TW201425278A - Platinum (IV) complexes and pharmaceutical composition containing the same - Google Patents
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本發明係關於一種新穎四價鉑錯合物及以其為有效成分之醫藥組成物、特別是惡性腫瘤治療劑。 The present invention relates to a novel tetravalent platinum complex and a pharmaceutical composition comprising the same as an active ingredient, particularly a therapeutic agent for malignant tumors.
近年來,惡性腫瘤佔據死亡原因之首位,而對此開發有各種抗腫瘤物質。其中,自先前以來發現鉑錯合物有抗腫瘤作用,而開發有順鉑(Cisplatin)[I]、卡鉑(Carboplatin)[II]、奧賽力鉑(Oxaliplatin)[III]等,並用於治療(例如參照非專利文獻1-非專利文獻3)。又,本申請案申請人已獲得關於作為發現抗腫瘤作用之鉑錯合物之以螺[4,4]壬烷-1,6-二胺為配位基的新穎鉑錯合物、與以其為有效成分之醫藥組成物的日本專利第46644245號(專利文獻1)之登錄。 In recent years, malignant tumors have been the leading cause of death, and various anti-tumor substances have been developed for this purpose. Among them, platinum complexes have been found to have anti-tumor effects, and Cisplatin [I], Carboplatin [II], Oxaliplatin [III], etc. have been developed and used for treatment. (For example, refer to Non-Patent Document 1 - Non-Patent Document 3). Further, the applicant of the present application has obtained a novel platinum complex which is a ligand of a spiro[4,4]decane-1,6-diamine as a platinum complex which is found to have an antitumor effect, and It is a registration of Japanese Patent No. 46644425 (Patent Document 1) which is a pharmaceutical composition of an active ingredient.
專利文獻1:日本專利第4664424號公報 Patent Document 1: Japanese Patent No. 4664424
專利文獻2:US Patent 4,140,707(February 20,1979) Patent Document 2: US Patent 4,140,707 (February 20, 1979)
非專利文獻1:Nature,1969 222 385-386 Non-Patent Document 1: Nature, 1969 222 385-386
非專利文獻2:Cancer Treat Reviews 1985 12 21-33 Non-Patent Document 2: Cancer Treat Reviews 1985 12 21-33
非專利文獻3:Cancer Letters 1985 27 135-143 Non-Patent Document 3: Cancer Letters 1985 27 135-143
然而,順鉑有如下問題:腎毒性、血液毒性、消化器官毒性、神經毒性之類之副作用較多。因此,開發了卡鉑作為減輕順鉑之腎毒性並增加水溶性者,但卡鉑價格較高,並且其抗腫瘤作用未必令人滿意。該等呈現抗腫瘤活性,另一方面為了使特定之抗腫瘤活性奏效,而必須投予對應其之預先所決定之需要量,因此存在有副作用之缺點。 However, cisplatin has the following problems: side effects such as nephrotoxicity, hematological toxicity, digestive organ toxicity, and neurotoxicity. Therefore, carboplatin has been developed as a kidney toxicity which reduces cisplatin and increases water solubility, but carboplatin is expensive and its antitumor effect is not necessarily satisfactory. These exhibit anti-tumor activity, and on the other hand, in order to make the specific anti-tumor activity work, it is necessary to give a predetermined amount corresponding to it, and thus there are disadvantages of side effects.
本發明之目的在於提供一種新穎四價鉑錯合物,其係以順,順-螺[4,4]壬烷-1,6-二胺及其光學活性二胺為配位基之四價鉑錯合物,具有更強之抗腫瘤活性,並且投予量為更少量即具有效果,因此相對地減輕副作用。 The object of the present invention is to provide a novel tetravalent platinum complex which is tetravalent with cis, cis-spiro[4,4]decane-1,6-diamine and its optically active diamine as a ligand. The platinum complex has a stronger antitumor activity, and the administration amount is a smaller amount, which is effective, and thus the side effects are relatively reduced.
特別是提供一種新穎四價鉑錯合物,其具有如下特徵:其係下式(G)所表示之以(S,S,S)-順,順-螺[4,4]壬烷-1,6二胺為配位基的四價鉑二氯丙二酸鹽錯合物(G),對惡性腫瘤特別是人類肺癌細胞、人類胃癌細胞、人類前列腺癌細胞、人類惡性黑色素瘤細胞、人類膀胱癌細胞、人類淋巴瘤細胞、人類白血病細胞具有較強之抗腫瘤性活性,且相對地減輕副作用。 In particular, a novel tetravalent platinum complex is provided which has the following characteristics: (S, S, S)-cis, cis-spiro[4,4]decane-1 represented by the following formula (G) , 6 diamine is a ligand of tetravalent platinum dichloromalonate complex (G), for malignant tumors, especially human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human malignant melanoma cells, humans Bladder cancer cells, human lymphoma cells, and human leukemia cells have strong antitumor activity and relatively reduce side effects.
為達成此種目的,本發明之惡性腫瘤劑係以下述通式所表示之順,順-螺[4,4]壬烷-1,6-二胺(A)為配位基之四價鉑錯合物。 In order to achieve such a purpose, the malignant tumor agent of the present invention is a tetravalent platinum represented by the following formula: cis, cis-spiro[4,4]decane-1,6-diamine (A) as a ligand. Complex compound.
本發明係以其光學活性物質即(S,S,S)-順,順-螺[4,4]壬烷-1,6二胺(B)及(R,R,R)-順,順-螺[4,4]壬烷-1,6二胺(C)為配位基之四價鉑錯合物。 The present invention is characterized by its optically active substance (S, S, S)-cis, cis-spiro[4,4]decane-1,6-diamine (B) and (R,R,R)-cis, - Spiro[4,4]decane-1,6-diamine (C) is a tetravalent platinum complex of a ligand.
本發明係下述通式所表示之以順,順-螺[4,4]壬烷-1,6-二胺(A)為配位基之四價鉑錯合物(D)。 The present invention is a tetravalent platinum complex (D) represented by the following formula, wherein cis, cis-spiro[4,4]nonane-1,6-diamine (A) is a ligand.
式中,X及Y、Z相同或不同,分別表示鹵素原子或含有乙酸酯基之1價的陰離子基,或者Y與Z共同表示式(b)所示之2價的殘基。 In the formula, X and Y and Z are the same or different and each represents a halogen atom or a monovalent anion group containing an acetate group, or Y and Z together represent a divalent residue represented by the formula (b).
式中R表示單鍵或碳原子數1至6個之直鏈狀或者支鏈狀之2價的烴殘基,該烴殘基亦可具有不飽和鍵,又該烴殘基亦可形成螺結 構。 Wherein R represents a single bond or a linear or branched divalent hydrocarbon residue having 1 to 6 carbon atoms, and the hydrocarbon residue may have an unsaturated bond, and the hydrocarbon residue may also form a snail. Knot Structure.
本發明係下式立體結構式所示之光學活性物質,即以(S,S,S)-順,順-螺[4,4]壬烷-1,6-二胺(B)為配位基之四價鉑錯合物(E)及以(R,R,R)-順,順-螺[4,4]壬烷-1,6-二胺(C)為配位基之四價鉑錯合物(F)。 The present invention is an optically active substance represented by the following three-dimensional structural formula, that is, (S, S, S)-cis, cis-spiro[4,4]nonane-1,6-diamine (B) is coordinated. a tetravalent platinum complex (E) and a tetravalent group with (R,R,R)-cis,cis-spiro[4,4]decane-1,6-diamine (C) as a ligand Platinum complex (F).
式中,X及Y、Z相同或不同,分別表示鹵素原子或含有乙酸酯基之1價的陰離子基,或者Y與Z共同表示式(b)所示之2價的殘基。 In the formula, X and Y and Z are the same or different and each represents a halogen atom or a monovalent anion group containing an acetate group, or Y and Z together represent a divalent residue represented by the formula (b).
式中R表示單鍵或碳原子數1至6個之直鏈狀或者支鏈狀之2價的烴殘基,該烴殘基亦可具有不飽和鍵,又該烴殘基亦可形成螺結構。 Wherein R represents a single bond or a linear or branched divalent hydrocarbon residue having 1 to 6 carbon atoms, and the hydrocarbon residue may have an unsaturated bond, and the hydrocarbon residue may also form a snail. structure.
本發明係下式(G)所示之以(S,S,S)-順,順-螺[4,4]壬烷-1,6-二胺為配位基之四價鉑二氯丙二酸鹽錯合物。 The present invention is a tetravalent platinum dichloropropyl group having a (S, S, S)-cis, cis-spiro[4,4]nonane-1,6-diamine as a ligand represented by the following formula (G). Diacid complex.
本發明係含有上述各式之四價鉑錯合物作為有效成分之醫藥組成物。 The present invention is a pharmaceutical composition containing the tetravalent platinum complex of the above formula as an active ingredient.
本發明係含有上述各式之四價鉑錯合物作為有效成分之惡性腫瘤治療劑。 The present invention relates to a malignant tumor therapeutic agent containing the above-described tetravalent platinum complex of each formula as an active ingredient.
為達成此種目的,本發明人等已發現下述通式(a)所表示之以螺[4,4]壬烷-1,6-二胺為配位基之新穎鉑(II)錯合物及以該錯合物為有效成分之醫藥組成物對惡性腫瘤治療有效一事,並進行了專利申請(日本特願2008-225698)。 In order to achieve such a purpose, the present inventors have found that a novel platinum (II) complex represented by the following formula (a) with a spiro[4,4]nonane-1,6-diamine as a ligand A pharmaceutical composition containing the compound as an active ingredient is effective for the treatment of malignant tumors, and a patent application has been made (Japanese Patent Application No. 2008-225698).
上述式中,X及Y相同或不同,分別表示鹵素原子,或X與Y共同表示式(b)所示之2價的殘基。 In the above formula, X and Y are the same or different and each represents a halogen atom, or X and Y together represent a divalent residue represented by the formula (b).
式中R表示單鍵或碳原子數1至6個之直鏈狀或者支鏈狀之2價的烴殘基,該烴殘基亦可具有不飽和鍵,又該烴殘基亦可形成螺結構。 Wherein R represents a single bond or a linear or branched divalent hydrocarbon residue having 1 to 6 carbon atoms, and the hydrocarbon residue may have an unsaturated bond, and the hydrocarbon residue may also form a snail. structure.
又,特別是已明瞭:特徵在於下式(c)所表示之以順,順-螺[4,4]壬烷-1,6-二胺為配位基之鉑草酸鹽錯合物(H)對惡性腫瘤,特別是人類淋巴瘤細胞之類之非實性瘤有較強之抗腫瘤活性,且相對地減輕副作用。 Further, it has been clarified that a platinum oxalate complex which is characterized by a cis, cis-spiro[4,4]decane-1,6-diamine as a ligand represented by the following formula (c) ( H) It has strong anti-tumor activity against malignant tumors, especially non-solid tumors such as human lymphoma cells, and relatively reduces side effects.
順,順-螺[4,4]壬烷-1,6-二胺係以具有2個立體結構(即 (S,S,S)與(R,R,R))之光學活性物質的消旋體之形式而存在。進一步推進發明而研究了該等光學活性二胺之鉑錯合物,從而進行專利申請(日本特願2009-155399),而獲得登錄(專利文獻1)。 Cis, cis-spiro[4,4]decane-1,6-diamine has two stereostructures (ie (S, S, S) and (R, R, R)) are present in the form of racemates of the optically active substance. Further, the platinum complex of the optically active diamine was studied in advance of the invention, and a patent application (Japanese Patent Application No. 2009-155399) was obtained, and registration was obtained (Patent Document 1).
只要利用本發明之新穎四價鉑錯合物,即可對惡性腫瘤,特別是人類肺癌細胞、人類胃癌細胞、人類前列腺癌細胞、人類惡性黑色素瘤細胞、人類膀胱癌細胞、人類淋巴瘤細胞、人類白血病細胞等多種惡性腫瘤有較強之抗腫瘤活性,且與先前之鉑錯合物惡性腫瘤治療劑相比,投予量為更少量即具有效果,因此相對地減輕副作用。 As long as the novel tetravalent platinum complex of the present invention is utilized, it can be used for malignant tumors, especially human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human malignant melanoma cells, human bladder cancer cells, human lymphoma cells, A variety of malignant tumors such as human leukemia cells have strong antitumor activity, and the administration amount is smaller in comparison with the previous therapeutic agent for platinum complex malignant tumors, so that side effects are relatively reduced.
以下,對本發明之四價鉑錯合物及包含其之惡性腫瘤治療劑之實施形態進行說明。 Hereinafter, embodiments of the tetravalent platinum complex of the present invention and a therapeutic agent for a malignant tumor comprising the same will be described.
關於順,順-螺[4,4]壬烷-1,6-二胺(A)、及其光學活性物質即(S,S,S)-順,順-螺[4,4]壬烷-1,6-二胺(B)、(R,R,R)-順,順-螺[4,4]壬烷-1,6-二胺(C)、自該等之2價鉑錯合物(H)、(I)、(J)之合成,已經於本發明人之專利中完成說明(日本特願2009-155399、國際專利申請PCT/JP2009/004077)。 About cis, cis-spiro[4,4]decane-1,6-diamine (A), and its optically active substance (S,S,S)-cis,cis-spiro[4,4]decane -1,6-diamine (B), (R,R,R)-cis,cis-spiro[4,4]decane-1,6-diamine (C), from these two-valent platinum The synthesis of the compounds (H), (I), and (J) has been described in the inventor's patent (Japanese Patent Application No. 2009-155399, International Patent Application No. PCT/JP2009/004077).
本發明之四價鉑錯合物(D)、(E)、(F)可應用公知之方法,例如J.Inorg.Biochem.1996,61,291-301.,J.Med.Chem.1997,40,112-116所記載之方法而輕易地獲得(反應式(i)及反應式(ii))。 The tetravalent platinum complex (D), (E), (F) of the present invention can be applied by a known method, for example, J. Inorg. Biochem. 1996, 61, 291-301., J. Med. Chem. 1997, 40, 112- It is easily obtained by the method described in 116 (reaction formula (i) and reaction formula (ii)).
本錯合物雖有含有水作為水錯合物(aquo complex)之情形,但水合物亦包含於本發明中。 Although the present complex contains water as a complex, a hydrate is also included in the present invention.
可知本發明之錯合物以低濃度即可阻礙人類肺癌細胞、人類胃癌細胞、人類前列腺癌細胞、人類惡性黑色素瘤細胞、人類膀胱癌細胞、人類淋巴瘤細胞、人類白血病細胞之增殖,而顯示出較強之抗腫瘤作用。可用作惡性腫瘤治療劑。 It can be seen that the complex of the present invention can inhibit the proliferation of human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human malignant melanoma cells, human bladder cancer cells, human lymphoma cells, and human leukemia cells at a low concentration, and shows Strong anti-tumor effect. It can be used as a therapeutic agent for malignant tumors.
於臨床中投予含有本發明之鉑錯合物之有效量之治療劑的情形時,可藉由經口或非經口而投予。其劑形包含錠劑、糖衣錠、丸劑、膠囊劑、散劑、喉錠、液劑、栓劑、注射劑等,該等可摻合醫藥上所容許之賦形劑而製造。作為賦形劑,可例示如下者。乳糖、蔗糖、葡萄糖、山 梨糖醇、甘露糖醇、馬鈴薯澱粉、支鏈澱粉、其他各種澱粉、纖維素衍生物(例如羧甲基纖維素、羥乙基纖維素等)、明膠、硬脂酸鈣、硬脂酸鎂、聚乙烯醇、聚乙二醇蠟、阿拉伯膠、滑石、二氧化鈦、橄欖油、花生油、芝麻油等植物油、石蠟油、中性脂肪基劑、乙醇、丙二醇、生理鹽水、殺菌水、甘油、著色劑、調味劑、濃厚劑、穩定劑、等張劑、緩衝劑等、及其他醫藥上所容許之賦形劑。 When a therapeutic agent containing an effective amount of the platinum complex of the present invention is administered clinically, it can be administered by oral or parenteral administration. The dosage form comprises a tablet, a sugar-coated tablet, a pill, a capsule, a powder, a throat, a liquid, a suppository, an injection, and the like, which can be produced by blending an excipient which is pharmaceutically acceptable. As an excipient, the following can be illustrated. Lactose, sucrose, glucose, mountain Pearitol, mannitol, potato starch, amylopectin, various other starches, cellulose derivatives (such as carboxymethyl cellulose, hydroxyethyl cellulose, etc.), gelatin, calcium stearate, magnesium stearate , polyvinyl alcohol, polyethylene glycol wax, gum arabic, talc, titanium dioxide, olive oil, peanut oil, sesame oil and other vegetable oils, paraffin oil, neutral fat base, ethanol, propylene glycol, physiological saline, sterilizing water, glycerin, coloring agent , flavoring agents, thickeners, stabilizers, isotonic agents, buffers, etc., and other pharmaceutically acceptable excipients.
本發明之治療劑可含有本發明之鉑錯合物0.001~85重量%,較佳為0.005~60重量%。 The therapeutic agent of the present invention may contain 0.001 to 85% by weight, preferably 0.005 to 60% by weight, of the platinum complex of the present invention.
本發明之治療劑之投予量雖主要根據症狀而決定,但為每天每成人體重0.005~200 mg,較佳為0.01~50 mg。 The dose of the therapeutic agent of the present invention is mainly determined depending on the symptoms, but is 0.005 to 200 mg per adult body weight per day, preferably 0.01 to 50 mg.
以下列舉實施例對本發明進行更具體之說明。 The invention is more specifically illustrated by the following examples.
《實施例1》 "Embodiment 1"
於50 ml之圓底燒瓶中放入Pt(II)((S,S,S)-順,順-螺[4,4]壬烷1,6-二胺)丙二酸鹽錯合物0.49 g,並加入蒸餾水22 ml、30%過氧化氫水5.4 ml而於70℃加熱攪拌2小時。冷卻至室溫,進而攪拌24小時。進行氟鎂石過濾並進行水洗。濃縮濾液後,加入丙酮(200 ml)而放置,過濾所析出之固體,利用丙酮進行清洗,並進行乾燥。利用水,繼而乙醇、進而二乙醚進行清洗並進行乾燥。獲得Pt(IV)((S,S,S)-順,順-螺[4,4]壬烷1,6-二胺)丙二酸鹽之二羥基化物0.48 g。產率為93.6%。 Pt(II)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate complex 0.49 was placed in a 50 ml round bottom flask. g, and adding 22 ml of distilled water and 5.4 ml of 30% hydrogen peroxide water, and heating and stirring at 70 ° C for 2 hours. It was cooled to room temperature and further stirred for 24 hours. The brucite is filtered and washed with water. After the filtrate was concentrated, acetone (200 ml) was added and allowed to stand, and the precipitated solid was filtered, washed with acetone, and dried. It is washed with water, followed by ethanol and further diethyl ether, and dried. 0.48 g of a dihydroxylate of Pt(IV)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate was obtained. The yield was 93.6%.
將該Pt(IV)化合物0.52 g放入200 ml之圓底燒瓶中,於其中加入0.02 N鹽酸98 ml並於暗處攪拌4天。進行氟鎂石過濾,利用水、甲醇進行清洗,蒸餾去除溶劑。 0.52 g of this Pt(IV) compound was placed in a 200 ml round bottom flask, to which 98 ml of 0.02 N hydrochloric acid was added and stirred in the dark for 4 days. The brucite is filtered, washed with water and methanol, and the solvent is distilled off.
將殘渣溶解於甲醇中,並再次進行氟鎂石過濾,蒸餾去除甲醇並進行乾燥。獲得Pt(IV)((S,S,S)-順,順-螺[4,4]壬烷1,6-二胺)丙二酸鹽之二氯化物(G)0.33 g。 The residue was dissolved in methanol, and the brucite was filtered again, and methanol was distilled off and dried. Pt(IV) ((S, S, S)-cis, cis-spiro[4,4]decane 1,6-diamine) malonate dichloride (G) 0.33 g was obtained.
產率為59.4%。 The yield was 59.4%.
元素分析值以C12H20N2O4Cl2Pt分析C、H、N、Cl、Pt Elemental analysis values were analyzed for C, H, N, Cl, Pt with C 12 H 20 N 2 O 4 Cl 2 Pt
計算值(%)27.60、3.86、5.36、13.58、37.4;實測值(%)26.95、3.92、5.16、13.11、36.7;IR(KBr):3177(N-H)、1645(C=0)、1371(C-0)cm-1 Calculated values (%) 27.60, 3.86, 5.36, 13.58, 37.4; measured values (%) 26.95, 3.92, 5.16, 13.11, 36.7; IR (KBr): 3177 (NH), 1645 (C=0), 1371 (C) -0)cm -1
MS(ESI)m/z 521 MS (ESI) m/z 521
根據以上之結果可確認本化合物具有(化合物1)所示之化學結構。 From the above results, it was confirmed that the present compound has the chemical structure represented by (Compound 1).
《實施例2》 <<Example 2》
於50 ml之圓底燒瓶中放入Pt(II)((R,R,R)-順,順-螺[4,4]壬烷1,6-二胺)丙二酸鹽錯合物1.23 g,並加入蒸餾水18 ml、30%過氧化氫水4.4 ml而於70℃加熱攪拌2小時。冷卻至室溫,進而攪拌24小時。進行氟鎂石過濾,並進行水洗。濃縮濾液後,加入丙酮(200 ml)而放置,過濾所析出之固體,利用丙酮進行清洗並進行乾燥。獲得Pt(IV)((R,R,R)-順,順-螺[4,4]壬烷1,6-二胺)丙二酸鹽之二羥基化物1.19 g。產率為90.0%。 Pt(II)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate complex 1.23 was placed in a 50 ml round bottom flask. g, and adding 18 ml of distilled water and 4.4 ml of 30% hydrogen peroxide water, and heating and stirring at 70 ° C for 2 hours. It was cooled to room temperature and further stirred for 24 hours. The brucite is filtered and washed with water. After concentrating the filtrate, acetone (200 ml) was added and allowed to stand, and the precipitated solid was filtered, washed with acetone and dried. 1.12 g of a dihydroxylate of Pt(IV)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate was obtained. The yield was 90.0%.
將該Pt(IV)化合物1.04 g放入300 ml之圓底燒瓶中,於其中加入0.02 N鹽酸204 ml並於暗處攪拌4天。進行氟鎂石過濾,利用水、甲醇進行清洗,蒸餾去除溶劑。 1.04 g of this Pt(IV) compound was placed in a 300 ml round bottom flask, to which 204 ml of 0.02 N hydrochloric acid was added and stirred in the dark for 4 days. The brucite is filtered, washed with water and methanol, and the solvent is distilled off.
將殘渣溶解於甲醇中,並再次進行氟鎂石過濾,蒸餾去除甲醇並進行乾燥。獲得Pt(IV)((R,R,R)-順,順-螺[4,4]壬烷1,6-二胺)丙二酸鹽之二氯化物(G)之光學異構物0.84 g。產率為74.8%。 The residue was dissolved in methanol, and the brucite was filtered again, and methanol was distilled off and dried. Obtaining optical isomers of Pt(IV)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine)malonate dichloride (G) 0.84 g. The yield was 74.8%.
IR測定之結果與實施例1之四價鉑錯合物一致,而確認為 (化合物2)。 The results of the IR measurement were consistent with the tetravalent platinum complex of Example 1, and were confirmed as (Compound 2).
《實施例3》 Example 3
於50 ml之圓底燒瓶中放入Pt(II)((S,S,S)-順,順-螺[4,4]壬烷1,6-二胺)草酸鹽錯合物1.07 g,並加入蒸餾水50 ml、30%過氧化氫水12.4 ml而於70℃加熱攪拌2小時。冷卻至室溫,進而攪拌2天。進行氟鎂石過濾並進行水洗。濃縮濾液後,加入丙酮(200 ml)而放置,過濾所析出之固體,利用丙酮進行清洗並進行乾燥。利用水,繼而乙醇,進而二乙醚進行清洗而進行乾燥。獲得Pt(IV)((S,S,S)-順,順-螺[4,4]壬烷1,6-二胺)草酸鹽之二羥基化物1.15 g。產率為99.6%。 Pt(II)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate complex 1.07 g was placed in a 50 ml round bottom flask. And adding 50 ml of distilled water and 12.4 ml of 30% hydrogen peroxide water, and heating and stirring at 70 ° C for 2 hours. Cool to room temperature and stir for 2 days. The brucite is filtered and washed with water. After concentrating the filtrate, acetone (200 ml) was added and allowed to stand, and the precipitated solid was filtered, washed with acetone and dried. It is dried by washing with water, followed by ethanol and diethyl ether. A 1.15 g of a dihydroxylate of Pt(IV)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate was obtained. The yield was 99.6%.
將該Pt(IV)化合物0.88 g放入300 ml之圓底燒瓶中,於其中加入蒸餾水165 ml、1.2 N鹽酸2.85 ml,並於暗處攪拌3天。進行氟鎂石過濾,利用水、甲醇進行清洗,並蒸餾去除溶劑。 0.88 g of this Pt(IV) compound was placed in a 300 ml round bottom flask, and 165 ml of distilled water and 2.85 ml of 1.2 N hydrochloric acid were added thereto, and stirred in the dark for 3 days. The brucite is filtered, washed with water and methanol, and the solvent is distilled off.
將殘渣溶解於甲醇中,並再次進行氟鎂石過濾,蒸餾去除甲醇並進行乾燥。獲得Pt(IV)((S,S,S)-順,順-螺[4,4]壬烷1,6-二胺)草酸鹽之二氯化物0.79 g。產率為83.1%。 The residue was dissolved in methanol, and the brucite was filtered again, and methanol was distilled off and dried. 0.79 g of Pt(IV)((S,S,S)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate dichloride was obtained. The yield was 83.1%.
元素分析值以C11H18N2O4Cl2Pt分析C、H、N、Cl、Pt Elemental analysis values were analyzed for C, H, N, Cl, Pt with C 11 H 18 N 2 O 4 Cl 2 Pt
計算值(%)25.99、3.57、5.51、13.95、38.4;實測值(%)25.55、3.65、5.26、13.35、37.9;IR(KBr):3175(N-H)、1715(C=0)、1357(C-0)cm-1 Calculated values (%) 25.99, 3.57, 5.51, 13.95, 38.4; measured values (%) 25.55, 3.65, 5.26, 13.35, 37.9; IR (KBr): 3175 (NH), 1715 (C=0), 1357 (C) -0)cm -1
MS(ESI)m/z 507 MS (ESI) m/z 507
根據該結果可確認本化合物具有(化合物3)所示之化學結構。 From the results, it was confirmed that the present compound has the chemical structure represented by (Compound 3).
《實施例4》 Example 4
於50 ml之圓底燒瓶中放入Pt(II)((R,R,R)-順,順-螺[4,4]壬烷1,6-二胺)草酸鹽錯合物1.06 g,並加入蒸餾水49 ml、30%過氧化氫水12.8 ml而於70℃加熱攪拌2小時。冷卻至室溫,進而攪拌3天。進行氟鎂石過濾並進行水洗。濃縮濾液後,加入丙酮(250 ml)而放置,過濾所析出之固體,利用丙酮進行清洗並進行乾燥。獲得Pt(IV)((R,R,R)-順,順-螺[4,4]壬烷1,6-二胺)草酸鹽之二羥基化物1.11 g。產率為97.3%。 Pt(II)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate complex 1.06 g was placed in a 50 ml round bottom flask. And adding 49 ml of distilled water and 12.8 ml of 30% hydrogen peroxide water, and heating and stirring at 70 ° C for 2 hours. Cool to room temperature and stir for 3 days. The brucite is filtered and washed with water. After concentrating the filtrate, acetone (250 ml) was added and allowed to stand, and the precipitated solid was filtered, washed with acetone and dried. 1.11 g of a dihydroxylate of Pt(IV)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate was obtained. The yield was 97.3%.
將該Pt(IV)化合物0.92 g放入300 ml之圓底燒瓶中,於其中加入蒸餾水190 ml、1.2 N鹽酸3.3 ml並於暗處攪拌3天。進行氟鎂石過濾,利用水、甲醇進行清洗,並蒸餾去除溶劑。 0.92 g of this Pt(IV) compound was placed in a 300 ml round bottom flask, and 190 ml of distilled water, 3.3 ml of 1.2 N hydrochloric acid was added thereto, and stirred in the dark for 3 days. The brucite is filtered, washed with water and methanol, and the solvent is distilled off.
將殘渣溶解於甲醇中,並再次進行氟鎂石過濾,蒸餾去除甲醇並進行乾燥。獲得Pt(IV)((R,R,R)-順,順-螺[4,4]壬烷1,6-二胺)草酸鹽之二氯化物0.92 g。產率為92.4%。 The residue was dissolved in methanol, and the brucite was filtered again, and methanol was distilled off and dried. 0.92 g of Pt(IV)((R,R,R)-cis,cis-spiro[4,4]decane 1,6-diamine) oxalate dichloride was obtained. The yield was 92.4%.
IR測定之結果與實施例3之四價鉑錯合物一致,而確認為(化合物4)。 The result of the IR measurement was identical to that of the tetravalent platinum complex of Example 3, and was confirmed to be (Compound 4).
《實施例5》 "Embodiment 5"
於100 ml圓底燒瓶中放入六氯鉑(IV)酸鉀0.49 g、氯化鈉0.24 g、蒸餾水60 ml而進行溶解。於該溶液中加入(S,S,S)-順,順-螺[4,4]壬烷-1,6 二胺0.16 g之水溶液10 ml溶液。漸漸地渾濁而析出固體。於暗處攪拌24小時。進行過濾、水洗、乾燥。獲得Pt(IV)((S,S,S)-順,順-螺[4,4]壬烷-1,6二胺)四氯化物0.22 g。產率為43.6%。 In a 100 ml round bottom flask, 0.49 g of potassium hexachloroplatinate (IV), 0.24 g of sodium chloride, and 60 ml of distilled water were placed and dissolved. Add (S,S,S)-cis,cis-spiro[4,4]decane-1,6 to the solution. A 10 ml solution of diamine 0.16 g in water. Gradually turbid and precipitated solids. Stir in the dark for 24 hours. It is filtered, washed with water, and dried. Pt(IV)((S,S,S)-cis,cis-spiro[4,4]decane-1,6-diamine) tetrachloride 0.22 g was obtained. The yield was 43.6%.
元素分析值以C9H18N2Cl4Pt分析C、H、N、Cl、Pt Elemental analysis values were analyzed for C, H, N, Cl, Pt with C 9 H 18 N 2 Cl 4 Pt
計算值(%)22.01、3.69、5.70、28.87、39.7;實測值(%)21.54、3.58、5.36、24.88、39.2;IR(KBr):3227(N-H)cm-1 Calculated values (%) 22.01, 3.69, 5.70, 28.87, 39.7; measured values (%) 21.54, 3.58, 5.36, 24.88, 39.2; IR (KBr): 3227 (NH) cm -1
MS(ESI)m/z 490 MS (ESI) m/z 490
根據該結果可確認本化合物具有(化合物5)所示之化學結構。 From the results, it was confirmed that the present compound has the chemical structure represented by (Compound 5).
《實施例6》 "Embodiment 6"
以與實施例5相同之方式,自六氯鉑(IV)酸鉀與(R,R,R)-順,順-螺[4,4]壬烷-1,6二胺0.16 g獲得Pt(IV)((R,R,R)-順,順-螺[4,4]壬烷-1,6二胺)四氯化物0.27 g。產率為55.0%。 In the same manner as in Example 5, Pt was obtained from potassium hexachloroplatinate (IV) and (R, R, R)-cis, cis-spiro[4,4]nonane-1,6-diamine 0.16 g. IV) ((R,R,R)-cis,cis-spiro[4,4]decane-1,6-diamine) tetrachloride 0.27 g. The yield was 55.0%.
IR測定之結果與實施例5之四價鉑錯合物一致,而確認為(化合物6)。 The results of the IR measurement were identical to those of the tetravalent platinum complex of Example 5, and were confirmed to be (Compound 6).
《實施例7》藥劑效果試驗 "Example 7" agent effect test
試驗溶液係藉由以8 mg/ml之濃度將(化合物1)溶解於DMSO(二甲基亞碸,dimethylsulfoxide)中而製備。 The test solution was prepared by dissolving (Compound 1) in DMSO (dimethyl sulfoxide) at a concentration of 8 mg/ml.
試驗係使用人類肺癌細胞(LU99)、2種人類胃癌細胞(KATO III、MKN-45)、人類前列腺癌細胞(DU145)、人類惡性黑色素瘤細胞(G-361)、人類膀胱癌細胞(T24)、2種人類淋巴瘤細胞(U937、Jurkat E6.1)、人類白血病細胞(HL60)作為癌細胞而進行。 The test used human lung cancer cells (LU99) and two human gastric cancer cells (KATO). III, MKN-45), human prostate cancer cells (DU145), human malignant melanoma cells (G-361), human bladder cancer cells (T24), two human lymphoma cells (U937, Jurkat E6.1), human Leukemia cells (HL60) are carried out as cancer cells.
該等細胞懸浮於添加10%血清之各培養基中,並分注於96孔盤中。其後於37℃、5%CO2中培養一晚。利用培養基而將試驗溶液製備成各種濃度,並分注於預先播種有細胞之盤中。進而於37℃、5%CO2中培養3天。 The cells were suspended in each medium supplemented with 10% serum and dispensed into 96-well plates. Thereafter, it was cultured overnight at 37 ° C, 5% CO 2 . The test solution was prepared into various concentrations using a medium, and dispensed into a disk in which cells were seeded in advance. Further, it was cultured for 3 days at 37 ° C in 5% CO 2 .
藥劑添加後之細胞之增殖係於藥劑添加後第1天至第3天,藉由MTS法(Promega公司製造之細胞增殖試驗用套組Cell Titer 96 Aqueous One Solution Cell Proliferation Assay)而測定。 The proliferation of the cells after the addition of the drug was measured by the MTS method (Cell Titer 96 Aqueous One Solution Cell Proliferation Assay manufactured by Promega) from the first day to the third day after the administration of the drug.
利用以下之式,根據所測定之MTS值求出細胞增殖之阻礙率(%)。 The inhibition rate (%) of cell proliferation was determined from the measured MTS value by the following formula.
阻礙率(%)=(1-藥劑添加群之MTS值/藥劑未添加群MTS值)×100 Obstruction rate (%) = (1 - MTS value of the drug addition group / drug not added group MTS value) × 100
以上述式所求出之值表示細胞增殖阻礙率,因此數值越高,藥劑效果變得越高。將該值為50(%)以上者作為有藥劑效果者。將效果較高之細胞種之結果示於以下。 The value obtained by the above formula indicates the cell proliferation inhibition rate, and therefore the higher the value, the higher the drug effect. The value of 50 (%) or more is used as a pharmaceutical effect. The results of the cell types with higher effects are shown below.
與自先前以來作為抗癌劑之奧賽力鉑相比,確認對於人類淋 巴瘤細胞及人類白血病細胞有較強之藥效。特別是低濃度(5μg/ml)時之細胞增殖阻礙率較高,少於奧賽力鉑之量即具有效果。 Compared with Oseliplatin, which has been used as an anticancer agent from the past, it has been confirmed to have a strong effect on human lymphoma cells and human leukemia cells. In particular the amount of cells at low concentrations (5 μ g / ml) higher impede proliferation rate, i.e. less than Orsay force has the effect of platinum.
《實施例8》藥劑效果試驗 "Example 8" agent effect test
將(化合物2)製備為試驗溶液,並藉由與實施例7相同之方法測定細胞增殖阻礙率。將效果較高之細胞種之結果示於以下。 (Compound 2) was prepared as a test solution, and the cell proliferation inhibition rate was measured by the same method as in Example 7. The results of the cell types with higher effects are shown below.
與自先前以來作為抗癌劑之奧賽力鉑相比,確認對於人類胃癌細胞、人類膀胱癌細胞及人類淋巴瘤細胞有較強之藥效。特別是低濃度(5及10 μg/ml)時之細胞增殖阻礙率較高,少於奧賽力鉑之量即具有效果。 Compared with Oseliplatin, which has been an anticancer agent since the past, it has been confirmed to have potent effects on human gastric cancer cells, human bladder cancer cells, and human lymphoma cells. In particular, the low cell concentration (5 and 10 μg/ml) has a high cell proliferation inhibition rate, and the effect is less than the amount of Osliplatin.
《實施例9》藥劑效果試驗 "Example 9" drug effect test
將(化合物5)製備為試驗溶液,並藉由與實施例7相同之方法測定細胞增殖阻礙率。將效果較高之細胞種之結果示於以下。 (Compound 5) was prepared as a test solution, and the cell proliferation inhibition rate was measured by the same method as in Example 7. The results of the cell types with higher effects are shown below.
[表3]
與自先前以來作為抗癌劑之奧賽力鉑相比,確認對於人類肺癌細胞、人類胃癌細胞、人類惡性黑色素瘤細胞及人類膀胱癌細胞有較強之藥效。特別是低濃度(5及10 μg/ml)時之細胞增殖阻礙率較高,少於奧賽力鉑之量即具有效果。 Compared with Oseliplatin, which has been used as an anticancer agent, it has been confirmed to have potent effects on human lung cancer cells, human gastric cancer cells, human malignant melanoma cells, and human bladder cancer cells. In particular, the low cell concentration (5 and 10 μg/ml) has a high cell proliferation inhibition rate, and the effect is less than the amount of Osliplatin.
《實施例10》藥劑效果試驗 "Example 10" agent effect test
將(化合物6)製備為試驗溶液,並藉由與實施例7相同之方法測定細胞增殖阻礙率。將效果較高之細胞種之結果示於以下。 (Compound 6) was prepared as a test solution, and the cell proliferation inhibition rate was measured by the same method as in Example 7. The results of the cell types with higher effects are shown below.
與自先前以來作為抗癌劑之奧賽力鉑相比,確認對於人類肺癌細胞、人類惡性黑色素瘤細胞及人類膀胱癌細胞有較強之藥效。特別是低濃度(5及10 μg/ml)時之細胞增殖阻礙率較高,少於奧賽力鉑之量即具有效果。 Compared with Oseliplatin, which has been used as an anticancer agent from the past, it has been confirmed to have a strong pharmacological effect on human lung cancer cells, human malignant melanoma cells, and human bladder cancer cells. In particular, the low cell concentration (5 and 10 μg/ml) has a high cell proliferation inhibition rate, and the effect is less than the amount of Osliplatin.
以上,根據實施例7~10之結果,只要利用本發明之新穎四 價鉑錯合物,即可對人類肺癌細胞、人類胃癌細胞、人類前列腺癌細胞、人類惡性黑色素瘤細胞、人類膀胱癌細胞、人類淋巴瘤細胞、人類白血病細胞等多種惡性腫瘤具有較強之抗腫瘤活性,與先前之鉑錯合物惡性腫瘤治療劑相比,投予量為更少之量即具有效果,因此相對地減輕副作用。 Above, according to the results of Embodiments 7 to 10, as long as the novel four of the present invention is utilized The valence platinum complex can be highly resistant to various malignant tumors such as human lung cancer cells, human gastric cancer cells, human prostate cancer cells, human malignant melanoma cells, human bladder cancer cells, human lymphoma cells, and human leukemia cells. Tumor activity, compared with the previous platinum complex tumor malignant therapeutic agent, is less effective in administering the amount, and thus relatively reduces side effects.
[產業上之可利用性] [Industrial availability]
如上所述,本發明之鉑錯合物具有較強之抗腫瘤活性,可用作惡性腫瘤治療劑。 As described above, the platinum complex of the present invention has strong antitumor activity and can be used as a therapeutic agent for malignant tumors.
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