CN101583280A - 作为抗癌剂的新的2-芳基-4-喹诺酮的亲水性衍生物 - Google Patents
作为抗癌剂的新的2-芳基-4-喹诺酮的亲水性衍生物 Download PDFInfo
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- CN101583280A CN101583280A CNA2007800447969A CN200780044796A CN101583280A CN 101583280 A CN101583280 A CN 101583280A CN A2007800447969 A CNA2007800447969 A CN A2007800447969A CN 200780044796 A CN200780044796 A CN 200780044796A CN 101583280 A CN101583280 A CN 101583280A
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
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Abstract
2-芳基-4-喹诺酮与焦磷酸四苄酯反应形成磷酸二苄酯,接着进行氢化反应将二苄基以氢取代,再与Amberlite IR-120(Na+型)反应而形成二钠盐。初步筛选结果显示,此类磷酸酯具有有效的抗癌活性。本发明也合成了新的中间体化合物2-硒吩基-4-喹诺酮及2-苯基-4-喹诺酮的N,N-二烷基胺烷基衍生物。这些中间体化合物也表现出有效的抗癌活性。
Description
发明领域
本发明涉及新的2-芳基-4-喹诺酮磷酸酯衍生物,及中间体2-硒吩-4-喹诺酮及2-苯基-4-喹诺酮的N,N-二烷基胺烷基衍生物,尤其是有关它们治疗人癌症的用途。
发明背景
喹诺酮衍生物起初被发现是作用于细菌DNA促旋酶的药剂,因此被开发为一种抗菌剂。最近,DNA拓扑异构酶II显示出可作为此类喹诺酮化合物的药理学靶点。我们已经合成了一系列取代的2-苯基-4-喹诺酮(A),其明显的具有一种新颖的抗有丝分裂的功能[Kuo,S.C.,Lee,H.Z.,Juang,J.P.,Lin,Y.T.,Wu,T.S.,Chang,J.J.,Lednicer,D.,Paull,K.D.,Lin,C.M.,Hamel,E.Synthesis and cytotoxicity of 1,6,7,8-substituted-(4′-substituedphenyl)-4-quinolones and related compounds:identification as antimitoticagents interacting with tubulin.J.Med.Chem.1993,36,1146-56;Li,L.,Wang,H.K.,Kuo,S.C.,Wu,T.S.,Mauger,A.,Lin.C.M.,Hamel,E.Lee,K.H.Antitumor agents.155.Synthesis and biological evaluation of 3′,6,7-substitued-phenyl-4-quinolones as antimicrotubule agents.J.Med.Chem.1994,37,3400-7]。接着,我们又合成了很多相关类似物,例如2-苯基萘啶-4-酮(B)[Chen,K.,Kuo,S.C.,Hsieh,M.C.,Mauger,SA.,Lin,C.M.,Hamel,E.,Lee,K.H.Antitumor agents.174.2′,3′,4′,5,6,7-substituted2-phenyl-1,8-naphthyridin-4-ones:their synthesis,cytotoxicity,and inhibitionof tubulin polymerization.J.Med.Chem.1997,40,2266-75],2-苯基-4-喹唑啉酮(C)[Xia,Y.,Yang,Z.Y.,Hour,M.J.,Kuo,S.C.,Xia,P.,Bastow,K.F.,Nakanishi,Y.,Namrpoothiri,P.,Hackl,T.,Hamel,E.,Lee,K.H.AntitumorAgents.Part 204:Synthesis and Biological Evaluation of substituted 2-ArylQuinazolinones,Bioorg.Med.Chem.Lett.2001,11,1193-6;Hour,M.J.,Huang,L.J.,Kuo,S.C.,Xia,Y.,Bastow,K.F.,Nakanishi,Y.,Hamel,E.,Lee,K.H.6-Alkylamino-and 2,3-dihydro-3′-methoxy-2-phenyl-4-quinazolinonesand related compounds:their synthesis,cytotoxicity,and inhibition of tubulinpolymerization.J.Med.Chem.2000,43,4479-87],及四氢-2-苯基-4-喹诺酮(D)[Xia,Y.,Yang,Z.Y.,Xia,P.,Bastow,K.F.,Tachibana,Y.,Kuo,S.C.,Hamel,E.,Hackl.T.,Lee,K.H.Antitumor agents.181.Synthesis andbiological evaluation of 6,7,2′,3′,4′-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolons as a new class of antimitotic antitumor agents.J.Med.Chem.1998,41.1155-62],建立了初步的构效关系(SAR)。在这些类似物中,我们发现为数不少的化合物具有有效的细胞致毒活性,例如3′,6-二取代的2-苯基-4-喹诺酮(A-1)等[Li,L.,Wang,H.K.,Kuo,S.C.,Wu,T.S.,Lednicer,D.,Lin,C.M.,Hamel,E.,Lee,K.H.Antitumor agents.150.2′,3′,4′,5′,5,6,7-substituted2-phenyl-4-quinolones and related compounds:their synthesis,cytotoxicity,and inhibition of tubulin polymerization.J.Med.Chem.1994,37,1126-35]。然而,大部份这些具有有效的细胞致毒活性化合物的亲脂性较强,因而不适合体内及体外的临床研究。因此,我们尝试在2-芳基-4-喹诺酮的架构上合成出亲水性衍生物来改善药物动力学性质,以适合用于体内及体外的临床研究。
发明简述
本发明的较佳实施例包括(但不限于)下列项目:
1.一种具有下列化学式Ia、Ib或Ic的2-芳基-4-喹诺酮磷酸酯衍生物,
其中
R2′,R3′,R4′,R5′和R6′独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、
其中n为0~4的整数,Y为O或S,X为F,Cl或Br,且R8和R9独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y如上所定义,且m为0~4的整数;
R2,R3,R4和R5独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、
或R3和R4一起为-Y(CH2)nY-,其中n、Y、X、R8及R9如上所定义;且R1及R1′独立地为H、Li+、Na+、K+、N+R8R9R10R11或苄基,其中R10及R11独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,且n、m、Y、R8及R9如上所定义。
2.如前述第1项的磷酸酯衍生物,其具有化学式Ia。
3.如前述第2项的磷酸酯衍生物,其中R2′、R3′、R4′、R5′及R6′全部为H;或R2′、R3′、R4′、R5′及R6′中之一为F、OCH3或(CH2)nNR8R9,且其它的为H,其中n、R8及R9如第1项所定义。
4.如前述第2项的磷酸酯衍生物,其中R2、R3、R4及R5全部为H;或R2、R3、R4及R5中之一为F、OCH3、Y(CH2)nCH3或(CH2)nNR8R9,且其它的为H;或R2及R5为H,且R3和R4一起为-O(CH2)nO-,其中n、Y、R8及R9如第1项所定义。
5.如前述第2项的磷酸酯衍生物,其中R1及R1′均为H或均为Na+。
6.如前述第5项的磷酸酯衍生物,其中R2及R5为H,且R3及R4一起为-O(CH2)O-;且R2′、R3′、R4′及R5′全部为H,且R6′为F。
7.如前述第5项的磷酸酯衍生物,其中R2及R5为H,及R3及R4一起为-O(CH2)O-;且R2′、R3′、R4′及R6′全部为H,且R5′为F。
8.如前述第5项的磷酸酯衍生物,其中R4为F,且R2、R3及R5为H;且R2′、R3′、R4′、R5′及R6′全部为H。
9.如前述第5项的磷酸酯衍生物,其中R2、R3、R4及R5全部为H;及R2′、R3′、R4′、R5′及R6′全部为H。
10.如前述第5项的磷酸酯衍生物,其中R4为OCH3,且R2、R3及R5为H;且R5′为F,且R2′、R3′、R4′及R6′为H。
11.如前述第5项的磷酸酯衍生物,其中R2及R5为H,且R3和R4一起为-O(CH2)O-;且R2′、R3′、R4′及R6′全部为H,且R5′为OCH3。
12.如前述第5项的磷酸酯衍生物,其中R4为CH2N(C2H5)2,且R2、R3及R5为H;且R6′为F,且R2′、R3′、R4′及R5′为H。
13.如前述第5项的磷酸酯衍生物,其中R4为CH2N(C2H5)2,且R2、R3及R5为H;且R2′、R3′、R4′、R5′及R6′全部为H。
14.如前述第5项的磷酸酯衍生物,其中R4为OCH3,且R2、R3及R5为H;且R5′为CH2N(C2H5)2,且R2′、R3′、R4′及R6′为H。
15.如前述第1项的磷酸酯衍生物,其具有化学式Ib。
16.如前述第15项的磷酸酯衍生物,其中R2、R3、R4及R5全部为H;或R2、R3、R4及R5中之一为F或OCH3,且其它的为H;或R2及R5为H,且R3和R4一起为-O(CH2)nO-,其中n如第1项所定义。
17.如前述第15项的磷酸酯衍生物,其中R2′、R3′、R4′、R5′及R6′全部为H;或R2′、R3′及R4′中之一为F或OCH3,及其它的为H。
18.如前述第15项的磷酸酯衍生物,其中R1及R1′为苄基。
19.如前述第18项的磷酸酯衍生物,其中R2′、R3′、R4′、R2及R5全部为H,及R3及R4一起为-O(CH2)O-。
20.一种用于杀灭实体癌细胞的药物组合物,包含治疗有效量的如前述第1至19项中任一项所述的2-芳基-4-喹诺酮磷酸酯衍生物或其药学上可接受的盐作为活性成份,和与之混合的用于该活性成份的药学上可接受的载体或稀释剂,其中该实体癌包含人乳腺癌、结肠癌、肺癌、黑色素瘤、卵巢癌、肾脏癌、胃癌、前列腺癌、回肠癌、神经胶质母细胞瘤、骨癌、鼻咽表皮样癌、肝癌或白血病。
21.如前述第20项的药物组合物,其中该实体癌为人乳腺癌、结肠癌、肺癌、肾脏癌、肝癌或白血病。
22.如前述第21项的药物组合物,其中该实体癌为人乳腺癌或结肠癌。
23.一种具有下列化学式IIb或IIc的2-硒吩基-4-喹诺酮化合物,
其中:
R2′、R3′和R4′独立地为H,(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3,Y(CH2)nYH,Y(CH2)nNR8R9、X或(CH2)nNR8R9,
其中n为0~4的整数,Y为O或S,X为F、Cl或Br,及R8和R9独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y如上所定义,及m为0~4的整数;
R2、R3、R4和R5独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、
或R3和R4一起为-Y(CH2)nY-,其中n、Y、X、R8及R9如上所定义。
24.如前述第23项的化合物,其中R2、R3、R4及R5全部为H;或R2、R3、R4及R5中之一为F或OCH3,且其它的为H;或R2及R5为H,且R3和R4一起为-O(CH2)nO-,其中n如前述第23项所定义。
25.如前述第24项的化合物,其中;或R2′、R3′及R4′中之一为F或OCH3,且其它的为H。
26.如前述第23项的化合物,其具有化学式IIb。
27.如前述第26项的化合物,其中R2′、R3′、R4′、R2及R5全部为H,且R3和R4一起为-O(CH2)nO-。
28.一种用于杀灭实体癌细胞的药物组合物,包含治疗有效量的如前述第23至27项中任一项所述的2-硒吩基-4-喹诺酮化合物或其药学上可接受的盐作为活性成份,和与之混合的用于该活性成份的药学上可接受的载体或稀释剂,其中该实体癌包含人乳腺癌、结肠癌、肺癌、黑色素瘤、卵巢癌、肾脏癌、胃癌、前列腺癌、回肠癌、神经胶质母细胞瘤、骨癌、鼻咽表皮样癌、肝癌或白血病。
29.如前述第28项的药物组合物,其中该实体癌细胞为人乳腺癌、结肠癌、肺癌、肾脏癌、肝癌或白血病。
30.一种具有下列化学式IIa的2-苯基-4-喹诺酮化合物:
其中:
R2′、R3′、R4′、R5′和R6′独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、
其中n为0~4的整数,Y为O或S,X为F,Cl或Br,及R8和R9独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y如上所定义,且m为0~4的整数;
R2、R3、R4和R5独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、
或R3和R4一起为-Y(CH2)nY-,其中n、Y、X、R8及R9如上所定义;
当R2、R3、R4和R5中之一是(CH2)qNR8R9,或者R2′、R3′、R4′、R5′和R6′中之一是(CH2)qNR8R9时,其中的q为1~4的整数及R8及R9如上所定义。
31.如前述第30项的化合物,其中R4是(CH2)qNR8R9,且R2、R3和R5是H,其中q,R8及R9如前述第30项中所定义。
32.如前述第30项的化合物,其中R5′是(CH2)qNR8R9,且R2′、R3′、R4′和R6′是H,其中q、R8及R9如前述第30项中所定义。
33.如前述第31项的化合物,其中R4是CH2N(C2H5)2,R6′是F,且R2′、R3′、R4′和R5′是H。
34.如前述第31项的化合物,其中R4是CH2N(C2H5)2,且R2′、R3′、R4′、R5′和R6′全部是H。
35.如前述第32项的化合物,其中R4是OCH3、R2、R3和R5是H,R5′是CH2N(C2H5)2,且R2′、R3′、R4′和R6′全部是H。
36.一种用于杀灭实体癌细胞的药物组合物,包含治疗有效量的如前述第30至35项中任一项所述的2-苯基-4-喹诺酮化合物或其药学上可接受的盐作为活性成份,和与之混合的用于该活性成份的药学上可接受的载体或稀释剂,其中该实体癌包含人乳腺癌、结肠癌、肺癌、黑色素瘤、卵巢癌、肾脏癌、胃癌、前列腺癌、回肠癌、神经胶质母细胞瘤、骨癌、鼻咽表皮样癌、肝癌或白血病。
37.如前述第36项的药物组合物,其中该实体癌为白血病。
附图的简要说明
图1显示小鼠移植瘤模型中,化合物I-1及I-1-b对MCF-7肿瘤的生长抑制作用。将MCF-7细胞注射于雌性SCID小鼠,转染诱导肿瘤移植。将SCID小鼠随机区分成五组,2至5组分别以腹腔内注射(i.p.)化合物I-1(15mg/kg、30mg/kg)及I-1-b(22.5mg/kg、45mg/kg),一周给药三次。与对照组比较,数据以肿瘤重量平均值(克)±S.E.M表示,p<0.05。
图2显示化合物I-1-b对动物存活率的影响,其中CT-26肿瘤细胞被腹腔注射入Balb/c小鼠,七天后使用化合物I-1-b进行治疗(5mg/kg/天及10mg/kg/天QD×7)。
图3显示喹诺酮衍生物对人乳腺癌细胞活性的影响。将MCF7细胞以DMSO(对照组)或不同浓度(0.125μM至10μM)的喹诺酮衍生物处理48小时,接着以MTT分析测量细胞的活性。三次试验的结果取平均值并以平均值±标准误差表示。
发明详述
如以下实施例1到6所示,当2-苯基-4-喹诺酮(I-1至I-6)在碱存在下与焦磷酸四苄酯反应以得到对应的磷酸二苄酯(I-1-a至I-6-a)。化合物(I-1-a至I-6-a)在醇里的催化氢化反应能产生对应的磷酸单酯(I-1-b至I-6-b),它们能被继续用于产生水可溶性盐(I-1-c至I-6-c)。
实施例1
2-(2′-氟苯基)-6,7-亚甲二氧基喹啉-4-基-磷酸二苄酯(I-1-a)
对溶于无水的四氢呋喃(10ml)的化合物I-1(64.5mg,0.23mmol)的溶液在搅拌及0℃下加入氢化钠(13.7mg,0.57mmol),1小时后加入焦磷酸四苄酯(100mg,0.19mmol)并继续搅拌20分钟。
将混合物过滤,滤液于真空下及低于35℃的温度下被浓缩。残留物被溶解于二氯甲烷,以碳酸氢钠水溶液洗涤、再以MgSO4干燥,在真空下浓缩而得到化合物I-1-a(69.1mg,67%)。
MP 101-104℃
1H-NMR(CDCl3,300MHz):δ8.01-8.02(m,1H,H-5′),7.77(s,1H,H-5),7.16-7.43(m,14H,H-3,H-3′,H-4′,H-6′,Ph),7.05(s,1H,H-8),6.12(s,2H,OCH2O),5.26(s,2H,-CH 2 -Ph),5.20(s,2H,-CH 2 -Ph)
MS(m/z)544(ES+)
C30H25FNO6P分析计算值:C,66.30;H,4.27;N,2.58.实测值:C,66.28;H,4.35;N,2.55.
2-(2′-氟苯基)-6,7-亚甲基二氧喹啉-4-基-磷酸酯(I-1-b)
将化合物I-1-a(97.7mg,0.18mmol)的无水甲醇(10ml)悬浮液于室温及10%的Pd/C(50mg)存在下氢化10分钟。收集催化剂及沉淀物并将之溶解于10%的NaHCO3水溶液,接着过滤。以稀盐酸(HCl)酸化该滤液,过滤收集生成的固体,再以丙酮洗涤以得到化合物I-1-b(63.5mg,97.2%)。
MP>300℃
1H-NMR(DMSO-d6,300MHz):δ7.93-7.98(m,1H,H-5′),7.74(s,1H,H-5),7.49-7.54(m,1H,H-4′),7.32-7.41(m,4H,H-3,H-8,H-3′,H-6′),6.22(s,2H,OCH2O).
MS(m/z)362(ES-)
C16H13FNO6P分析计算值:C,52.91;H,3.05;N,3.86.实测值:C,52.73;H,3.10;N,3.81.
2-(2′-氟苯基)-6,7-亚甲二氧基喹啉-4-基-磷酸钠盐(I-1-c)
将化合物I-1-b加入到20ml Amberlite IR-120(Na+型)及20ml水的混合物中,接着于室温搅拌6小时。然后过滤去除Amberlite,接着冷冻干燥得到化合物I-1-c(49.1mg,69%).
1H-NMR(D2O,200MHz):δ7.48-7.66(m,2H,H-4′,H-6′),7.40(s,1H,H-8),7.31-7.35(m,1H,H-5),7.11-7.19(m,2H,H-3′,H-5′),7.03(s,1H,H-3),5.92(s,2H,OCH2O).
实施例2
2-(3′-氟苯基)-6,7-亚甲二氧基喹啉-4-基-磷酸二苄酯(I-2-a)
将氢化钠(13.7mg,0.57mmol)在0℃下加入溶于无水的四氢呋喃(10ml)的化合物I-2(64.5mg,0.23mmol)的搅拌溶液中。1小时后加入焦磷酸四苄酯(100mg,0.19mmol)并继续搅拌20分钟。
将混合物过滤,并且将滤液于真空下及低于35℃的温度下浓缩。残留物被溶解于二氯甲烷,以碳酸氢钠水溶液洗涤、再以MgSO4干燥,并且于真空下浓缩而得到化合物I-2-a(85.6mg,83%)。
MP 94-96℃
1H-NMR(DMSO-d6,200MHz):δ7.61-7.78(m,2H,H-2′,H-4′),7.48-7.56(m,1H,H-5′),7.24-7.45(m,13H,H-5,H-8,H-6′,Ph),7.10(s,1H,H-3),6.21(s,2H,OCH2O),5.29(s,2H,-CH 2 -Ph),5.24(s,2H,-CH 2 -Ph)
MS(m/z)544(ES+)
C30H25FNO6P分析计算值:C,66.30;H,4.27;N,2.58.实测值:C,66.25;H,4.34;N,2.55.
2-(3′-氟苯基)-6,7-亚甲二氧基喹啉-4-基-磷酸酯(I-2-b)
于室温及10%的Pd/C(50mg)存在下将化合物I-2-a(97.7mg,0.18mmol)的无水甲醇(10ml)悬浮液氢化10分钟。收集催化剂及沉淀物并将之溶解于10%的NaHCO3水溶液,接着过滤。以稀盐酸(HCl)酸化该滤液,过滤收集生成的固体,再以丙酮洗涤以得到化合物I-2-b(60.8mg,93.1%)。
MP>300℃
1H-NMR(DMSO-d6,200MHz):δ7.91(s,1H,H-2′),7.87(s,1H,H-4′),7.83(s,1H,H-5′),7.50-7.62(m,2H,H-5,H-8),7.25-7.36(m,2H,H-5′,H-6′),6.24(s,2H,OCH2O).
MS(m/z)362(ES-)
C16H13FNO6P分析计算值:C,52.91;H,3.05;N,3.86.实测值:C,52.86;H,3.12;N,3.79.
2-(3′-氟苯基)-6,7-亚甲二氧基喹啉-4-基-磷酸钠盐(I-2-c)
化合物I-2-b被加入到20ml Amberlite IR-120(Na+型)及20ml水的混合物中,接着于室温搅拌6小时。然后将所述混合物过滤去除Amberlite,并且接着冷冻干燥得到化合物I-2-c(68.2mg,71%).
1H-NMR(D2O,200MHz):δ7.26-7.78(m,5H,H-5,H-8,H-2′,H-5′,H-6′),6.90-6.96(m,2H,H-3,H-4′),6.03(s,2H,OCH2O).
实施例3
6-氟-2-苯基喹啉-4-基-磷酸二苄酯(I-3-a)
在0℃下将氢化钠(13.7mg,0.57mmol)加入到溶于无水的四氢呋喃(10ml)的化合物I-3(55.0mg,0.23mmol)的搅拌溶液中。1小时后焦磷酸四苄酯(100mg,0.19mmol)被加入并继续搅拌20分钟。
将混合物过滤,并且将滤液于真空下及低于35℃的温度下浓缩。残留物被溶解于二氯甲烷,以碳酸氢钠水溶液洗涤、再以MgSO4干燥,并且在真空下浓缩而得到一无色油状化合物I-3-a(84.4mg,89%)。
1H-NMR(DMSO-d6,200MHz):δ8.07-8.14(m,1H,H-8),7.92-7.97(m,2H,H-2′,H-6′),7.67-7.77(m,2H,H-3′,H-5′),7.40-7.50(m,10H,Ph),5.31(s,2H,-CH 2 -Ph),5.27(s,2H,-CH 2 -Ph)
MS(m/z)500(ES+)
C29H23FNO6P分析计算值:C,69.74;H,4.64;N,2.80.实测值:C,69.75;H,4.60;N,2.81.
6-氟-2-苯基喹啉-4-基-磷酸酯(I-3-b)
于室温及在10%的Pd/C(50mg)存在下将化合物I-3-a(89.8mg,0.18mmol)的无水甲醇(10ml)悬浮液氢化10分钟。收集催化剂及沉淀物并将之溶解于10%的NaHCO3水溶液,接着过滤。以稀盐酸(HCl)酸化该滤液,过滤收集生成的固体,再以丙酮洗涤以得到化合物I-3-b(50.5mg,88%)。
MP>300℃
1H-NMR(DMSO-d6,200MHz):δ8.07-8.14(m,3H,H-8,H-2′,H-6′),7.95(s,1H,H-5),7.70-7.74(m,2H,H-3′,H-5′),7.50-7.56(m,3H,H-3,H-7,H-4′)
MS(m/z)318(ES-)
C15H11FNO4P分析计算值:C,56.44;H,3.47;N,4.39.实测值:C,56.42;H,3.49;N,4.30。
6-氟-2-苯基喹啉-4-基-磷酸钠盐(I-3-c)
化合物I-3-b被加入到20ml Amberlite IR-120(Na+型)及20ml水的混合物中,接着于室温下搅拌6小时。过滤去除Amberlite,接着冷冻干燥得到化合物I-3-c(41.9mg,73%)。
1H-NMR(D2O,200MHz):δ7.20-7.83(m,5H,H-5,H-7,H-8,H-2′,H-6′),7.25-7.31(m,4H,H-3,H-3′,H-4′,H-5′)。
实施例4
2-苯基喹啉-4-基-磷酸二苄酯(I-4-a)
在0℃下将氢化钠(13.7mg,0.57mmol)加入到溶于无水的四氢呋喃(10ml)的化合物I-4(50.8mg,0.23mmol)的搅拌溶液中,1小时后焦磷酸四苄酯(100mg,0.19mmol)被加入并继续搅拌20分钟。
将混合物过滤,并且将滤液于真空下及低于35℃的温度下浓缩。残留物被溶解于二氯甲烷,以碳酸氢钠水溶液洗涤、再以MgSO4干燥,在真空下浓缩而得到一无色油状化合物1-4-a(71.3mg,78%)。
1H-NMR(DMSO-d6,200MHz):δ8.05(d,J=8.2Hz,1H,H-5),7.73-7.98(m,5H,H-6,H-7,H-8,H-2′,H-6′),7.58(d,J=8.0Hz,1H,H-4′),7.48-7.51(m,3H,H-3,H-3′,H-5′),7.29-7.40(m,10H,Ph),5.31(s,2H,-CH2-Ph),5.27(s,2H,-CH2-Ph)
MS(m/z)482(ES+)
C29H24NO6P分析计算值:C,72.34;H,5.02;N,2.90.实测值:C,71.89;H,5.13;N,2.88.
2-苯基喹啉-4-基-磷酸酯(I-4-b)
将化合物I-4-a(86.8mg,0.18mmol)的无水甲醇(10ml)悬浮液于室温及在10%的Pd/C(50mg)存在下氢化10分钟。收集催化剂及沉淀物并将之溶解于10%的NaHCO3水溶液,接着过滤。以稀盐酸(HCl)酸化该滤液,过滤收集生成的固体,并且以丙酮洗涤以得到化合物I-4-b(48.9mg,90.3%)。
MP>300℃
1H-NMR(DMSO-d6,200MHz):δ7.80-8.12(m,4H,H-5,H-8,H-2′,H-6′),7.49-7.78(m,6H,H-3,H-6,H-7,H-3′,H-4′,H-5′),7.78(s,1H,H-7),7.66(t,J=8.0Hz),7.42-7.50(m,4H,H-3,H-3′,H-4′,H-5′)
MS(m/z)300(ES-)
C15H12NO6P分析计算值:C,59.81;H,4.02;N,4.65.实测值:C,59.52;H,4.13;N,4.72.
6-氟-2-苯基喹啉-4-基-磷酸钠盐(I-4-c)
化合物I-4-b被加入到20ml Amberlite IR-120(Na+型)及20ml水的混合物中,接着于室温下搅拌6小时。过滤去除Amberlite,接着冷冻干燥得到化合物I-4-c(41.2mg,74%)。
1H-NMR(D2O,200MHz):δ8.21(d,J=8.2Hz,1H,H-5),7.80-7.89(m,3H,H-8,H-2′,H-6′),7.78(s,1H,H-7),7.66(t,J=8.0Hz),7.42-7.50(m,4H,H-3,H-3′,H-4′,H-5′)
实施例5
6-甲氧基-2-(3′-氟苯基)-喹啉-4-基-磷酸二苄酯(I-5-a)
对溶于无水的四氢呋喃(10ml)的化合物I-5(61.9mg,0.23mmol)的溶液在搅拌及0℃下加入氢化钠(13.7mg,0.57mmol)。1小时后焦磷酸四苄酯(100mg,0.19mmol)被加入并继续搅拌20分钟。
将混合物过滤,并将滤液于真空下及低于35℃的温度下浓缩。残留物被溶解于二氯甲烷,以碳酸氢钠水溶液洗涤、再以MgSO4干燥,并且在真空下浓缩而得到一无色油状化合物I-5-a(85.4mg,85%)。
1H-NMR(DMSO-d6,200MHz):δ7.98(d,J=9.4Hz,1H,H-8),7.74-7.83(m,3H,H-5,H-7,H-5′),7.43-7.54(m,1H,H-6′),7.41-7.48(m,1H,H-2′),7.20-7.22(m,H-3),5.31(s,2H,-CH2-Ph),5.27(s,2H,-CH2-Ph),3.78(s,3H,OCH3).
MS(m/z)530(ES+)
C30H25FNO5P分析计算值:C,68.05;H,4.76;N,2.65.实测值:C,67.32;H,4.33;N,2.78.
6-甲氧基-2-(3′-氟苯基)-喹啉-4-基-磷酸酯(I-5-b)
将化合物I-5-a(95.2mg,0.18mmol)的无水甲醇(10ml)悬浮液于室温及10%的Pd/C(50mg)存在下氢化10分钟。收集催化剂及沉淀物并将之溶解于10%的NaHCO3水溶液,接着过滤。以稀盐酸(HCl)酸化该滤液,过滤收集生成的固体,再以丙酮洗涤以得到化合物I-5-b(56.5mg,89.9%)。
MP>300℃
1H-NMR(DMSO-d6,200MHz):δ7.93-7.89(m,4H,H-5,H-7,H-8,H-5′),7.45-7.58(m,1H,H-6′),7.35-7.41(m,2H,H-2′,H-4′),7.20-7.32(m,1H,H-3),3.81(s,3H,OCH3)
MS(m/z)348(ES-)
C16H13FNO5P分析计算值:C,55.02;H,3.75;N,4.01.实测值:C,54.90;H,3.89;N,4.35.
实施例6
2-(3′-甲氧基苯基)-6,7-亚甲二氧基喹啉-4-基-磷酸二苄酯(I-6-a)
在0℃下将氢化钠(13.7mg,0.57mmol)加入到溶于无水的四氢呋喃(10ml)的化合物I-6(67.9mg,0.23mmol)的搅拌溶液中,1小时后焦磷酸四苄酯(100mg,0.19mmol)被加入并继续搅拌20分钟。
将混合物过滤,并且将滤液于真空下及低于35℃的温度下浓缩。残留物被溶解于二氯甲烷,以碳酸氢钠水溶液洗涤、再以MgSO4干燥,在真空浓缩而得到一无色油状化合物I-6-a(88.6mg,84%)。
1H-NMR(DMSO-d6,200MHz):δ7.60(s,1H,H-6′),7.55(s,1H,H-2′),7.25-7.40(m,14H,H-5,H-8,H-4′,H-5′,Ph),6.21(s,2H,OCH2O),5.28(s,2H,-CH2-Ph),5.24(s,2H,-CH2-Ph),3.80(s,3H,OCH3)
MS(m/z)556(ES+)
C31H26NO7P分析计算值:C,67.02;H,4.72;N,2.52.实测值:C,68.15;H,4.68;N,2.61.
2-(3′-甲氧基苯基)-6,7-亚甲二氧基喹啉-4-基-磷酸酯(I-6-b)
将化合物I-6-a(97.74mg,0.18mmol)的无水甲醇(10ml)悬浮液于室温及10%的Pd/C(50mg)存在下氢化10分钟。收集催化剂及沉淀物并将之溶解于10%的NaHCO3水溶液,接着过滤。以稀盐酸(HCl)酸化该滤液,过滤收集生成的固体,再以丙酮洗涤以得到化合物I-6-b(63.5mg,94%)。
MP>300℃
MS(m/z)374(ES-)
C17H14NO7P分析计算值:C,54.41;H,3.76;N,3.73.实测值:C,53.86;H,3.66;N,3.81.
2-(3′-甲氧基苯基)-6,7-亚甲二氧基喹啉-4-基-磷酸钠盐(I-6-c)
化合物I-6-b被加入到20ml Amberlite IR-120(Na+型)及20ml水的混合物中,接着于室温下搅拌6小时。过滤去除Amberlite,接着冷冻干燥得到化合物I-6-c(53.9mg,76%)。
1H-NMR(D2O,200MHz):δ7.56(s,1H,H-6′),7.25-7.42(m,4H,H-5,H-8,H-2′,H-5′),7.12(s,1H,H-4′),6.95(s,1H,H-3),6.00(s,2H,OCH2O),3.62(s,3H,OCH3)
在下面的实施例7中,一种新的中间体化合物2-硒吩基-4-喹诺酮(I-7-d)被合成。2-硒吩基-4-喹诺酮(I-7-d)与焦磷酸四苄酯在碱存在下反应而得到对应的磷酸二苄酯(I-7-e)。
实施例7
硒吩-2-羧酸(I-7-a)
将TMEDA(25.5ml,170.0mmol)及正丁基锂(66.1ml的2.5M的己烷溶液,152.8mmol)加入到溶解于乙醚(150ml)的硒吩(20g,152.8mmol)溶液中。所得到的溶液被加热回流1.5小时,接着于丙酮/CO2浴中冷却,再将压碎的固态二氧化碳(40g,909.1mmol)加入。使得反应混合物返回到室温,并且加入10%KOH溶液骤冷。水层被以8M的盐酸(HCl)酸化至pH3,用乙醚萃取,以盐水洗涤、MgSO4干燥、过滤、真空干燥而得到化合物I-7-a(24.6g,92.1%)。
MP 122-124℃
1H-NMR(CDCl3-d1,200MHz):δ8.92(s,1H,-COOH),8.37(dd,J=1.0Hz,5.6Hz,1H,H-3),8.13(dd,J=0.8Hz,3.8Hz,1H,H-5),7.37(dd,J=3.8Hz,5.6Hz,1H,H-4).
MS(m/z)175.0(EI+)
C5H4O2Se分析计算值:C,34.31;H,2.30.实测值:C,34.33;H,2.28.
N-(5-乙酰基苯[d][1,3]二氧-6-基)硒吩-2-羰酰胺(I-7-c)
将化合物I-7-a(2g,11.40mmol)以二氯亚砜(4.1ml,56.18mmol)回流氯化20小时以得到化合物I-7-b,未进行进一步纯化,接着将化合物I-7-b与2-胺基-(4,5-亚甲二氧基)-苯乙酮(1.63g,9.12mmol)及三乙胺(2ml,14.80mmol)于100ml甲苯中反应,并且回流3小时。反应混合物被真空浓缩,所得到的固态物质被连续的以乙醇洗涤,再于80℃干燥2小时而获得粗化合物I-7-c(2.7g,74%)。
MP 198.5-198.8℃
1H-NMR(DMSO-d6,200MHz):δ12.85(s,1H,NHCO),8.52(d,J=5.1Hz,1H,H-3′),8.16(s,1H,H-4),7.93(d,J=3.8Hz,1H,H-5′),7.61(s,1H,H-7),7.49-7.46(m,1H,H-4′),6.13(s,2H,OCH2O),2.58(s,3H,CH3).
MS(m/z)336.2(EI+)
C14H11NO4Se分析计算值:C,50.01;H,3.30;N,4.17.实测值:C,50.11;H,3.32;N,4.15。
2-(2′-硒吩基)-6,7-(亚甲二氧基)-4-喹诺酮(I-7-d)
I-7-c(2.7g,8.0mmol)被悬浮于100ml叔丁醇中。叔丁醇钾(4.49g,40mmol)接着被加入,并且该混合物被加热回流24小时。然后,混合物被冷却至室温,接着被倒入于100ml的NH4Cl水溶液。得到黄棕色固体,收集后以蒸馏水洗涤得到化合物I-7-d(3.1g,85%)。
MP>300℃
1H-NMR(DMSO-d6,200MHz):δ8.27(s,1H,H-3′),7.83(s,1H,H-5′),7.39(t,J=4.5Hz,1H,H-4′),7.31(s,1H,H-5),7.14(s,1H,H-8),6.11(s,3H,H-3,OCH2O).
MS(m/z)318.2(EI+)
C14H9NO3Se分析计算值:C,52.85;H,2.85;N,4.40.实测值:C,52.87;H,2.82;N,4.45.
2-(2′-硒吩基)-6,7-(亚甲二氧基)-4-喹啉-4-基-磷酸二苄酯(I-7-e)
在搅拌及0℃下将氢化钠(30mg,1.25mmol)加入到溶于无水的四氢呋喃(10ml)的化合物I-7-d(100.0mg,0.32mmol)的溶液,1小时后焦磷酸四苄酯(204.6mg,0.38mmol)被加入并继续搅拌20分钟。
将混合物过滤,并将滤液于真空下及低于35℃的温度下浓缩。残留物被溶解于二氯甲烷,以碳酸氢钠水溶液洗涤、再以MgSO4干燥,在真空下浓缩而得到一固体。将该固体使用硅胶柱层析处理,以CH2Cl2洗脱而得到浅黄色化合物I-7-e(151.8mg,82%)。
MP 110.5-110.8℃
1H-NMR(DMSO-d6,200MHz):δ8.24(d,J=5.6Hz,1H,H-3′),7.65(d,J=3.8Hz,1H,H-5′),7.57(s,1H,H-5),7.05(s,1H,H-8),7.39-7.26(m,11H,H-4′,Ph),6.19(s,2H,OCH2O),5.28(s,2H,-CH2-Ph),5.24(s,2H,-CH2-Ph).MS(m/z)580(ES+)
280H22NO6PSe分析计算值:C,58.14;H,3.83;N,2.42.实测值:C,57.28;H,3.56;N,2.59.
实施例8
6-甲基-2-苯基喹啉-4(1H)-酮(I-8-a)
对甲苯胺(2.14g,0.02mole)、苯甲酰基乙酸乙酯(4.9g,0.025mole)及多聚磷酸(PPA)的混合物在130℃及搅拌下被加热。反应完成后,该反应混合物被冷却至室温并以4M NaOH溶液中和。得到的黄色固体被滤出并以水洗涤,干燥后以乙醇重结晶而得到白色的固体化合物I-8-a(2.9g,48.9%)。
MP 290.2-291.5℃
1H-NMR(DMSO-d6,200MHz):δ11.55(1H,s,H-1),7.88(1H,s,H-5),7.79-7.82(2H,m,H-2′,H-3′),7.66(1H,d,J=8.5Hz,H-8),7.54-7.57(3H,m,H-3′,H-4′,H-5′),7.48(1H,d,J=8.5Hz,H-7),6.31(1H,s,H-3),2.40(3H,s,CH3)
MS(m/z)235(EI+)
C16H13NO分析计算值:C,81.68;H,5.57;N,5.95.实测值:C,81.60;H,5.63;N,5.88.
4-(苄氧基)-6-甲基-2-苯基喹啉(I-8-b)
I-8-a(700mg,3mmole)被溶解于无水的DMF(30ml),将NaH(360mg,15mmole)分批加入于室温搅拌30分钟。苄基氯化物(750mg,6mmole)接着被滴入,于室温搅拌过夜。该反应混合物被倒入于冰水中并以CH2Cl2萃取。有机层以水洗涤,以MgSO4干燥及挥发其中的溶剂。残留物以硅胶柱进行层析,并以正己烷/乙酸乙酯(3∶1)混合液洗脱,且以正己烷/CH2Cl2重结晶而得到白色结晶I-8-b(536mg,54.9%)。
MP 138.6-139.3℃
1H-NMR(DMSO-d6,200MHz):δ8.23-8.26(2H,m,H-2′,H-6′),7.88-7.91(2H,m,H-5,H-8),7.37-7.62(9H,m,H-7,H-3′,H-4′,H-5′,Ph),5.51(2H,s,OCH2Ph),2.48(3H,s,CH3)
C23H19NO分析计算值:C,84.89;H,5.89;N,4.30.实测值:C,84.93;H,5.85;N,4.33.
N-{[4-(苄氧基)-2-苯基喹啉-6-基]甲基}-N-乙基乙胺(I-8-d)
将I-8-b(650mg,2mmol)、N-溴代-丁二酰亚胺(NBS,360mg,2mmol)及2,2′-偶氮双(异丁腈)(AIBN,30mg,0.19mmol)加入一干燥的圆底烧瓶内,再通入氩气冲洗。将50ml的无水的苯加入至该反应混合物,于氩气气氛下及室温下搅拌30分钟,并随后于80℃回流1小时,冷却至室温后得到I-7-c,在未进一步纯化下以二乙胺(3.0ml,29.0mmole)处理,再回流1小时。挥发去除其中的溶剂后,以乙酸乙酯及50ml的10%HCl进行分层,接着其中的酸性层以10%的NaHCO3中和至pH7-8,再以乙酸乙酯萃取(100ml×5)。有机层以MgSO4干燥并挥发其中的溶剂。残留物进一步以硅胶柱进行层析,并以CH2Cl2/甲醇(3∶1)混合液洗脱,并以正己烷/乙酸乙酯重结晶而得到淡黄色固体I-8-d(120mg,15.1%)。
MP 107.7-108.6℃
1H-NMR(DMSO-d6,200MHz):δ8.22(2H,m,H-2′,H-6′),8.01(1H,s,H-5),7.91(1H,d,H-8),7.33-7.69(9H,m,H-7,H-3′,H-4′,H-5′,Ph),5.49(2H,s,OCH2Ph),3.65(2H,s,CH2N(CH2CH3)2),2.43(4H,q,J=7Hz,CH2N(CH2CH3)2),0.93(6H,t,J=7Hz,CH2N(CH2CH3)2)
MS(m/z)396(EI+)
C27H28N2O分析计算值:C,81.78;H,7.12;N,7.06.实测值:C,81.68;H,7.03;N,7.15.
6-[(二乙基胺基)甲基]-2-苯基喹啉-4(1H)-酮(I-8-e)
I-8-d(120mg,0.3mmol)被溶解于冰醋酸(5ml)。HBr(3ml)被接着加入同时将溶液加热至60℃,混合物于90℃加热3小时。反应完成后,将反应混合物倒入水中,并以乙酸乙酯萃取。酸性层被加入10%的NaHCO3中和至pH7-8,并以乙酸乙酯萃取(100ml×5)。有机层以MgSO4干燥,并且挥发其中的溶剂。残留物以正己烷/乙酸乙酯重结晶而得到灰色固体I-8-d(55mg,59.9%)。
MP 227.9-229.7℃
1H-NMR(DMSO-d6,200MHz):δ7.96(1H,s,H-5),7.78(2H,m,H-2′,H-6′),7.69(1H,d,H-8),7.50-7.58(4H,m,H-7,H-3′,H-4′,H-5′),6.31(1H,s,H-3),3.55(2H,s,CH2N(CH2CH3)2),2.41(4H,q,J=7Hz,CH2N(CH2CH3)2),0.92(6H,t,J=7Hz,CH2N(CH2CH3)2)
MS(m/z)306(EI+)
C20H22N2O分析计算值:C,78.40;H,7.24;N,9.14.实测值:C,78.43;H,7.35;N,9.08.
实施例9
2-(2-氟苯基)-6-甲基喹啉-4(1H)-酮(I-9-a)
将对甲苯胺(2.14g,0.02mole)、2-氟-苯甲酰基乙酸乙酯(5.25g,0.025mole)及多聚磷酸(PPA)的混合物在130℃及搅拌下加热。反应完成后,该反应混合物被冷却至室温并以4M NaOH中和之。得到的黄色固体被滤出并以水洗涤,干燥后以乙醇重结晶而得到白色的固体化合物I-9-a(2.6g,51.3%)。
MP 259.1-259.9℃
1H-NMR(DMSO-d6,200MHz):δ7.86(1H,s,H-5),7.64(1H,td,J=7.58,H-4′),7.47-7.57(3H,m,H-7,H-8,H-6′),7.30-7.43(2H,d,J=7.02,dd,J=7.36,H-3′,5′),6.12(1H,s,H-3),2.36(3H,s,CH3)
MS(m/z)253(EI+)
C16H22FNO分析计算值:C,75.88;H,4.78;N,5.53.实测值:C,75.94;H,4.70;N,5.46.
4-(苄氧基)-2-(2-氟苯基)6-甲基喹啉(I-9-b)
I-9-a(750mg,3mmole)被溶解于无水的DMF(30ml),并将NaH(360mg,15mmole)分批加入于室温搅拌30分钟。苄基氯化物(750mg,6mmole)接着被滴入,于室温下搅拌过夜。该反应混合物被倒入于冰水中并以CH2Cl2萃取。有机层以水洗涤,以MgSO4干燥并挥发其中的溶剂。残留物进一步以硅胶柱进行层析,并以正己烷/乙酸乙酯(3∶1)混合液洗脱,且以正己烷/CH2Cl2重结晶而得到白色结晶I-9-b(515mg,50.0%)。
MP 91.5-92.8℃
1H-NMR(DMSO-d6,200MHz):δ7.84-7.97(3H,m,H-5,H-8,H-4′),7.26-7.58(10H,m,H-3,H-7,H-3′,H-5′,H-6′,Ph),5.38(2H,s,OCH2Ph),2.45(3H,s,CH3)
MS(m/z)343(EI+)
分析计算值C23H18FNO:C,80.45;H,5.28;N,4.08.实测值:C,80.51;H,5.29;N,4.17.
N-{[4-(苄氧基)-2-(2-氟苯基)喹啉-6-基]甲基}-N-乙基乙胺(I-9-d)
将I-9-b(680mg,2mmol)、N-溴代-丁二酰亚胺(NBS,360mg,2mmol)及2,2′-偶氮双(异丁腈)(AIBN,30mg,0.19mmol)加入一干燥的圆底烧瓶内,再通入氩气冲洗。将50ml的无水的苯被加入该反应混合物中,于氩气气氛下及室温下搅拌30分钟,接着于80℃回流1小时,随后冷却至室温后得到I-9-c,在未进一步纯化下以二乙胺(3.0ml,29.0mmole)处理,再回流1小时。挥发去除其中的溶剂后,以乙酸乙酯及50ml的10%HCl进行分层,并且接着其中的酸性层以10%的NaHCO3中和至pH7-8,以乙酸乙酯萃取(100ml×5)。有机层以MgSO4干燥并挥发其中的溶剂。残留物以硅胶柱进行层析,并以CH2Cl2/甲醇(3∶1)混合液洗脱,且以正己烷/乙酸乙酯重结晶而得到黄色固体I-9-d(120mg,15.1%)。
MP 51.2-51.5℃
1H-NMR(DMSO-d6,200MHz):δ8.04(1H,s,H-5),7.84-7.96(2H,m,H-8,H-5′),7.69(1H,dd,H-4′),7.28-7.54(9H,m,H-3,H-7,H-3′,H-6′,Ph),5.41(2H,s,OCH2Ph),3.68(2H,s,CH2N(CH2CH3)2),2.46(4H,q,J=7,CH2N(CH2CH3)2),0.94(6H,t,J=7,CH2N(CH2CH3)2)
MS(m/z)414(EI+)
分析计算值C27H27FN2O:C,78.23;H,6.57;N,6.76.实测值:C,78.25;H,6.67;N,6.74.
6-[(二乙基胺基)甲基]-2-(2-氟苯基)喹啉-4(1H)-酮(I-9-e)
I-9-d(120mg,0.3mmol)被溶解于冰醋酸(5ml)。HBr(3ml)被接着加入同时将溶液加热至60℃,混合物于90℃加热3小时。反应完成后,将反应混合物倒入水中,并以乙酸乙酯萃取。酸性层被加入10%的NaHCO3中和至pH7-8,并以乙酸乙酯萃取(100ml×5)。有机层以MgSO4干燥,挥发其中的溶剂。残留物以正己烷/乙酸乙酯重结晶而得到灰色固体I-9-e(58mg,59.6%)。
MP 184.2-184.7℃
1H-NMR(DMSO-d6,200MHz):δ11.9(1H,s,H-1),7.97(1H,s,H-5),7.52-7.69(4H,m,H-7,H-8,H-4′,H-6′),7.31-7.43(2H,m,H-3′,H-5′),6.12(1H,s,H-3),3.57(2H,s,CH2N(CH2CH3)2),2.40(4H,q,J=7Hz,CH2N(CH2CH3)2),0.92(6H,t,J=7Hz,CH2N(CH2CH3)2)
MS(m/z)324(EI+)
C20H21FN2O分析计算值:C,74.05;H,6.53;N,8.64.实测值:C,73.94;H,6.62;N,8.67.
实施例10
3-甲基-苯甲酰基-乙酸乙酯(1-10-a)
在剧烈搅拌的NaH(564mg,48.5mmol)和CO(OC2H5)2(5.73g,48.5mmol)的无水甲苯(50ml)悬浮液中,于回流状态下滴入3-甲基乙酰苯(4.33g,32.3mmole)的甲苯溶液。在添加完成后该混合物被回流及搅拌30分钟。该混合物于冷却至室温后以冰酯酸加以酸化,加入冰水再以甲苯萃取。有机层以MgSO4干燥并挥发去除其中的溶剂。残留物以硅胶柱进行层析,并以CH2Cl2/正己烷(3∶2)混合液洗脱而得到淡黄色液体I-10-b(3.13g,46.9%)。
1H-NMR(DMSO-d6,200MHz):δ7.68-7.72(2H,m,H-4,H-6),7.32-7.36(2H,m,H-2,H-3),4.16(2H,q,J=7,CH2CH3),3.94(2H,s,H-10),2.38(3H,s,CH3),1.2(3H,t,J=7,CH2CH3)
MS(m/z)206(EI+)
C12H14O3分析计算值:C,69.88;H,6.84;实测值:C,69.72;H,6.95.
6-甲氧基-2-间-甲苯基喹啉-4(1H)-酮(I-10-b)
将对甲氧基苯胺(2.14g,0.02mole)、I-10-a(5.1g,0.025mole)及多聚磷酸(PPA)的混合物于搅拌下及130℃加热。反应完成后该混合物被冷却至室温并以4M NaOH中和之。过滤出黄色固体、水洗、干燥及以乙醇重结晶而得到淡紫色固体化合物I-10-b(2.6g,25.8%)。
MP 262.2-264.1℃
1H-NMR(DMSO-d6,200MHz):δ7.70(1H,d,H-8),7.55-7.60(2H,m,H-5,7),7.25-7.47(4H,m,H-2′,H-4′,H-5′,H-6′),6.33(1H,s,H-3),3.80(3H,s,OCH3),2.37(3H,s,CH3)
MS(m/z)265(EI+)
C17H15NO分析计算值:C,76.79;H,5.70;N,5.28.实测值:C,76.81;H,5.62;N,5.34.
4-(苄氧基)-6-甲氧基-2-间-甲苯基喹啉(I-10-c)
I-10-b(795mg,3mmole)被溶解于无水的DMF(30ml),并且于室温下将NaH(360mg,15mmole)分批加入并搅拌30分钟。苄基氯化物(750mg,6mmole)接着被滴入,于室温下搅拌过夜。该反应混合物被倒入于冰水中并以CH2Cl2萃取。有机层以水洗涤,以MgSO4干燥并挥发其中的溶剂。残留物以硅胶柱进行层析,并以正己烷/乙酸乙酯(3∶1)混合液洗脱,并且以正己烷/CH2Cl2重结晶而得到白色结晶I-10-c(530mg,49.7%)。
MP 133.0-134℃
1H-NMR(DMSO-d6,200MHz):δ8.00(1H,s,H-5),7.96(1H,d,H-8),7.89(1H,d,J=8Hz,H-7),7.32-7.58(6H,m,H-3,H-2′,H-5′,H-6′,Ph),7.22(1H,d,J=7Hz,H-4′),5.50(2H,s,OCH2Ph),3.83(3H,s,OCH3),δ2.38(3H,s,CH3)
MS(m/z)355(EI+)
C24H21NO2分析计算值:C,81.10;H,5.96;N,3.94.实测值:C,81.9;H,5.81;N,3.97.
N-{[3-(4-(苄氧基)-6-甲氧基喹啉-2-基)苯基]甲基}-N-乙基乙胺(I-10-e)
将I-10-c(530mg,2mmol)、N-溴代-丁二酰亚胺(NBS,360mg,2mmol)及2,2′-偶氮双(异丁腈)(AIBN,30mg,0.19mmol)加入到一干燥的圆底烧瓶内,再通入氩气冲洗。50ml的无水的苯被加入该反应混合物中,于氩气气氛下及室温下搅拌30分钟,接着于80℃回流1小时,冷却至室温后得I-10-d,在未进一步纯化下以二乙胺(3.0ml,29.0mmole)处理,再回流1小时。挥发去除其中的溶剂后,以乙酸乙酯及50ml的10%HCl溶液进行分层,接着其中的酸性层以10%的NaHCO3溶液中和至pH7-8,再以乙酸乙酯萃取(100ml×5)。萃取的有机层以MgSO4干燥并挥发其中的溶剂。残留物以硅胶柱进行层析,并以CH2Cl2/甲醇(3∶1)混合液洗脱,并以正己烷/乙酸乙酯重结晶而得到黄色固体I-10-e(25mg,2.9%)。
MP 89.2-89.5℃
1H-NMR(DMSO-d6,200MHz):δ8.13(1H,s,H-3).7.87-8.04(2H,m,H-7,8),7.34-7.43(10H,m,H-3,H-2′,H-4′,H-5′,H-6′,Ph),5.51(2H,s,OCH2Ph),3.84(3H,s,OCH3),3.69(2H,s,CH2N(CH2CH3)2),2.53(4H,q,J=7Hz,CH2N(CH2CH3)2),0.99(6H,t,J=7Hz,CH2N(CH2CH3)2)
MS(m/z)426(EI+)
C28H30N2O2分析计算值:C,78.83;H,7.90;N,6.57.实测值:C,78.95;H,7.14;N,6.48.
2-{3-[(二乙基胺基)甲基]苯基}-6-甲氧基喹啉-4(1H)-酮(I-10-f)
I-10-e(42mg,0.1mmol)被溶解于冰醋酸(5ml)。HBr(3ml)被接着加入同时将溶液加热至60℃,混合物于90℃加热3小时。反应完成后,将反应混合物倒入水中,并以乙酸乙酯萃取。酸性层被加入10%的NaHCO3溶液中和至pH7-8,再以乙酸乙酯萃取(100ml×5)。有机层以MgSO4干燥,挥发其中的溶剂。残留物以正己烷/乙酸乙酯重结晶而得到灰色固体I-10-f(20.8mg,61.9%)。
MP 152.1-152.7℃
1H-NMR(DMSO-d6,200MHz):δ11.76(1H,s,H-1),7.67-7.74(3H,m,H-5,H-8,H-6′),7.46-7.49(3H,m,H-7,H-2′,H-4′),7.27(1H,dd,H-5′),6.27(1H,s,H-3),3.80(3H,s,OCH3),3.67(2H,s,CH2N(CH2CH3)2),2.53(4H,q,J=7Hz,CH2N(CH2CH3)2),0.97(6H,t,J=7Hz,CH2N(CH2CH3)2).
C21H24N2O2分析计算值:C,74.97;H,7.19;N,8.33.实测值:C,74.81;H,7.33;N,8.31.
抗癌活性
化合物I-1及I-1-b对体内抗肿瘤活性的作用
(I)化合物I-1及I-1-b对MCF-7肿瘤移植模型的作用
I-1材料与方法
雌性GALB/cAnN-Foxnl.E SCID小鼠(18至20克;6至8周龄),购自国家动物中心,并且依动物中心管理办法豢养于增压通风笼中。肿瘤移植前两天以皮下注射(s.c.)植入0.7毫克的雌二醇(estradiol),每天各一次。MCF-7细胞(2×106)以皮下注射移种于小鼠右腰,肿瘤约150立方毫米时,随机将30只肿瘤携带小鼠分成五组,分别以载体(PBS)、I-1或I-1-b进行治疗。第一组仅接受载体。第二至五组分别给予如下腹腔内注射(i.p.)治疗每周三次:I-1(15mg/kg)、I-1(30mg/kg)、I-1-b(22.5mg/kg)和I-1-b(45mg/kg)。小鼠每周称重并用测径器测量肿瘤。肿瘤体积以以下公式计算:L+W/2,其中L为长、W为宽。在治疗期的最后一天,实验小鼠被处死,将肿瘤切除、秤重及切片,并将所述肿瘤切片包埋于OCT化合物,并于-70℃冻存。
I-2结果
体内检测I-1或I-1-b的作用。将MCF-7细胞(2×106)以皮下注射(s.c.)各自注入于三十只雌性SCID小鼠。将小鼠随机分成五组(每组六只),并且以单独载体、I-1(15或30mg/kg)、I-1-b(22.5、45mg/kg)治疗。如图1所示,该体内肿瘤模型显示:与对照组相比,以45mg/kg的I-1-b治疗的小鼠,其肿瘤体积显著减少(P<0.001)。这些结果证实,在小鼠移植瘤模型中,I-1-b能明显抑制MCF-7肿瘤的生长。
(II)化合物I-1及I-1-b对CT-26大肠直肠癌腹膜内模型的抗肿瘤作用
II-1材料与方法
30只雄性的6周龄的Balb/c小鼠,购自国家动物中心,并且依动物中心管理办法豢养于增压通风笼中。在开始时(第0天)将CT-26细胞(1×106)注入腹腔。将动物随机分配用于抗肿瘤作用研究(n=10)。肿瘤植入7天后,对于取出的小鼠口服给予5mg/kg和10mg/kg的I-1-b(QD×7)。监测小鼠的存活率与体重。
II-2结果
II-2-1治疗后小鼠外观
给予赋型剂的对照组小鼠有腹水现象,而口服给予I-1-b(5mg/kg/天,QD×7)与I-1-b(10mg/kg/天,QD×7)的小鼠则可缓解和减少腹水现象。
II-2-2小鼠服药后的平均寿命延长效果
如图2所示,给予赋型剂的对照组小鼠于给药后40天全部死亡,而那些给予化合物I-1-b(5mg/kg/天,QD×7)和I-1-b(10mg/kg/天,QD×7)的小鼠则分别于给药后45天和50天全部死亡。剂量为(10mg/kg QD×7)其平均寿命延长140%,且剂量为(5mg/kg QD×7)其平均寿命延长120%。最大耐受量未被获得。
细胞活性分析(MTT分析)
将细胞接种于24孔盘(2×104细胞/孔),培养过夜。随后以DMSO(对照组)或不同浓度的测试化合物处理并孵育48小时。以MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物)来检测测试化合物对细胞生长的作用。简而言之,每孔加入40μl的MTT溶液(2mg/ml,Sigma Chemical Co.)至最终体积为500μl,并于置于37℃孵育1小时。去除上清液,并以溶解在200μl DMSO中的代谢活力细胞来形成MTT甲状结晶。最后,在酶联免疫吸附分析(ELISA)的读取器中,检测其在O.D.550nm下的吸光度。
结果:
测试化合物I-1-b、I-2-b、I-3-b、I-4-b、I-5-b、I-7-d、I-7-e对抗人乳腺癌MCF-7细胞的毒性作用
化合物I-1-b,I-2-b,I-3-b,I-4-b,I-5-b,I-7-d,I-7-e的细胞毒性作用在人乳腺癌MCF-7细胞中被评估。如图3所示,这些化合物以0.125至10μM治疗导致细胞活性的剂量依赖性的降低。这些结果说明:化合物I-1-b、I-2-b、I-3-b、I-4-b、I-5-b、I-7-d、I-7-e显示出抗MCF-7细胞的显著细胞毒性作用。所以,2-芳基喹啉的这些衍生物被建议为用于癌症治疗的有潜力的治疗药物。
化合物I-7-d的细胞毒性活性
在HCT-116、Hep G2、NCI-H226、A549、A498和HL-60细胞中检测化合物I-7-d的体外细胞毒性活性。如表1中所示,化合物I-7-d对所述六种癌症细胞系中的大部份显示显著抑制作用,并且最明显的是对HCT-116及HL-60细胞最具活性。化合物I-7-d对HCT-116的IC50为0.9μM且对HL-60的IC50为0.5μM。化合物I-7-d是被开发成为新型抗癌药物的有力候选化合物。
表1
*六种癌细胞以化合物I-7-d处理48小时,接着细胞被收集并以MTT法分析。
*IC50的值代表导致50%成长抑制效果的浓度。
*HCT-116,结肠癌细胞系;Hep G2,肝癌细胞系;NCI-H226,非小细胞肺癌细胞系;A549,肺癌细胞系;A498,肾癌细胞系;HL-60,白血病癌细胞系。
化合物I-8-e,I-9-e及I-10-f的杀细胞活性
化合物I-8-e,I-9-e及I-10-f对HL-60细胞进行体外细胞致毒活性试验。如表2所示,化合物I-8-e及I-9-e对HL-60癌细胞系显示显著抑制性。化合物I-8-e对HL-60的IC50为15μM且I-9-e对HL-60的IC50为5.8μM。化合物I-9-e很可能被开发成为一种新型的抗癌药。
表2
化合物 | IC50(μM) |
I-8-e | 15 |
I-9-e | 5.8 |
I-10-f | >50 |
*HL-60细胞以化合物I-8-e,I-9-e及I-10-f处理48小时,接着细胞被收集并以MTT法分析。
*IC50的值代表导致50%成长抑制效果的浓度。
*HL-60,白血病癌细胞系。
Claims (37)
1.一种具有下列化学式Ia、Ib或Ic的2-芳基-4-喹诺酮磷酸酯衍生物,
其中:
R2′,R3′,R4′,R5′和R6′独立地为H,(CH2)nCH3,(CH2)nYH,Y(CH2)nCH3,Y(CH2)nYH,Y(CH2)nNR8R9,X,(CH2)nNR8R9,
其中n为0~4的整数,Y为O或S,X为F、Cl或Br,且R8和R9独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y如上所定义,且m为0~4的整数;
R2,R3,R4和R5独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、
或R3和R4一起为-Y(CH2)nY-,其中n、Y、X、R8及R9如上所定义;并且
R1及R1′独立地为H、Li+、Na+、K+、N+R8R9R10R11或苄基,其中R10及R11独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,且n、m、Y、R8及R9如上所定义。
2.根据权利要求1所述的磷酸酯衍生物,其具有化学式Ia。
3.根据权利要求2所述的磷酸酯衍生物,其中R2′、R3′、R4′、R5′及R6′全部为H;或R2′,R3′,R4′,R5′及R6′中之一为F、OCH3或(CH2)nNR8R9,及其它的为H,其中n、R8及R9如权利要求1中所定义。
4.根据权利要求2所述的磷酸酯衍生物,其中R2,R3,R4及R5全部为H;或R2,R3,R4及R5中之一为F、OCH3、Y(CH2)nCH3或(CH2)nNR8R9,且其它的为H;或R2及R5为H,且R3和R4一起为-O(CH2)nO-,其中n、Y、R8及R9如权利要求1所定义。
5.根据权利要求2所述的磷酸酯衍生物,其中R1及R1′均为H或均为Na+。
6.根据权利要求5所述的磷酸酯衍生物,其中R2和R5为H,且R3和R4一起为-O(CH2)O-;且R2′,R3′,R4′及R5′全部为H,且R6′为F。
7.根据权利要求5所述的磷酸酯衍生物,其中R2及R5为H,且R3及R4一起为-O(CH2)O-;且R2′,R3′,R4′及R6′全部为H,且R5′为F。
8.根据权利要求5所述的磷酸酯衍生物,其中R4为F,且R2,R3及R5为H;且R2′,R3′,R4′,R5′及R6′全部为H。
9.根据权利要求5所述的磷酸酯衍生物,其中R2,R3,R4及R5全部为H;且R2′,R3′,R4′,R5′及R6′全部为H。
10.根据权利要求5所述的磷酸酯衍生物,其中R4为OCH3,且R2,R3及R5为H;且R5′为F,且R2′,R3′,R4′及R6′为H。
11.根据权利要求5所述的磷酸酯衍生物,其中R2及R5为H,且R3和R4一起为-O(CH2)O-;且R2′,R3′,R4′及R6′全部为H,且R5′为OCH3。
12.根据权利要求5所述的磷酸酯衍生物,其中R4为CH2N(C2H5)2,且R2,R3及R5为H;且R6′为F,及R2′,R3′,R4′且R5′为H。
13.根据权利要求5所述的磷酸酯衍生物,其中R4为CH2N(C2H5)2,且R2,R3及R5为H;且R2′,R3′,R4′,R5′及R6′全部为H。
14.根据权利要求5所述的磷酸酯衍生物,其中R4为OCH3,且R2,R3及R5为H;且R5′为CH2N(C2H5)2,且R2′,R3′,R4′及R6′为H。
15.根据权利要求1所述的磷酸酯衍生物,其具有化学式Ib。
16.根据权利要求15所述的磷酸酯衍生物,其中R2,R3,R4及R5全部为H;且R2,R3,R4及R5中之一为F或OCH3,且其它的为H;或R2及R5为H,且R3和R4一起为-O(CH2)nO-,其中n如权利要求1所定义。
17.根据权利要求15所述的磷酸酯衍生物,其中R2′,R3′,R4′,R5′及R6′全部为H;或R2′,R3′及R4′中之一为F或OCH3,及其它的为H。
18.根据权利要求15所述的磷酸酯衍生物,其中R1及R1′为苄基。
19.根据权利要求18所述的磷酸酯衍生物,其中R2′,R3′,R4′,R2及R5全部为H,及R3及R4一起为-O(CH2)O-。
20.一种用于杀灭实体癌细胞的药物组合物,该组合物包含治疗有效量的如权利要求1至19中任一项所述的2-芳基-4-喹诺酮磷酸酯衍生物或其药学上可接受的盐作为活性成份,以及与之混合的用于该活性成份的药学上可接受的载体或稀释剂,其中所述实体癌细胞包含人乳腺癌、结肠癌、肺癌、黑色素瘤、卵巢癌、肾癌、胃癌、前列腺癌、回肠癌、神经胶质母细胞瘤、骨癌、鼻咽表皮样癌、肝癌或白血病。
21.根据权利要求20所述的药物组合物,其中所述实体癌细胞为人乳腺癌、结肠癌、肺癌、肾脏癌、肝癌或白血病。
22.根据权利要求21所述的药物组合物,其中所述实体癌细胞为人乳腺癌或结肠癌。
23.一种具有下列化学式IIb或IIc的2-硒吩基-4-喹诺酮化合物,
其中:
R2′、R3′和R4′独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X或(CH2)nNR8R9,
其中n为0~4的整数,Y为O或S,X为F,Cl或Br,且R8和R9独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y如上所定义,且m为0~4的整数;
R2、R3、R4和R5独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9,
或R3和R4一起为-Y(CH2)nY-,其中n、Y、X、R8及R9如上所定义。
24.根据权利要求23所述的化合物,其中R2、R3、R4及R5全部为H;或R2、R3、R4及R5中之一为F或OCH3,且其它的为H;或R2及R5为H,且R3和R4一起为-O(CH2)nO-,其中n如权利要求23中所定义。
25.根据权利要求24所述的化合物,其中:R2′、R3′及R4′均为H;或R2′、R3′及R4′中之一为F或OCH3,且其它的为H。
26.根据权利要求23所述的化合物,其具有化学式IIb。
27.根据权利要求26所述的化合物,其中R2′、R3′、R4′、R2及R5全部为H,且R3和R4一起为-O(CH2)nO-。
28.一种用于杀灭实体癌细胞的药物组合物,所述药物组合物包含治疗有效量的如前述权利要求23至27中任一项所述的2-硒吩基-4-喹诺酮化合物或其药学上可接受的盐作为活性成份,和与之混合的用于该活性成份的药学上可接受的载体或稀释剂,其中所述实体癌细胞包含人乳腺癌、结肠癌、肺癌、黑色素瘤、卵巢癌、肾脏癌、胃癌、前列腺癌、回肠癌、神经胶质母细胞瘤、骨癌、鼻咽表皮样癌、肝癌或白血病。
29.根据权利要求28所述的药物组合物,其中所述实体癌细胞为人乳腺癌、结肠癌、肺癌、肾脏癌、肝癌或白血病。
30.一种具有下列化学式IIa的2-苯基-4-喹诺酮化合物:
IIa
其中:
R2′、R3′、R4′、R5′和R6′独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH,Y(CH2)nNR8R9、X、(CH2)nNR8R9,
其中n为0~4的整数,Y为O或S,X为F,Cl或Br,且R8和R9独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y如上所定义,且m为0~4的整数;
R2、R3、R4和R5独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、
或R3和R4一起为-Y(CH2)nY-,其中n、Y、X、R8及R9如上所定义;
当R2、R3、R4和R5中之一是(CH2)qNR8R9,或者R2′、R3′、R4′、R5′和R6′中之一是(CH2)qNR8R9时,其中的q为1~4的整数及R8及R9如上所定义。
31.根据权利要求30所述的化合物,其中R4是(CH2)qNR8R9,及R2、R3和R5是H,其中q、R8及R9如权利要求30中所定义。
32.根据权利要求30所述的化合物,其中R5′是(CH2)qNR8R9,且R2′、R3′、R4′和R6′是H,其中q,R8及R9如权利要求30中所定义。
33.根据权利要求31所述的化合物,其中R4是CH2N(C2H5)2,R6′是F,且R2′、R3′、R4′和R5′是H。
34.根据权利要求31所述的化合物,其中R4是CH2N(C2H5)2,且R2′、R3′、R4′、R5′和R6′全部是H。
35.根据权利要求32所述的化合物,其中R4是OCH3,R2、R3和R5是H,R5′是CH2N(C2H5)2,且R2′、R3′、R4′和R6′全部是H。
36.一种用于杀灭实体癌细胞的药物组合物,包含治疗有效量的如前述权利要求30至35中任一项所述的2-苯基-4-喹诺酮化合物或其药学上可接受的盐作为活性成份,和与之混合的用于该活性成份的药学上可接受的载体或稀释剂,其中所述实体癌细胞包含人乳腺癌、结肠癌、肺癌、黑色素瘤、卵巢癌、肾脏癌、胃癌、前列腺癌、回肠癌、神经胶质母细胞瘤、骨癌、鼻咽表皮样癌、肝癌或白血病。
37.根据权利要求36所述的药物组合物,其中所述实体癌细胞为白血病。
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CN102675200A (zh) * | 2012-05-16 | 2012-09-19 | 中国药科大学 | 一类具有抗肿瘤活性的2-苯基-4-喹诺酮化合物、其制备方法及用途 |
CN103347859A (zh) * | 2010-07-15 | 2013-10-09 | 台睿生物科技股份有限公司 | 芳基及杂芳基喹啉衍生物之合成及抗癌活性 |
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KR101817221B1 (ko) | 2010-11-18 | 2018-01-10 | 카시나 라일라 이노바 파마슈티칼스 프라이빗 리미티드 | 치환된 4-(셀레노펜-2(또는 3)-일아미노)피리미딘 화합물 및 이의 사용방법 |
KR101460207B1 (ko) * | 2011-12-07 | 2014-11-11 | 세종대학교산학협력단 | 셀레노펜-접합 방향족 화합물을 포함하는 항암제 |
US9624235B2 (en) * | 2012-01-31 | 2017-04-18 | University of Pittsburgh—of the Commonwealth System of Higher Education | Compounds and methods for inhibition of AP endonuclease-1/redox factor-1 (HAPE1) activity |
BR112017026104A2 (pt) * | 2015-06-03 | 2018-08-14 | Tairx Inc | novos usos de derivados de aril-quinolina como inibidores de mimetismo vasculogênico |
WO2016201257A2 (en) * | 2015-06-10 | 2016-12-15 | The Johns Hopkins University | Compositions and methods for identifying adp-ribosylated sites by mass spectrometry |
WO2023078252A1 (en) | 2021-11-02 | 2023-05-11 | Flare Therapeutics Inc. | Pparg inverse agonists and uses thereof |
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IL89840A (en) * | 1988-04-06 | 1996-10-31 | Lipha | Substituted flavonoid compounds and salts thereof their preparation and pharmaceutical composition containing them |
EP0649410B1 (en) * | 1992-07-10 | 1997-05-02 | Laboratoires Glaxo Sa | Anilide derivatives |
WO1994002145A2 (en) * | 1992-07-22 | 1994-02-03 | Genelabs Technologies, Inc. | 2-aryl-4-quinolones as antitumor compounds |
JPH0733743A (ja) * | 1993-07-22 | 1995-02-03 | Kyorin Pharmaceut Co Ltd | 2−アリール−4−キノリノール誘導体 |
US5571822A (en) * | 1994-09-30 | 1996-11-05 | The University Of North Carolina At Chapel Hill | Antitumor compounds |
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AU2001255538B2 (en) * | 2000-04-24 | 2006-03-30 | Bristol-Myers Squibb Company | Heterocycles that are inhibitors of IMPDH enzyme |
US7078552B2 (en) * | 2000-04-27 | 2006-07-18 | Arizona Board Of Regents | Combretastatin A-1 phosphate and combretastatin B-1 phosphate prodrugs |
TW490462B (en) * | 2000-06-01 | 2002-06-11 | Nat Science Council | 2-Phenyl-4-quinazolinones compounds, 2-phenyl-4-alkoxy-quinazoline compounds and their pharmaceutical compositions |
US6569870B1 (en) * | 2000-09-25 | 2003-05-27 | The University Of North Carolina At Chapel Hill | Fluorinated quinolones as antimitotic and antitumor agents |
US6916831B2 (en) * | 2003-02-24 | 2005-07-12 | The University Of North Carolina At Chapel Hill | Flavone acetic acid analogs and methods of use thereof |
US6897316B2 (en) * | 2003-08-08 | 2005-05-24 | China Medical University | Substituted 2-phenyl-4-quinolone-3-carboxylic acid compounds and their use as antitumor agents |
WO2006039721A2 (en) * | 2004-10-08 | 2006-04-13 | The Board Of Trustees Of The University Of Illinois | Bisphosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases |
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CN103347859A (zh) * | 2010-07-15 | 2013-10-09 | 台睿生物科技股份有限公司 | 芳基及杂芳基喹啉衍生物之合成及抗癌活性 |
CN102675200A (zh) * | 2012-05-16 | 2012-09-19 | 中国药科大学 | 一类具有抗肿瘤活性的2-苯基-4-喹诺酮化合物、其制备方法及用途 |
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