JPH01163192A - Novel platinum(ii) complex and remedy for malignant tumor - Google Patents
Novel platinum(ii) complex and remedy for malignant tumorInfo
- Publication number
- JPH01163192A JPH01163192A JP62322301A JP32230187A JPH01163192A JP H01163192 A JPH01163192 A JP H01163192A JP 62322301 A JP62322301 A JP 62322301A JP 32230187 A JP32230187 A JP 32230187A JP H01163192 A JPH01163192 A JP H01163192A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- present
- complex
- group
- platinum
- 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
- 201000011510 cancer Diseases 0.000 title claims abstract description 8
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 34
- 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 4
- 229910001854 alkali hydroxide Inorganic materials 0.000 abstract description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 abstract description 2
- 230000037396 body weight Effects 0.000 abstract description 2
- 150000004682 monohydrates Chemical class 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 20
- 239000003814 drug Substances 0.000 description 12
- 229910052697 platinum Inorganic materials 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 206010029155 Nephropathy toxic Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000007694 nephrotoxicity Effects 0.000 description 4
- 231100000417 nephrotoxicity Toxicity 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229910004679 ONO2 Inorganic materials 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
- 239000002253 acid Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 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
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- POQBJIOLWPDPJE-UHFFFAOYSA-N cyclohexane-1,2-diamine;platinum Chemical compound [Pt].NC1CCCCC1N POQBJIOLWPDPJE-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 231100000053 low toxicity Toxicity 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
- 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 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 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
- 206010051779 Bone marrow toxicity Diseases 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
- 241001465754 Metazoa Species 0.000 description 1
- 101100498160 Mus musculus Dach1 gene Proteins 0.000 description 1
- 206010028980 Neoplasm 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
- 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
- 238000000862 absorption spectrum Methods 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
- 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
- 238000004458 analytical method Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 239000006172 buffering agent Substances 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
- 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
- 238000001816 cooling Methods 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
- 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
- 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
- -1 etc.) Polymers 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
- 239000003721 gunpowder Substances 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
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 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
- 239000003446 ligand Substances 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000012046 mixed solvent Substances 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
- 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
- 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
- 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
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 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
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet 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
- 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
- 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
- 239000002023 wood Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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■錯体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 complex and a therapeutic agent for malignant tumors containing the same as an active ingredient.
〈従来の技術〉
悪性ＨＵＥ、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、ＣＤＤ
Ｐ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 HUE 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, C.D.D.
P has serious side effects such as nephrotoxicity and bone marrow toxicity, which is a problem in clinical use.
一方、特にＤ Ｌ Ｆ （ｄｏｓｅ Ｉｉｎｉｔｉｎｇ
ｆａｃｔｏｒ）となっている腎毒性を改善すべく、さ
まざまな研究が重ねられ、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０（以下、ＣＩ
ＩＤＣＡ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 initiating
Various studies have been carried out to improve nephrotoxicity, which has become a factor in nephrotoxicity.
A second generation platinum complex of cis-0,0-glycolate (abbreviated as IDCA) and cis-0,0-glycolate (diammine) platinum has been developed (Japanese Patent Laid-Open Publication No. 154493/1983, etc.).
〈発明が解決しようとする問題点〉
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はと高くはない、このため、
抗腫瘍作用が強く、かつ毒性が弱い白金錯体の開発が望
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.
It is desired to develop platinum complexes 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■錯体を提供するこ
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。The purpose of the present invention is to provide a novel platinum complex 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.
く問題点を解決するための手段〉 上記目的は、以下の本明により達成される。Means to solve problems〉 The above object is achieved by the following invention.
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■錯体（以下、本発明化合物と略す
）および上記式（＾）で示される新規白金■錯体を有効
成分とする悪性腫瘍治療剤である。That is, the present invention provides a novel platinum complex (hereinafter abbreviated as the compound of the present invention) represented by the following general formula (A) (in the formula, R represents an alkyl group having 1 to 17 carbon atoms) and the above formula This is a malignant tumor therapeutic agent containing a novel platinum complex indicated by (^) as an active ingredient.
上記式（Ａ）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、ヘプタデシル基、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 (A), R represents an alkyl group having 1 to 17 carbon atoms. Specific examples of R include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group,
heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group,
Examples include pentadecyl group, heptadecyl group, and heptadecyl group. R preferably represents a lower alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl group.
ここで、本発明化合物の配位子 は下記式 で示される共役系を意味する。Here, the ligand of the compound of the present invention is the following formula means a conjugated system shown by
本発明化合物は以下に示す反応式にしたがって合成する
ことができる。The compound of the present invention can be synthesized according to the reaction formula shown below.
（Ｂ） （Ｃ）
（Ａ）
（Ｄ）
（Ａ＞
すなわち、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（Ｂ））を水
酸化アルカリの存在下で、５−アシル−２，４，６（Ｉ
Ｈ１３Ｈ１５Ｈ）−ピリミジントリオン（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
酸化カリウムなどが好ましく用いられ、化合物（Ｃ）に
対して通常２倍モル用いる。(B) (C) (A) (D) (A> That is, the compound of the present invention (^) is dinitrate (1,2-
diaminocyclohexane) platinum (compound (B)) was dissolved in 5-acyl-2,4,6(I
H13H15H)-pyrimidinetrione (compound (C)
) can be synthesized by reacting with Here, as the alkali hydroxide, sodium hydroxide, potassium hydroxide, etc. are preferably used, and are usually used twice in mole relative to compound (C).
また、本発明化合物（＾）は化合物（Ｂ）の水溶液を１
１アンバーライトＩ ＲＡ−４００” ”ダイヤイオン
５Ａ−１ＯＡ”などの陰イオン交換樹脂（０１４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 prepared by adding an aqueous solution of compound (B) to 1
Dihydroxo (1,2
-diaminocyclohexane) platinum (compound (D)) and compound (C).
これらの反応は通常、常温、常圧下、化合物ｆＢ）また
は化合物ＣＤ＞の水溶液に１当量の５−アシル−２，４
，６（ＬＨ１３Ｈ１５Ｈ）−ピリミジントリオンを混合
することにより実施できる。These reactions are usually carried out at room temperature and under normal pressure by adding 1 equivalent of 5-acyl-2,4 to an aqueous solution of compound fB) or compound CD>.
, 6(LH13H15H)-pyrimidinetrione.
このようにして得られた本発明化合物（Ａ）はアコ錯体
として水を含む場合があるが、アコ銘木も本発明化合物
の範囲に含まれる。Although the compound (A) of the present invention thus obtained may contain water as an Aco complex, Aco precious wood 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（Ｂ））は次の方法
により合成することができる。Dinitrato(1,2-diaminocyclohexane)platinum (compound (B)), which is a raw material for the compound of the present invention, can be synthesized by the following method.
（Ｅ）
（Ｂ）
上記反応式で示される化合物（８）には、原料として用
いる１、２−ジアミノシクロヘキサンく以下、ｄａｃｈ
と略す）の立木配置によりＰｌ＜）ランス−ｊ！−ｄａ
ｃｈ）（ＯＮＯ２）２、Ｐｔ（トランス−ｄ−ｄａｃｈ
）（ＯＮＯ２）２、ｐｔ（シス−ｄａｃｈ）（ＯＮＯ２
）２の三種の異性体が存在する。(E) (B) Compound (8) represented by the above reaction formula includes 1,2-diaminocyclohexane used as a raw material, dach
Pl<) Lance-j! -da
ch) (ONO2)2, Pt(trans-d-dach
)(ONO2)2, pt(cis-dach)(ONO2
) There are three isomers of 2.
本発明のもう一つの原料である化合物（Ｃ）は、バルビ
ッール酸と酸無水物とを反応させることにより得ること
ができる。Compound (C), which is another raw material of the present invention, can be obtained by reacting barbylic acid with an acid anhydride.
かくして得られる本発明化合物は抗腫瘍剤すなわち悪性
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, an agent for treating malignant tumors.
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１．散剤、
トローチ剤、液剤、全開、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（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、等銀剤、緩
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. Its dosage forms include tablets, sugar-coated tablets, gunpowder, and capsules.1. powder,
It includes lozenges, liquids, whole tablets, injections, etc., and these are manufactured by incorporating pharmaceutically acceptable excipients. 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, silvering agents, buffering 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Ｏ，ＯＯ５〜６０ｆｆｉ量％含有する
ことができる。The therapeutic agent of the present invention may contain the compound of the present invention in an amount of 0.001 to 85% by weight, preferably 5 to 60% by weight of O,OO.
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成人体重島なり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 it is 0.005 to 200 square meters per 18 adult body weight, preferably 0.01 to 50 square meters.
〈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
ａ、５−アセチル−２，４，６（Ｉ Ｈ１３Ｈ１５Ｈ）
−ピリミジントリオンの合成
バルビッール酸５．００ ｇ （０，０３９モル）を無
水酢酸３０ｒｏｌ中で１１時間加熱還流した。Example 1 a,5-acetyl-2,4,6 (I H13H15H)
-Synthesis of pyrimidinetrione 5.00 g (0.039 mol) of barbylic acid was heated under reflux in 30 mol of acetic anhydride for 11 hours.
反応溶液を熱濾過して結晶を枦取したのち、水／エタノ
ール＝１：１の混合溶媒３００ ｍｌに加熱溶解し、活
性炭処理をして精製した。After the reaction solution was filtered hot to collect crystals, the crystals were heated and dissolved in 300 ml of a mixed solvent of water/ethanol = 1:1, and purified by treatment with activated carbon.
冷却後、晶析物を枦取して１．１８ｇの５−アセチル−
２，４，６（ＩＨ１３Ｍ、５Ｈ）−ピリミジントリオン
を得た（収率１８％）。After cooling, the crystallized product was collected and 1.18 g of 5-acetyl-
2,4,6(IH13M,5H)-pyrimidinetrione was obtained (yield 18%).
得られた化合物の分析結果は次のとおりであった。The analysis results of the obtained compound were as follows.
融点〉２９０℃
ｂ、錯体の合成
Ｐｔ （トランス−ｆｌ−ｄａｃｈＨＯＮＯ２）２水溶
液を陰イオン交換樹脂゛ダイヤイオン５Ａ−１０Ａ”
（ＯＨ型）を充填したカラムに通して得られたＰｔ（ト
ランス〜ｊ！−ｄａｃｈＨＯＨ）２水溶液１００ａ＋Ｉ
（４，２ミリモル）に５−アセチル−２，４，６（ＩＨ
１３Ｈ１５１１）−ピリミジントリオン０．７１ ｇ
（４，２ミリモル）を加え、室温で２４時間撹拌した。Melting point>290℃ b, Synthesis of complex Pt (trans-fl-dachHONO2) 2 aqueous solution was mixed with anion exchange resin “Diaion 5A-10A”.
Pt(trans~j!-dachHOH)2 aqueous solution 100a+I obtained by passing through a column packed with (OH type)
(4,2 mmol) to 5-acetyl-2,4,6 (IH
13H1511)-pyrimidinetrione 0.71 g
(4.2 mmol) was added and stirred at room temperature for 24 hours.
反応溶液を乾固したのち、＃酸エチルで洗浄、減圧乾燥
して５−アセチル−２，４，６（ＩＨ１３Ｈ２Ｓ Ｈ）
−ピリミジントリオン−ヒドロキソ（トランス−ｊ！−
１，２−ジアミノシクロヘキサン）白金■錯体の１水和
物（以下、本発明化合物（Ａ１）と略す）１．９３ｇを
得た（収率９０％）。After drying the reaction solution, it was washed with ethyl #acid and dried under reduced pressure to give 5-acetyl-2,4,6 (IH13H2S H).
-pyrimidinetrione-hydroxo(trans-j!-
1.93 g of platinum (1,2-diaminocyclohexane) complex monohydrate (hereinafter abbreviated as the compound of the present invention (A1)) was obtained (yield: 90%).
本発明化合物（Ａ１）のＩＲを第１図、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〉２９０℃
元素分析値（％）Ｃ１２Ｈ２２Ｎ４ｏ６Ｐｔとして実施
例２
ＣＤＦ＋ マ’７ス（ａ性、６適齢、１群６〜１０匹便
用）腹腔内に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日目、５日目、９１１目の計３回本発明化合物
（Ａ１）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ＣＢＤＣＡ、ＣＤＤＰを用いた。各薬剤は０
゜０５％” Ｔｗｅｅｎ ８０”溶液に溶解または懸濁
してｆ！Ｉ！用した。Ｌ１２１０移植マウスに対する白
金錯体の抗腫鳩作用の効果判定は、以下の式によつ求め
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 > 290°C Elemental analysis value (%) as C12H22N4o6Pt Example 2 CDF+ mouse leukemia cells (A sex, 6 suitable ages, 6 to 10 animals per group) subcultured intraperitoneally in DBA/2 mice 105 L1210 were transplanted. The compound of the present invention (A1) was intraperitoneally administered as a test drug three times in total, on the 1st day, the 5th day, and the 911th day, with the transplant day being set as day 0. CBDCA and CDDP were used as comparative drugs in this experiment. Each drug is 0
Dissolve or suspend in ゜05%” Tween 80” solution and f! I! used. The antitumor action of the platinum complex on mice transplanted with L1210 was evaluated based on the T/C value determined by the following formula and the number of surviving mice on day 300.
結果を表１に示す。The results are shown in Table 1.
表 １
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、２００■／ ｋｇ投与群において、２９９％ノ
Ｔ ／ Ｃ＠を示し、３０日［，１ｍおける生存マウス
ら２／６であった。これは明らかにＣＤＤＰおよびＣＢ
ＤＣＡよりも強力な抗腫瘍作用であるといえる。Table 1 As is clear from the results shown in Table 1, the compound of the present invention (A
1) showed 299% T/C in the 200 kg/kg administration group, with 2/6 mice surviving after 30 days [,1 m]. This is clearly CDDP and CB
It can be said that it has a stronger antitumor effect than DCA.
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。ｓ２ｃ：ＩｃＲマウス（
雄性：５適齢）の腹腔内に本発明化合物（Ａｌ、）を被
検薬として投与した。Example 3 An acute toxicity test of the compound (A1) of the present invention in mice was conducted using CDDP as a control. s2c: IcR mouse (
The compound of the present invention (Al, ) was administered intraperitoneally to a male (5 years old) as a test drug.
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１４４日目死亡率がらＬ
Ｄ５ｏ値を算出しな。The test drug was dissolved or suspended in a 0.05% "Tween 80" solution. Mortality rate on day 144 after administration
Calculate the D5o value.
その結果を表２に示す。The results are shown in Table 2.
表 ２
表２に示す結果から明らかなように、本発明化合物はＣ
ＤＤＰに比べ低毒性である。Table 2 As is clear from the results shown in Table 2, the compound of the present invention has C
It is less toxic than DDP.
〈発明の効果〉
本発明の化合物は強い抗腫瘍活性を有し、かつ悪性も弱
く、悪性腫瘍治療剤として有効である。<Effects of the Invention> The compounds of the present invention have strong antitumor activity, are weakly malignant, and are effective 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 (2)
瘍治療剤。(2) A novel platinum (II) complex represented by the following general formula (A) ▲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 as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62322301A JPH01163192A (en) | 1987-12-18 | 1987-12-18 | Novel platinum(ii) complex and remedy for malignant tumor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62322301A JPH01163192A (en) | 1987-12-18 | 1987-12-18 | Novel platinum(ii) complex and remedy for malignant tumor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01163192A true JPH01163192A (en) | 1989-06-27 |
Family
ID=18142104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62322301A Pending JPH01163192A (en) | 1987-12-18 | 1987-12-18 | Novel platinum(ii) complex and remedy for malignant tumor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01163192A (en) |
-
1987
- 1987-12-18 JP JP62322301A patent/JPH01163192A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0041792B1 (en) | Platinum compounds having antitumor or antimicrobial activity, and pharmaceutical preparations containing them | |
| CA2046313C (en) | Platinum (ii) complex and agent for treating malignant tumor | |
| JPH01163192A (en) | Novel platinum(ii) complex and remedy for malignant tumor | |
| JPH0232086A (en) | Novel platinum-containing compound and malignant tumor remedy | |
| EP0258655B1 (en) | Complexes of platinum (ii) 2,3-dinitrilo-2-butene-2,3-dithiolate, a process for preparing them and pharmaceutical compositions containing them | |
| JPH01163191A (en) | Novel platinum(ii) complex and remedy for malignant tumor | |
| JP2778043B2 (en) | New platinum-containing compounds and therapeutic agents for malignant tumors | |
| EP0341318A1 (en) | Novel platinum (ii) complex, process for preparing the same, and therapeutic agent for malignant tumor | |
| JPH01246246A (en) | Novel platinum(ii) complex and remedy of malignant tumor | |
| JPH01143884A (en) | Novel platinum (ii) complex and remedy for malignant tumor | |
| JPH02279691A (en) | Novel platinum-containing compound and treating agent of malignant tumor | |
| JPH01311089A (en) | Novel platinum-containing compound and malignant tumor remedy | |
| JPH01313488A (en) | Novel platinum-containing compound and remedy for malignant tumor | |
| JP2737240B2 (en) | Novel platinum complex and tumor therapeutic composition | |
| JPH0242094A (en) | Novel platinum-containing compound and remedy for malignant tumor | |
| JPH0269490A (en) | Novel platinum-containing compound and remedy for malignant tumor | |
| JPH02286694A (en) | New platinum (ii) complex and malignant tumor remedy | |
| JPH0245494A (en) | Novel platinum-containing compound and remedy for malignant tumor | |
| JPH0311090A (en) | Novel platinum-containing compound and remedy for malignant tumor | |
| JPH0311091A (en) | Novel platinum (ii) complex and remedy for malignant tumor | |
| JPH01165593A (en) | Novel platinum(ii)complex and remedy for malignant tumor | |
| JPH01165594A (en) | Novel platinum(ii)complex and remedy for malignant tumor | |
| JPH01132596A (en) | Novel pt(ii) complex and remedy for malignant tumor | |
| JPH01163190A (en) | Novel platinum(ii) complex and remedy for malignant tumor | |
| JPH01128991A (en) | Novel platinum (ii) complex and remedy for malignant tumor |