回本発明化合物（
Ａ１）、（Ａ２）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ＣＤＤＰを用いた。各薬剤は０．０
５％”Ｔｗｅｅｎ 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: 251-252℃ (decomposition) Elemental analysis value (
%) CI7H25N30S Pt as Example 3 CDFT mice (male, 6 weeks old, 6 to 10 mice per group)
105 murine leukemia cells t,12xo passaged in DBA/2 mice were intraperitoneally transplanted. The compound of the present invention (
CDDP was used as a comparative drug in 0 experiments in which A1) and (A2) were administered intraperitoneally as test drugs. Each drug is 0.0
It was used after being dissolved or suspended in a 5% "Tween 80" solution. The effectiveness of the antitumor effect of platinum compounds on L1210-implanted mice is determined by T/
The evaluation was performed based on the C value 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、１０ｍ
ｔ／ｌｑｒ投与群において、３２７％のＴ／Ｃ値を示し
、３０日８における生存マウスも３／６であった。また
、本発明化合物（Ａ２）は、２５ｒｅｘ／ｋｇ投与群に
おいて、２６３％のＴ／Ｃ値を示した。これらは、明ら
かに、ＣＤＤＰおよびＣＢＤＣＡよりも強力な抗腫瘍作
用を示したといえる。From the results shown in Table 1, the compound (A1) of the present invention
In the t/lqr administration group, the T/C value was 327%, and 3/6 mice survived on day 30. Furthermore, the compound (A2) of the present invention showed a T/C value of 263% in the 25rex/kg administration group. It can be said that these clearly showed stronger antitumor effects than CDDP and CBDCA.
実施例４
本発明化合物（Ａ１）および（Ａ２）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。ＳＪ！
ｃ：ＩＣＲマウス（雄性：５通計）の腹腔内に本発明化
合物（Ａ１）および（Ａ２）を被検薬として投与した。Example 4 An acute toxicity test of compounds (A1) and (A2) of the present invention in mice was conducted using CDDP as a control. SJ!
c: Compounds (A1) and (A2) of the present invention were administered intraperitoneally to ICR mice (male: 5 doses in total) as test drugs.
被検薬は０゜０５％” Ｔｗｅｅｎ 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
しＤ５ｏ１ｉ！［を算出した。The test drug was dissolved or suspended in a 0.05% "Tween 80" solution. Mortality rate 14 days after administration Karashi D5o1i! [was calculated.
その結果を表２に示す。The results are shown in Table 2.
表
表２に示す結果から明らかなように、本発明化合物（Ａ
１）および（Ａ２）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) and (A2) have lower toxicity than CDDP.
〈発明の効果〉
本発明の化合物は強い抗腫瘍活性を有し、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 antitumor activity and low toxicity, and are useful as therapeutic agents for malignant tumors.
第１図および第２図は、実施例１および２で得られた本
発明化合物（Ａ１）および（Ａ２）の赤外吸収スペクト
ル（ＩＲ）をそれぞれ示す。FIG. 1 and FIG. 2 show infrared absorption spectra (IR) of the compounds (A1) and (A2) of the present invention obtained in Examples 1 and 2, respectively.
Claims (3)
＾２はアルキル基または▲数式、化学式、表等がありま
す▼で 示される基（ここでＲ＾３、Ｒ＾４は同一もしくは異な
り、アルキル基もしくはフェニル基を示す。）を示す。 ） で示される新規白金含有化合物。(1) The following general formula (A) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(A) (In the formula, R^1 represents a hydrogen atom or an alkyl group, and R
^2 represents an alkyl group or a group represented by ▲A mathematical formula, a chemical formula, a table, etc. are available (where R^3 and R^4 are the same or different and represent an alkyl group or a phenyl group). ) A new platinum-containing compound.
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） （式中、Ｒ＾１は水素原子またはアルキル基を示し、Ｒ
＾２はアルキル基または▲数式、化学式、表等がありま
す▼で 示される基（ここでＲ＾３、Ｒ＾４は同一もしくは異な
り、アルキル基もしくはフェニル基を示す。）を示す。 ）。 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^5) 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 (II) compound represented by (c) the following formula (D) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ... (D) (In the formula, R^1 represents a hydrogen atom or an alkyl group. ,R
^2 represents an alkyl group or a group represented by ▲A mathematical formula, a chemical formula, a table, etc. are available (where R^3 and R^4 are the same or different and represent an alkyl group or a phenyl group). ). A malignant tumor therapeutic agent containing as an active ingredient a platinum-containing compound obtained by reacting the compound represented by the formula.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63181221A JPH0232086A (en) | 1988-07-20 | 1988-07-20 | Novel platinum-containing compound and malignant tumor remedy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63181221A JPH0232086A (en) | 1988-07-20 | 1988-07-20 | Novel platinum-containing compound and malignant tumor remedy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0232086A true JPH0232086A (en) | 1990-02-01 |
Family
ID=16096936
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63181221A Pending JPH0232086A (en) | 1988-07-20 | 1988-07-20 | Novel platinum-containing compound and malignant tumor remedy |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0232086A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1377552A1 (en) * | 2001-02-23 | 2004-01-07 | University of Sydney | Metal complexes and therapeutic uses thereof |
| CN110078770A (en) * | 2019-05-24 | 2019-08-02 | 聊城大学 | A kind of compound, preparation method and its application in preparation of anti-tumor drugs with quinolinone tetravalence platinum structure |
| WO2023282236A1 (en) * | 2021-07-05 | 2023-01-12 | 東ソー株式会社 | Rare earth complex |
-
1988
- 1988-07-20 JP JP63181221A patent/JPH0232086A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1377552A1 (en) * | 2001-02-23 | 2004-01-07 | University of Sydney | Metal complexes and therapeutic uses thereof |
| EP1377552A4 (en) * | 2001-02-23 | 2004-06-16 | Univ Sydney | Metal complexes and therapeutic uses thereof |
| US7410960B2 (en) | 2001-02-23 | 2008-08-12 | The University Of Western Sydney | Metal complexes and therapeutic uses thereof |
| AU2002231463B2 (en) * | 2001-02-23 | 2008-08-21 | The University Of Western Sydney | Metal complexes and therapeutic uses thereof |
| CN110078770A (en) * | 2019-05-24 | 2019-08-02 | 聊城大学 | A kind of compound, preparation method and its application in preparation of anti-tumor drugs with quinolinone tetravalence platinum structure |
| WO2023282236A1 (en) * | 2021-07-05 | 2023-01-12 | 東ソー株式会社 | Rare earth complex |
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