JPH0242094A - Novel platinum-containing compound and remedy for malignant tumor - Google Patents
Novel platinum-containing compound and remedy for malignant tumorInfo
- Publication number
- JPH0242094A JPH0242094A JP63194020A JP19402088A JPH0242094A JP H0242094 A JPH0242094 A JP H0242094A JP 63194020 A JP63194020 A JP 63194020A JP 19402088 A JP19402088 A JP 19402088A JP H0242094 A JPH0242094 A JP H0242094A
- Authority
- JP
- Japan
- Prior art keywords
- platinum
- compound
- formula
- present
- 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 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 47
- 229910052697 platinum Inorganic materials 0.000 title claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims abstract description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 16
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- -1 platinum (II) compound Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 6
- 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
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 abstract 2
- WYBUYWCJZMQESH-UHFFFAOYSA-N 2-acetylcyclopentane-1,3-dione Chemical compound CC(=O)C1C(=O)CCC1=O WYBUYWCJZMQESH-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 7
- 229940079593 drug Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
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- 238000012360 testing method Methods 0.000 description 3
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- 238000000921 elemental analysis Methods 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
- 230000003211 malignant effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
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- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000003058 platinum compounds Chemical class 0.000 description 2
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- 244000215068 Acacia senegal Species 0.000 description 1
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- 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
- 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
- 206010029155 Nephropathy toxic Diseases 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
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- 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
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
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- 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
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 238000001479 atomic absorption spectroscopy Methods 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
- 230000037396 body weight Effects 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
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- 238000002512 chemotherapy Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- LOGSONSNCYTHPS-UHFFFAOYSA-N cyclopentane-1,3-dione Chemical compound O=C1CCC(=O)C1 LOGSONSNCYTHPS-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
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- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 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
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 231100001231 less toxic Toxicity 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- KIDPOJWGQRZHFM-UHFFFAOYSA-N platinum;hydrate Chemical compound O.[Pt] KIDPOJWGQRZHFM-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229910000367 silver sulfate Inorganic materials 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
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- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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Ｈ療治療剤に関する。DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel platinum-containing compound and a therapeutic agent for treating malignant H, which contains 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件器癌
に著効を示したためである。以来、抗腫瘍活性を有する
白金銘木の研究が盛んに行われるようになってきなく例
えば、特開昭５４−７０２４６号公報）。<Prior Art> Chemotherapy for malignant tumors has made dramatic progress in recent years with the application of cis-dichloro(diammine)platinum (hereinafter abbreviated as CDDP). That is, CDDP has shown remarkable efficacy against organ cancers such as ovarian cancer and testicular cancer, which were previously difficult to treat with chemotherapeutic agents. Since then, research on precious platinum wood having antitumor activity has been actively conducted (for example, Japanese Patent Application Laid-Open No. 70246/1983).
〈発明が解決しようとする課題〉
しかしながら、ＣＤＤＰをはじめとする従来の白金Ｉ？
Ｉ木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。このため毒性が弱い
白金錯体の開発が望まれている。<Problem to be solved by the invention> However, conventional platinum I including CDDP?
I trees have serious side effects such as nephrotoxicity and bone marrow toxicity.
This has become a problem in clinical use. Therefore, the development of platinum complexes with low toxicity is desired.
本発明の目的は、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新規白金含有
化合物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 antitumor activity and having low toxicity, and further to provide a novel platinum-containing compound that satisfies both of these conditions. be.
く課題を解決するための手段〉 上記目的は、以下の本発明により達成される。Means to solve problems〉 The above object is achieved by the present invention as described below.
すなわち、本発明は、下記一般式（Ａ）（式中、Ｒは炭
素原子数１〜１７のアルキル基を示す。）
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 a novel platinum-containing compound (hereinafter abbreviated as the present compound) represented by the following general formula (A) (wherein R represents an alkyl group having 1 to 17 carbon atoms) and the above formula This is a malignant tumor therapeutic agent containing the novel platinum-containing compound represented by (A) as an active ingredient.
また、本発明は、（イ）下記式ＦＢ）
（式中、（Ｒ１）は（ＯＮＯ２） または（Ｏ５０３
）を示す。）
で示される白金■化合物と（ロ）下記式（Ｃ）（式中、
Ｒは炭素原子数１〜１７のアルキル基を示す。）
で示される化合物および（）９水酸化アルカリを反応さ
せて得られる白金含有化合物を有効成分とする悪性８瘍
治療剤であり、さらに、本発明は（イ）下記式（０）
で示される白金■化合物と（ロ）下記式（Ｃ）（式中、
Ｒは炭素原子数１〜１７のアルキル基を示す。）
で示される化合物を反応させて得られる白金含有化合物
を有効成分とする悪性１１ｆ、治療剤である。Further, the present invention provides (a) the following formula FB) (wherein (R1) is (ONO2) or (O503
) is shown. ) A platinum compound represented by (b) the following formula (C) (in the formula,
R represents an alkyl group having 1 to 17 carbon atoms. ) The present invention is a therapeutic agent for malignant tumor 8 which contains as an active ingredient a platinum-containing compound obtained by reacting the compound represented by (a) and ()9 alkali hydroxide, and furthermore, the present invention provides (a) a compound represented by the following formula (0) Platinum compound and (b) the following formula (C) (in the formula,
R represents an alkyl group having 1 to 17 carbon atoms. ) This is a therapeutic agent for malignant 11f, which contains as an active ingredient a platinum-containing compound obtained by reacting the compound shown below.
上記式においてＲは炭素原子数１〜１７のアルキル基を
示す、Ｒの具体的例としては、メチル基、エチル基、プ
ロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチ
ル基、オクチル基、ノニル基、デシル基、ウンデシル基
、ドデシル基、トリデシル基、テトラデシル基、ペンタ
デシル基、ヘキサデシル基、ヘプタデシル基などが挙げ
られる。Ｒは好ましくは炭素原子数１〜４の低級アルキ
ル基を示し、特に好ましくはメチル基を示す。In the above formula, R represents an alkyl group having 1 to 17 carbon atoms. Specific examples of R include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group. group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, etc. R preferably represents a lower alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl group.
ここで、本発明化合物の は下記式 で示される共役系を意味する。Here, 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（Ｂｌ））またはスルファト（
１，２−ジアミノシクロヘキサン）白金■（化合物（Ｂ
２ ））を水酸化アルカリの存在下で、上記式（Ｃ）
で示される化合物（化合物（Ｃ））と反応させることに
よって合成することができる。ここで、水酸化アルカリ
としては、水酸化ナトリウム、水酸化カリウム、水酸化
バリウムなどが好ましく用いられ、化合物（Ｃ）に対し
て通常０．７〜１．３倍モル、好ましくは１倍モル用い
る。The compound of the present invention is dinitrato(1,2-diaminocyclohexane)platinum (compound (Bl)) or sulfato(
1,2-diaminocyclohexane) platinum (compound (B)
2)) in the presence of an alkali hydroxide, the above formula (C)
It can be synthesized by reacting with the compound shown in (compound (C)). Here, as the alkali hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. are preferably used, and the amount is usually 0.7 to 1.3 times mole, preferably 1 times mole, relative to compound (C). .
また、本発明化合物は化合物（Ｂ１）または（Ｂ２）の
水溶液をゝ′アンバーライトＩＲＡ−４００”ダイヤイ
オン５Ａ−１０Ａ”などの陰イオン交換樹脂（ＯＩ−１
型）を充填したカラムに通して得られたジヒドロキソ（
１，２−ジアミノシクロヘキサン）白金■（化合物（Ｄ
））と化合物（Ｃ）とを反応させることにより合成する
ことができる。In addition, the compound of the present invention can be used by adding an aqueous solution of compound (B1) or (B2) to an anion exchange resin (OI-1
Dihydroxo (type) obtained by passing it through a column packed with
1,2-diaminocyclohexane) platinum (compound (D
)) and compound (C).
（Ｂ） （Ｃ）
（Ａ）
（Ｄ）
（Ａ）
反応は通常、常温〜６０℃、好ましくは常温で、常圧下
に化合物（Ｂ１）、（Ｂ２）または化合物（Ｄ）に対し
て化合物（Ｃ）を水溶液中あるいは水−エタノール溶液
中で混和、加熱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を含む場
合があるが、アコ錯体も本発明化合物の範囲に含まれる
。(B) (C) (A) (D) (A) The reaction is usually carried out between compound (B1), (B2) or compound (D) at room temperature to 60°C, preferably room temperature, and under normal pressure. This can be carried out by mixing C) in an aqueous solution or a water-ethanol solution and heating. Although the compound of the present invention thus obtained may contain water as an aco complex, the aco complex is also included within the scope of the compound 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.
（Ｅ）
（Ｂ１）
化合物（Ｂ２）は上記反応式においてＡｇＮＯ３の代り
にＡｇ２ＳＯ４を用いることによって合成することがで
きる。(E) (B1) Compound (B2) can be synthesized by using Ag2SO4 instead of AgNO3 in the above reaction formula.
上記反応式で得られる化合物（Ｂ１）、（Ｂ２）、（Ｄ
）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（トラン
ス−１−ｄ ａ ｃ ｈ ）（ＯＮＯ２） 、Ｐｔ（ト
ランス−ｄ−ｄａｃｈ）（ＯＮＯ２） 、Ｐｔ （シ
ス−ｄａｃｈ）（ＯＮ０２） の三種の異性体、Ｐｔ
ｌランス−ぶ−ｄａｃｈ）（０３０３） 、Ｐｔ （ト
ランス−ｄ−ｄａｃｈ）（Ｏ３Ｏ３） 、Ｐｔ （シス
−ｄａｃｈ）（Ｏ３Ｏ３）の三種の異性体、〔Ｐｔ（ト
ランス−１−ｄａｃｈ）（ＯＨ）２）、〔Ｐｔ（トラン
ス−ｄ−ｄａｃｈＨＯＨ）２ ）およびＣＰｔ（シス−
ｄａｃｈ）（ＯＨ）２ ）の三種の異性体がそれぞれ存
在する。Compounds (B1), (B2), (D
), depending on the configuration of 1,2-diaminocyclohexane (hereinafter abbreviated as dach) used as a raw material, (trans-1-d ach ) (ONO2) , Pt (trans-d-dach) (ONO2) , Pt (cis-dach) (ON02) three isomers, Pt
Three isomers of Pt (trans-dach) (0303), Pt (trans-d-dach) (O3O3), and Pt (cis-dach) (O3O3), [Pt (trans-1-dach) (OH) 2), [Pt(trans-d-dachHOH)2) and CPt(cis-
There are three isomers of dach)(OH)2).
本発明化合物のもう一つの原料である化合物（Ｃ）
はＪ、 八ｌ Ｃｈｅｎ＋、 Ｓｏｃ、、 ７−ゴ
５１、５０３０〜５０３２ （１９５３＞に記載の方法
に準じて、シクロペンタン−１，３−ジオンをＢＰ３触
媒触媒酸無水物でアシル化することにより合成すること
ができる。Compound (C) which is another raw material for the compound of the present invention
by acylating cyclopentane-1,3-dione with a BP3-catalyzed acid anhydride according to the method described in J. Can be synthesized.
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、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（ＯＸＣｉ １３１ｅｎｔ
）を配合して製造される。賦形剤としては次のようなも
のを例示することができる。乳糖、ショ糖、ブドウ糖、
ソルビトール、マンニトール、ばれいしょでんぷん、ア
ミロペクチン、その他各種でんぷん、セルローズ誘導体
（例えば、カルボキシメチルセルローズ、ハイドロキシ
エチルセルローズなど）、ゼラチン、ステアリン酸マグ
ネシウム、ポリビニルアルコール、ステアリン酸カルシ
ウム、ポリエチレングリコールワックス、アラビアゴム
、タルク、二酸化チタン、オリーブ油、ピーナツ油、ゴ
マ油などの植物油、パラフィン油、中性脂肪基剤、エタ
ノール、プロピレングリコール、生理食塩水、滅菌水、
グリセリン、着色剤、調味剤、濃厚剤、安定剤、等張剤
、榎街剤などおよびその他医薬上許容される賦形剤。When administering a therapeutic agent containing an effective amount of the compound of the present invention in a clinical setting, it is administered by oral or parenteral routes. The dosage forms include tablets, sugar-coated tablets, gunpowders, capsules, powders, troches, solutions, suppositories, injections, etc., which may be prepared using pharmaceutically acceptable excipients (OXCi 131ent
). 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, dioxide Titanium, vegetable oils such as olive oil, peanut oil, and sesame oil, paraffin oil, neutral fat base, ethanol, propylene glycol, physiological saline, sterile water,
Glycerin, colorants, flavoring agents, thickeners, stabilizers, isotonic agents, tonic agents, etc. and other pharmaceutically acceptable excipients.
本発明の治療剤は、本発明化合物を０．００１〜８５重
量％、好ましくは０．００５〜６０重量％含有すること
ができる。The therapeutic agent of the present invention may contain 0.001 to 85% by weight, preferably 0.005 to 60% by weight of the compound of the present invention.
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０．００５〜２００ｒ＠ｔ
、好ましくはｏ、０１〜５ｏｆｌＩｌｒである。The dosage of the therapeutic agent of the present invention mainly depends on the symptoms, but is 0.005 to 200 r@t per 18 adult body weight.
, preferably o, 01-5oflIlr.
〈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Ｉ
Ｐｔ（トランス−１−ｄａｃｈＨＯＮＯ２）２水洛液を
陰イオン交換樹脂゛１ダイヤイオン５Ａ−１ＯＡ”（Ｏ
Ｈ型）を充填したカラムに通して得られたＰｔ （）ラ
ンス−ｆｌ−ｄａｃｈ）（ＯＨ）２水溶液１００ｍ１（
４，２ミリモル）ニ２−アセチルシクロペンタン−１，
３−ジオン０゜５８＋ｒ（４，２ミリモル）を加え、室
温で２４時間撹拌した。反応溶液を乾固したのち、酢酸
エチルで洗浄、減圧乾燥して２−アセチルシクロペンタ
ン−１，３−ジオン−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（以下、
本発明化合物（Ａ１）と略す）を１．８０ｒ得た（収率
８９％）。Example I Pt (trans-1-dachHONO2)2 aqueous solution was treated with anion exchange resin ``1Diaion 5A-1OA'' (O
100 ml of an aqueous solution of Pt ()lance-fl-dach)(OH)2 obtained by passing it through a column packed with
4,2 mmol) di-2-acetylcyclopentane-1,
3-dione 0°58+r (4.2 mmol) was added and stirred at room temperature for 24 hours. After drying the reaction solution, it was washed with ethyl acetate and dried under reduced pressure to give 2-acetylcyclopentane-1,3-dione-hydroxo (trans-1-1,
2-diaminocyclohexane) platinum monohydrate (hereinafter referred to as
1.80 r of the compound of the present invention (abbreviated as A1) was obtained (yield: 89%).
本発明化合物（Ａ１）の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 IR of the compound (A1) of the present invention is shown in FIG. 1, and the melting point and elemental analysis values are shown below (pt was determined by atomic absorption spectrometry).
融 点 ２４８〜２５０℃ （分解）元素分析
Ｍ（％）ＣＩ４Ｈ２４Ｎ２０５ Ｐｔとして実施例２
ＣＤＦ、マウス（雄性、６週齢、１群６〜ｌＯ匹使用）
Ｍ、腔内にＤＢＡ／２マウスで継代したマウス白血病細
胞Ｌ１２１０ １０５個を移植した。移植日を０日とし
て、１日日、５日日、９日日の計３回本発明化合物（Ａ
Ｉ）を被検薬として腹腔的投与した。本実験の比較薬と
してはＣＤＤＰを用いた。各薬剤は０．０５％” Ｔｙ
ｔｅｅｎ８０′″溶液に溶解または懸濁して使用した。Melting point 248-250°C (decomposition) Elemental analysis M (%) CI4H24N205 as Pt Example 2 CDF, mice (male, 6 weeks old, 6-10 mice per group)
M, 105 murine leukemia cells L1210 passaged in DBA/2 mice were implanted into the cavity. The compound of the present invention (A
I) was administered intraperitoneally as a test drug. CDDP was used as a comparative drug in this experiment. Each drug is 0.05%” Ty
It was used by dissolving or suspending it in teen80'' solution.
Ｌ１２１０移植マウスに対する白金８＃の抗Ｉｌ！！！
瘍作用の効果判定は、以下の式により求められるＴ／Ｃ
ｌｉならびに３０日ｎ６おける生存マウス数によって行
った。Anti-Il of platinum 8# against L1210 implanted mice! ! !
The effect of tumor action is determined by T/C determined by the following formula:
li and the number of surviving mice at 30 days n6.
結果を表１に示す。The results are shown in Table 1.
表
表１に示す結果から明らかなように、本発明化合物（Ａ
１）は、１０■／ ｋｓｒ投与群において２３１％のＴ
／Ｃ値を示し、３０日百日おける生存マウスも１／６で
あった。これは明らかにＣＤＤＰと同等な強い抗腫瘍作
用であるといえる。As is clear from the results shown in Table 1, the compound of the present invention (A
1) was 231% T in the 10/ksr administration group.
/C value, and survival of mice after 30 days and 100 days was also 1/6. This can clearly be said to be a strong antitumor effect equivalent to that of CDDP.
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
行った。Ｓ、ｅｃ：ＩＣＲマウス（雄性；５適齢）の腹
腔内に本発明化合物（Ａ１）を被検薬として投与した。Example 3 An acute toxicity test was conducted on the compound (A1) of the present invention in mice. The compound (A1) of the present invention was administered intraperitoneally to S, ec: ICR mice (male; age 5) as a test drug.
被検薬は０．０５％” Ｔｗｅｎｅ ８０”溶液に溶解
または懸濁して用いた。The test drug was dissolved or suspended in a 0.05% "Tween 80" solution.
投与後１４日０の死亡率からしＤ５ｏｇＭを算出した。D5ogM was calculated from the mortality rate on day 14 after administration.
その結果を表２に示す。The results are shown in Table 2.
表 ２
表２より、本発明化合物（Ａ１）はＣＤＤＰよりも一低
毒性であった。Table 2 From Table 2, the compound (A1) of the present invention was less toxic 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図は実施例１で得られた本発明化合物（Ａ１）の赤
外吸収スペクトルを示す。FIG. 1 shows the infrared absorption spectrum of the compound (A1) of the present invention obtained in Example 1.
Claims (4)
瘍治療剤。(2) Shown by the following general formula (A) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(A) (In the formula, R represents an alkyl group having 1 to 17 carbon atoms.) A malignant tumor treatment agent containing a new platinum-containing compound as an active ingredient.
Ｏ＿３）を示す。） で示される白金（II）化合物と（ロ）下記式（Ｃ）▲数
式、化学式、表等があります▼・・・・・・（Ｃ） （式中、Ｒは炭素原子数１〜１７のアルキル基を示す。 ） で示される化合物および（ハ）水酸化アルカリを反応さ
せて得られる白金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). ) and (b) the following formula (C) ▲ Numerical formulas, chemical formulas, tables, etc. ▼・・・・・・(C) a malignant tumor therapeutic agent containing as an active ingredient a compound represented by (representing an alkyl group) and (iii) a platinum-containing compound obtained by reacting an alkali hydroxide;
式、化学式、表等があります▼・・・・・・（Ｃ） （式中、Ｒは炭素原子数１〜１７のアルキル基を示す。 ） で示される化合物を反応させて得られる白金含有化合物
を有効成分とする悪性腫瘍治療剤。(4) (A) The following formula (D) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ...... (D) A platinum (II) compound shown by (B) The following formula (C) ▲ Mathematical formula, There are chemical formulas, tables, etc. ▼・・・・・・(C) (In the formula, R represents an alkyl group having 1 to 17 carbon atoms.) A platinum-containing compound obtained by reacting a compound represented by the following formula is effective. A therapeutic agent for malignant tumors.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63194020A JPH0242094A (en) | 1988-08-02 | 1988-08-02 | Novel platinum-containing compound and remedy for malignant tumor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63194020A JPH0242094A (en) | 1988-08-02 | 1988-08-02 | Novel platinum-containing compound and remedy for malignant tumor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0242094A true JPH0242094A (en) | 1990-02-13 |
Family
ID=16317609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63194020A Pending JPH0242094A (en) | 1988-08-02 | 1988-08-02 | Novel platinum-containing compound and remedy for malignant tumor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0242094A (en) |
-
1988
- 1988-08-02 JP JP63194020A patent/JPH0242094A/en active Pending
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