TWI402066B - 新穎１，２－雙取代醯胺基蒽醌衍生物、其製備方法及其應用 - Google Patents
新穎１，２－雙取代醯胺基蒽醌衍生物、其製備方法及其應用 Download PDFInfo
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- TWI402066B TWI402066B TW99105903A TW99105903A TWI402066B TW I402066 B TWI402066 B TW I402066B TW 99105903 A TW99105903 A TW 99105903A TW 99105903 A TW99105903 A TW 99105903A TW I402066 B TWI402066 B TW I402066B
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- indole
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- ethyl acetate
- chloroacetamido
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- MOLASEUYCMCIJJ-UHFFFAOYSA-N n-[2-[[2-[4-(2-fluorophenyl)piperazin-1-yl]acetyl]amino]-9,10-dioxoanthracen-1-yl]benzamide Chemical compound FC1=CC=CC=C1N1CCN(CC(=O)NC=2C(=C3C(=O)C4=CC=CC=C4C(=O)C3=CC=2)NC(=O)C=2C=CC=CC=2)CC1 MOLASEUYCMCIJJ-UHFFFAOYSA-N 0.000 description 1
- ASGORIDSORWQHK-UHFFFAOYSA-N n-[2-[[2-[4-(2-hydroxyethyl)piperazin-1-yl]acetyl]amino]-9,10-dioxoanthracen-1-yl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=1C(=O)C2=CC=CC=C2C(=O)C=1C=C1)=C1NC(=O)CN1CCN(CCO)CC1 ASGORIDSORWQHK-UHFFFAOYSA-N 0.000 description 1
- JVOJPXCDYNACNI-UHFFFAOYSA-N n-[2-[[2-[4-(2-methoxyphenyl)piperazin-1-yl]acetyl]amino]-9,10-dioxoanthracen-1-yl]-4-methylbenzamide Chemical compound COC1=CC=CC=C1N1CCN(CC(=O)NC=2C(=C3C(=O)C4=CC=CC=C4C(=O)C3=CC=2)NC(=O)C=2C=CC(C)=CC=2)CC1 JVOJPXCDYNACNI-UHFFFAOYSA-N 0.000 description 1
- ZNTMPXFGHOZUQS-UHFFFAOYSA-N n-[9,10-dioxo-2-[(2-piperidin-1-ylacetyl)amino]anthracen-1-yl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=1C(=O)C2=CC=CC=C2C(=O)C=1C=C1)=C1NC(=O)CN1CCCCC1 ZNTMPXFGHOZUQS-UHFFFAOYSA-N 0.000 description 1
- TZYABSSOMURSRW-UHFFFAOYSA-N n-[9,10-dioxo-2-[(2-thiomorpholin-4-ylacetyl)amino]anthracen-1-yl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=1C(=O)C2=CC=CC=C2C(=O)C=1C=C1)=C1NC(=O)CN1CCSCC1 TZYABSSOMURSRW-UHFFFAOYSA-N 0.000 description 1
- UYSUXZGNUQDSBP-UHFFFAOYSA-N n-[9,10-dioxo-2-[[2-(4-phenylpiperazin-1-yl)acetyl]amino]anthracen-1-yl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=1C(=O)C2=CC=CC=C2C(=O)C=1C=C1)=C1NC(=O)CN1CCN(C=2C=CC=CC=2)CC1 UYSUXZGNUQDSBP-UHFFFAOYSA-N 0.000 description 1
- AISRYWZLJNNJGV-UHFFFAOYSA-N n-[9,10-dioxo-2-[[2-(4-phenylpiperazin-1-yl)acetyl]amino]anthracen-1-yl]benzamide Chemical compound C=1C=C2C(=O)C3=CC=CC=C3C(=O)C2=C(NC(=O)C=2C=CC=CC=2)C=1NC(=O)CN(CC1)CCN1C1=CC=CC=C1 AISRYWZLJNNJGV-UHFFFAOYSA-N 0.000 description 1
- XRIFVHQHVKTPLO-UHFFFAOYSA-N n-[9,10-dioxo-2-[[2-(4-pyridin-2-ylpiperazin-1-yl)acetyl]amino]anthracen-1-yl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=1C(=O)C2=CC=CC=C2C(=O)C=1C=C1)=C1NC(=O)CN1CCN(C=2N=CC=CC=2)CC1 XRIFVHQHVKTPLO-UHFFFAOYSA-N 0.000 description 1
- ZCZCBESVDXUGDW-UHFFFAOYSA-N n-[9,10-dioxo-2-[[2-(4-pyrimidin-2-ylpiperazin-1-yl)acetyl]amino]anthracen-1-yl]-4-methylbenzamide Chemical compound C1=CC(C)=CC=C1C(=O)NC(C=1C(=O)C2=CC=CC=C2C(=O)C=1C=C1)=C1NC(=O)CN1CCN(C=2N=CC=CN=2)CC1 ZCZCBESVDXUGDW-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 231100000916 relative toxicity Toxicity 0.000 description 1
- 230000008943 replicative senescence Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940056729 sodium sulfate anhydrous Drugs 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- 108010057210 telomerase RNA Proteins 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本發明係關於癌症藥物發展的技術領域，特別涉及新穎之1,2-雙取代醯胺基蒽醌衍生物、其抗癌活性應用及評估。
染色體尾端又稱端粒(telomere)，具有與染色體其他部分完全不同之結構與功能。端粒用以保護染色體的完整性及防止染色體重組(recombination)、降解(degradation)及末端與末端的融合(end-to-end fusion)。若是失去了這結構則染色體無法完全的複製(replication)。端粒通常是由短，但重複的序列所組成。這序列從5'端到3'端含高比率的鳥糞嘌呤(Guanine,G)。而所有脊椎動物(包括人類)的端粒是由非常多重複的TTAGGG所組成。
在正常的體細胞內，染色體末端會因每次的複製而減少一部分的RNA引子(RNA primer)，且在每次的細胞分裂後，端粒會縮短約50-60bp，當端粒縮短到一定程度後，細胞便會凋亡，此即細胞的末端複製問題(end-replication problem)。
在大多數的生物體中，端粒長度的複製與維持，必須依賴端粒酶(telomerase)。端粒酶為一種核糖核酸蛋白酶，是由RNA與蛋白質次單元組成之複合體。目前，部分重要的端粒酶次單元已被鑑定出來，就人類端粒酶組成而言，包括具反轉錄酶活性的人類的端粒酶反轉錄酶(human telomerase reverse transcriptase,hTERT)，以及作為模板的人類端粒酶RNA組成體(human telomerase RNA component)，和一些與端粒酶結合的蛋白如：人類端粒酶結合蛋白(human telomerase-associated protein)、p23、hsp90、hsp40、hsp70等。
許多研究指出，人類端粒酶活性僅存在一些具高度增生能力的細胞中，例如：生殖細胞(germ cell)、造血細胞、部分幹細胞(stem cell)、大部分的不死細胞(immortalized cell)及絕大部分的腫瘤細胞。在一般體細胞中，由於不含有端粒酶活性，因此端粒會隨細胞分裂次數的增加而逐漸減短，這可視為細胞計算分裂次數的指標(mitotic clock)。而當端粒短至一定程度時，細胞會停止分裂而進入老化階段，且細胞會在此階段停留一段時間，而後走向死亡，此時期稱之為M1期(mortality stage 1)；若於M1期，細胞內之抑制腫瘤基因(tumor suppressor gene)發生突變，如p53和Rb，會促使細胞逃離老化階段而繼續進行細胞分裂，此時期稱之為M2期(mortality stage 2)。此時期因不具端粒酶活性的存在，因此端粒長度仍會縮短，而此時端粒無法保護染色體末端的完整性，進而導致染色體不穩定現象產生，細胞無法完整的將遺傳訊息傳遞而逐漸死亡，因此M2期又稱之為危機期(crisis)；大部分的細胞會於M2期死亡，僅有少數細胞會因端粒酶活性的表達而存活，此細胞可不受限制的持續性分裂，成為不死細胞(或癌細胞)。
因此一般認為：活化端粒酶，可維持端粒長度而避免細胞進入複製性衰老，或將端粒酶活性去除，抑制其活性，以限制癌細胞的分裂，兩者可為細胞朝向不老及癌化發展的關鍵。綜合上述，由於正常人類體細胞不具有端粒酶活性，因此，一個能夠抑制端粒酶活性的藥物，在對端粒酶產生抑制作用時，對正常細胞之生理狀況並不會產生影響，相反地，此活性抑制藥物卻能減弱癌細胞的增生能力，所以若能找尋到端粒酶活性抑制劑，藉由抗癌機轉的探討，朝癌症治療藥物發展是深具潛力的。
本案發明人鑑於癌症治療藥物發展的重要性，乃亟思加以創新發展，終於成功研發完成本件新穎1,2-雙取代醯胺基蒽醌衍生物、其製備方法及其應用。
本發明之目的即在於提供一系列新穎1,2-雙取代醯胺基蒽醌衍生物，化學修飾及合成步驟，得到具有如式I結構式之1,2-雙取代醯胺基蒽醌衍生物，其中Ra
、Rb
如文中定義。
本發明之次一目的係在於提供一種製備具有如式I結構式之新穎1,2-雙取代醯胺基蒽醌衍生物，其中Ra
、Rb
如文中定義。
本發明之另一目的係在於提供一種含有新穎1,2-雙取代醯胺基蒽醌衍生物之醫藥組合物，該醫藥組合物係包含具有如式I結構式之化合物用以治療癌症，其中Ra
、Rb
如文中定義。
為達成上述發明目的，本案發明人係以市售之1,2-二胺基蒽醌(1,2-diaminoanthraquinone)做為反應起始物，利用化學合成反應，進行不同官能基之修飾，以產生新穎1,2-雙取代醯胺基蒽醌衍生物，該些衍生物分別為化合物CC-01~
CC-50。
此外，本發明進一步於實施例探討及評估該些衍生物其藥理結果是偏向標靶藥物或是化療藥物，以供抑制腫瘤細胞或癌細胞生長，進而治療癌症。
本發明提供一系列新穎1,2-雙取代醯胺基蒽醌衍生物、其製備方法及其應用，其中該應用包含將該些衍生物製備為醫藥組合物之組成份，用以治療癌症。其中該醫藥組合物至少包含由具有如式I結構式所組成之化合物群組中至少一者，其中Ra
、Rb
如文中定義：
，及藥學上可接受賦形劑。
該醫藥組合物係用以治療癌症、抑制腫瘤、癌細胞之生長，其中所述癌症包含但不限於血癌(Leukemia)、非小細胞肺癌(Non-Small Cell Lung Cancer)、大腸癌(Colon Cancer)、中樞神經癌(CNS Cancer)、黑色素瘤(Melanoma)、卵巢癌(Ovarian Cancer)、腎癌(Renal Cancer)、前列腺癌(Prostate Cancer)、乳癌(Breast Cancer)等癌症。
該賦形劑包含但不限於稀釋劑、填充劑、結合劑、崩解劑、潤滑劑等。其中該賦形劑包含但不限於微晶纖維素(microcrystalline cellulose)、聚乙烯吡咯烷酮(polyvinylpyrrolidone,PVP)、玉米澱粉、修飾澱粉(modified starches)羧甲澱粉鈉(sodium starch glycolate)、樹脂、糊化澱粉(gelatinized starches)、糖類、聚乙二醇(polyethylene glycol,PEG)、聚乙烯醇(polyvinyl alcohol)、羥丙纖維素(hydroxypropyl cellulose)、甲基纖維素(methylcellulose)、氫氧甲基纖維素(hydroxymethyl cellulose)、羥丙基甲基纖維素(hydroxypropyl methylcellulose)等。
術語"治療有效量
"意謂治療疾病、改善、減弱或消除特定疾病(如：癌症)之一或多個症狀，或抑制或延遲癌細胞生長之一或多個症狀之發作的化合物或化合物之組合的量。術語"藥學上可接受
"意謂物質或組合物必須與調配物之其他成份相容，且對患者無害。
本發明係以下面的實施例予以示範闡明，但本發明不受下述實施例所限制。
本發明所用之藥物、材料皆市售易於取得，下列僅為示例可取得之管道。
TLC 60 F254
,甲醇(methanol),二氯甲烷(dichloromethane),氯仿(Chloroform-d1
),二甲基亞碸(Dimethyl sulfoxide-d6
99.8%,DMSO-d6
)。
1,2-二胺基蒽醌(1,2-diaminoanthraquinone),N
,N
-二異丙基乙胺(N,N-Diisopropylethylamine,DIPEA),三乙胺(triethylamine，TEA),吡啶(pyridine),二甲基甲醯胺(N,N
-dimethylformamide anhdrous 99.8%,DMF),四氫呋喃(tetrahydrofuran anhdrous 99.9%,THF),氯乙醯氯(chloroacetyl chloride),3-氯丙醯氯(3-chloropropionyl chloride),4-氯丁醯氯(4-chlorobutyryl chloride),2-氯丙醯氯(2-chloropropionyl chloride),5-氯戊醯氯(5-chlorovaleroyl chloride),苯甲醯氯(benzoyl chloride),4-甲基苯甲醯氯(4-toluoyl chloride),3-甲基苯甲醯氯(3-toluoyl chloride),2-甲基苯甲醯氯(2-toluoyl chloride),4-氟苯甲醯氯(4-fluorobenzoyl chloride),3-氟苯甲醯氯(3-fluorobenzoyl chloride),2-氟苯甲醯氯(2-fluorobenzoyl chloride),4-氯苯甲醯氯(4-chlorobenzoyl chloride),3-氯苯甲醯氯(3-chlorobenzoyl chloride),2-氯苯甲醯氯(2-chlorobenzoyl chloride),4-(三氟乙基)苯甲醯氯(4-(trifluoromethyl) benzoyl chloride),3-三氟甲基苯甲醯氯(3-(trifluoromethyl) benzoyl chloride),2-三氟甲基苯甲醯氯(2-(trifluoromethyl) benzoyl chloride),2,5-雙-三氟甲基苯甲醯氯(2,5-(trifluoromethyl) benzoyl chloride,phenylacetyl chloride),環丙基甲醯氯(cyclopropane carbonyl chloride),環己基甲醯氯(cyclohexanecarbonyl chloride),2-呋喃甲醯氯(2-furoyl chloride),2-噻吩甲醯氯(2-thiophenecarbonyl chloride),異惡唑-5-碳醯氯(isoxazole-5-carbonyl chloride),2,5-二甲基-3-呋喃甲醯氯(2,5-dimethylfuran-3-carbonyl chloride),苯氧乙醯氯(phenoxyacetyl chloride),苯硫乙醯氯((phenylthio) acetyl chloride),N-苯基呱嗪(N
-phenylpiperazine),1-(2-氟苯基)呱嗪(1-(2-fluorophenyl) piperazine),二甲胺(dimethylamine),2-甲基胺甲基-1,3-二氧戊環(2-methylaminomethyl-1,3 dioxolane),2-(2-甲基胺乙基-吡啶)(2-(2-methylaminoethyl pyridine)),呱啶(piperidine),1,4-二氧-8-氮雜螺[4.5]癸烷(1,4-dioxa-8-azaspiro[4.5]decane),嗎啉(morpholine),硫代嗎啉(thiomorpholine),N
-甲基呱嗪(N
-methylpiperazine),2-羥乙基呱嗪(2-(piperazin-1-yl)ethanol),1-(2-苯甲腈)呱嗪(1-(2-cyanophenyl) piperazine),1-(2-甲氧基苯基)呱嗪(1-(2-methoxyphenyl) piperazine),1-(2-吡啶基)呱嗪(1-(2-pyridyl) piperazine),1-(2-嘧啶基)呱嗪(1-(2-pyrimidyl) piperazine)。
乙酸乙酯(Ethyl acetate),正己烷(n-Hexane),N,N-二甲基乙醯胺(N
,N
-dimethyl acetamide),乙醚(Ether),無水硫化鈉(Sodium sulfate anhydrous,Na2
SO4
),硫酸鎂(Magnessium sulfate,MgSO4
)
丙酮(Acetone,工業級),乙醇(Ethanol,工業級95%)
取化合物1,2-二胺基蒽醌(1,2-diaminoanthraquinone)溶於DMF中，先後加入吡啶(pyridine)與一系列的醯基氯化物(acyl chloride)進行攪拌後，將反應完的混合液降溫，過濾取沉澱，最後將沉澱物以酒精沖洗，得到化合物CC-01至CC-03。
取化合物1,2-二胺基蒽醌(1,2-diaminoanthraquinone)溶於DMF中，加入氯乙醯氯(chloroacetyl chloride)進行攪拌後，將反應完的混合液降溫，過濾取沈澱，最後將沉澱物以酒精沖洗，得到化合物CC-05。
取化合物CC-05溶於DMF中，分別先後加入(1)吡啶(pyridine)與2-氯丙醯氯(2-chloropropionyl chloride)、(2)吡啶(pyridine)與3-氯丙醯氯(3-chloropropionyl chloride)或(3)吡啶(pyridine)與4-氯丁醯氯(4-chlorobutyryl chloride)進行攪拌後，將反應完的混合液降溫，過濾取沈澱，最後將沉澱物以酒精沖洗再結晶，即分別可得到化合物CC-06、CC-07及CC-08。
取化合物1,2-二胺基蒽醌(1,2-diaminoanthraquinone)溶於THF中，先後加入吡啶(pyridine)與4-甲基苯甲醯氯(4-toluoyl chloride)進行攪拌，再將此混合液於油浴溫度120-130℃中攪拌，將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以乙酸乙酯(Ethyl acetate)進行萃取，再經由硫酸鎂(MgSO4
)除水、減壓濃縮後，用乙酸乙酯/正己烷(ethyl acetate/hexane)沖洗粗產物，最後將粗產物以酒精再結晶，即可得到化合物CC-04。
取化合物CC-05溶於THF中，先後加入吡啶(pyridine)與一系列的苯甲醯氯(benzoyl chloride)進行攪拌，再將此混合液於油浴溫度120-130℃中攪拌，將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以乙酸乙酯(Ethyl acetate)萃取，再經由硫酸鎂(MgSO4
)除水、減壓濃縮後，用乙酸乙酯/正己烷(ethyl acetate/hexane)沖洗粗產物，最後將粗產物以酒精再結晶，即可得到化合物CC-09至CC-22。
取化合物CC-05溶於THF中，先後加入吡啶(pyridine)與一系列的氯化乙醯(acetyl chloride)進行攪拌，再將此混合液於油浴溫度120-130°進行攪拌，將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以乙酸乙酯(Ethyl acetate)萃取，再經由硫酸鎂(MgSO4
)除水、減壓濃縮後，用乙酸乙酯/正己烷(ethyl acetate/hexane)沖洗粗產物，最後將粗產物以酒精再結晶，即可得到化合物CC-23至CC-32。
取化合物CC-09溶於THF中，先後加入N
,N
-二異丙基乙胺(DIPEA)與一系列的呱嗪(piperazine)進行攪拌，再將此混合液加熱迴流，將反應完的混合液過濾，取其上層析出的粗產物，最後將粗產物以酒精再結晶，即可得到化合物CC-33及CC-34。
取化合物CC-12溶於THF中，先後加入N
,N
-二異丙基乙胺(DIPEA)與一系列的二級胺(secondary amine)進行攪拌，再將此混合液加熱迴流，將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以乙酸乙酯(Ethyl acetate)萃取，再經由硫酸鎂(MgSO4
)除水、減壓濃縮後，用乙酸乙酯/正己烷(ethyl acetate/hexane)沖洗粗產物，最後將粗產物以酒精再結晶，即可得到化合物CC-35至CC-50。
在藥理試驗方面，將化學合成出的化合物結構CC-01
至CC-50
(共五十種化合物)，進行下列三個部份的藥理活性試驗：3-1.端粒序列複製法(Telomeric repeat amplification protocol,TRAP)；3-2.分泌型鹼性磷酸酶分析(Secreted alkaline phosphatase assay,SEAP assay)，以及MTT assay來檢測癌細胞之細胞存活率；3-3.美國癌症研究中心(NCI)篩選出五個化合物結構，針對這五個化合物進行五十五至六十種癌細胞株的毒殺試驗。
端粒序列複製法是目前較常使用來偵測端粒酶活性的方法，其分析方法簡述如下：首先將市售之2nM CX引子(0.05μM，2μl)，1nM NT引子(0.05μM，1μl)，與4nM寡核酸TSNT置於試管底部，並於試管中置入蠟塊(PERKIN ELMER Ampli Wax PCR Gem 50)，利用PCR熱循環機(PERKIN ELMER 9700)以90℃、5分鐘，72℃、3分鐘，50℃、1分鐘，20℃、1分鐘待温度降至4℃，再將封好蠟塊之試管取出。將欲分析之細胞萃出物(約含0.5-2μl細胞萃出物總蛋白含量)之蛋白質濃度稀釋為約0.5mg/ml，取4μl(相當於103
-104
個細胞的萃出物)，置於50μl反應混合試劑中。將細胞萃出物與反應試劑置於0.2ml PCR專用試管，30℃反應30分鐘，使細胞萃出物中之端粒酶延長TS引子，再將整個反應混合物加熱至94℃、3分鐘，終止端粒酶反應，並溶化蠟塊(混入PCR反應所需要之引子CX)，再將整個反應混合物加熱至94℃、3分鐘，再以94℃、30秒，50℃、30秒，72℃、1分鐘的條件下進行34次的PCR熱循環反應，最後以72℃、7分鐘使反應進行完全，降至4℃終止整個反應。TRAP分析法中的陽性對照組(不添加合成之藥物，而加入5μl mg/ml 0.1% DEPC水)；TRAP分析法中的陰性對照組(不添加合成之藥物，而加入5μl mg/ml RNase A)。取適量PCR反應後之反應混合物進行膠體電泳(10% acrylamide gel)，再以UV燈下進行顯影，經由顯影結果來斷定端粒酶活性之作用影響。
H1299為一非小細胞肺癌細胞株，且具端粒酶活性，故適合作為篩選端粒酶抑制劑的模式細胞株。且該細胞株含有人類端粒酶反轉錄酵素(hTERT，端粒酶活性主要由hTERT之表現來決定)，故，H1299適用於篩選本發明之化合物，藉此評估該些化合物抑制端粒酶活性的能力。惟，hTERT不易偵測，故，另將一帶有hTERT啟動子(PhTERT
)的質體，該hTERT啟動子帶有SEAP通訊基因(易於偵測)，轉染(transfection)入H1299細胞株內。藉此系統，用以評估化合物之抑制hTERT啟動子(PhTERT
)的能力。
取2×103
個hTERT-H1299+PTERT
(3.4)-SEAP細胞種於96 well細胞培養盤中，以4:1之DMEM(GIBCO BRL)+Glucose:Medium 199(GIBCO BRL)+10% FBS+1mM sodiumpyruvate(GIBCO BRL)+4mM L-glutamine(GIBCO BRL)於37℃下培養24小時後，再以一系列不同濃度(最後濃度分別為100、10、1μM)的CC-01至CC-50化合物，處理細胞24小時，以不加藥物處理之PTERT
-SEAP細胞做為控制組。藥物處理24小時以後，收集培養液，進行SEAP活性分析(以405nm吸光值增加之速率表示SEAP之酵素活性)，另將細胞進行MTT分析法比較藥物對細胞增生及活性的相對毒性或影響。
MTT assay常用以測定細胞存活率或增殖作用的方法，方法簡述如下：將前述細胞培養於96 well，加入25μl MTT溶液，置入37℃二氧化碳培養箱4小時，再加入100μl Lysis buffer置入37℃二氧化碳培養箱隔夜，使用ELISA reader(Bio-Rad Model 450)測光學活性(optical densitry,O.D.) 550nm之吸光值。
此部分之試驗結果為美國癌症研究中心(NCI)從本發明所提供之五十種化合物結構中，被篩選出了五個化合物結構(並已有認證號碼)(圖四)，並進行六十種癌細胞株的毒殺試驗。
承實施例2所揭示1,2-雙取代醯胺基蒽醌衍生物的化學合成步驟，於下述實施例進一步揭露各衍生化合物的製備方法及其分析結果。
熔點測定是使用Bchi 545熔點測定儀。IR(KBr)所使用的儀器則是Perkin-Elmer 983G spectrometer。MS委請國立交通大學貴儀中心代測。1
H-NMR及13
C-NMR的測定是使用Varian GEMINI-300(300MHz)或BRUKER AV 500MHz。
取化合物1,2-diaminoanthraquinone(0.92g,4mmole)溶於無水N
,N
-dimethylformamide(30ml)中，在室溫下通入氮氣於反應瓶，先後加入吡啶(pyridine)(0.5ml)、氯乙醯氯(chloroacetyl chloride)(1ml,1.2mmole)，置於室溫攪拌24小時後；將反應完的混合液倒入冰水浴(200ml)，靜置10至20分鐘，此時會出現沉澱，過濾取沉澱，最後將沉澱物以ethanol沖洗，即可得到土黃色化合物CC-01
。Mol. Wt.:391.2049(C18
H12
Cl2
N2
O4
);Rf
:0.27(ethyl acetate:n-hexane=1:2)；產率(Yield)：56%;Mp.：254-255℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,390.0174(C18
H12
Cl2
N2
O4 +
)；found,390.0170;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.43(s,2H,-CH2
Cl),4.45(s,2H,-CH2
Cl),7.90-7.93(m,2H,Ar-H),8.12-8.18(m,2H,Ar-H),8.22(d,J
=8.1Hz,1H,Ar-H),8.38(d,J
=9.0Hz,1H,Ar-H),9.83(s,1H,Ar-NH-),10.29(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.25,126.20,126.93,128.14,130.33,132.28,134.25,134.42,134.63,139.77,165.61(NCO),166.02(NCO),181.60(CO),183.25(CO),
取化合物1,2-diaminoanthraquinone(0.92g,4mmole)溶於無水N,N
-dimethylformamide(30ml)中，在室溫下通入氮氣於反應瓶，先後加入三乙胺(triethylamine，TEA)(0.5ml)、3-氯丙醯氯(3-chloropropionyl chloride)(1.2ml,12mmole)，置於室溫攪拌24小時後；將反應完的混合液倒入冰水浴(200ml)，靜置10至20分鐘，此時會出現沉澱，過濾取沉澱，最後將沉澱物以ethanol沖洗，即可得到土黃色化合物CC-02
。Mol. Wt.:419.2580(C20
H16
Cl2
N2
O4
);Rf
:0.23(ethyl acetate:n-hexane=1:2);Yield：51%;Mp.：179-180℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,418.0487(C20
H16
Cl2
N2
O4 +
);found,418.0494;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：2.94-3.03(m,4H,-CH2
-),3.86-3.94(m,4H,-CH2
Cl),7.88-7.90(m,2H,Ar-H),8.10-8.15(m,2H,Ar-H),8.08(d,J
=8.1Hz,1H,Ar-H),8.42(d,J
=8.7Hz,1H,Ar-H),9.50(s,1H,Ar-NH-),10.02(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：40.20,40.26,125.94,126.29,126.87,127.61,127.79,128.33,129.79,132.27,134.26,134.36,134.52,140.28,168.86(NCO),169.43(NCO),181.63(CO),183.22(CO)。
取化合物1,2-diaminoanthraquinone(0.92g,4mmole)溶於無水N
,N
-dimethylformamide(30ml)中，在室溫下通入氮氣於反應瓶，先後加入pyridine(0.5ml)、4-氯丁醯氯(4-chlorobutyryl chloride)(1.4ml,12mmole)，置於室溫攪拌24小時後；將反應完的混合液倒入冰水浴(200ml)，靜置10至20分鐘，此時會出現沉澱，過濾取沉澱，最後將沉澱物以ethanol沖洗，得到土黃色化合物CC-03
。Mol. Wt.:447.3112(C22
H20
Cl2
N2
O4
);Rf
:0.37(ethyl acetate:n-hexane=1:2);Yield:45%;Mp.:154-155℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,446.0800(C22
H20
Cl2
N2
O4 +
)；found,446.0793;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：2.04-2.12(m,4H,-CH2
-),2.57-2.66(m,4H,-CH2
-),3.71(t,J
=6.6Hz,2H,-CH2
-),3.78(t,J
=6.6Hz,2H,-CH2
-),7.88-7.91(m,2H,Ar-H),8.08-8.16(m,3H,Ar-H),8.36(d,J
=8.7Hz,1H,Ar-H),9.52(s,1H,Ar-NH-),9.82(s,1H,Ar-NH-);13
C-NMR(300MHz,DMSO-d6
)d(ppm)：27.68,27.76,33.11,33.37,44.75,44.99,125.55,126.28,126.85,127.88,128.21128.40,129.57,132.28,134.23,134.47,134.53,140.45,171.12(NCO),171.60(NCO),181.71(CO),183.46(CO)。
取化合物1,2-diaminoanthraquinone(0.92g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、4-甲基苯甲醯氯(4-toluoyl chloride)(1.6ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethylacetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土褐色化合物CC-04
。Mol. Wt.：474.5067(C30
H22
N2
O4
);Rf
：0.51(ethyl acetate：n-hexane=1:2);Yield：62%;Mp.：227-229℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,474.1580(C30
H22
N2
O4 +
)；found,474.1572;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：2.36(s,3H,-CH3
),2.42(s,3H,-CH3
),7.33(d,J
=8.4Hz,2H,Ar-H),7.42(d,J
=8.4Hz,2H,Ar-H),7.79(d,J
=8.1Hz,2H,Ar-H),7.90-7.93(m,2H,Ar-H),8.01(d,J
=8.1Hz,1H,Ar-H),8.13-8.16(m,1H,Ar-H),8.18-8.20(m,1H,Ar-H),8.42(d,J
=8.7Hz,1H,Ar-H),10.06(s,1H,Ar-NH-),10.90(s,1H,Ar-NH-);13
C-NMR(300MHz,DMSO-d6
)d(ppm)：20.37,20.48,125.02,125.90,126.61,126.90,127.45,128.88,128.92,129.28,129.70,129.99,130.39,130.57,131.79,133.85,134.00,134.14,138.94,142.12,142.20,164.50(NCO),165.85(NCO),181.21(CO),183.84(CO)。
取化合物1,2-diaminoanthraquinone(1.19g,5mmole)溶於無水N,N
-dimethylformamide(30ml)中，在室溫下通入氮氣於反應瓶，加入chloroacetyl chloride(0.5ml,6mmole)，置於室溫攪拌2小時後；將反應完的混合液倒入冰水浴(200ml)，靜置10至20分鐘，此時會出現沉澱，過濾取沉澱，最後將沉澱物以hot ethanol沖洗，得到紅色化合物CC-05
。Mol. Wt.：314.7231(C16
H11
N2
O3
);Rf
:0.82(ethyl acetate:n-hexane=1:4);Yield:65%;Mp.：193-194℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,314.0458(C16
H11
N2
O3 +
)；found,314.0455;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.38(s,2H,-CH2
Cl),7.48(d,J
=7.8Hz,1H,Ar-H),7.74(d,J
=8.1Hz,1H,Ar-H),7.84(dd,J
=8.1Hz,J
=1.8Hz,1H,Ar-H),7.88(t,J
=1.5Hz,1H,Ar-H),7.91(dd,J
=7.5Hz,J
=1.5Hz,1H,Ar-H),7.96(br,2H,Ar-NH2
),8.14(dd,J
=7.2Hz,J
=1.8Hz,1H,Ar-H),8.22(dd,J
=7.8Hz,J
=1.5Hz,1H,Ar-H),9.80(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.25,112.98,115.62,126.69,126.55,129.88,128.88,128.92,130.25,131.01,132.64,133.65,134.37,165.72(NCO),182.28(CO),184.38(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水N
,N
-dimethylformamide(30ml)中，在室溫下通入氮氣於反應瓶，先後加入pyridine(0.5ml)、2-氯丙醯氯(2-chloropropanoyl chloride)(1.32ml,12mmole)，置於室溫攪拌1小時後；將反應完的混合液倒入冰水浴(200ml)，靜置10至20分鐘，此時會出現沉澱，過濾取沉澱，最後將沉澱物以ethanol沖洗再結晶，即可得到土黃色化合物CC-06
。Mol. Wt.：405.2315(C19
H14
Cl2
N2
O4
);Rf
:0.61(ethyl acetate:n-hexane=1:2);Yield:28%;Mp.：175-176℃(EtOH);HRMS(EI)m
/z
：calcd[M]+
,404.0331(C19
H14
Cl2
N2
O4 +
)；found,404.0339;1
H-NMR(300MHz,CDCl3
)d(ppm)：1.92(s,3H,-CH3
),4.23(s,2H,-CH2
Cl),4.67-4.74(m,1H,-CH2
-),7.79-7.86(m,2H,Ar-H),8.27-8.37(m,4H,Ar-H),9.50(s,1H,Ar-NH-),11.930(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：21.35,43.04,54.64,125.99,126.29,126.84,128.53,128.68,130.59,132.21,134.19,134.32,134.52,139.18,165.27(NCO),168.58(NCO),181.51(CO),183.34(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水N,N
-dimethylformamide(30ml)中，在室溫下通入氮氣於反應瓶，先後加入pyridine(0.5ml)、3-氯丙醯氯(3-chloropropionyl chloride)(1.2ml,12mmole)，置於室溫攪拌24小時後；將反應完的混合液倒入冰水浴(200ml)，靜置10至20分鐘，此時會出現沉澱，過濾取沉澱，最後將沉澱物以ethanol沖洗再結晶，即可得到土黃色化合物CC-07
。Mol. Wt.：405.2315(C19
H14
C12
N2
O4
);Rf
:0.43(ethyl acetate：n-hexane=1:2);Yield:33%;Mp：182-183℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,404.0331(C19
H14
C12
N2
O4 +
)；found,404.0334;1
H-NMR(300MHz,CDCl3
)d(ppm)：3.13(t,J
=6.3Hz,2H,-CH3
),3.96(t,J
=6.6Hz,2H,-CH3
),4.21(s,2H,-CH2
Cl),7.81-7.84(m,2H,Ar-H),8.25-8.34(m,4H,Ar-H),9.73(s,1H,Ar-NH-),11.51(s,1H,Ar-NH-);13
C-NMR(125MHz,DMSO-d6
)d(ppm)：43.33,125.92,126.28,126.46,126.82,126.97,127.90,128.00,128.92,130.28,132.18,134.19,134.28,134.52,139.56,164.50(NCO),165.85(NCO),183.09(CO),183.09(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水N,N
-dimethylformamide(30ml)中，在室溫下通入氮氣於反應瓶，先後加入pyridine(0.5ml)、4-氯丁醯氯(4-chlorobutyryl chloride)(1.4ml,12mmole)，置於室溫攪拌24小時後；將反應完的混合液倒入冰水浴(200ml)，靜置10至20分鐘，此時會出現沉澱，過濾取沉澱，最後將沉澱物以ethanol沖洗再結晶，即可得到土黃色化合物CC-08
。Mol. Wt.：419.2580(C20
H16
Cl2
N2
O4
);Rf
:0.52(ethyl acetate:n-hexane=1:2);Yield:38%;Mp：163-164℃(EtOH);HRMS(EI)m/z
：calcd [M]+
,418.0487(C20
H16
Cl2
N2
O4 +
)；found,418.0494;1
H-NMR(300MHz,CDCl3
)d(ppm)：2.28-2.34(m,2H,-CH2
-),3.13(t,J
=6.3Hz,2H,-CH3
),2.88(t,J
=7.2Hz,2H,-CH2
-),3.73(t,J
=6.3Hz,2H,-CH2
-),4.22(s,2H,-CH2
Cl),7.81-7.83(m,2H,Ar-H),8.26-8.34(m,4H,Ar-H),9.84(s,1H,Ar-NH-),11.46(s,1H,Ar-NH-);13
C-NMR(125MHz,DMSO-d6
)d(ppm)：44.99,125.67,126.26,126.79,127.91,128.01,128.73,130.21,132.16,134.23,134.26,134.52,165.34(NCO),171.81(NCO),181.49(CO),183.21(CO)。
取化合物CC-05
(1.28g,4mole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、苯甲醯氯(benzoyl chloride)(1.23ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-09
。Mol. Wt.：418.8292(C23
H15
ClN2
O4
)；Rf
：0.83(ethyl acetate:n-hexane=1:1);Yield:67%;Mp.：203-204℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,418.0720(C23
H15
ClN2
O4 +
)；found,418.0716;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.42(s,2H,-CH2
Cl),7.57-7.67(m,2H,Ar-H),7.78-7.92(m,2H,Ar-H),8.09-8.18(m,4H,Ar-H),8.24(d,J
=8.7Hz,1H,Ar-H),8.40(d,J
=8.7Hz,1H,Ar-H),9.86(s,1H,Ar-NH-),10.58(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.19,125.76,126.28,126.95,127.79,127.95,128.40,128.51,129.56,130.43,132.00,132.22,133.97,134.23,134.34,134.50,139.44,165.42(NCO),166.35(NCO),181.55(CO),183.77(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、2-甲基苯甲醯氯(2-toluoyl chloride)(1.62ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-10
。Mol. Wt.：432.8558(C24
H17
ClN2
O4
);Rf
:0.47(ethyl acetate:n-hexane=1:2)；Yield:47%;Mp.:179-180℃(EtOH);HRMS(EI)m/z
:calcd[M]+
,432.0877(C24
H17
ClN2
O4 +
)；found,432.0877;1
H-NMR(300MHz,CDCl3
)d(ppm)：2.52(s,3H,-CH3
),4.20(s,2H,-CH2
Cl),7.48-7.50(m,2H,Ar-H),7.79-7.83(m,2H,Ar-H),7.99-8.01(m,2H,Ar-H),8.26-8.33(m,4H,Ar-H),10.08(s,1H,Ar-NH-),12.35(s,1H,Ar-NH-);13
C-NMR(75MHz,CDCl3
)d(ppm)：21.39,43.12,124.08,125.16,125.16,125.60,127.24,127.63,128.91,128.91,129.06,131.71,132.07,132.91,133.32,133.81,134.35,134.83,136.53,139.15165.44(NCO),168.03(NCO),181.68(CO),187.58(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、3-甲基苯甲醯氯(3-toluoylchloride)(1.62ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-11
。Mol. Wt.：432.8558(C24
H17
ClN2
O4
);Rf
:0.62(ethyl acetate:n-hexane=1:2);Yield:56%;Mp.：202-203℃(EtOH);HRMS(EI)m/z
calcd[M]+
,432.0877(C24
H17
ClN2
O4 +
)；found,432.0873;1
H-NMR(300MHz,CDCl3
)d(ppm)：2.52(s,3H,-CH3
),4.20(s,2H,-CH2
Cl),7.48-7.50(m,2H,Ar-H),7.80-7.83(m,2H,Ar-H),7.99-8.01(m,2H,Ar-H),8.26-8.32(m,4H,Ar-H),10.08(s,1H,Ar-NH-),12.36(s,1H,Ar-NH-);13
C-NMR(75MHz,CDCl3
)d(ppm)：21.39,43.12,124.07,125.15,125.60,127.24,127.63,128.91,128.91,129.06,131.70,132.08,132.91,133.30,133.81,134.29,134.36,136.84,136.51,139.15,165.45(NCO),168.03(NCO),181.69(CO),187.58(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、4-甲基苯甲醯氯(4-toluoyl chloride)(1.62ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-12
。Mol. Wt.：432.8558(C24
H17
ClN2
O4
);Rf
:0.76(ethyl acetate:n-hexane=1:2);Yield:66%;Mp.：198-199℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,432.0877(C2
4H17
ClN2
O4 +
)；found,432.0881;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：2.43(s,3H,-CH3
),4.43(s,2H,-CH2
Cl),7.41(d,J
=7.8Hz,2H,Ar-H),7.88-7.91(m,2H,Ar-H),8.01(d,J
=8.1Hz,2H,Ar-H),8.10-8.13(m,1H,Ar-H),8.16-8.19(m,1H,Ar-H),8.24(d,J
=8.7Hz,1H,Ar-H),8.39(d,J
=9.0Hz,1H,Ar-H),9.84(s,1H,ArNH-),10.58(s,1H,Ar-NH-);13
C-NMR(300MHz,CDCl3
)d(ppm)：20.90,43.53,123.99,125.52,127.23,127.60,128.24,129.87,130.52,131.66,132.02,132.94,133.01,134.29,134.33,136.80,136.51,143.22,164.83(NCO),167.15(NCO),181.07(CO),187.00(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、2-氟苯甲醯氯(2-fluorobenzoyl chloride)(1.42ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethylacetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-13
。Mol. Wt.：436.8197(C23
H14
ClFN2
O4
);Rf
:0.62(ethyl acetate:n-hexane=1:2);Yield:31%;Mp.：245-246℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,436.0626(C23
H14
ClFN2
O4 +
)；found,436.0630;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.41(s,2H,-CH2
Cl),7.40-7.47(m,2H,Ar-H),7.65-7.72(m,1H,Ar-H),7.86-7.93(m,2H,Ar-H),8.03-8.19(m,3H,Ar-H),8.24(d,J
=8.4Hz,1H,Ar-H),8.37(d,J
=8.7Hz,1H,Ar-H),9.83(s,1H,Ar-NH-),10.48(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.11,116.43,116.65,124.71,125.86,126.29,126.94,127.83,128.50,128.96,130.98,132.23,133.80,133.92,134.24,134.35,134.51,139.27,162.97(NCO),165.41(NCO),181.55(CO),183.82(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、3-氟苯甲醯氯(3-fluorobenzoyl chloride)(1.42ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-14
。Mol. Wt.:436.8197(C23
H14
ClFN2
O4
);Rf
:0.48(ethyl acetate:n-hexane=1:2);Yield:47%;Mp.:197-198℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,436.0626(C23
H14
ClFN2
O4 +
)；found,436.0623;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.43(s,2H,-CH2
Cl),7.48-7.55(m,1H,Ar-H),7.63-7.70(m,1H,Ar-H),7.86-7.96(m,4H,Ar-H),8.10-8.13(m,1H,Ar-H),8.15-8.19(m,1H,Ar-H),8.26(d,J
=8.7Hz,1H,Ar-H),8.44(d,J
=8.7Hz,1H,Ar-H),9.85(s,1H,Ar-NH-),10.49(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.21,114.61,114.91,118.63,118.90,124.18,126.12,126.30,126.96,128.14,128.24,128.84,130.37,130.64,130.74,132.23,134.23,134.35,134.54,136.55,140.00,162.97(NCO),165.54(NCO),181.55(CO),183.41(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、4-氟苯甲醯氯(4-fluorobenzoyl chloride)(1.42ml,12mmo,e)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到綠褐色化合物CC-15。Mol. Wt.：436.8197(C23
H14
ClFN2
O4
);Rf
:0.72(ethyl acetate:n-hexane=1:2);Yield:62%；Mp.:184-185℃(EtOH)；HRMS(EI)m/z
：calcd[M]+
,436.0626(C23
H14
ClFN2
O4 +
)；found,436.0625;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.42(s,2H,-CH2
Cl),7.44(t,J
=9.0Hz,2H,Ar-H),7.88-7.91(m,2H,Ar-H),8.09-8.18(m,4H,Ar-H),8.25(d,J
=8.7Hz,1H,Ar-H),8.42(d,J
=8.7Hz,1H,Ar-H),9.84(s,1H,Ar-NH-),10.51(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm):43.21,114.61,114.91,118.63,118.90,124.18,126.12,126.30,126.96,128.14,128.24,128.84,130.37,130.64,130.74,132.23,134.23,134.35,134.54,136.55,140.00,162.97(NCO),165.54(NCO),181.55(CO),183.41(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、2-氯苯甲醯氯(2-chlorobenzoyl chloride)(1.42ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-16
。Mol. Wt.：453.2743(C23
H14
Cl2
N2
O4
);Rf
:0.47(ethyl acetate:n-hexane=1:2);Yield:46%;Mp.：193-194℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,452.0331(C23
H14
Cl2
N2
O4 +
)；found,436.0325;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.43(s,2H,-CH2
Cl),7.57-7.60(m,3H,Ar-H),7.89-7.94(m,2H,Ar-H),8.08-8.19(m,3H,Ar-H),8.26(d,J
=8.7Hz,1H,Ar-H),8.37(d,J
=8.7Hz,1H,Ar-H),9.76(s,1H,Ar-NH-),10.44(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.16,126.16,126.32,126.93,127.19,128.37,128.53,129.49,130.14,130.63,130.76,131.73,134.24,134.34,134.56,135.29,139.44,165.36(NCO),165.54(NCO),181.55(CO),183.44(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、3-氯苯甲醯氯(3-chlorobenzoyl chloride)(1.42ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-17
。Mol. Wt.：453.2743(C23
H14
Cl2
N2
O4
);Rf
:0.53(ethyl acetate:n-hexane=1:2);Yield:51%;Mp.：188-189℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,452.0331(C23
H14
Cl2
N2
O4 +
)；found,436.0330;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.43(s,2H,-CH2
Cl),7.72-7.64(m,2H,Ar-H),7.87-7.91(m,2H,Ar-H),8.02-8.19(m,4H,Ar-H),8.26(d,J
=8.4Hz,1H,Ar-H),8.45(d,J
=8.4Hz,1H,Ar-H),9.79(s,1H,Ar-NH-),10.49(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.28,126.11,126.24,126.36,126.79,127.01,127.88,128.01,128.37,128.74,130.36,130.53,131.73,132.27,133.33,134.17,134.26,134.41,134.60,136.28,165.23(NCO),165.64(NCO),181.61(CO),183.36(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、4-氯苯甲醯氯(4-chlorobenzoyl chloride)(1.44ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌3小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-18
。Mo1. Wt.：453.2743(C23
H14
Cl2
N2
O4
);Rf
：0.64(ethyl acetate:n-hexane=1:2);Yie1d:67%;Mp.：224-225℃(EtOH);HRMS(EI)m/z
：caLcd[M]+
,452.0331(C23
H14
Cl2
N2
O4 +
)；found,436.0333;1
H-NMR(300MHz,DMso-d6
)d(ppm)：4.42(s,2H,-CH2
Cl),7.68-7.71(m,2H,Ar-H),7.88-7.91(m,2H,Ar-H),8.08-8.18(m,4H,Ar-H),8.25(d,J
=8.4Hz,1H,Ar-H),8.43(d,J
=8.7Hz,1H,Ar-H),9.86(s,1H,Ar-NH-),10.52(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.23,126.06,126.33,126.96,128.21,128.61,129.06,129.93,130.40,132.25,132.92,134.38,134.56,136.91,139.87,165.50(NCO),165.53(NCO),181.58(CO),183.51(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、2-三氟甲基苯甲醯氯(2-(trifluoromethyl)benzoylchl oride)(1.78ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌4小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-19
。Mol. Wt.：486.8272(C24
H14
ClF3
N2
O4
);Rf
:0.42(ethyl acetate:n-hexane=1:2);Yield:32%;Mp.：248-250℃(EtOH);HRMS(EI)m
/z
：calcd[M]+
,486.0594(C24
H14
ClF3
N2
O4 +
);found,486.0587;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.38(s,2H,-CH2
Cl),7.80(t,J
=7.4Hz,1H,Ar-H),7.90-7.97(m,4H,Ar-H),8.13-8.29(m,4H,Ar-H),8.37(d,J
=8.4Hz,1H,Ar-H),9.72(s,1H,Ar-NH-),10.49(s,1H,Ar-NH-);13
C-NMR(125MHz,DMSO-d6
)d(ppm)：43.32,126.27,126.33,126.63,126.87,128.13,128.64,129.01,130.66,130.76,132.18,132.59,134.23,134.35,134.58,139.39,165.31(NCO),166.00(NCO),181.45(CO),183.24(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中,於室溫下,先後加入pyridine(0.5ml)、3-三氟甲基苯甲醯氯(3-(trifluoromethyl)benzoyl chloride)(1.78ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌4小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到金黃色化合物CC-20
。Mol. Wt.：486.8272(C24
H14
ClF3
N2
O4
);Rf
:0.52(ethyl acetate:n-hexane=1:2);Yield:48%;Mp.：190-191℃(EtOH);HRMS(EI)m
/z
：calcd[M]+
,486.0594(C24
H14
ClF3
N2
O4 +
);found,486.0596;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.38(s,2H,-CH2
Cl),7.84-7.93(m,3H,Ar-H),8.04(d,J
=7.5Hz,1H,Ar-H),8.08-8.11(m,1H,Ar-H),8.16-8.19(m,1H,Ar-H),8.27(d,J
=9.0Hz,1H,Ar-H),8.38-8.49(m,3H,Ar-H),9.90(s,1H,Ar-NH-),10.58(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.25,124.66,126.32,126.96,127.98,128.39,128.48,128.55,129.82,130.34,132.07,132.25,134.22,134.37,134.55,135.27,140.30,165.24(NCO),165.63(NCO),181.56(CO),183.25(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、4-三氟甲基苯甲醯氯(4-(trifluoromethyl)benzoylchloride)(1.78ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌4小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到褐棕色化合物CC-21
。Mol. Wt.：486.8272(C24
H14
ClF3
N2
O4
)；Rf
:0.63(ethyl acetate:n-hexane=1:2);Yield:57%；Mp.：203-204℃(EtOH);HRMS(EI)m
/z
：calcd[M]+
,486.0594(C24
H14
ClF3
N2
O4 +
)；found,486.0597;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.43(s,2H,-CH2
Cl),7.88-7.91(m,2H,Ar-H),8.01(d,J
=8.4Hz,2H,Ar-H),8.08-8.11(m,1H,Ar-H),8.16-8.19(m,1H,Ar-H),8.25-8.32(m,3H,Ar-H),8.45(d,J
=8.3Hz,1H,Ar-H),9.90(s,1H,Ar-NH-),10.60(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.25,122.15,125.48,125.53,125.77,126.27,126.34,126.95,128.11,128.39,128.66,128.93,130.37,131.56,131.99,132.26,134.24,134.39,134.57,138.02,140.12,165.42(NCO),165.61(NCO),181.57(CO),183.35(CO)。
取化合物CC-05
(1.28g，4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、2,5-雙-三氟甲基苯甲醯氯(2,5-bis
-(trifluoromethyl)benzoyl chloride)(1ml,6mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌4小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-22
。Mol. Wt.：554.8251(C24
H14
ClF3
N2
O4
);Rf
：0.63(ethyl acetate：n-hexane=1:2);Yield:42%;Mp.:187-188℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,554.0468(C24
H14
ClF3
N2
O4 +
)；found,554.0468;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.38(s,2H,-CH2
Cl),7.90-7.95(m,2H,Ar-H),8.11-8.22(m,5H,Ar-H),8.29(d,J
=8.4Hz,1H,Ar-H),8.40(d,J
=8.7Hz,1H,Ar-H),8.69(s,1H,Ar-H),9.85(s,1H,Ar-NH-),10.69(s,1H,Ar-NH-);13
C-NMR(300MHz,DMSO-d6
)d(ppm)：42.94,126.35,126.59,126.83,127.77,127.90,128.21,128.27,128.68,128.75,130.75,134.21,134.42,134.63,136.22,139.90,164.63(NCO),165.39(NCO),181.50(CO),183.26(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、苯乙醯氯(phenylacetyl chloride)(1.6ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌4小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土褐色化合物CC-23
。Mol. Wt.：432.8558(C24
H17
ClN2
O4
);Rf
:0.46(ethyl acetate:n-hexane=1:2);Yield:34%;Mp.：184-185℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,432.0877(C24
H17
ClN2
O4 +
)；found,432.0885;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：3.86(s,2H,-CH2
-),4.36(s,2H,-CH2
Cl),7.23-7.93(m,5H,Ar-H),7.89-7.93(m,2H,Ar-H),8.11-8.20(m,3H,Ar-H),8.31(d,J
=8.7Hz,1H,Ar-H),9.66(s,1H,Ar-NH-),10.25(s,1H,Ar-NH-);13
C-NMR(125MHz,DMSO-d6
)d(ppm)：25.08,42.51,43.20,43.34,66.97,125.59,126.26,126.53,126.83,127.92,128.15,128.86,129.30,129.66,128.75,130.30,132.16,134.22,134.29,134.52,135.35,142.78,145.07,165.25(NCO),170.57(NCO),181.51(CO),183.25(CO)。
取化合物CC05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、4-氟苯乙醯氯(4-fluorophenylacetyl chloride)(1.7ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌4小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-24
。Mol. Wt.：450.8462(C24
H16
ClFN2
O4
);Rf
:0.37(ethyl acetate:n-hexane=1:2);Yield:37%;Mp.：213-214℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,450.0783(C24
H16
ClFN2
O4 +
)；found,450.0782;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：3.86(s,2H,-CH2
-),4.37(s,2H,-CH2
Cl),7.17(t,J
=9.0Hz,1H,Ar-H),7.42-7.47(m,2H,Ar-H),7.90-7.93(m,2H,Ar-H),8.11-8.23(m,3H,Ar-H),8.32(d,J
=8.7Hz,1H,Ar-H),9.64(s,1H,Ar-NH-),10.20(s,1H,Ar-NH-);13
C-NMR(300MHz,DMSO-d6
)d(ppm)：41.48,43.03,114.69,114.97,125.67,126.26,126.79,127.79,128.15,128.28,129.14,130.45,131.42,131.53,132.23,134.27,134.50,139.18,165.23(NCO),170.70(NCO),181.54(CO),183.46(CO)。
取化合物CC-
05(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、環丙基甲醯氯(cyclopropanecarbonyl chloride)(0.6ml,6mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mlni-reactor中攪拌4小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃褐色化合物CC-25
。Mol. Wt.：382.7971(C20
H15
ClN2
O4
);Rf
:0.43(ethyl acetate:n-hexane=1:2);Yield:27%;Mp.：191-192℃(EtOH);HRMS(EI)m/z
:calcd[M]+
,382.0720(C20
H15
ClN2
O4 +
)；found,382.0712;1
H-NMR(300MHz,CDCl3
)d(ppm)：1.02-1.08(m,2H,-CH2
-),1.26-1.80(m,2H,-CH2
-),1.92-1.97(m,1H,-CH2
-),4.20(s,2H,-CH2
Cl),7.80-7.85(m,2H,Ar-H),8.26-8.33(m,4H,Ar-H),10.01(s,1H,Ar-NH-),11.75(s,1H,Ar-NH-);13
C-NMR(75MHz,CDCl3
)d(ppm)：0.86,9.16,16.15,43.14,123.55,125.35,127.21,127.53,131.49,131.80,132.61,132.94,134.33,134.75,136.41,165.29(NCO),175.30(NCO),181.69(CO),187.40(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、環己基甲醯氯(cyclohexanecarbonyl chloride)(0.88ml,6mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌4小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土黃色化合物CC-26
。Mol. Wt.：424.8768(C23
H21
ClN2
O4
);Rf
:0.47(ethyl acetate：n-hexane=1:2);Yield:52%;Mp.：216-217℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,424.1190(C23
H21
ClN2
O4 +
)；found,424.1194;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：1.20-1.49(m,6H,-CH2
-),1.67-1.83(m,2H,-CH2
-),2.06(d,J
=11.4Hz,2H,-CH2
-),4.43(s,2H,-CH2
Cl),7.89-7.92(m,2H,Ar-H),8.13-8.19(m,3H,Ar-H),8.28(d,J
=8.7Hz,1H,Ar-H),9.57(s,1H,Ar-NH-),10.12(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：25.03,25.32,28.68,43.15,44.36,125.34,126.30,126.92,127.27,128.74,129.89,130.61,132.22,134.29,134.32,134.55,138.65,165.16(NCO),175.60(NCO),181.61(CO),183.80(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、2-呋喃甲醯氯(2-furoyl chloride)(1.22ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌2小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到褐色化合物CC-27
。Mol. Wt.：408.7913(C21
H13
ClN2
O5
);Rf
:0.57(ethyl acetate:n-hexane=1:2);Yield:63%;Mp.：211-212℃(EtOH);HRM S(EI)m
/z
：calcd[M]+
,408.0513(C21
H13
ClN2
O5 +
)；found,408.0518;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.43(s,2H,-CH2
Cl),6.77-6.79(m,2H,-HC=CH-),7.38(d,J
=3.0Hz,1H,-HC=CH-),7.88-7.92(m,2H,Ar-H),8.06(d,J
=0.9Hz,1H,-HC=CH-),8.22(d,J
=8.7Hz,1H,Ar-H),8.39(d,J
=8.7Hz,1H,Ar-H),9.93(s,1H,Ar-NH-),10.60(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.26,112.51,115.71,125.74,126.37,127.05,127.56,128.59,128.82,130.37,132.27,134.26,134.47,134.61,139.34,157.15(NCO),165.60(NCO),181.60(CO),184.03(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、2-噻吩甲醯氯(2-thiophenecarbonyl chloride)(1.28ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌2小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到紅褐色化合物CC-28
。Mol. Wt.：424.8569(C21
H13
ClN2
O4
S);Rf
：0.52(ethyl acetate:n-hexane=1:2);Yield:55%;Mp.：190-191℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,424.0285(C21
H13
ClN2
O4
S+
)；found,424.0288;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.45(s,2H,-CH2
Cl),7.30-7.33(m,1H,-HC=CH-),7.88-7.94(m,1H,-HC=CH-),7.88-7.94(m,3H,Ar-H),8.10-8.20(m,1H,-HC=CH-),8.10-8.20(m,1H,Ar-H),8.24(d,J
=8.4Hz,1H,Ar-H),8.42(d,J
=6.9Hz,1H,Ar-H),9.45(s,1H,Ar-NH-),10.53(s,1H,Ar-NH-)；13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.25,125.95,126.36,127.01,128.04,128.24,128.37,128.88,130.36,132.26,134.26,134.42,134.60,139.08,139.79,161.17(NCO),165.60(NCO),181.55,181.61(CO),183.59(CO)。
取化合物CC-05
(1.28 g,4 mmole)溶於無水tetrahydrofuran(30 ml)中，於室溫下，先後加入pyridine(0.5 ml)、異惡唑-5-碳醯氯(isoxazole-5-carbonyl chloride)(1.14 ml,12 mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌2小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到褐色化合物CC-29
。Mol.Wt.：409.7794(C20
H12
ClN3
O5
)；Rf
：0.43(ethyl acetate：n-hexane=1：2)；Yield：52%；Mp.：212-213℃(EtOH)；HRMS(EI)m/z
：calcd[M]+
,409.0465(C20
H12
ClN3
O5 +
)；found,409.0472；1
H-NMR(300 MHz,DMSO-d6
)δ(ppm)：4.43(s,2H,-CH2
Cl),7.31(d,J
=1.8 Hz,1H,-HC=CH-),7.88-7.94(m,1H,-HC=CH-),7.88-7.92(m,2H,Ar-H),8.08-8.11(m,1H,Ar-H),8.15-8.18(m,1H,Ar-H),8.27(d,J
=8.7 Hz,1H,Ar-H),8.49(d,J
=8.7 Hz,1H,Ar-H),8.88(d,J
=1.8 Hz,1H,-HC=N-),10.03(s,1H,Ar-NH-),10.69(s,1H,Ar-NH-)；13
C-NMR(75 MHz,DMSO-d6
)δ(ppm)：43.25,107.12,126.35,126.66,126.82,126.98,127.84,128.56,130.17,132.24,134.18,134.42,134.59,140.46,151.99,155.50,162.77(NCO),165.79(NCO),181.50(CO),183.06(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、2,5-二甲基-3-呋喃甲醯氯(2,5-dimethylfuran-3-carbonyl chloride)(1.51ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌2小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane 沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃色化合物CC-30
。Mol. Wt.：436.8445(C23
H17
ClN2
O5
);Rf
:0.54(ethyl acetate:n-hexane =1:2);Yield:63%;Mp.：207-208℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,436.0826(C23
H17
ClN2
O5 +
)；found,436.0832;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：2.33(s,3H,-CH3
),2.52(s,3H,-CH3
),4.44(s,2H,-CH2
Cl),6.70(s,1H,-HC=CCH3
),7.89-7.92(m,2H,Ar-H),8.13-8.19(m,2H,Ar-H),8.21(d,J
=8.7Hz,1H,Ar-H),8.34(d,J
=8.7Hz,1H,Ar-H),9.83(s,1H,Ar-NH-),10.29(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：12.74,13.04,43.14,105.21,116.20,125.29,126.29,126.98,128.82,129.93,130.50,132.23,134.23,134.39,134.52,138.67,149.74,156.05,162.99(NCO),165.30(NCO),181.55(CO),184.22(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、苯氧乙醯氯(phenoxyacetyl chloride)(1.65ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌2小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-31
。Mol. Wt.：448.8552(C24
H17
ClN2
O5
);Rf
:0.61(ethyl acetate:n-hexane=1:2);Yield:55%;Mp.：217-218℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,448.0826(C24
H17
ClN2
O5 +
)；found,448.0824;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.40(s,2H,-CH2
Cl),4.82(s,2H,-CH2
O-),7.02(t,J
=6.0Hz,1H,Ar-H),7.16(d,J
=7.5Hz,1H,Ar-H),7.35-7.40(m,2H,Ar-H),7.90-7.93(m,2H,Ar-H),8.13-8.18(m,2H,Ar-H),8.20(d,J
=8.7Hz,1H,Ar-H),8.33(d,J
=8.4Hz,1H,Ar-H),9.86(s,1H,Ar-NH-),10.58(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.12,67.24,114.94,118.49,121.48,125.60,126.29,126.89,127.44,128.64,129.54,132.22,134.21,134.37,134.52,135.11,138.87,157.66,165.41(NCO),168.03(NCO),181.50(CO),183.94(CO)。
取化合物CC-05
(1.28g,4mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入pyridine(0.5ml)、苯硫乙醯氯((phenylthio)acetyl chloride)(1.79ml,12mmole)，攪拌5至10分鐘，再將此混合液置於油浴溫度120-130℃的mini-reactor中攪拌2小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hotethanol再結晶，即可得到褐色化合物CC-32
。Mol. Wt.：464.9208(C24
H17
ClN2
O4
S)；Rf
:0.57(ethyl acetate:n-hexane=1:2);Yield:59%;Mp.：161-162℃(EtOH);HRMS(EI)m/z
:calcd[M]+
,464.0598(C24
H17
ClN2
O4
S+
);found,464.0602;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：4.10(s,2H,-CH2
S-),4.43(s,2H,-CH2
Cl),7.33(td,J
=6.6Hz,J
=1.8Hz,2H,Ar-H),7.45(d,J
=7.2Hz,2H,Ar-H),7.86-7.93(m,2H,Ar-H),8.08-8.16(m,2H,Ar-H),8.21(d,J
=8.7Hz,1H,Ar-H),8.30(d,J
=8.7Hz,1H,Ar-H),9.71(s,1H,Ar-NH-),10.46(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：43.82,126.43,126.58,127.00,127.51,128.56,129.20,129.52,129.66,131.16,132.93,134.96,135.23,136.69,139.82,166.05(NCO),168.92(NCO),182.23(CO),184.16(CO)。
取化合物CC-09
(0.83g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、N-苯基呱嗪(N-phenylpiperazine)(1.22ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其上層析出的粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-33
。Mol. Wt.：544.5998(C33
H28
N4
O4
);Rf
:0.33(ethyl acetate:n-hexane=1:2);Yield:57%;Mp.：225-226℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,544.2111(C33
H28
N4
O4 +
);found,544.2119;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：2.56(br,4H,-CH2
-),2.78(br,4H,-CH2
-),3.23(s,2H,-CH2
N-),6.25(d,J
=7.8Hz,2H,Ar-H),6.78(t,J
=7.2Hz,1H,Ar-H),7.18(t,J
=8.7Hz,2H,Ar-H),7.37(t,J
=7.5Hz,2H,Ar-H),7.47(t,J
=7.5Hz,1H,Ar-H),7.87-7.93(m,2H,Ar-H),8.10(d,J
=6.0Hz,2H,Ar-H),8.16-8.19(m,2H,Ar-H),8.30(d,J
=8.7Hz,1H,Ar-H),8.79(d,J
=8.7Hz,1H,Ar-H),10.06(s,1H,Ar-NH-),10.58(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：47.81,52.74,61.47,115.56,118.87,125.38,126.29,126.65,126.91,127.72,127.91,128.03,128.48,128.62,129.35,132.14,132.31,133.10,134.12,134.44,140.53,150.77,166.36(NCO),169.06(NCO),181.42(CO),183.64(CO)。
取化合物CC-09
(0.83g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、1-(2-氟苯基)呱嗪(1-(2-fluorophenyl)piperazine)(1.26ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其上層粗產物；最後將粗產物以hot ethanol再結晶，即可得到橘紅色化合物CC-34
。Mol. Wt.：562.5903(C33
H27
FN4
O4
);Rf
:0.37(ethyl acetate:n-hexane=1:2);Yield:65%;Mp.：228-229℃(EtoH);HRMS(EI)m/z
：calcd[M]+
,562.2016(C33
H27
FN4
O4 +
)；found,562.2012;1
H-NMR(300MHz,DMSO-d6
)d(ppm)：2.59(br,4H,-CH2
-),2.61(br,4H,-CH2
-),3.23(s,2H,-CH2
N-),6.41(t,J
=8.1Hz,1H,Ar-H),6.95-7.10(m,3H,Ar-H),7.48-7.60(m,3H,Ar-H),7.87-7.93(m,2H,Ar-H),8.09-8.20(m,4H,Ar-H),8.30(d,J
=8.7Hz,1H,Ar-H),8.80(d,J
=9.0Hz,1H,Ar-H),10.06(s,1H,Ar-NH-),10.62(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
)d(ppm)：49.53,52.81,61.50,114.20,115.51,115.78,119.13,119.17,122.24,122.35,124.47,124.51,125.31,126.30,126.67,126.92,127.69,128.01,128.66,129.34,132.28,133.27,134.11,134.44,139.32,139.43,140.50,153.20,156.44,166.38(NCO),169.03(NCO),181.41(CO),183.68(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、二甲胺(dimethylamine)(0.8ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃褐色化合物CC-35
。Mol. Wt.：441.4785(C26
H23
N3
O4
);Rf
:0.33(ethyl acetate:n-hexane=1:2);Yield:54%;Mp.：190-191℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,441.1689(C26
H23
N3
O4 +
)；found,441.1689;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.11(s,6H,-NCH3
),2.44(s,3H,-CH3
),3.09(s,2H,-CH2
N-),7.43(d,J
=8.1Hz,1H,Ar-H),7.88-7.91(m,2H,Ar-H),8.11-8.19(m,2H,Ar-H),8.26(d,J
=8.7Hz,1H,Ar-H),8.64(d,J
=8.4Hz,1H,Ar-H),10.16(s,1H,Ar-NH-),10.54(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.86,45.16,62.82,125.73,126.30,126.47,127.79,127.99,128.12,128.89,129.09,129.39,130.93,132.32,134.13,134.36,134.43,140.34,142.23,166.35(NCO),169.14(NCO),181.45(CO),183.63(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1 ml,6 mmole)、2-甲基胺甲基-1,3-二氧戊環(2-methylaminomethyl-1,3 dioxolane)(0.91 ml,8 mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-36
。Mol.Wt.：513.5412(C29
H27
N3
O6
)；Rf
：0.31(ethyl acetate：n-hexane=1：2)；Yield：43%；Mp.：156-157℃(EtOH)；HRMS(EI)m/z
：calcd[M]+
,513.1900(C29
H27
N3
O6 +
)；found,513.1902；1
H-NMR(300 MHz,DMSO-d6
)d(ppm)：2.18(s,3H,-CH3
),2.44(s,3H,-CH3
),2.54(d,J
=8.7 Hz,2H,-NCH2
-),3.26(s,2H,-CH2
N-),3.52-3.55(m,2H,-OCH2
-),3.72-3.77(m,2H,-OCH2
-),4.58(t,J
=4.5 Hz,1H,-OCHO-),7.43(d,J
=7.8 Hz,2H,Ar-H),7.88-7.92(m,2H,Ar-H),8.04(d,J
=8.1 Hz,2H,Ar-H),8.10-8.19(m,2H,Ar-H),8.27(d,J
=8.4 Hz,1H,Ar-H),8.70(d,J
=8.7 Hz,1H,Ar-H),10.15(s,1H,Ar-NH-),10.53(s,1H,Ar-NH-)；13
C-NMR(75 MHz,DMSO-d6
)d(ppm)：20.87,43.49,59.43,61.73,63.91,102.61,125.50,126.31,126.48,126.90,127.89,128.06,129.06,129.31,130.75,132.33,134.16,134.38,134.45,140.42,142.29,166.25(NCO),169.59(NCO),181.46(CO),183.70(CO)。
取化合物CC-12
(0.86 g,2 mmole)溶於無水tetrahydrofuran(30 ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、2-(2-甲基胺乙基-吡啶)(2-(2-methylaminoethyl pyridine))(1.1ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到亮黃色化合物CC-37
。Mol. Wt.：532.5891(C32
H28
N4
O4
);Rf
:0.29(ethyl acetate:n-hexane=1:2);Yield:32%;Mp.：166-167℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,532.2111(C32
H28
N4
O4 +
)；found,532.2119;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.15(s,3H,-CH3
),2.40(s,3H,-CH3
),2.68(d,J
=7.2Hz,4H,-CH2
-),3.20(s,2H,-CH2
N-),7.03(d,J
=7.0Hz,1H,Ar-H),7.13-7.18(m,1H,Ar-H),7.39(d,J
=8.1Hz,2H,Ar-H),7.60-7.65(m,1H,Ar-H),7.89-7.93(m,2H,Ar-H),8.03(d,J
=8.1Hz,2H,Ar-H),8.11-8.20(m,2H,Ar-H),8.28(d,J
=8.7Hz,1H,Ar-H),8.40-8.42(m,1H,Ar-H),8.69(d,J
=8.7Hz,1H,Ar-H),10.18(s,1H,Ar-NH-),10.54(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.81,42.45,56.92,61.03,63.91,121.62,122.81,125.50,126.29,126.44,126.88,127.83,127.88,128.07,129.08,129.30,130.72,132.33,134.13,134.36,134.42,136.24,140.37,142.30,148.86,159.40,166.19(NCO),169.59(NCO),181.43(CO),183.74(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、吡咯啶(pynolidine)(0.8ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到深褐色化合物CC-38
。Mol. Wt.：467.5158(C28
H25
N3
O4
);Rf
:0.37(ethyl acetate:n-hexane=1:2);Yield:39%;Mp.：193-194℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,467.1845(C28
H25
N2
O4 +
)；found,467.1840;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：1.31(br,10H,-CH2
-),2.43(s,3H,-CH3
),3.27(s,2H,-CH2
N-),7.42(d,J
=8.1Hz,2H,Ar-H),7.87-7.91(m,2H,Ar-H),8.09-8.19(m,2H,Ar-H),8.27(d,J
=8.7Hz,1H,Ar-H),8.73(d,J
=8.4Hz,1H,Ar-H),10.12(s,1H,Ar-NH-),10.54(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.86,23.20,53.65,59.09,126.30,126.54,126.88,127.80,127.88,127.92,129.05,129.25,130.59,132.33,134.12,134.38,134.42,136.24,140.44,142.43,166.26(NCO),169.56(NCO),181.42(CO),183.68(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、呱啶(piperidine)(0.79ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-39
。Mol. Wt.：481.5424(C29
H27
N3
O4
);Rf
:0.36(ethylacetate:n-hexane=1:2);Yield:43%;Mp.：213-214℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,481.2002(C29
H27
N3
O4 +
)；found,481.2000;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：1.08(d,J
=3.6Hz,2H,-CH2
-),1.19(br,4H,-CH2
-),2.33(br,4H,-CH2
-),2.43(s,3H,-CH3
),3.07(s,2H,-CH2
N-),7.43(d,J
=7.8Hz,1H,Ar-H),7.87-7.91(m,2H,Ar-H),8.07-8.19(m,4H,Ar-H),8.27(d,J
=8.7Hz,1H,Ar-H),8.78(d,J
=8.7Hz,1H,Ar-H),10.13(s,1H,Ar-NH-),10.52(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.85,22.80,24.79,54.13,62.39,125.19,126.27,126.53,126.89,127.84,127.92,128.02,129.00,129.22,130.57,132.31,134.13,134.36,134.42,140.63,142.40,166.25(NCO),169.55(NCO),181.42(CO),183.67(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、1,4-二氧-8-氮雜螺[4.5]癸烷(1,4-dioxa-8-azaspiro[4.5]decane)(1.03ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到褐色化合物CC-40
。Mol. Wt.：539.5785(C31
H29
N3
O6
);Rf
:0.34(ethyl acetate:n-hexane=1:2);Yield:55%;Mp.：197-198℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,539.2056(C31
H29
N3
O6 +
)；found,539.2051;1
H-NMR(300MHz,DMSO-d6
) d(ppm):1.39(d,J
=5.4Hz,8H,-CH2
-),2.43(s,3H,-CH3
),3.15(s,2H,-CH2
N-),3.77(s,4H,-CH2
-),7.41(d,J
=7.8Hz,1H,Ar-H),7.88-7.91(m,2H,Ar-H),8.06(d,J
=8.1Hz,2H,Ar-H),8.10-8.19(m,2H,Ar-H),8.26(d,J
=8.7Hz,1H,Ar-H),8.70(d,J
=8.7Hz,1H,Ar-H),10.03(s,1H,Ar-NH-),10.60(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.88,33.68,51.35,61.29,63.34,63.52,105.58,125.90,126.28,126.32,126.91,127.75,127.86,128.18,129.18,129.40,130.44,132.29,134.13,134.38,134.44,140.32,142.46,166.29(NCO),169.31(NCO),181.44(CO),183.81(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、嗎啉(morpholine)(0.69ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-41
。Mol. Wt.：483.5152(C28
H25
N3
O5
);Rf
:0.38(ethyl acetate:n-hexane=1:2);Yield:47%;Mp.：225-226℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,483.1794(C28
H25
N3
O5 +
)；found,483.1793;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.39(br,4H,-CH2
-),2.45(s,3H,-CH3
),3.15(s,2H,-CH2
N-),3.22(br,4H,-CH2
-),7.45(d,J
=7.8Hz,2H,Ar-H),7.88-7.91(m,2H,Ar-H),8.07-8.12(m,3H,Ar-H),8.27(d,J
=8.7Hz,1H,Ar-H),8.73(d,J
=8.7Hz,1H,Ar-H),9.99(s,1H,Ar-NH-),10.61(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.95,53.17,61.94,65.59,125.73,126.37,126.53,126.98,127.82,128.05,129.28,129.46,130.55,132.35,134.16,134.53,140.31,142.66,166.32(NCO),168.97(NCO),181.50(CO),183.84(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、硫代嗎啉(thiomorpholine)(0.80ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-42
。Mol. Wt.：499.5808(C28
H25
N3
O4
S);Rf
:0.43(ethyl acetate:n-hexane=1:2);Yield:51%;Mp.：210-211℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,499.1566(C28
H25
N3
O4
S+
)；found,499.1570;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.39(br,4H,-CH2
-),2.45(s,3H,-CH3
),3.15(s,2H,-CH2
N-),3.23(br,4H,-CH2
-),7.45(d,J
=8.1Hz,2H,Ar-H),7.88-7.91(m,2H,Ar-H),8.07-8.19(m,4H,Ar-H),8.27(d,J
=8.4Hz,1H,Ar-H),8.73(d,J
=8.4Hz,1H,Ar-H),10.00(s,1H,Ar-NH-),10.61(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.89,26.48,53.13,54.62,61.92,65.54,127.72,126.30,126.40,126.92,127.69,127.92,127.98,129.22,129.43,130.53,132.30,134.12,134.41,134.45,140.21,142.61,166.27(NCO),168.89,169.15(NCO),181.42(CO),183.84(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、N
-甲基呱嗪(N
-methylpiperazine)(0.88ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-43
。Mol. Wt.：496.5570(C29
H28
N4
O4
);Rf
:0.28(ethyl acetate:n-hexane=1:2);Yield:55%;Mp.：214-215℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,496.2111(C29
H28
N4
O4 +
)；found,496.2115;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：1.76(s,3H,-CH3
),1.96(br,4H,-CH2
-),2.38(br,4H,-CH2
-),2.43(s,3H,-CH3
),3.13(s,2H,-CH2
N-),7.45(d,J
=7.8Hz,2H,Ar-H),7.87-7.93(m,2H,Ar-H),8.08-8.16(m,4H,Ar-H),8.27(d,J
=9.0Hz,1H,Ar-H),8.81(d,J
=8.7Hz,1H,Ar-H),10.01(s,1H,Ar-NH-),10.50(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.89,26.48,53.13,54.62,61.92,65.54,127.72,126.30,126.40,126.92,127.69,127.92,127.98,129.22,129.43,130.53,132.30,134.12,134.41,134.45,140.21,142.61,166.27(NCO),168.89,169.15(NCO),181.42(CO),183.84(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、2-羥乙基呱嗪(2-(piperazin-1-yl) ethanol)(0.97ml,8mol)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-44
。Mol. Wt.：526.5830(C30
H30
N4
O5
);Rf
:0.41(ethyl acetate:n-hexane=1:2);Yield:48%;Mp.：210-211℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,526.2216(C30
H30
N4
O5 +
)；found,526.2219;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：1.92(t,J
=6.0Hz,2H,-NCH2
-),2.03(br,4H,-CH2
-),2.39(br,4H,-CH2
-),2.43(s,3H,-CH3
),3.01(s,2H,-CH2
N-),3.26-3.30(m,2H,-CH2
OH),4.29(t,J
=5.4Hz,1H,-CH2
OH),7.43(d,J
=8.1Hz,2H,Ar-H),7.87-7.91(m,2H,Ar-H),8.07-8.19(m,4H,Ar-H),8.27(d,J
=8.7Hz,1H,Ar-H),8.79(d,J
=8.7Hz,1H,Ar-H),10.00(s,1H,Ar-NH-),10.50(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.93,52.32,52.93,58.21,59.1,61.69,125.11,126.37,126.72,126.98,127.81,128.04,128.33,129.24,130.53,130.53,140.68,142.70,166.37(NCO),169.28(NCO),181.50(CO),183.67(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、N-苯基呱嗪(N
-phenylpiperazine)(1.22ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其上層析出的粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-45
。Mol. Wt.：558.6264(C34
H30
N4
O4
);Rf
:0.36(ethyl acetate:n-hexane=1:2);Yield:53%;Mp.：270-271℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,558.2267(C34
H30
N4
O4 +
);found,558.2271;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.21(s,3H,-CH3
),2.55(br,4H,-CH2
-),2.73(br,4H,-CH2
-),3.22(s,2H,-CH2
N-),6.64(d,J
=7.5Hz,2H,Ar-H),6.79(d,J
=7.2Hz,1H,Ar-H),7.12-7.21(m,4H,Ar-H),7.87-7.92(m,2H,Ar-H),7.98(d,J
=8.1Hz,2H,Ar-H),8.08-8.19(m,2H,Ar-H),8.29(d,J
=8.7Hz,1H,Ar-H),8.80(d,J
=8.7Hz,1H,Ar-H),10.07(s,1H,Ar-NH-),10.52(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.76,47.66,52.81,61.52,115.40,118.74,125.16,126.28,126.57,126.88,127.84,127.95,128.58,129.05,129.27,130.28,134.11,134.42,140.51,142.46,150.77,166.21(NCO),169.05(NCO),181.42(CO),183.65(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、1-(2-氟苯基)呱嗪(1-(2-fluorophenyl) piperazine)(1.26ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其上層析出的粗產物；最後將粗產物以hot ethanol再結晶，即可得到橘紅色化合物CC-46
。Mol. Wt.：576.6169(C34
H29
FN4
O4
);Rf
:0.32(ethyl acetate:n-hexane=1:2);Yield:62%;Mp.：228-229℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,576.2173(C34
H29
FN4
O4 +
)；found,576.2181;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.29(s,3H,-CH3
),2.58(br,8H,-CH2
-),3.17(s,2H,-CH2
N-),6.42(t,J
=7.2Hz,1H,Ar-H),6.97-7.10(m,3H,Ar-H),7.30(d,J
=7.5Hz,2H,Ar-H),7.87-7.91(m,2H,Ar-H),8.04-8.11(m,4H,Ar-H),8.16-8.19(m,1H,Ar-H),8.29(d,J
=8.4Hz,1H,Ar-H),8.81(d,J
=8.4Hz,1H,Ar-H),10.06(s,1H,Ar-NH-),10.56(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：21.54,50.19,53.61,62.30,114.94,116.26,116.54,119.71,122.85,122.96,127.04,127.33,127.65,128.61,128.81,129.97,130.04,131.26,133.07,134.86,135.18,141.20,143.28,153.96,167.00(NCO),169.77(NCO),182.17(CO),184.48(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、1-(2-苯甲腈)呱嗪(1-(2-cyanophenyl) piperazine)(1.35ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其上層析出的粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃色化合物CC-47
。Mol. Wt.：583.6359(C35
H29
N5
O4
);Rf
:0.37(ethyl acetate:n-hexane=1:2);Yield:55%;Mp.：238-239℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,583.2220(C35
H29
N5
O4 +
)；found,583.6359;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.30(s,3H,-CH3
),2.62(br,4H,-CH2
-),2.71(br,4H,-CH2
-),3.22(s,2H,-CH2
N-),6.50(d,J
=8.4Hz,1H,Ar-H),7.11(t,J
=7.5Hz,1H,Ar-H),7.34(d,J
=8.1Hz,2H,Ar-H),7.58(t,J
=8.4Hz,1H,Ar-H),7.66(dd,J
=9.0Hz,J
=1.5Hz,2H,Ar-H),7.87-7.91(m,2H,Ar-H),8.06-8.19(m,4H,Ar-H),8.29(d,J
=9.0Hz,1H,Ar-H),8.82(d,J
=8.7Hz,1H,Ar-H),10.06(s,1H,Ar-NH-),10.58(s,1H,Ar-NH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：21.54,50.19,53.61,62.30,114.94,116.26,116.54,119.71,122.85,122.96,127.04,127.33,127.65,128.61,128.81,129.97,130.04,131.26,133.07,134.86,135.18,141.20,143.28,153.96,167.00(NCO),169.77(NCO),182.17(CO),184.48(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、1-(2-甲氧基苯基)呱嗪(1-(2-methoxyphenyl) piperazine)(1.38ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其上層析出的粗產物；最後將粗產物以hot ethanol再結晶，即可得到橘黃色化合物CC-48
。Mol. Wt.：588.6524(C35
H32
N4
O5
);Rf
:0.34(ethyl acetate:n-hexane=1:2);Yield:58%;Mp.：215-216℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,588.2373(C35
H32
N4
O5 +
)；found,588.2378;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.20(s,3H,-CH3
),2.69(br,8H,-CH2
-),3.22(s,2H,-CH2
N-),3.72(s,3H,-OCH3
),6.16(t,J
=2.4Hz,1H,Ar-H),6.24(d,J
=8.1Hz,1H,Ar-H),6.38(d,J
=9.0Hz,1H,Ar-H),7.05-7.14(m,2H,Ar-H),7.88-7.93(m,2H,Ar-H),7.97(d,J
=8.1Hz,2H,Ar-H),8.08-8.19(m,2H,Ar-H),8.29(d,J
=8.7Hz,1H,Ar-H),8.80(d,J
=8.7Hz,1H,Ar-H),10.08(s,1H,Ar-NH-),10.52(s,1H,Ar-NH-);13
C-NMR(125MHz,DMSO-d6
) d(ppm)：20.86,47.63,52.86,54.81,61.53,101.53,103.94,108.06,124.95,126.32,126.74,126.90,127.65,127.97,129.04,129.25,130.12,132.26,134.06,134.41,134.48,140.55,142.50,153.05,159.97,163.71,166.17(NCO),169.05(NCO),181.35(CO),183.44(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、1-(2-吡啶基)呱嗪(1-(2-pyridyl) piperazine)(1.21ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到土橘色化合物CC-49
。Mol. Wt.：559.6145(C33
H29
N5
O4
);Rf
:0.28(ethyl acetate:n-hexane=1:2);Yield:63%;Mp.：258-259℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,559.2220(C33
H29
N5
O4 +
)；found,559.2224;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.16(s,3H,-CH3
),3.05(br,8H,-CH2
-),3.22(s,2H,-CH2
N-),6.54(d,J
=8.4Hz,1H,Ar-H),6.66(t,J
=6.3Hz,1H,Ar-H),7.08(d,J
=7.8Hz,2H,Ar-H),7.52(td,J
=7.7Hz,J
=2.1Hz,1H,Ar-H),7.87-7.91(m,2H,Ar-H),7.97(d,J
=8.1Hz,2H,Ar-H),8.07-8.19(m,2H,Ar-H),8.29(d,J
=8.7Hz,1H,Ar-H),8.82(d,J
=9.0Hz,1H,Ar-H),10.16(s,1H,Ar-NH-),10.51(s,1H,ArNH-);13
C-NMR(75MHz,DMSO-d6
) d(ppm)：20.88,44.21,52.56,61.54,107.00,113.11,124.91,126.42,126.89,126.99,127.63,128.03,128.21,129.01,129.29,132.26,133.39,134.19,134.52,134.58,137.30,140.73,142.51,147.49,159.15,166.26,166.31(NCO),169.23(NCO),181.54(CO),183.63(CO)。
取化合物CC-12
(0.86g,2mmole)溶於無水tetrahydrofuran(30ml)中，於室溫下，先後加入DIPEA(1ml,6mmole)、1-(2-嘧啶基)呱嗪(1-(2-pyrimidyl) piperazine)(1.13ml,8mmole)，攪拌5至10分鐘，再將此混合液加熱迴流16小時。將反應完的混合液過濾，取其濾液，減壓濃縮抽乾，以ethyl acetate做萃取數次，再經由magnessium sulfate除水、減壓濃縮後，用ethyl acetate/hexane沖洗粗產物；最後將粗產物以hot ethanol再結晶，即可得到黃綠色化合物CC-50
。Mol. Wt.：560.6025(C32
H28
N6
O4
);Rf
:0.32(ethyl acetate:n-hexane=1:2);Yield:41%;Mp.：267-268℃(EtOH);HRMS(EI)m/z
：calcd[M]+
,560.2172(C32
H28
N6
O4 +
)；found,560.2170;1
H-NMR(300MHz,DMSO-d6
) d(ppm)：2.20(s,3H,-CH3
),3.05(br,8H,-CH2
-),3.11(s,2H,-CH2
N-),3.22(br,8H,-CH2
-),6.66(d,J
=4.8Hz,1H,Ar-H),7.16(d,J
=7.8Hz,1H,Ar-H),7.87-7.91(m,2H,Ar-H),8.01(d,J
=6.0Hz,2H,Ar-H),8.08-8.19(m,2H,Ar-H),8.32(d,J
=7.2Hz,1H,Ar-H),8.82(d,J
=8.7Hz,1H,Ar-H),10.19(s,1H,Ar-NH-),10.54(s,1H,Ar-NH-);13
C-NMR(125MHz,DMSO-d6
) d(ppm)：20.98,42.53,43.01,52.46,61.44,110.28,111.11,124.77,126.32,126.89,127.44,127.92,128.14,128.90,129.18,130.18,132.26,134.06,134.48,142.39,157.65,158.07,161.24,166.12,(NCO),169.08(NCO),181.35(CO),183.39(CO)。
端粒序列複製法，期望以市售TS引子模擬端粒序列，在正常生理情形下能自行形成G-quadruplex的特殊結構，當化合物穩定此結構時，會使端粒酶無法延長端粒長度，進而達到抑制端粒酶的作用，因此將合成出的CC-01~
CC-50利用端粒序列複製法，找出對端粒酶具有抑制效果的化合物。
在膠體電泳的結果中(圖五A至圖五C)，陽性對照組(P)是以滅菌三次水來替代化合物；陰性對照組(N)是以5μl 0.1mg/ml RNase A(CLONTECH)來替代化合物，在陽性對照組(P)製造出許多的端粒片段，但在陰性對照組(N)中則無。選取10μM來當做篩選化合物的濃度，並先將所有化合物先做初篩，之後在從中找出比較有效的化合物做不同濃度的篩選，結果如圖五A至圖五C所示，化合物結構CC-01至CC-50都無顯著的端粒酶抑制作用；因此推測，不論是對稱雙取代或是不對稱的1,2-雙取代醯胺基anthraquinone衍生物，對於端粒酶的抑制作用效果都比較差。
SEAP及MTT分析結果請參閱表1至表5，結果可發現化合物結構中具有對稱(CC-01至CC-03)與不對稱(CC-06至CC-08)的支鏈結構，在1μM、10μM、100μM中的毒殺能力，都較1,2-diaminoanthraquinone好很多。另，化合物結構CC-01與CC-06是較具有毒殺潛力的，其毒殺能力甚至較米托蒽醌(mitoxantrone)與阿黴素(doxorubicin)好。化合物CC-09至CC-22大多數的化合物結構在高濃度(100μM、10μM)的作用下都具有很強的毒殺能力。此外，可發現較具毒殺潛力的化合物結構CC-14與CC-15，這兩個化合物結構在低濃度(1μM)的作用下依然保有著很強的毒殺效果，其抑制能力甚至較mitoxantrone與doxorubicin的結構好。另，在化合物CC-23至CC-32中，可發現CC-28的化合物結構是較具潛力的，其對於癌細胞活性抑制的能力並不亞於mitoxantrone與doxorubicin的結構。CC-33至CC-50的化合物結構在高濃度(100μM、10μM)的環境下，其細胞毒殺的能力降低了，尤其是在10μM的毒殺作用下，差異性最為明顯(毒性降低)，唯有化合物CC-43與CC-44在此濃度下，是這一系列化合物(CC-35至CC-50)中較具有抑制作用的結構。
綜上所述，在SEAP與MTT的藥理試驗中，於低濃度(1μM)即有很強的毒殺效果者(細胞存活率低於50%)，為CC-01、CC-06、CC-14、CC-15及CC-28化合物，意即該些化合物較具有毒殺H1299非小細胞肺癌細胞株的毒殺能力，其作用效果甚至較mitoxantrone與doxorubicin的結構具潛力。CC-33化合物於低、高濃度(1μM、10μM、100μM)時皆無明顯的毒殺效果。餘者則於高濃度時(100μM、10μM)皆有毒殺效果。
本發明化合物之代表結構式，如式I所示：
其中當Ra
及Rb
皆為相同取代基，皆為表2之R1
所定義者時，即為化合物CC-01、CC-02、CC-03及CC-04；其中當Ra
為表3之R2
所定義者，且Rb
為式II時，即為化合物CC-05~
CC-32；其中當Ra
為式III，Rb 式IV，且R3
為氫(H)或氟(F)時，即分別為化合物CC-33、CC-34之結構式；其中當Ra
為式V，Rb
為式VI，且R4
為表5所定義者，即為化合物CC-35~
CC-50。
美國癌症中心NCI著篩選系統是由60種不同人體的腫瘤細胞組成，測定每一個化合物在一定的濃度下一致各種癌症和腫瘤的生長能力或細胞毒性程度。
NCI以CC-04、CC-12、CC-23、CC-38、CC-43為測試化合物(如表6所示)，進行測試之結果(如表7及附件1至附件5所示)。其中，對於Leukemia、Non-Small Cell Lung Cancer、Colon Cancer、CNS Cancer、Melanoma、Ovarian Cancer、Renal Cancer、Prostate Cancer、Breast Cancer等癌細胞，化合物CC-12可抑制其生長之效果。化合物CC-23可抑制Leukemia、Melanoma癌細胞之生長。化合物CC-43可抑制Leukemia、Melanoma、Ovarian Cancer癌細胞之生長。另，於人類多重抗藥性乳癌細胞NCI/ADR-RES(源於卵巢癌)之試驗中，發現化合物CC-12、CC-23、CC-43具有阿霉素(adriamycin,ADR)之抗藥性。將化合物CC-12與CC-43結構相較於NCI資料庫數值中的化合物mitoxantrone與doxorubicin，甚至可發現CC-43(0.13μM)的化合物結構其抑制百分之五十癌細胞株的生長能力(GI50
)與doxorubicin(0.11μM)的化合物結構相當(圖六)。
上列詳細說明係針對本發明之一可行實施例之具體說明，惟該實施例並非用以限制本發明之專利範圍，凡未脫離本發明技藝精神所為之等效實施或變更，均應包含於本案之專利範圍中。
綜上所述，本案不但在1,2-雙取代醯胺基蒽醌衍生物確屬創新，且其製備方法及治療癌症上之應用亦為創新，應已充分符合新穎性及進步性之法定發明專利要件，爰依法提出申請，懇請 貴局核准本件發明專利申請案，以勵發明，至感德便。
請參閱以下有關本發明一較佳實施例之詳細說明及其附圖，將可進一步瞭解本發明之技術內容及其目的功效；有關該實施例之附圖為：
圖一為化合物CC-01~
CC-03、CC-05~
CC-08的製備流程圖。
圖二為化合物CC-04、CC-09~
CC-22、CC-23~
CC-32的製備流程圖。
圖三為化合物CC-09、CC-12、CC-33、CC-34、CC-35~
CC-50的製備流程圖。
圖四為送交至美國癌症中心(NCI)化驗藥物篩選之受測化合物。
圖五A為化合物CC-01~
CC-18端粒序列複製法分析結果；圖五B為化合物CC-19~
CC-42端粒序列複製法分析結果；圖五C為化合物CC-43~
CC-50端粒序列複製法分析結果；D代表處理doxrubicin、M代表處理mitoxantrone、A代表處理1,2-diaminoanthrquione。
圖六為化合物CC-12、CC-43、mitoxantrone及doxorubicin之抑制百分之五十癌細胞株的生長能力(GI50
)的測試結果。
Claims (4)
- 一種新穎1,2-雙取代醯胺基蒽醌衍生物系選自於由1-(2-氟苯甲醯胺基)-2-(氯乙醯胺基)-蒽醌、1-(3-氟苯甲醯胺基)-2-(氯乙醯胺基)-蒽醌、1-(4-氟苯甲醯胺基)-2-(氯乙醯胺基)-蒽醌、1-(2-氯苯甲醯胺基)-2-(氯乙醯胺基)-蒽醌、1-(3-氯苯甲醯胺基)-2-(氯乙醯胺基)-蒽醌、1-(4-氯苯甲醯胺基)-2-(氯乙醯胺基)-蒽醌、1-[2-(三氟甲基)苯甲醯胺基]-2-(氯乙醯胺基)-蒽醌、1-[3-(三氟甲基)苯甲醯胺基]-2-(氯乙醯胺基)-蒽醌、1-[4-(三氟甲基)苯甲醯胺基]-2-(氯乙醯胺基)-蒽醌、1-[2,5-雙-(三氟甲基)苯甲醯胺基]-2-(氯乙醯胺基)-蒽醌、1-[(2-呋喃甲醯基)胺基]-2-(氯乙醯胺基)-蒽醌、1-[(2-噻吩甲醯基)胺基]-2-(氯乙醯胺基)-蒽醌、1-[(5-異惡唑甲醯基)胺基]-2-(氯乙醯胺基)-蒽醌、N -[2-(2-氯乙醯胺基)-9,10-二氧代-9,10-二氫蒽-1-基]-2,5-二甲基呋喃-3-甲醯胺、1-[2-(苯氧)乙醯胺基]-2-(氯乙醯胺基)-蒽醌、1-[2-(苯硫基)乙醯胺基]-2-(氯乙醯胺基)-蒽醌、1-(苯甲醯胺基)-2-[2-[4-(2-氟苯基)呱嗪]乙醯胺基]-蒽醌、1-(4-甲基苯甲醯胺基)-2-[2-[(1,3-二氧戊環-2-基甲基)(甲基)胺基]乙醯胺基]-蒽醌、 4-甲基-N -(2-(2-甲基(2-(吡啶基-2-乙基)胺)乙醯胺基)-9,10-二氧代-9,10-二氫蒽-1)苯醯胺、1-(4-甲基苯甲醯胺基)-2-[2-(1,4-二氧-8-氮雜螺[4.5]癸烷-8-基)乙醯胺基]-蒽醌、1-(4-甲基苯甲醯胺基)-2-[2-(4-苯基呱嗪)乙醯胺基]-蒽醌、1-(4-甲基苯甲醯胺基)-2-[2-[4-(2-氟苯基)呱嗪]乙醯胺基]-蒽醌、1-(4-甲基苯甲醯胺基)-2-[2-[4-(2-苯甲腈)呱嗪]乙醯胺基]-蒽醌、1-(4-甲基苯甲醯胺基)-2-[2-[4-(2-甲氧苯基)呱嗪]乙醯胺基]-蒽醌、1-(4-甲基苯甲醯胺基)-2-[2-[4-(2-吡啶基)呱嗪]乙醯胺基]-蒽醌、及1-(4-甲基苯甲醯胺基)-2-[2-[4-(2-嘧啶基)呱嗪]乙醯胺基]-蒽醌所組成之群組。
- 一種治療癌症之醫藥組合物，包含治療有效量之如申請專利範圍第1項之化合物，及藥學上可接受之賦形劑。
- 如申請專利範圍第2項所述之醫藥組合物，其中該醫藥組合物可用以毒殺癌細胞。
- 如申請專利範圍第3項所述之醫藥組合物，其中該癌細胞為非小細胞肺癌細胞。
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| US9192602B2 (en) | 2014-03-11 | 2015-11-24 | National Central University | Indication of anthra[2,1,c][1,2,5]thiadiazole-6,11-dione compound in alleviating pain |
| US9284281B2 (en) | 2014-03-11 | 2016-03-15 | National Central University | Indication of naphtho[2,3-F]quinoxaline-7,12-dione compound in alleviating pain |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI256383B (en) * | 2000-10-05 | 2006-06-11 | Ind Tech Res Inst | Anthraquinone compound |
| TW200942226A (en) * | 2008-04-02 | 2009-10-16 | Nat Defense Medical Ct | Synthesis, telomerase inhibition and cytotoxic studies on 2,7-disubstituted anthraquinone derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI256383B (en) * | 2000-10-05 | 2006-06-11 | Ind Tech Res Inst | Anthraquinone compound |
| TW200942226A (en) * | 2008-04-02 | 2009-10-16 | Nat Defense Medical Ct | Synthesis, telomerase inhibition and cytotoxic studies on 2,7-disubstituted anthraquinone derivatives |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9192602B2 (en) | 2014-03-11 | 2015-11-24 | National Central University | Indication of anthra[2,1,c][1,2,5]thiadiazole-6,11-dione compound in alleviating pain |
| US9284281B2 (en) | 2014-03-11 | 2016-03-15 | National Central University | Indication of naphtho[2,3-F]quinoxaline-7,12-dione compound in alleviating pain |
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