CN1176252A - 新的香豆素喹诺酮羧酸及其制备方法 - Google Patents
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Abstract
新的香豆素喹诺酮羧酸及其制备方法本发明涉及通式Ⅰ的新的香豆素喹诺酮羧酸,其中吡啶酮系统在香豆素系统的3,4-,6,7-,和7,8-位置稠合其中R1R2=-NHCH=C(CO2R6)CO-,R3=NO2或NH2,R4=R5=H,R6=H或C2H5;R1R2=-NHCH=C(CO2R6)CO-,R3=R4=H,R5=F,R6=H或C2H5;R1R2=-CO(CO2R6)C=CHNH-,R3=R4=R5=H,R6=H或C2H5;R1R2=R3R4=-NHCH=C(CO2R6)CO-,R5=H,R6=H或C2H5;R1=H或OH,R2=R5=H,R3R4=-NHCH=C(CO2R6)CO-,R6=H或C2H5;R1=OH,R2=R3=H,R4R5=-CO(CO2R6)C=CHNH-,R6=H或C2H5;R1=R5=H,R2=CH3或CF3,R3R4=-CO(CO2R6)C=CHNH-,R6=H或C2H5;及其药物上可接受的盐。新的香豆素喹诺酮羧酸的制备方法及其生物学作用也是本发明的目的。
Description
本发明涉及通式I的新的香豆素喹诺酮羧酸,其中吡啶酮系统在香豆素系统的3,4-,6,7-和7,8-位置稠合其中
R1R2=-NHCH=C(CO2R6)CO-,R3=NO2或NH2,R4=R5=H,R6=H或C2H5;
R1R2=-NHCH=C(CO2R6)CO-,R3=R4=H,R5=F,R6=H或C2H5;
R1R2=-CO(CO2R6)C=CHNH-,R3=R4=R5=H,R6=H或C2H5;
R1R2=R3R4=-NHCH=C(CO2R6)-,R5=H,R6=H或C2H5;
R1=H或OH,R2=R5=H,R3R4=-NHCH=C(CO2R6)CO-,R6=H或C2H5;
R1=OH,R2=R3=H,R4R5=-CO(CO2R6)C=CHNH-,R6=H或C2H5;
R1=R5=H,R2=CH3或CF3,R3R4=-CO(CO2R6)C=CHNH-,R6=H或C2H5,及其药学上可接受的盐。
本发明的目的也是制备新的香豆素喹喏酮羧酸的方法及其生物学作用。
按照本发明,通式I的新香豆素喹诺酮羧酸是从1996年7月2日的克罗地亚专利申请P-960308A(欧洲专利申请号…)中公开的结构式II表示的香豆素丙二酸酯为起始原料制备的其中
R1=-NHCH=C(CO2C2H5)2,R2=R4=H,R3=H或NO2,R5=H或F;
R1=R3=-NHCH=C(CO2C2H5)2,R2=R4=R5=H;
R1=H或OH,R3=-NHCH=C(CO2C2H5)2,R2=R4=R5=H;
R1=OH,R2=R3=R4=H,R5=-NHCH=C(CO2C2H5)2;
R1=R3=R5=H,R2=CH3或CF3,R4=-NHCH=C(CO2C2H5)2,
该化合物在道氏热载体A中,于250-260℃下加热10分钟-13小时,得到通式III表示的环状酯其中
R1R2=-NHCH=C(CO2C2H5)CO-,R3=R4=H,R5=F;
R1R2=-NHCH=C(CO2C2H5)CO-,R3=NO2,R4=R5=H;
R1R2=-CO(CO2C2H5)C=CHNH-,R3=R4=H,R5=H或F;
R1R2=R3R4=-NHCH=C(CO2C2H5)CO-,R5=H;
R1=H或OH,R2=R5=H,R3R4=-NHCH=C(CO2C2H5)CO-;
R1=OH,R2=R3=H,R4R5=-CO(CO2C2H5)C=CHNH-;
R1=R5=H,R2=CH3或CF3,R3R4=-CO(CO2C2H5)C=CHNH-,对于结构式III的化合物,其中R1R2=-CO(CO2C2H5)C=CHNH-,R3=R4=H,R5=H,在D.T.Connor,P.A,Young,M.von Strandtaman,J.Heterocyclic Chem.18(1981)697-702中明确地记述着要将相应的香豆素丙二酸酯环化成结构式III中含有上述取代基的酯的尝试是不成功的,而且也没有得到相应的酸,所说的酸,除了结构式III的酯外,也是本发明的目的且具有通式I的结构,其中R1R2=-CO(CO2C2H5)C=CHNH,R3=R4=H,R5=H。
式III的化合物,其中R1R2=-NHCH=C(CO2C2H5)CO-,R3=R4=H,R5=H(D.T.Connor(瓦尔讷-兰博特公司)的美国专利4,210,758中早就公开了的)先被硝化,然后还原,最后与二乙基-乙氧基亚甲基丙二酸酯稠合,得到结构式IV化合物其中R=NO2或NH2。
为了得到通式I的化合物,其中R1R1=-NHCH=C(CO2C2H5)CO,R3=NH2,R4=R5=H,将通式III的化合物,其中R1R2=-NHCH=C(CO2C2H5)CO-,R3=NO2,R4=R5=H在催化剂钯/活性炭的作用下,在3巴的N2气流中,于冰乙酸中还原6个小时的时间。
通过式III的化合物的水解,得到式I的香豆素喹诺酮羧酸,其中R1,R2,R3,R4和R5具有早先公开的含意,R6=H。
作为本发明目的的香豆素喹诺酮羧酸及其药物可接受的盐是参试菌株的抑制剂。在这些试验中,微量稀释试验被用于依据方法NCCLS(M7-A2,Vol.Co,No.8,1990;M100-S4,Vol.12,No.20,1992)而进行的细菌敏感性的研究。用于这些试验的对照试验微生物是金黄色葡萄球菌ATCC29213,粪内孢菌ATCC29212和绿脓杆菌ATCC29213,用诺氟沙星和异诺氟沙星作为抗生素比较的工作标准。试验了下列菌株:金黄色葡萄球菌(Staphilocaureus)ATCC6538P,枯草杆菌NCTC8236,黄细球菌(Micrococcus flavus)ATCC10240,绿脓杆菌(Pseudomonas aerug)NCTC10490,巴拿马沙门氏菌(Salmonela Panama)6117,大肠杆菌Lac+6131,大肠杆菌Lac-6130,链球溶血杆菌(b-Haemol Streptococc)BJ-22,链球溶血杆菌AJ-21,酿脓链球菌(Streptococcus pyogenes)20F,粪链球菌(Streptococcus faecalis)ATCC8043,大肠杆菌ATCC10536,表皮葡萄球菌(Staphyloc epidermis)ATCC12228,蜡状芽孢杆菌(B.Cereus)AYCC11778,短小芽孢杆菌(B.Pumilus)ATCC8241和枯草芽孢杆菌(B.Subtilis)ATCC6633。
4,5-二氢-4,5-二氧代-1H-[1]苯并吡喃并[4,3-b]吡啶-3-羧酸抑制大肠杆菌Lac+6131和链球溶血杆菌-AJ-21。
1,5-二氢-1,5-二氧代-7-氟-4H-[1]苯并吡喃并[3,4,-b]吡啶-3-羧酸抑制所有参试的菌株。
4,7-二氢-4,7-二氧代-1H-[1]苯并吡喃并[6,7-b]吡啶-3-羧酸抑制枯草芽孢杆菌NCTC8236,酿脓链球菌20F和粪链球菌ATCC8043。
对按照本发明的香豆素喹诺酮酸及其药物上可接受的盐的体外抗肿瘤作用也进行了研究。试验了该抗肿瘤作用对乳腺癌(MCF7),宫颈癌(HeLa),胰腺癌(MiaPaCa2),喉癌(HeP2)细胞系的生长以及对正常人成纤维细胞(Hef522)的作用。
1,7-二氢-1,7-二氧代-9-(三氟甲基)-4H-[1]苯并吡喃并[6,7-b]吡啶-3-羧酸抑制乳腺癌(MCF7),胰腺癌(MiaPaCa2)和喉癌(HeP2)细胞的生长,并在高浓度下能轻微地刺激宫颈癌(HeLa)细胞的生长,它对成纤维细胞(HefS22)的生长没有显著的作用。
对MCF7生长的抑制依赖于浓度,在浓度为10-5M和10-8M时,抑制效果最佳。
该药物在浓度10-8-10-6M的范围内对HeLa细胞的生长没有影响,而在高浓度(10-5和10-4M)时,刺激HeLa细胞的生长。
对MiaPaCa2细胞生长的抑制依赖于浓度,在浓度为10-4M,抑制达到35%。
该试验物质抑制HeP2细胞的生长,随着浓度的增大,抑制作用降低,在10-7-10-5M的浓度范围,抑制效果最佳。
该试验物质对正常的成纤维细胞(Hef522)的生长没有影响。
通过下列实施例来说明本发明而这并非是限制性的解释。实施例1
二乙基-{[(8-氟-2-氧代-2H-[1]-苯并吡喃酮-3-基)氨基]-亚甲基}丙二酸酯(2.40g;0.871mmol)的溶液在道氏热载体A(55ml)中沸腾加热40分钟。待冷却后,向溶液中加入低沸点的石油醚以帮助所得酯完全沉淀。得到的棕灰色沉淀1,5-二氢-1,5-二氧代-7-氟-4H-[1]-苯并吡喃并[3,4-b]吡啶-2-羧酸乙酯先用石油醚洗,然后用乙醚洗(1.85g;89%)。熔点:288-290℃。
分析:C15H10FNO5的计算值: C59.41;H3.32;N4.62
实验值 C59.74;H2.97;N4.72
1H-NMR(DMSO-d6)δ/ppm:1.3(t,CH3);
4.3(q,CH2);6.8-7.6(m,ArH);8.3(S,PyH);
9.3(d,NH).实施例2
4,5-二氢-4,5-二氧代-1H-[1]-苯并吡喃并[3,4-b]吡啶-3-羧酸乙酯
该化合物是按照实施例1中公开的方法,以二乙基-{[(2-氧代-4H-[1]-苯并吡喃酮-3-基)氨基]亚甲基}丙二酸酯(3.96g;0.012mol)为原料制备的。反应周期:13小时。得到4,5-二氢-4,5-二氧代-1H-[1]-苯并吡喃并[3,4-b]吡啶-3-羧酸乙酯(1.90g;56%)。
分析:C11H15NO5的计算值: C63.16;H3.89;N4.91
实验值 C62.98;H3.92;N5.071H-NMR(TFA)δ/ppm:1.2(t,CH3);4.3(q,CH2);
7.3-8.0(m,ArH);8.4(S,PyH);11.3(S,NH).实施例3
按照实例1中公开的方法,以四乙基-{[(2-氧代-2H-[1]-苯并吡喃酮-3,6-二基)二氨基]二亚乙基}丙二酸酯(2.00g;3.872mmol)为原料制备该化合物。反应周期:50分钟。将得到的棕色的1,5,8-三氢-1,5,8-三氧代-4,11H-[1]-苯并吡喃并[3,4-b][7,6-c]二吡啶-2,9-二羧酸二乙酯用无水乙醇重结晶(1.43g,87%).熔点:175-177℃。
分析:C21H16N2O5的计算值 C59.43;H3.80;N6.60
实验值 C59.72;H3.89;N6.891H-NMR(DMSO-d6)δ/ppm:1.3(2t,2CH3);
4.2(2q,2CH2);7-10(m,CH,ArH,PyH);
10.6和12.3(2d,2NH).实施例4
按照实例1公开的方法,以二乙基-{[(2-氧代-2H-[1]-苯并吡喃酮-3-基)氨基]亚甲基}丙二酸酯(3.10g,9.357mmol)为原料制备该化合物。反应周期:45分钟。将得到的棕黄色沉淀4,7-二氢-4,7-二氧代-1H-[1]-苯并吡喃并[6,7-b]吡啶-3-羧酸乙酯用N,N-二甲基甲酰胺重结晶(2.23g;84%)。熔点>300℃。
分析:C15H11NO5的计算值 C63.16;H3.89;N4.91
实验值 C63.05;H3.92;N4.881H-NMR(DMSO-d6)δ/ppm:1.3(t,CH3);4.2(q.CH2);
6.5(d,H8),7.4-8.0(m,ArH,PyH);8.4(d,H9);
10.7(d,NH).m/z:284(M-),258,256,239,212,183,127,79实施例5
4,7-二氢-4,7-二氧代-3-羟基-1H-[1]-苯并吡喃并[6,7-b]吡啶-3-羧酸乙酯
按照实例1公开的方法,以二乙基-{[(3-羟基-2-氧代-2H-[1]-苯并吡喃酮-6-基)氨基]亚甲基}丙二酸酯(3.63g 0.011mol)为原料制备该化合物。反应周期:15分钟。得到一淡棕黄色沉淀4,7-二氢-4,7-二氧代-3-羟基-1H-[1]-苯并吡喃并[6,7-b]吡啶-3-羧酸乙酯(3.63g;95%)。熔点>300℃。
分析:C15H11NO6的计算值 C59.80;H3.68;N4.65
实验值 C59.66;H3.61;N4.27
1H-NMR(DMSD-d6)δ/ppm: 1.3(t,CH3);
4.2(q,CH2);7.2-9.3(m,ArH,PyH);10.7(s,OH);
12.4(s,NH).
m/z:300(M-),273,272,255,227,178,136,91,68,54.实施例6
按照实施例1公开的方法,以二乙基-{[(4-甲基-2-氧代-2H-[1]-苯并吡喃酮-7-基)氨基]亚甲基}丙二酸酯(5.70g;0.017mol)为原料制备该化合物。反应周期:10分钟。得到一棕灰色沉淀1,7-二氢-1,7-二氧代-9-甲基-4H-[1]苯并吡喃并[6,7-b]吡啶-2-羧酸乙酯(3.43g;69%),熔点>300℃。
分析:C16H13NO5的计算值 C64.21;H4.38;N4.68
实验值 C64.36;H4.14;N4.50
1H-NMR(DMSO-d6)δ/ppm: 1.3(S,CH3);2.1(t,CH3);
4.1(q,CH2);6.2(d,H8);7.4(d,H5);7.7(t,H10);
10.3(S,PyH);12.4(bs,NH)实施例7
4,7-二氢-4,7-二氧代-9-(三氟甲基)-1H-[1]-苯并吡喃并[6,7-b]-吡啶-2-羧酸乙酯
按照实施例1公开的方法,以二乙基-{[(4-(三氟甲基)-2-氧代-2H-[1]-苯并吡喃酮-7-基)氨基]亚甲基}丙二酸酯(2.00g;0.005mol)为原料制备该化合物。反应周期:15分钟。得到一淡黄色酯的沉淀(1.67g;94%),M.P.>300℃。
分析:C16H10F3NO5的计算值 C54.40;H2.85;N3.97
实验值 C54.41;H2.97;N3.86
1H-NMR(DMSO-d6)δ/ppm:1.3(t,CH3);4.2(q,CH2);7.0(d,H8);7.4(S,H5);7.9(d,H10);8.5(d,PyH);12.4(bs,NH).实施例8
按照实例1公开的方法,以二乙基-{[(3-羟基-2-氧代-2H-[1]-苯并吡喃酮-8-基)氨基]亚甲基}丙二酸酯(3.15g;9.070mol)为原料制备该化合物。反应周期:40分钟。得到棕橙色的1,6-二氢-1,6-二氧代-7-羟基-4H-[1]-苯并吡喃并[7,8-b]吡啶-2-羧酸乙酯(2.35g;86%),熔点>300℃。
分析:C15H11NO6的计算值 C59.80;H3.68;N4.65
实验值 C59.45;H3.29;N4.28
1H-NMR(DMSO-d6)δ/ppm:1.3(t,CH3);4.2(q,CH2);7.1-8.3(m,ArH,PyH);10.4(S,OH);11.8(S,NH)m/z:302(M+),171,155,141.实施例9
向1,5-二氢-1,5-二氧代-4H-[1]-苯并吡喃并[3,4-b]吡啶-2-羧酸乙酯(0.81g;2,840mmol)溶于冷却至0-5℃的浓H2SO4(3.73g;0.038mol)溶液中,滴加入硝酸(d=1.4;1.01g;0.016mol)和浓H2SO4(1.96g;0.020mol)的混合物并同时搅拌。反应混合物达到室温后再搅拌10分钟,然后将其倒入冰水混合物中。得到的1,5-二氢-1,5-二氧代-9-硝基-4H-[1]-苯并吡喃并[3,4-b]吡啶-2-羧酸乙酯用乙醇重结晶(0.89g;95%).熔点:246-247℃。
分析:C15H10N2O7的计算值 C54.55;H3.05;N8.48
实验值 C54.50;H2.87;N8.65
1H-NMR(TFA)δ/ppm: 1.2(t,CH3);4.3(q,CH2);
7.4(d,H7);8.3(d,H8);9.1(S,H10);9.6(S,PyH);11.3(S,NH).
m/z:329(M-),313,301,284,269,257,256,241,228,151.实施例10
向1,5-二氢-1,5-二氧代-9-硝基-4H-[1]-苯并吡喃并[3,4-b]-吡啶-2-羧酸乙酯(0.50g;1.514mmol)溶于冰醋酸(150ml)的溶液中,加入一种催化剂(4.92%Pd/c;0.15g),在3巴的H2气流下还原6小时。反应完成后,过滤反应混合物,再蒸去乙酸。得到的胺(0.59g;100%)用冰醋酸重结晶,熔点:270-272℃。
分析:C15H22N2O5×C2H4O2的计算值 C58.18;H4.28;N8.48
实测值 C57.94;H4.14;N8.24
1H-NMR(TFA)δ/ppm:1.3(t,CH3);4.4(q,CH2);
7.4-7.8(m,ArH);9.2(m,PyH);11.3(S,NH).实施例11
1,5-二氢-1,5-二氧代-7-氟-4H-[1]-苯并吡喃并[3,4-b]吡啶-2-羧酸
把1,5-二氢-1,5-二氧代-7-氟-4H-[1]-苯并吡喃并[3,4-b]-吡啶-2-羧酸乙酯(1.70g;5.606mmol)溶于10%NaOH(22ml)的溶液,在沸点温度下加热90分钟,然后将它和活性炭煮沸5分钟。滤液中的酸用10%的盐酸水溶液沉淀(达到PH2-3),冷却后的溶液在+4℃下静置几小时,得到的淡黄色酸沉淀(1.50g;97%)用乙酸乙酯/乙醇的混合物(1∶1)或用N,N-二甲基甲酰胺重结晶,熔点大于300℃。
分析:C13H6FNO5的计算值 C56.74;H2.20;N5.09
实测值 C56.52;H1.84;N5.11
1H-NMR(TFA)δ/ppm: 7.3-7.4(m,3ArH);8.7(m,PyH);
9.2(S,NH);11.3(S,COOH).实施例12
把4,5-二氢-4,5-二氧代-4H-[1]-苯并吡喃并[4,3-b]吡啶-3-羧酸乙酯(1.90g;6.661mmol)溶于1M NaOH(50ml)的溶液,在沸点温度下加热90分钟,然后与活性炭煮沸片刻,过滤,滤液用10%的盐酸水溶液酸化(达到PH2-3),酸就沉淀出来(1.54g;95%),熔点大于300℃。
分析:C13H7NO5的计算值 C60.70;H2.74;N5.45
实测值 C60.37;H2.43;N5.51
1H-NMR(DMSO-d6)δ/ppm; 7.5(d,H7);7.8(t,H9);
8.4(d,H10);8.7(m,H8,PyH);9.2(S,NH);11.3(S,COOH).
m/z:256(M-1),240,239,223,212,211,183,120,82.实施例13
按照实施例12中公开的方法,以1,5,8-三氢-1,5,8-三氧代-4,11H-[1]-苯并吡喃并[3,4-b][7,6-c]二吡啶-2,9-二羧酸二乙酯(0.90g;121mmol)为原料制备该化合物。反应周期:45分钟。得到的酸为棕黄色(0.45g;58%),熔点大于300℃。
分析:C17H8N2O8的计算值 C55.44;H2.19;N7.61
实测值 C55.22;H2.58;N7.50
1H-NMR(DMSO-d6)δ/ppm:7.1-9.5(m,ArH,PyH);
12.3(d,2NH);14.8(S,COOH);15.4(S,COOH).
m/z:368(M+),341,264,256,213,198,188,156,137,129,91,81,69.实施例14
4,7-二氢-4,7-二氧代-1H-[1]-苯并吡喃并[6,7-b]吡啶-3-羧酸
该化合物是按照实例11中公开的方法,以4,7-二氢-4,7-二氧代-1H-[1]-苯并吡喃并[6,7-b]吡啶-3-羧酸乙酯(1.10g;3.856mmol)为原料制备的。反应周期:3小时。得到淡黄色的该羧酸的沉淀(0.84g;85%),熔点大于300℃。
分析:C13H7NO5的计算值 C60.70;H2.74;N5.45
实测值 C60.37;H2.80;N5.76
m/z:258(M+),254,249,213,151,138,125,109,98,74,62.实施例15
4,7-二氢-4,7-二氧代-8-羟基-1H-[1]-苯并吡喃并[6,7-b]吡啶-3-羧酸
该化合物按照实例12中公开的方法,以4,7-二氢-4,7-二氧代-8-羟基-1H-[1]-苯并吡喃并[6,7-b]吡啶-3-羧酸乙酯(2.83g;9.394mmol)为原料来制备。反应周期:3小时。得到黄色的该酸的沉淀(2.13g;83%),熔点大于300℃。
1H-NMR(DMSO-d6)δ/ppm:7.6-8.7(m,ArH);
9.4(S,PyH);13.4(S,NH);15.2(S,COOH):
m/z:273(M+),256,239,229,181,125,114,95,73.实施例16
1,7-二氢-1,7-二氧代-9-甲基-4H-[1]-苯并吡喃并[6,7-b]吡啶-2-羧酸
该化合物是按照实例11公开的方法,以1,7-二氢-1,7-二氧代-9-甲基-4H-[1]-苯并吡喃并[6,7-b]吡啶-2-羧酸乙酯(3.40g;0.011mol)为原料制备的。反应周期:20分钟。得到的灰白色沉淀用N,N-二甲基甲酰胺重结晶(2.32g;75%)。
分析:C14H9NO5×C3H7NO C59.30;H4.68;N8.14
实测值 C59.50;H4.61;N7.81
1H-NMR(DMSO-d6)δ/ppm: 1.9(S,CH3);6.3(S,H8);
7.6(d,H5);8.0(S,H10);9.0(S,PyH);13.2(bs,NH);14.9(S,COOH).实施例17
1,7-二氢-1,7-二氧代-9-(三氟甲基)-4H-[1]-苯并吡喃并[6,7-b]吡啶-2-羧酸
按照实例12公开的方法,以1,7-二氢-1,7-二氧代-9-(三氟甲基)-4H-[1]-苯并吡喃并[6,7-b]吡啶-2-羧酸乙酯(1.40g;3.963mmol)为原料制备该化合物。反应周期:2小时。得到的酸用N,N-二甲基甲酰胺/乙醇混合物重结晶(1.28g;99%),熔点大于300℃。
分析:C14H6F3NO5的计算值 C51.70;H1.86;N4.31
实测值 C51.48;H1.82;N4.27
1H-NMR(DMSO-d6)δ/ppm:7.2(S,H8);7.8(S,H5);
8.6(S,H10);9.0(S,PyH);13.4(bs,NH);14.5(bs,COOH).实施例18
按照实例13公开的方法,以1,5-二氢-1,5-二氧代-7-羟基-4H-[1]-苯并吡喃并[7,8-b]吡啶-2-羧酸乙酯(2.12g;7.037mmol)为原料制备该化合物。反应周期:3小时。得到棕绿色的酸(1.27g;66%);熔点大于300℃。
1H-NMR(DMSO-d6)δ/ppm:
7.1-7.8(m,ArH,PyH);8.6(S,OH);10.6(S,NH);15.2(S,COOH).
m/z:237(M+),212,179,81,79,61,59,45,43.
Claims (21)
R1R2=-NHCH=C(CO2R6)CO-,R3=NO2或NH2,R4=R5=H,R6=H或C2H5;
R1R2=-NHCH=C(CO2R6)CO-,R3=R4=H,R5=F,R6=H或C2H5;
R1R2=-CO(CO2R6)C=CHNH-,R3=R4=R5=H,R6=H或C2H5;
R1R2=R3R4=-NHCH=C(CO2R6)CO-,R5=H,R6=H或C2H5;
R1=H或OH,R2=R5=H,R3R4=-NHCH=C(CO2R6)CO-,R6=H或C2H5;
R1=OH,R2=R3=H,R4=R5=-CO(CO2R6)C=CHNH-,R6=H或C2H5;
R1=R5=H,R2=CH3或CF3,R3R4=-CO(CO2R6)C=CHNH-,R6=H或C2H5,及其药理上可接受的盐。
2、按照权利要求1的通式I的化合物,其特征在于R1R2=-NHCH=C(CO2C2H5)CO-,R3=R4=H,R5=F。
3、按照权利要求1的通式I的化合物,其特征在于R1R2=-CO(CO2C2H5)C=CHNH,R3=R4=R5=H。
4、按照权利要求1的通式I的化合物,其特征在于R1R2=R3R4=-NHCH=C(CO2C2H5)CO-,R5=H。
5、按照权利要求1的通式I的化合物,其特征在于R1=H,R2=R5=H,R3R4=-NHCH=C(CO2C2H5)CO-。
6、按照权利要求1的通式I的化合物,其特征在于R1=OH,R2=R5=H,R3R4=-NHCH=C(CO2C2H5)CO-。
7、按照权利要求1的通式I的化合物,其特征在于R1=R5=H,R2=CH3,R3R4=-CO(CO2C2H5)C=CHNH-。
8、按照权利要求1的通式I的化合物,其特征在于R1=R3=R5=H,R2=CF3,R4=-NHCH=C(CO2C2H5)。
9、按照权利要求1的通式I的化合物,其特征在于R1=OH,R2=R3=H,R4R5=-CO(CO2C2H5)C=CHNH-。
10、按照权利要求1的通式I的化合物,其特征在于R1R2=-NHCH=C(CO2C2H5)CO-,R3=NO2,R4=R5=H。
11、按照权利要求1的通式I的化合物,其特征在于R1R2=-NHCH=C(CO2C2H5)CO-,R3=NH2,R4=R5=H。
12、按照权利要求1的通式I的化合物,其特征在于R1R2=-NHCH=C(CO2H)CO-,R3=R4=H,R5=F。
13、按照权利要求1的通式I的化合物,其特征在于R1R2=-CO(CO2H)C=CHNH-,R3=R4=R5=H。
14、按照权利要求1的通式I的化合物,其特征在于R1R2=R3=R4=-NHCH=C(CO2H)CO-,R5=H。
15、按照权利要求1的通式I的化合物,其特征在于R1=H,R2=R5=H,R3R4=-NHCH=C(CO2H)CO-。
16、按照权利要求1的通式I的化合物,其特征在于R1=OH,R2=R5=H,R3R4=-NHCH=C(CO2H)CO-。
17、按照权利要求1的通式I的化合物,其特征在于R1=R5=H,R2=CH3,R3R4=-CO(CO2H)C=CHNH-。
18、按照权利要求1的通式I的化合物,其特征在于R1=R3=R5=H,R2=CF3,R4=-NHCH=C(CO2H)2。
19、按照权利要求1的通式I的化合物,其特征在于R1=OH,R2=R3=H,R4R5=-CO(CO2H)C=CHNH-。
R1=-NHCH=C(CO2C2H5)2,R2=R4=H,R3=NO2,R5=H或F;
R1=R3=-NHCH=C(CO2C2H5)2,R2=R4=R5=H;
R1=H或OH,R3=-NHCH=C(CO2C2H5)2,R2=R4=R5=H;
R1=OH,R2=R3=R4=H,R5=-NHCH=C(CO2C2H5)2;
R1=R3=R5=H,R2=CH3或CF3,R4=-NHCH=C(CO2C2H5)2,在杜氏热载体A中于250-260℃加热10分钟-13小时,得到式III的环化的香豆素喹诺酮酯其中
R1R2=-NHCH=C(CO2C2H5)CO-,R3=R4=H,R5=F;
R1R2=-NHCH=C(CO2C2H5)CO-,R3=NO2,R4=R5=H;
R1R2=-CO(CO2C2H5)C=CHNH-,R3=R4=R5=H;
R1R2=R3R4=-NHCH=C(CO2C2H5)CO-,R5=H;
R1=H或OH,R2=R5=H,R3R4=-NHCH=C(CO2C2H5)CO-;
R1=OH,R2=R3=H,R4R5=-CO(CO2C2H5)C=CHNH-;
R1=R5=H,R2=CH3或CF3,R3R4=-CO(CO2C2H5)C=CHNH-;该化合物为其中R6=C2H5的式I化合物,
为了得到通式I的化合物,其中R1R2=-NH-CH=C(CO2C2H5)CO-,R3=NH2;R4=R5=H,将通式III的化合物,其中R1R2=-NHCH=C(CO2C2H5)CO-,R3=NO2,R4=R5=H还原,
为了得到通式I的化合物,其中R1,R2,R3,R4和R5的含意如权利要求1中定义且R6=H,将其中R6=C2H5的通式III的化合物水解。
21、式I的化合物用作生物活性剂如抗微生物、抗肿瘤和抗病毒药剂。
Applications Claiming Priority (2)
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HR960352A HRP960352A2 (en) | 1996-07-26 | 1996-07-26 | Novel coumarin quinoline carboxylic acids |
HRP960352A | 1996-07-26 |
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CN1176252A true CN1176252A (zh) | 1998-03-18 |
CN1075500C CN1075500C (zh) | 2001-11-28 |
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CN97117456A Expired - Fee Related CN1075500C (zh) | 1996-07-26 | 1997-07-25 | 香豆素喹诺酮羧酸及其制备方法和用途 |
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US (1) | US5908933A (zh) |
EP (1) | EP0820998B1 (zh) |
JP (1) | JPH1087668A (zh) |
CN (1) | CN1075500C (zh) |
AT (1) | ATE205211T1 (zh) |
BG (1) | BG63085B1 (zh) |
CA (1) | CA2210448A1 (zh) |
CZ (1) | CZ238297A3 (zh) |
DE (1) | DE69706487T2 (zh) |
ES (1) | ES2163694T3 (zh) |
HR (1) | HRP960352A2 (zh) |
HU (1) | HUP9701298A3 (zh) |
PL (1) | PL321308A1 (zh) |
PT (1) | PT820998E (zh) |
RU (1) | RU2166504C2 (zh) |
SI (1) | SI9700197B (zh) |
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CN105218531A (zh) * | 2015-10-14 | 2016-01-06 | 西南大学 | 香豆素喹诺酮杂合体或其可药用盐及其制备方法和应用 |
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HRP960308A2 (en) * | 1996-07-02 | 1998-08-31 | Ljerka Poljak | New coumarine derivatives, process for the preparation thereof and their use |
PL349348A1 (en) * | 1999-01-13 | 2002-07-15 | Millennium Pharmaceuticals | Functionalized heterocycles as chemokine receptor modulators |
DE60203029T2 (de) * | 2001-06-28 | 2006-02-23 | Dainippon Ink And Chemicals, Inc. | Benzopyran Derivate und diese enthaltende antiallergische Mittel |
FR2827864B1 (fr) * | 2001-07-25 | 2005-09-16 | Servier Lab | Nouveaux derives de benzo[b]pyrano[3,2-h]acridin-7-one, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US8058427B2 (en) * | 2008-06-12 | 2011-11-15 | National Health Research Institutes | Coumarin compounds and their use for treating cancer |
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US4060619A (en) * | 1976-01-14 | 1977-11-29 | Ayerst Mckenna And Harrison Ltd. | 1,4-Dihydro-4-oxo-benzothiopyrano (4,3-b)pyridine-2-carboxylates and derivatives |
US4198511A (en) * | 1979-03-21 | 1980-04-15 | Warner-Lambert Company | 1,5-Dihydro-1,5-dioxo-N-1H-tetrazol-5-yl-4H-[1]benzopyrano[3,4-b]pyridine-3-carboxamides and process thereof |
US4210758A (en) * | 1979-03-21 | 1980-07-01 | Warner-Lambert Company | 1,5-Dihydro-1,5-dioxo-N-1H-tetrazol-5-yl-4H-[1]benzopyrano[3,4-b]pyridine-2-carboxamides |
GB9306062D0 (en) * | 1993-03-24 | 1993-05-12 | Lilly Industries Ltd | Pharmaceutical compounds |
US5688810A (en) * | 1994-12-22 | 1997-11-18 | Ligand Pharmaceuticals Incorporated | Steroid receptor modulator compounds and methods |
-
1996
- 1996-07-26 HR HR960352A patent/HRP960352A2/hr not_active Application Discontinuation
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1997
- 1997-07-18 US US08/897,057 patent/US5908933A/en not_active Expired - Fee Related
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- 1997-07-24 PT PT97112743T patent/PT820998E/pt unknown
- 1997-07-24 EP EP97112743A patent/EP0820998B1/en not_active Expired - Lifetime
- 1997-07-24 SK SK1016-97A patent/SK101697A3/sk unknown
- 1997-07-24 AT AT97112743T patent/ATE205211T1/de not_active IP Right Cessation
- 1997-07-24 JP JP9198505A patent/JPH1087668A/ja active Pending
- 1997-07-24 ES ES97112743T patent/ES2163694T3/es not_active Expired - Lifetime
- 1997-07-24 PL PL97321308A patent/PL321308A1/xx unknown
- 1997-07-24 DE DE69706487T patent/DE69706487T2/de not_active Expired - Fee Related
- 1997-07-24 CA CA002210448A patent/CA2210448A1/en not_active Abandoned
- 1997-07-25 HU HU9701298A patent/HUP9701298A3/hu unknown
- 1997-07-25 RU RU97113254/04A patent/RU2166504C2/ru active
- 1997-07-25 UA UA97073970A patent/UA45383C2/uk unknown
- 1997-07-25 BG BG101796A patent/BG63085B1/bg unknown
- 1997-07-25 CN CN97117456A patent/CN1075500C/zh not_active Expired - Fee Related
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Cited By (2)
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CN105218531A (zh) * | 2015-10-14 | 2016-01-06 | 西南大学 | 香豆素喹诺酮杂合体或其可药用盐及其制备方法和应用 |
CN105218531B (zh) * | 2015-10-14 | 2018-03-16 | 西南大学 | 香豆素喹诺酮杂合体或其可药用盐及其制备方法和应用 |
Also Published As
Publication number | Publication date |
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SI9700197A (sl) | 1998-02-28 |
RU2166504C2 (ru) | 2001-05-10 |
SI9700197B (sl) | 2002-02-28 |
PT820998E (pt) | 2002-02-28 |
HUP9701298A2 (hu) | 1999-06-28 |
CZ238297A3 (cs) | 1998-03-18 |
JPH1087668A (ja) | 1998-04-07 |
UA45383C2 (uk) | 2002-04-15 |
HRP960352A2 (en) | 1998-08-31 |
HUP9701298A3 (en) | 1999-07-28 |
CN1075500C (zh) | 2001-11-28 |
EP0820998A3 (en) | 1998-04-29 |
ES2163694T3 (es) | 2002-02-01 |
ATE205211T1 (de) | 2001-09-15 |
EP0820998A2 (en) | 1998-01-28 |
EP0820998B1 (en) | 2001-09-05 |
BG63085B1 (bg) | 2001-03-30 |
CA2210448A1 (en) | 1998-01-26 |
US5908933A (en) | 1999-06-01 |
HU9701298D0 (en) | 1997-09-29 |
DE69706487D1 (de) | 2001-10-11 |
SK101697A3 (en) | 1998-05-06 |
BG101796A (en) | 1998-10-30 |
PL321308A1 (en) | 1998-02-02 |
DE69706487T2 (de) | 2002-05-08 |
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