CN1091103C - Compounds of carbostyrils and their preparation and use - Google Patents
Compounds of carbostyrils and their preparation and use Download PDFInfo
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- CN1091103C CN1091103C CN99113598A CN99113598A CN1091103C CN 1091103 C CN1091103 C CN 1091103C CN 99113598 A CN99113598 A CN 99113598A CN 99113598 A CN99113598 A CN 99113598A CN 1091103 C CN1091103 C CN 1091103C
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- cyclopropyl
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- piperazine
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- -1 quinolone compound Chemical class 0.000 claims description 52
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一类喹诺酮类化合化物具有抗支原体活性，可用于抗支原体感染。A class of quinolone compounds has anti-mycoplasma activity and can be used for anti-mycoplasma infection.
Description
本发明涉及一类喹诺酮类化合物的合成及其生物活性，具体地说是一类喹诺酮类化合物的制备方法及其作为抗支原药物的用途，The present invention relates to the synthesis of a class of quinolone compounds and their biological activity, specifically the preparation method of a class of quinolone compounds and their use as anti-mycoplasma drugs,
支原体和细菌及病毒一样，是一种常见的致病微生物。支原体污染常给人体健康、动植物及细胞生物学研究造成巨大危害[唐树人抗支原体抗生素的研究进展.国外医药-抗生素分册，1985，6：351]。人体常见的有八种支原体，其中肺炎支原体能引起原发性非典型性肺炎，这一顽固的呼吸道疾病对人体健康危害极大。支原体感染还会引起非淋球菌性尿道炎，类风湿性关节炎以及某些不孕症、流产及新生儿低体重等疾病。支原体还能引起牲畜、家禽及实验动物多种病害。细胞培养中的支原体污染是一个极普遍的世界性问题，特别是传代细胞培养[郭永军.细胞培养中支原体污染的除去。国外医药-微生物学分册，1989，4：166]。据报道1992年欧洲各实验室细胞系被检出的阳性率为55％。1993年首都儿科研究所应用培养法检测了国内77个传代细胞样品，支原体污染率为49％。这种污染不但影响细胞的生长和代谢，有时还能影响细胞的功能，严重影响细胞生物学的研究工作。进入90年代后，在支原体分离，培养，检测方面取得了飞速发展，这使得人们对支原体危害的严重性有了更深的认识，加之近年来支原体污染有上升的趋势[Kobayashi H et al.J Vet Med Sci 1996，11：1107]，所以国内外都十分重视支原体感染的防治研究。控制支原体感染通常使用大环内酯类抗生素如红霉素(EM)、交沙霉素(JM)、柱晶白霉素(LM)等，四环素(TC)和强力霉素也常用，其中红霉素是控制各种支原体污染的首选药物。然而象细菌感染一样，支原体对红霉素等抗生素已产生了严重的耐药性，这已成为支原体治疗面临的最棘手问题，所以开发新型抗支原体药物十分必要且有重要意义。喹诺酮类药物是细菌拓扑异构酶II特异性抑制剂，研究发现某些新一代喹诺酮药物如司帕沙星(Sparfloxacin)，超威沙星(trovafloxacin)等具有良好的抗支原体活性。Mycoplasma, like bacteria and viruses, is a common pathogenic microorganism. Mycoplasma pollution often causes great harm to human health, animal and plant and cell biology research [Research progress of Tang Shuren's anti-mycoplasma antibiotics. Foreign Medicine-Antibiotics Volume, 1985, 6: 351]. There are eight kinds of mycoplasma commonly found in the human body, among which mycoplasma pneumoniae can cause primary atypical pneumonia, which is a stubborn respiratory disease that is extremely harmful to human health. Mycoplasma infection can also cause non-gonococcal urethritis, rheumatoid arthritis, and some diseases such as infertility, miscarriage, and low birth weight of newborns. Mycoplasma can also cause various diseases of livestock, poultry and experimental animals. Mycoplasma contamination in cell culture is a very common worldwide problem, especially in subcultured cell culture [Guo Yongjun. Removal of mycoplasma contamination in cell culture. Foreign Medicine-Microbiology Volume, 1989, 4:166]. According to reports, in 1992, the positive rate of cell lines detected in European laboratories was 55%. In 1993, the Capital Institute of Pediatrics tested 77 subcultured cell samples in China with the culture method, and the mycoplasma contamination rate was 49%. This kind of pollution not only affects the growth and metabolism of cells, but also sometimes affects the function of cells, seriously affecting the research work of cell biology. After entering the 1990s, the separation, cultivation and detection of mycoplasma have achieved rapid development, which has enabled people to have a deeper understanding of the severity of mycoplasma damage, and in recent years, mycoplasma pollution has an upward trend [Kobayashi H et al.J Vet Med Sci 1996, 11: 1107], so both at home and abroad attach great importance to the research on the prevention and treatment of mycoplasma infection. To control mycoplasma infection, macrolide antibiotics such as erythromycin (EM), josamycin (JM), leucomycin (LM) etc. are usually used. Tetracycline (TC) and doxycycline are also commonly used, among which erythromycin Mycomycin is the drug of choice to control various mycoplasma contamination. However, like bacterial infection, mycoplasma has developed severe resistance to antibiotics such as erythromycin, which has become the most difficult problem facing mycoplasma treatment, so it is necessary and significant to develop new anti-mycoplasma drugs. Quinolones are specific inhibitors of bacterial topoisomerase II. Studies have found that some new-generation quinolones, such as Sparfloxacin and trovafloxacin, have good anti-mycoplasma activity.
所以本发明的一个目的是寻找一系列具有抗支原体活性的喹诺酮化合物。另一个目的是研究它们抗支原体活性，以发现效果更好的抗支原体药物。本发明的一类喹诺酮化合物可用下列通式表示：其中It is therefore an object of the present invention to find a series of quinolone compounds with anti-mycoplasma activity. Another purpose is to study their anti-mycoplasma activity to find better anti-mycoplasma drugs. A class of quinolone compounds of the present invention can be represented by the following general formula: in
R1＝CH2CH3，环丙基等C1-C5的烷基或环烷基R 1 ＝CH 2 CH 3 , C 1 -C 5 alkyl or cycloalkyl such as cyclopropyl
R5＝H，NH2R8＝H，F
化合物1分别与1～8倍摩尔量的1-位氮原子是杂环取代的哌嗪衍生物在吡啶，二甲基甲酰胺，二甲基亚砜或任何一种适当的非质子极性溶剂中于室温到180℃温度范围内反应4～12小时，最佳条件为化合物1与哌嗪衍生物的摩尔比是1∶2～4，吡啶中回流6小时。减压蒸去溶剂，用氯仿、甲醇、乙醇、二甲基甲酰胺等或它们之间任意比例的混合物为溶剂重结晶，得哌嗪环含杂环取代的上述化合物6～11。
与制备化合物6～11反应条件相同，化合物2与1-位氮原子是杂环取代的哌嗪衍生物反应得12～16。
化合物1～5在吡啶，二甲基甲酰胺，二甲基亚砜等非质子极性溶剂中分别和哌嗪，2-甲基哌嗪，高哌嗪等哌嗪衍生物缩合得7-位被哌嗪衍生物所取代的喹诺酮化合物17；Compounds 1-5 are condensed with piperazine derivatives such as piperazine, 2-methylpiperazine and homopiperazine respectively in pyridine, dimethylformamide, dimethyl sulfoxide and other aprotic polar solvents to obtain the 7-position Quinolones compound 17 substituted by piperazine derivatives;
化合物17在碱性水溶液如碳酸氢钠，碳酸钠，氢氧化钾，氢氧化钠等其它任何无机碱水溶液或四氢呋喃、氯仿、二氯甲烷、乙酸乙酯、乙醚等极性非质子有机溶剂(含有机碱如三乙胺等作除酸剂)中，与直链或支链烷基氯甲酸酯在零下10℃到80℃反应1～24小时，酸化，过滤沉淀或减压蒸去有机溶剂，沉淀或残留物用乙酸乙酯，乙醇，甲醇，水及它们之间任意比例的混合溶剂重结晶，可得7-位含氨基甲酸酯取代的上述化合物18～35。
其中in
R1＝CH2CH3，环丙基等C1 C5的烷基或环烷基R 1 ＝CH 2 CH 3 , C 1 C 5 alkyl or cycloalkyl such as cyclopropyl
R5＝H，NH2 R 5 =H, NH 2
R8＝H，F R8 = H, F
R3＝CH3，CH2CH3，CH2CHMe2，CH2CCl3等C1 C5的支链或直链烷烃R 3 ＝CH 3 , CH 2 CH 3 , CH 2 CHMe 2 , CH 2 CCl 3 and other C 1 C 5 branched or linear alkanes
R4＝H，CH3等C1 C5的支链或直链烷烃R 4 ＝H, CH 3 and other C 1 C 5 branched or linear alkanes
n＝1，2本发明涉及的化合物结构式见表1。其中
抗支原体活性测定采用常规方法。培养基组成如下：1∶1牛心消化液，0.5％氯化钠，0.15％磷酸二氢钾，10％自制新鲜酵母浸出液，0.002酚红，10％小牛血清。UU4添加0.1％尿素，pH＝6.0±0.5。Mh、Mo、Ms添加0.1％精氨酸，pH＝6.8～7.0。Mg、Mp添加1％的葡萄糖血清增到15％，pH＝7.6～7.8。螺原体添加10％蔗糖，pH＝7.2～7.4。最低抑制支原体药物浓度MIC(μg/ml)采用连续倍数稀释法测定。MIC测定值见表2。表2化合物6～16，18～36及其它对照药物的抗支原体活性(MIC：μg/ml)Anti-mycoplasma activity was determined using conventional methods. The composition of the culture medium is as follows: 1:1 bovine heart digestate, 0.5% sodium chloride, 0.15% potassium dihydrogen phosphate, 10% self-made fresh yeast extract, 0.002 phenol red, and 10% calf serum. U U4 add 0.1% urea, pH=6.0±0.5. Add 0.1% arginine to Mh, Mo, Ms, pH=6.8～7.0. Mg and Mp were increased to 15% by adding 1% glucose serum, pH=7.6～7.8. Add 10% sucrose to spiroplasma, pH=7.2～7.4. The minimum drug concentration MIC (μg/ml) for inhibiting mycoplasma was determined by serial multiple dilution method. The measured values of MIC are shown in Table 2. The antimycoplasma activity (MIC: μ g/ml) of compound 6～16 of table 2, 18～36 and other control drugs
支 原 体*样品号 Uu4 Uu8 Mh Ms Mg Mgal CH-1 CR-16 0.25 0.25 0.125 0.125 1 0.031 0.5 0.57 2 0.5 2 2 ＞8 0.5 4 48 0.25 0.062 0.062 0.062 0.25 0.031 0.125 0.1259 8 4 2 2 8 1 4 810 0.25 0.125 0.062 0.062 0.5 ＜0.004 0.125 0.2511 2 0.5 1 0.5 4 0.125 1 212 0.25 0125 ＜0.004 0.031 2 0.031 1 0.513 8 8 1 1 8 0.125 4 814 0.5 0.5 4 0.062 4 0.031 0.5 0.2515 0.25 0.125 0.062 0.031 1 0.062 0.5 0.516 0.5 0.125 0.008 0.002 4 0.008 1 118 0.5 0.5 0.25 0.125 0.5 0.016 0.25 0.12519 2 0.5 1 1 8 0.25 2 220 0.5 0.25 0.125 0.25 0.5 0.031 0.125 0.12521 0.5 0.25 0.062 0.125 1 0.031 0.25 0.2522 0.5 0.5 0.25 0.25 1 0.061 0.25 0.2523 0.5 0.125 0.125 0.125 0.25 0.031 0.125 0.12524 2 1 1 1 2 0.25 1 125 0.25 0.25 0.016 0.016 1 ＜0.004 0.25 0.2526 4 1 0.125 0.125 4 0.008 2 127 0.25 0.062 0.016 0.031 2 0.031 0.25 0.528 0.5 0.25 0.008 0.25 2 ＜0.004 0.05 0.2529 2 0.5 4 2 4 0.125 1 130 4 1 ＞8 2 4 0.25 1 131 0.5 0.5 2 1 2 0.125 0.5 0.532 1 1 0.5 0.25 2 0.002 0.5 0.533 2 2 1 0.25 4 0.125 1 134 1 1 0.25 0.25 2 0.031 0.5 0.535 4 4 4 2 8 0.25 2 2CPLX 8 4 2 1 2 0.032 0.125 0.25LEVO 0.5 0.5 0.5 0.25 0.5 0.016 0.125 0.125SPLX 0.25 0.25 0.031 0.031 0.062 ＜0.004 0.062 0.125JM 0.125 0.125 0.125 0.25 0.004 ＜0.004 0.125 0.062LM 0.25 0.125 0.25 0.25 0.04 0.04 0.125 0.125Uu4，Uu8-解脲脲原体；Mh-人型支原体：Ms-唾液支原体；Mg-生殖支原体：Mgal-鸡毒支原体；CH-1-蜜蜂螺原体；CR-1-油菜花螺原体。 CPLX-环丙沙星；LEVO-左旋氧氟沙星；SPLX-司帕沙星；JM-交沙霉素；LM-柱晶白霉素。从表2可知，本专利所涉及的喹诺酮化合物有很强的抗支原体活性，特别是化合物8、10、18、20、23、25等，其活性比环丙沙星及左旋氧氟沙星强，和司帕沙星、交沙霉素及柱晶霉素相当。对于Uu及Mh许多化合物表现出比司帕沙星、交沙霉素及柱晶霉素更强的抗支原体活性。本专利所涉及的喹诺酮化合物可用于人体、动物、植物及细胞培养中支原体感染或污染的治疗及清除。The original body * sample number UU 4 UU 8 MH MS Mg Mgal CH-1 CR-16 0.25 0.25 0.125 0.031 0.5 0.57 2 0.5 2 2> 8 0.5 48 0.25 0.062 0.25 0.031 0.1259 8 4 2 8 1 4 810 0.25 0.125 0.062 0.062 0.5 ＜0.004 0.125 0.2511 2 0.5 1 0.5 4 0.125 1 212 0.25 0125 ＜0.004 0.031 2 0.031 1 0.513 8 8 1 1 8 0.125 4 814 0.5 0.5 4 0.062 4 0.031 0.5 0.2515 0.25 0.125 0.062 0.031 1 0.062 0.5 0.516 0.5 0.125 0.008 0.002 4 0.008 1 118 0.5 0.5 0.25 0.125 0.5 0.016 0.25 0.12519 2 0.5 1 1 8 0.25 2 220 0.5 0.25 0.125 0.25 0.5 0.031 0.125 0.12521 0.5 0.25 0.062 0.125 1 0.031 0.25 0.2522 0.5 0.5 0.25 0.25 1 0.061 0.25 0.2523 0.5 0.125 0.125 0.125 0.25 0.031 0.125 0.12524 2 1 1 1 2 0.25 1 125 0.25 0.25 0.016 0.016 1 ＜0.004 0.25 0.2526 4 1 0.125 0.125 4 0.008 2 127 0.25 0.062 0.016 0.031 2 0.031 0.25 0.528 0.5 0.25 0.008 0.25 2 ＜0.004 0.05 0.2529 2 0.5 4 2 4 0.125 1 130 4 1 ＞ 8 2 4 0.25 1 131 0.5 0.5 2 1 2 0.5 0.532 1 0.5 0.25 2 0.002 0.5 0.533 2 1 0.25 4 0.125 1 0.25 0.031 0.5 0.535 4 4 4 4 4 4 4 2 8 0.25 2 2CPLX 8 4 2 1 2 0.032 0.125 0.25LEVO 0.5 0.5 0.5 0.25 0.5 0.016 0.125 0.125SPLX 0.25 0.25 0.031 0.031 0.062 ＜0.004 0.062 0.125JM 0.125 0.125 0.125 0.25 0.004 ＜0.004 0.125 0.062LM 0.25 0.125 0.25 0.25 0.04 0.04 0.125 0.125Uu 4 , Uu 8 - Ureaplasma urealyticum; Mh-Mycoplasma hominis: Ms-Mycoplasma salivarius; Mg-Mycoplasma genitalium: Mgal-Mycoplasma gallisepticum; Spiroplasma. CPLX-ciprofloxacin; LEVO-levofloxacin; SPLX-sparfloxacin; JM-josamycin; LM-leucomycin. As can be seen from Table 2, the quinolone compounds involved in this patent have strong anti-mycoplasma activity, especially compounds 8, 10, 18, 20, 23, 25, etc., which are more active than ciprofloxacin and levofloxacin , comparable to sparfloxacin, josamycin and column crystal mycin. For Uu and Mh, many compounds showed stronger anti-mycoplasma activity than sparfloxacin, josamycin and cylindromycin. The quinolone compound involved in this patent can be used for the treatment and elimination of mycoplasma infection or pollution in human body, animal, plant and cell culture.
下面进一步用实施例说明本发明，它并不限制本发明。Further illustrate the present invention with embodiment below, it does not limit the present invention.
核磁共振谱在Bruker AM-400上测定，质谱在MAT-95型质谱仪上进行。元素分析由中科院上海有机化学研究所分析室完成。熔点仪型号为BUeHI 510型，温度计未经校正。柱层析用硅胶，未加说明均为200-300目，青岛海洋化工厂生产。NMR spectra were determined on a Bruker AM-400, and mass spectrometry was performed on a MAT-95 mass spectrometer. Elemental analysis was done by the analysis room of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. The model of the melting point apparatus is BUeHI 510, and the thermometer is not calibrated. Silica gel for column chromatography, 200-300 mesh unless otherwise specified, is produced by Qingdao Ocean Chemical Factory.
最佳实施例实验1 1-环丙基-6，8-二氟-1，4-二氢-7-(4-(2-吡啶基)-1-哌嗪基)-4-氧代喹啉-3-羧酸(6)4(140mg，0.495mmol)和1-(2-吡啶基)哌嗪(170mg，1.04mmol)溶解于吡啶(10ml)中，在80～100℃反应4小时。减压蒸去溶剂，残留物用1摩尔浓度的氢氧化钠水溶液(10ml)溶解，加入氯仿(10ml)产生沉淀，过滤，干燥后用乙醇-二甲基甲酰胺重结晶，得淡黄色固体140mg(66％)。mp243～244℃。MS(EI，m/z)[426+]。1HNMR(CF3COOD)δ：1.45(2H，m，环丙基CH2)，1.65(2H，m，环丙基CH2)，4.00(4H，m，2×NCH2)，4.15(4H，m，2×CH2N)，4.55(1H，m，环丙基CH)，7.15(1H，m，吡啶环C3-H)，7.35(1H，m，吡啶环C5-H)，8.05(1H，m，C5-H)，8.25(2H，m，吡啶环C4-H，C6-H)，9.35(1H，s，C2-H).实验2 1-环丙基-6，8-二氟-1，4-二氢-7-(4-(2-嘧啶基)-1-哌嗪)-4-氧代喹啉-3-羧酸(7)实验操作同实验1。产率67％。mp273～274℃。MS(EI，m/z)[427+]。1HNMR(CF3COOD)δ：1.75(2H，m，环丙基CH2)，1.90(2H，m，环丙基CH2)，4.25(4H，m，2×NCH2)，4.55(4H，m，2×CH2N)，4.85(1H，m，环丙基CH)，7.45(1H，m，C5-H)，8.50(1H，m，嘧啶环C5-H)，9.00(2H，m，嘧啶环C4-H，C6-H)，9.65(1H，s，C2-H).实验3 1-环丙基-6，8-二氟-1，4-二氢-7-(4-(2-吡嗪基)-1-哌嗪基)-4-氧代喹啉-3-羧酸(8)4(100mg，0.353mmol)和1-(2-吡嗪基)哌嗪(121mg，0.737mmol)溶解于吡啶(10ml)中，在80℃反应4小时。减压蒸去溶剂，残留物用1摩尔浓度的氢氧化钠水溶液(10ml)溶解，水相用氯仿洗涤(2×10ml)，加入2摩尔的盐酸酸化到PH＝3～4，过滤生产的沉淀，沉淀依次用水、乙醇洗涤，干燥，二甲基甲酰胺-乙醇重结晶得橘黄色固体100mg(47％)。mp236～238℃。MS(EI，m/z)[427+]。1HNMR(CF3COOD)δ：1.35(2H，m，环丙基CH2)，1.55(2H，m，环丙基CH2)，3.80(4H，m，2×NCH2)，4.05(4H，m，2×CH2N)，4.45(1H，m，环丙基CH)，7.85(1H，s，吡嗪环C3-H)，8.10(1H，m，C5-H)，8.45(1H，m，吡嗪环C5-H)，8.65(1H，m，吡嗪环C6-H)，9.30(1H，s，C2-H).实验4 1-环丙基-6，8-二氟-1，4-二氢-7-(4-(2-(5-三氟甲基吡啶基)-1-哌嗪基)-4-氧代喹啉-3-羧酸(9)操作同实验1。产率67％。mp 247～249℃。MS(EI，m/z)[494+]。1HNMR(CF3COOD)δ：1.90(2H，m，环丙基CH2)，2.05(2H，m，环丙基CH2)，4.45(4H，m，2×NCH2)，4.60(4H，m，2×CH2N)，5.00(1H，m，环丙基CH)，7.95(1H，m，C5-H)，8.60(2H，m，吡啶环C3-H，C4-H)，8.70(1H，s，吡啶环C6-H)，9.80(1H，s，C2-H).实验5 1-环丙基-6，8-二氟-1，4-二氢-7-(4-(2-噻唑基)-1-哌嗪基)-4-氧代喹啉-3-羧酸(10)实验操作同实验1。产率33％。mp261～262℃。MS(EI，m/z)[432+]。1HNMR(CF3COOD)δ：1.40(2H，m，环丙基CH2)，1.55(2H，m，环丙基CH2)，3.85(4H，m，2×NCH2)，3.95(4H，m，2×CH2N)，4.45(1H，m，环丙基CH)，6.90(1H，m，噻唑环C4-H)，7.25(1H，m，噻唑环C5-H)，8.15(1H，m，C5-H)，9.30(1H，s，C2-H).实验6 1-环丙基-6，8-二氟-1，4-二氢-7-(4-(4-(7-氯代喹咛基))-1-哌嗪)-4-氧代喹啉-3-羧酸(11)实验操作同实验3。产率56％。mp＞275℃。MS(EI，m/z)[510+]。1HNMR(CF3COOD)δ：1.45(2H，m，环丙基CH2)，1.55(2H，m，环丙基CH2)，4.00(4H，m，2×NCH2)，4.25(4H，m，2×CH2N)，4.50(1H，m，环丙基CH)，7.15(1H，m，喹咛环C3-H)，7.60(1H，m，喹咛环C5-H)，7.95(1H，s，喹咛环C8-H)，8.15(2H，m，喹咛环C5-H，C6-H)，8.40(1H，m，喹咛环C2-H)，9.30(1H，s，C2-H).实验7 1-环丙基-5-氨基-6，8-二氟-1，4-二氢-7-(4-(2-吡啶基)-1-哌嗪基)-4-氧代喹啉-3-羧酸(12)5(100mg，0.336mmol)和1-(2-吡啶基)哌嗪(215mg，1.32mmol)溶解于吡啶(10ml)中，在100℃反应5小时。减压蒸去溶剂，残留物用1摩尔浓度的氢氧化钠水溶液(10ml)溶解，过滤，滤液用盐酸酸化到pH＝3，过滤生产的沉淀，沉淀依次用水、乙醇洗涤，干燥，二甲基甲酰胺-乙醇重结晶得淡黄色固体100mg(67％)。mp250～251℃。MS(EI，m/z)[441+]。1HNMR(CF3COOD)δ：1.25(2H，m，环丙基CH2)，1.45(2H，m，环丙基CH2)，3.75(4H，m，2×NCH2)，3.95(4H，m，2×CH2N)，4.25(1H，m，环丙基CH)，7.00(1H，m，吡啶环C5-H)，7.30(1H，m，吡啶环C3-H)，7.85(1H，m，吡啶环C4-H)，8.05(1H，m，吡啶环C2-H)，9.10(1H，s，C2-H).实验8 1-环丙基-5-氨基-6，8-二氟-1，4-二氢7-(4-(2-(5-三氟甲基吡啶基))-1-哌嗪基)-4-氧代喹啉-3-羧酸(13)5(78mg，0.261mmol)和1-(2-三氟甲基吡啶基)哌嗪(230mg，1.00mmol)溶解于吡啶(10ml)中，在100℃反应5小时。减压蒸去溶剂，残留物用1摩尔浓度的氢氧化钠水溶液(10ml)溶解，放置析出油状物，分出油状物，加水(10ml)，用盐酸酸化到pH＝3，过滤生产的沉淀，沉淀依次用水、乙醇洗涤，干燥，得淡黄色固体40mg(30％)。mp263～264℃。MS(EI，m/z)[509+]。1HNMR(CF3COOD)δ：1.30(2H，m，环丙基CH2)，1.50(2H，m，环丙基CH2)，3.85(4H，m，2×NCH2)，4.10(4H，m，2×CH2N)，4.30(1H，m，环丙基CH)，7.45(1H，m，吡啶环C3-H)，8.15(1H，m，吡啶环C4-H)，8.25(1H，s，吡啶环C2-H)，9.10(1H，s，C2-H).实验9 1-环丙基-5-氨基-6，8-二氟-1，4-二氢-7-(4-(2-嘧啶基)-1-哌嗪)-4-氧代喹啉-3-羧酸(14)操作同实验8。产率54％。mp274～275℃。MS(EI，m/z)[442+]。1HNMR(CF3COOD)δ：1.20(2H，m，环丙基CH2)，1.40(2H，m，环丙基CH2)，3.75(4H，m，2×NCH2)，4.15(4H，m，2×CH2N)，4.30(1H，m，环丙基CH)，7.00(1H，m，嘧啶环C5-H)，8.60(2H，m，嘧啶环C4-H，C6-H)，9.10(1H，s，C2-H).实验10 1-环丙基-5-氨基-6，8-二氟-1，4-二氢-7-(4-(2-吡嗪基)-1-哌嗪基)-4-氧代喹啉-3-羧酸(15)操作同实验7。收率47％。mp293～294℃。MS(EI，m/z)[442+]。1HNMR(CF3COOD)δ：1.25(2H，m，环丙基CH2)，1.45(2H，m，环丙基CH2)，3.70(4H，m，2×NCH2)，4.00(4H，m，2×CH2N)，4.25(1H，m，环丙基CH)，7.85(1H，s，吡嗪环C3-H)，8.40(1H，m，吡嗪环C5-H)，8.60(1H，m，吡嗪环C6-H)，9.10(1H，s，C2-H).实验11 1-环丙基-5-氨基-6，8-二氟-1，4-二氢-7-(4-(2-噻唑基)-1-哌嗪基)-4-氧代喹啉-3-羧酸(16)操作同实验7。产率56％。mp267～268℃。MS(EI，m/z)[448+]。1HNMR(CF3COOD)δ：1.25(2H，m，环丙基CH2)，1.40(2H，m，环丙基CH2)，4.80(4H，m，2×NCH2)，3.90(4H，m，2×CH2N)，4.25(1H，m，环丙基CH)，6.90(1H，m，噻唑环C4-H)，7.20(1H，m，噻唑环C5-H)，9.10(1H，s，C2-H).实验12 1-环丙基-6，8-二氟-1，4-二氢-7-(4-乙氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(18)17a(R1＝环丙基，R4＝R5＝H，R8＝F，n＝1)(40mg，0，115mmol)溶解在0.1摩尔的氢氧化钠水溶液(4ml)中，冷却到0℃，加入氯甲酸乙酯(24mg，0.221mmol)。0℃反应30分钟，室温反应1小时。2摩尔浓度的盐酸酸化到pH＝3～4，氯仿(3×10ml)萃取。合并氯仿溶液，依次用水、饱和食盐水洗一次，干燥。减压蒸去氯仿，残留物二氯甲烷-甲醇重结晶得30mg白色固体(63％)。mp228～229℃。MS(EI，m/z)[421+]。1HNMR(CDCl3)δ：1.30(3H，t，J＝7Hz，CH3)，1.65(4H，m，环丙基CH2CH2)，3.35(4H，m，2×NCH2)，3.65(4H，m，2×CH2N)，4.00(1H，m，环丙基CH)，4.20(2H，m，J＝7Hz，OCH2)，7.95(1H，m，C5-H)，8.80(1H，s，C2-H).实验13 1-环丙基-6，8-二氟-1，4-二氢-7-(2-甲基-4-乙氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(19)17b(R1＝环丙基，R5＝H，R4＝CH3，R8＝F，n＝1)(50mg，0.138mmol)，氯甲酸乙酯(30mg，0.271mmol)。操作同实验12。产率83％。mp225～227℃。MS(EI，m/z)[435+]。1HNMR(CDCl3)δ：1.25(3H，t，J＝7Hz，乙基CH3)，1.35(3H，t，J＝7Hz，哌嗪环CH3)，1.65(4H，m，环丙基CH2CH2)，3.35(7H，m，2×CH2N，NCH2，NCH)，3.95(1H，m，环丙基CH)，4.15(2H，m，J＝6Hz，OCH2)，7.95(1H，m，C5-H)，8.80(1H，s，C2-H).实验14 1-环丙基-6，8-二氟-1，4-二氢-7-(4-乙氧羰基-1-高哌嗪基)-4-氧代喹啉-3-羧酸(20)17c(R1＝环丙基，，R4＝R5＝H，R8＝F，n＝2)(50mg，0.138mmol)，氯甲酸乙酯(30mg，0.271mmol)。操作同实验12。产率75％。mp176～177℃。MS(EI，m/z)[435+]。1HNMR(CDCl3)δ：1.25(3H，t，J＝7Hz，乙基CH3)，1.65(4H，m，环丙基CH2CH2)，2.05(2H，m，高哌嗪环CH2)，3.60(8H，m，2×CH2N，2×NCH2)，4.00(1H，m，环丙基CH)，4.15(2H，m，J＝7Hz，OCH2)，7.95(1H，m，C5-H)，8.80(1H，s，C2-H).实验15 1-环丙基-6，8-二氟-1，4-二氢-7-(4-异丁氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(21)17a(40mg，0,115mmol)，氯甲酸异丁酯(30mg，0.220mmol)。操作同实验12。产率90％。mp215～217℃。MS(EI，m/z)[449+]。1HNMR(CDCl3)δ：0.95(6H，d，J＝7Hz，2×CH3)，1.25(2H，m，环丙基CH2)，1.30(2H，m，环丙基CH2)，2.00(1H，m，异丁基CH)，3.35(4H，m，2×NCH2)，3.65(4H，m，2×CH2N)，3.90(2H，d，J＝6Hz，OCH2)，4.00(1H，m，环丙基CH)，7.90(1H，m，C5-H)，8.80(1H，s，C2-H).实验16 1-环丙基-6，8-二氟-1，4-二氢-7-(2-甲基-4-甲氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(22)17b(50mg，0.138mmol)，氯甲酸乙酯(26mg，0.276mmol)。操作同实验12。产率78％。mp229～230℃。MS(EI，m/z)[421+]。1HNMR(CDCl3)δ：1.15(2H，m，环丙基CH2)，1.30(2H，m，环丙基CH2)，1.38(3H，t，J＝7Hz，哌嗪环CH3)，3.35(7H，m，2×CH2N，NCH2，NCH)，3.75(3H，s，OCH3)，4.00(1H，m，环丙基CH)，7.90(1H，m，C5-H)，8.80(1H，s，C2-H).实验17 1-环丙基-6，8-二氟-1，4-二氢-7-(4-甲氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(23)17a(40mg，0,115mmol)，氯甲酸乙酯(26mg，0.276mmol)。操作同实验12。产率75％。mp204～205℃。MS(EI，m/z)[407+]。1HNMR(CDCl3)δ：1.15(2H，m，环丙基CH2)，1.30(2H，m，环丙基CH2)，3.35(4H，m，2×NCH2)，3.65(4H，m，2×CH2N)，3.75(3H，s，OCH3)，4.00(1H，m，环丙基CH)，7.90(1H，m，C5-H)，8.75(1H，s，C2-H)。实验18 1-环丙基-6，8-二氟-1，4-二氢-7(4-4-异丁氧羰基-1-高哌嗪基)-4-氧代喹啉-3-羧酸(24)17c(50mg，0.138mmol)，氯甲酸异丁酯(37mg，0.270mmol)。操作同实验12。产率63％。mp176～177℃。MS(EI，m/z)[463+]。1HNMR(CDCl3)δ：0.95(6H，d，J＝7Hz，2×CH3)，1.15(2H，m，环丙基CH2)，1.30(2H，m，环丙基CH2)，2.00(3H，m，异丁基CH，高哌嗪环CH2)，3.60(8H，m，2×NCH2，2×CH2N)，3.85(2H，d，J＝7Hz，OCH2)，4.00(1H，m，环丙基CH)，7.90(1H，m，C5-H)，8.75(1H，s，C2-H).实验19 1-环丙基-5-氨基-6，8-二氟-1，4-二氢-7-(4-乙氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(25)17d(R1＝环丙基，R4＝H，R5＝NH2，R8＝F，n＝1)(50mg，0,137mmol)，氯甲酸乙酯(30mg，0.270mmol)。操作同实验12。产率75％。mp283～284℃。MS(EI，m/z)[436+]。1HNMR(CDCl3)δ：1.05(2H，m，环丙基CH2)，1.20(2H，m，环丙基CH2)，1.30(3H，t，J＝7Hz，CH3)，3.30(4H，m，2×NCH2)，3.60(4H，m，2×CH2N)，3.90(1H，m，环丙基CH)，4.20(2H，m，J＝7Hz，OCH2)，8.65(1H，s，C2-H)。实验20 1-环丙基-5-氨基-6，8-二氟-1，4-二氢-7-(4-异丁氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(26)17d(40mg，0,115mmol)，氯甲酸异丁酯(37mg，0.270mmol)。操作同实验12。产率70％。mp257～258℃。MS(EI，m/z)[464+]。1HNMR(CDCl3)δ：0.95(6H，d，J＝7Hz，2×CH3)，1.05(2H，m，环丙基CH2)，1.25(2H，m，环丙基CH2)，2.00(1H，m，异丁基CH)，3.35(4H，m，2×NCH2)，3.65(4H，m，2×CH2N)，3.95(2H，d，J＝6Hz，OCH2)，4.10(1H，m，环丙基CH)，8.65(1H，s，C2-H).实验21 1-环丙基-5-氨基-6，8-二氟-1，4-二氢-7-(4-甲氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(27)17d(40mg，0,115mmol)，氯甲酸甲酯(26mg，0.276mmol)。操作同实验12。产率69％。mp277～278℃。MS(EI，m/z)[422+]。1HNMR(CDCl3)1.05(2H，m，环丙基CH2)，1.25(2H，m，环丙基CH2)，3.35(4H，m，2×NCH2)，3.55(4H，m，2×CH2N)，3.75(3H，s，OCH3)，3.95(1H，m，环丙基CH)，8.75(1H，s，C2-H).实验22 1-环丙基-5-氨基-6，8-二氟-1，4-二氢-7-(4-乙氧羰基-1-高哌嗪基)-4-氧代喹啉-3-羧酸(28)17e(R1＝环丙基，，R4＝H，R5＝NH2，R8＝F，n＝2)(50mg，0.137mmol)，氯甲酸乙酯(30mg，0.271mmol)。操作同实验12。产率60％。mp216～217℃。MS(EI，m/z)[450+]。1HNMR(CDCl3)δ：1.05(2H，m，环丙基CH2)，1.20(2H，m，环丙基CH2)，1.28(3H，t，J＝7Hz，乙基CH3)，2.00(2H，m，高哌嗪环CH2)，3.45(4H，m，2×CH2N)，3.65(4H，m，2×CH2N)，3.90(1H，m，环丙基CH)，4.15(2H，m，J＝7Hz，OCH2)，8.50(1H，s，C2-H).实验23 1-乙基-6，8-二氟-1，4-二氢-7-(4-乙氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(29)17f(R1＝乙基，，R4＝R5＝H，R8＝F，n＝1)(70mg，0.208mmol)，氯甲酸乙酯(40mg，0.380mmol)。操作同实验12。产率53％。mp248～249℃。MS(EI，m/z)[410+]。1HNMR(CDCl3)δ：1.30(3H，t，J＝7Hz，氧乙基CH3)，1.30(3H，t，J＝6Hz，氮乙基CH3)，3.40(4H，m，2×NCH2)，3.70(4H，m，2×CH2N)，4.20(2H，m，J＝7Hz，OCH2)，4.50(2H，m，J＝7Hz，NCH2)，8.00(1H，m，C5-H)，8.60(1H，s，C2-H).实验24 1-乙基-6，8-二氟-1，4-二氢-7-(4-异丁氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(30)17f(70mg，0.208mmol)，氯甲酸异丁酯(52mg，0.380mmol)。操作同实验12。产率55％。mp261～262℃。MS(EI，m/z)[438+]。1HNMR(CDCl3)δ：0.95(6H，d，J＝7Hz，2×CH3)，1.55(3H，t，J＝7Hz，氮乙基CH3)，1.95(1H，m，异丁基CH)，3.35(4H，m，2×NCH2)，3.75(4H，m，2×CH2N)，3.90(2H，d，J＝6Hz，OCH2)，4.45(2H，m，J＝7Hz，NCH2)，4.65(4H，m，2×CH2N)，8.00(1H，m，C5-H)，8.60(1H，s，C2-H)。实验25 1-乙基-6，8-二氟-1，4-二氢-7-(4-甲氧羰基-1-哌嗪基)-4-氧代喹啉-3-羧酸(31)17f(70mg，0.208mmol)，氯甲酸甲酯(40mg，0.417mmol)。操作同实验12。产率49％。mp242～243℃。MS(EI，m/z)[396+]。1HNMR(CDCl3)δ：1.65(3H，t，J＝6Hz，氮乙基CH3)，3.35(4H，m，2×NCH2)，3.50(4H，m，2×CH2N)，3.55(3H，s，OCH3)，4.45(2H，m，J＝4Hz，NCH2)，8.00(1H，m，C5-H)，8.60(1H，s，C2-H).实验25 1-环丙基-6-氟-7-(4-乙氧羰基-1-哌嗪基)-1，4-二氢-4-氧代喹啉-3-羧酸(32)17g(R1＝环丙基，，R4＝R5＝R8＝H，n＝1)(70mg，0.211mmol)，氯甲酸乙酯(40mg，0.368mmol)。操作同实验12。产率59％。mp＞295℃。MS(EI，m/z)[403+]。1HNMR(CDCl3)δ：1.20(2H，m，环丙基CH2)，1.30(3H，t，J＝7Hz，CH3)，1.40(2H，m，环丙基CH2)，3.30(4H，m，2×NCH2)，3.50(1H，m，环丙基CH)，3.70(4H，m，2×CH2N)，4.20(2H，d，J＝7Hz，OCH2)，7.35(H，d，J＝7H，C8-H)，8.05(1H，d，J＝7Hz，C5-H)，8.75(1H，s，C2-H)。实验27 1-环丙基-6-氟-7-(4-异丁氧羰基-1-哌嗪基)-1，4-二氢-4-氧代喹啉-3-羧酸(33)17g(70mg，0.211mmol)，氯甲酸异丁酯(50mg，0.367mmol)。操作同实验12。产率55％。mp 286～287℃。MS(EI，m/z)[431+]。1HNMR(CDCl3)δ：0.95(6H，d，J＝7Hz，2×CH3)，1.20(2H，m，环丙基CH2)，1.40(2H，m，环丙基CH2)，1.95(1H，m，异丁基CH)，3.30(4H，m，2×NCH2)，3.50(1H，m，环丙基CH)，3.70(4H，m，2×CH2N)，4.90(2H，d，J＝6Hz，OCH2)，7.35(H，d，J＝7Hz，C8-H)，8.05(1H，d，J＝7Hz，C5-H)，8.75(1H，s，C2-H)。实验28 1-环丙基-6-氟-7-(4-甲氧羰基-1-哌嗪基)-1，4-二氢-4-氧代喹啉-3-羧酸(34)17g(70mg，0.211mmol)，氯甲酸甲酯(40mg，0.432mmol)。操作同实验12。产率61％。mp 282～283℃。MS(EI，m/z)[389+]。1HNMR(CDCl3)δ：1.20(2H，m，环丙基CH2)，1.40(2H，m，环丙基CH2)，3.30(4H，m，2×NCH2)，3.50(1H，m，环丙基CH)，3.70(4H，m，2×CH2N)，3.75(3H，s，OCH3)，7.40(H，d，J＝7Hz，C8-H)，8.05(1H，d，J＝7H，C5-H)，8.75(1H，s，C2-H)。实验31 1-乙基-6-氟-7-(4-乙氧羰基-1-哌嗪基)-1，4-二氢-4-氧代喹啉-3-羧酸(35)17h(R1＝乙基，，R4＝R5＝R8＝H，n＝1)(70mg，0.219mmol)，氯甲酸乙酯(40mg，0.368mmol)。操作同实验12。产率59％。mp＞295℃。MS(EI，m/z)[391+]。1HNMR(CDCl3)δ：1.30(3H，t，J＝6Hz，氧乙基CH3)，1.65(3H，t，J＝6Hz，氮乙基CH3)，3.25(4H，m，2×NCH2)，3.50(4H，m，2×CH2N)，4.15(2H，m，J＝4Hz，NCH2)，3.70(4H，m，2×CH2N)，4.90(2H，d，J＝7Hz，OCH2)，6.85(H，d，J＝7Hz，C8-H)，8.10(1H，d，J＝7Hz，C5-H)，8.65(1H，s，C2-H)。Best Example Experiment 1 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-(2-pyridyl)-1-piperazinyl)-4-oxoquine Phenyl-3-carboxylic acid (6)4 (140mg, 0.495mmol) and 1-(2-pyridyl)piperazine (170mg, 1.04mmol) were dissolved in pyridine (10ml) and reacted at 80-100°C for 4 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in 1 molar sodium hydroxide aqueous solution (10ml), and chloroform (10ml) was added to produce a precipitate, which was filtered, dried, and recrystallized with ethanol-dimethylformamide to obtain 140mg of a light yellow solid (66%). mp243～244℃. MS (EI, m/z) [ 426+ ]. 1 HNMR (CF 3 COOD) δ: 1.45 (2H, m, cyclopropyl CH 2 ), 1.65 (2H, m, cyclopropyl CH 2 ), 4.00 (4H, m, 2×NCH 2 ), 4.15 (4H , m, 2×CH 2 N), 4.55 (1H, m, cyclopropyl CH), 7.15 (1H, m, pyridine ring C 3 -H), 7.35 (1H, m, pyridine ring C 5 -H), 8.05 (1H, m, C 5 -H), 8.25 (2H, m, pyridine ring C 4 -H, C 6 -H), 9.35 (1H, s, C 2 -H). Experiment 2 1-cyclopropyl -6,8-difluoro-1,4-dihydro-7-(4-(2-pyrimidinyl)-1-piperazine)-4-oxoquinoline-3-carboxylic acid (7) experimental operation is the same Experiment 1. Yield 67%. mp273～274℃. MS (EI, m/z) [ 427+ ]. 1 HNMR (CF 3 COOD) δ: 1.75 (2H, m, cyclopropyl CH 2 ), 1.90 (2H, m, cyclopropyl CH 2 ), 4.25 (4H, m, 2×NCH 2 ), 4.55 (4H , m, 2×CH 2 N), 4.85 (1H, m, cyclopropyl CH), 7.45 (1H, m, C 5 -H), 8.50 (1H, m, pyrimidine ring C 5 -H), 9.00 ( 2H, m, pyrimidine ring (C 4 -H, C 6 -H), 9.65 (1H, s, C 2 -H). Experiment 3 1-cyclopropyl-6,8-difluoro-1,4-dihydro -7-(4-(2-pyrazinyl)-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (8) 4 (100mg, 0.353mmol) and 1-(2-pyrazine Base) piperazine (121mg, 0.737mmol) was dissolved in pyridine (10ml) and reacted at 80°C for 4 hours. Evaporate the solvent under reduced pressure, dissolve the residue with 1 molar sodium hydroxide aqueous solution (10ml), wash the aqueous phase with chloroform (2×10ml), add 2 molar hydrochloric acid to acidify to PH=3～4, and filter the produced precipitate , the precipitate was washed with water and ethanol in turn, dried, and recrystallized from dimethylformamide-ethanol to obtain 100 mg (47%) of an orange solid. mp236～238℃. MS (EI, m/z) [ 427+ ]. 1 HNMR (CF 3 COOD) δ: 1.35 (2H, m, cyclopropyl CH 2 ), 1.55 (2H, m, cyclopropyl CH 2 ), 3.80 (4H, m, 2×NCH 2 ), 4.05 (4H , m, 2×CH 2 N), 4.45 (1H, m, cyclopropyl CH), 7.85 (1H, s, pyrazine ring C 3 -H), 8.10 (1H, m, C 5 -H), 8.45 (1H, m, pyrazine ring C 5 -H), 8.65 (1H, m, pyrazine ring C 6 -H), 9.30 (1H, s, C 2 -H). Experiment 4 1-cyclopropyl-6 , 8-difluoro-1,4-dihydro-7-(4-(2-(5-trifluoromethylpyridyl)-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (9) The operation is the same as experiment 1. The yield is 67 % . CH 2 ), 2.05 (2H, m, cyclopropyl CH 2 ), 4.45 (4H, m, 2×NCH 2 ), 4.60 (4H, m, 2×CH 2 N), 5.00 (1H, m, cyclopropyl CH), 7.95 (1H, m, C 5 -H), 8.60 (2H, m, pyridine ring C 3 -H, C 4 -H), 8.70 (1H, s, pyridine ring C 6 -H), 9.80 (1H, s, C 2 -H). Experiment 5 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-(2-thiazolyl)-1-piperazinyl )-4-oxoquinoline-3-carboxylic acid (10) was performed the same as experiment 1. The yield was 33%. mp261～262°C. MS (EI, m/z) [432 + ]. 1 HNMR (CF 3 COOD) δ: 1.40 (2H, m, cyclopropyl CH 2 ), 1.55 (2H, m, cyclopropyl CH 2 ), 3.85 (4H, m, 2×NCH 2 ), 3.95 (4H, m, 2× CH 2 N), 4.45 (1H, m, cyclopropyl CH), 6.90 (1H, m, thiazole ring C 4 -H), 7.25 (1H, m, thiazole ring C 5 -H), 8.15 (1H, m , C 5 -H), 9.30 (1H, s, C 2 -H). Experiment 6 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-(4-( 7-Chloroquinoline))-1-piperazine)-4-oxoquinoline-3-carboxylic acid (11) experimental operation is the same as experiment 3. Yield 56%. mp>275 ° C. MS (EI, m/z) [510 + ] .1 HNMR (CF 3 COOD) δ: 1.45 (2H, m, cyclopropyl CH 2 ), 1.55 (2H, m, cyclopropyl CH 2 ), 4.00 (4H, m, 2×NCH 2 ), 4.25 (4H, m, 2×CH 2 N), 4.50 (1H, m, cyclopropyl CH), 7.15 (1H, m, quinotropic ring C 3 -H), 7.60 (1H, m, quinoquinone C 5 -H), 7.95 (1H, s, quinoquinone C 8 -H), 8.15 (2H, m, quinoquinone C 5 -H, C 6 -H), 8.40 (1H, m, quinoquinone (C 2 -H), 9.30 (1H, s, C 2 -H). Experiment 7 1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-7 -(4-(2-pyridyl)-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (12)5 (100mg, 0.336mmol) and 1-(2-pyridyl)piperazine (215mg, 1.32mmol) was dissolved in pyridine (10ml) and reacted at 100°C for 5 hours. The solvent was evaporated under reduced pressure, the residue was dissolved with 1 molar aqueous sodium hydroxide solution (10ml), filtered, the filtrate was acidified with hydrochloric acid to pH=3, the precipitate produced was filtered, washed with water and ethanol in turn, dried, and dimethyl Recrystallization from formamide-ethanol gave 100 mg (67%) of a pale yellow solid. mp250～251℃. MS (EI, m/z) [ 441+ ]. 1 HNMR (CF 3 COOD) δ: 1.25 (2H, m, cyclopropyl CH 2 ), 1.45 (2H, m, cyclopropyl CH 2 ), 3.75 (4H, m, 2×NCH 2 ), 3.95 (4H , m, 2×CH 2 N), 4.25 (1H, m, cyclopropyl CH), 7.00 (1H, m, pyridine ring C 5 -H), 7.30 (1H, m, pyridine ring C 3 -H), 7.85 (1H, m, pyridine ring C 4 -H), 8.05 (1H, m, pyridine ring C 2 -H), 9.10 (1H, s, C 2 -H). Experiment 8 1-cyclopropyl-5- Amino-6,8-difluoro-1,4-dihydro 7-(4-(2-(5-trifluoromethylpyridyl))-1-piperazinyl)-4-oxoquinoline-3 -Carboxylic acid (13)5 (78mg, 0.261mmol) and 1-(2-trifluoromethylpyridyl)piperazine (230mg, 1.00mmol) were dissolved in pyridine (10ml) and reacted at 100°C for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved with 1 molar aqueous sodium hydroxide solution (10ml), and the oily substance was separated out on standing, and the oily substance was separated, added water (10ml), acidified to pH=3 with hydrochloric acid, and the produced precipitate was filtered. The precipitate was washed with water and ethanol successively, and dried to obtain 40 mg (30%) of a pale yellow solid. mp263～264℃. MS (EI, m/z) [ 509+ ]. 1 HNMR (CF 3 COOD) δ: 1.30 (2H, m, cyclopropyl CH 2 ), 1.50 (2H, m, cyclopropyl CH 2 ), 3.85 (4H, m, 2×NCH 2 ), 4.10 (4H , m, 2×CH 2 N), 4.30 (1H, m, cyclopropyl CH), 7.45 (1H, m, pyridine ring C 3 -H), 8.15 (1H, m, pyridine ring C 4 -H), 8.25 (1H, s, pyridine ring C 2 -H), 9.10 (1H, s, C 2 -H). Experiment 9 1-cyclopropyl-5-amino-6,8-difluoro-1,4-di Hydrogen-7-(4-(2-pyrimidinyl)-1-piperazine)-4-oxoquinoline-3-carboxylic acid (14) was the same as Experiment 8. Yield 54%. mp274～275℃. MS (EI, m/z) [ 442+ ]. 1 HNMR (CF 3 COOD) δ: 1.20 (2H, m, cyclopropyl CH 2 ), 1.40 (2H, m, cyclopropyl CH 2 ), 3.75 (4H, m, 2×NCH 2 ), 4.15 (4H , m, 2×CH 2 N), 4.30 (1H, m, cyclopropyl CH), 7.00 (1H, m, pyrimidine ring C 5 -H), 8.60 (2H, m, pyrimidine ring C 4 -H, C 6 -H), 9.10(1H, s, C 2 -H). Experiment 10 1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-7-(4-(2 -Pyrazinyl)-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (15) The operation is the same as Experiment 7. Yield 47%. mp293～294℃. MS (EI, m/z) [ 442+ ]. 1 HNMR (CF 3 COOD) δ: 1.25 (2H, m, cyclopropyl CH 2 ), 1.45 (2H, m, cyclopropyl CH 2 ), 3.70 (4H, m, 2×NCH 2 ), 4.00 (4H , m, 2×CH 2 N), 4.25 (1H, m, cyclopropyl CH), 7.85 (1H, s, pyrazine ring C 3 -H), 8.40 (1H, m, pyrazine ring C 5 -H ), 8.60 (1H, m, pyrazine ring C 6 -H), 9.10 (1H, s, C 2 -H). Experiment 11 1-cyclopropyl-5-amino-6,8-difluoro-1, 4-Dihydro-7-(4-(2-thiazolyl)-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (16) was operated in the same way as Experiment 7. Yield 56%. mp267～268℃. MS (EI, m/z) [ 448+ ]. 1 HNMR (CF 3 COOD) δ: 1.25 (2H, m, cyclopropyl CH 2 ), 1.40 (2H, m, cyclopropyl CH 2 ), 4.80 (4H, m, 2×NCH 2 ), 3.90 (4H , m, 2×CH 2 N), 4.25 (1H, m, cyclopropyl CH), 6.90 (1H, m, thiazole ring C 4 -H), 7.20 (1H, m, thiazole ring C 5 -H), 9.10(1H, s, C 2 -H). Experiment 12 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-ethoxycarbonyl-1-piperazinyl)- 4-Oxoquinoline-3-carboxylic acid (18) 17a (R 1 = cyclopropyl, R 4 = R 5 = H, R 8 = F, n = 1) (40 mg, 0, 115 mmol) was dissolved in 0.1 Molar sodium hydroxide aqueous solution (4ml), cooled to 0°C, added ethyl chloroformate (24mg, 0.221mmol). React at 0°C for 30 minutes and at room temperature for 1 hour. It was acidified with 2 molar hydrochloric acid to pH=3-4, and extracted with chloroform (3×10ml). The chloroform solutions were combined, washed with water and saturated brine in turn, and dried. Chloroform was distilled off under reduced pressure, and the residue was recrystallized from dichloromethane-methanol to obtain 30 mg of white solid (63%). mp228～229℃. MS (EI, m/z) [ 421+ ]. 1 HNMR (CDCl 3 ) δ: 1.30 (3H, t, J=7Hz, CH 3 ), 1.65 (4H, m, cyclopropyl CH 2 CH 2 ), 3.35 (4H, m, 2×NCH 2 ), 3.65 (4H, m, 2×CH 2 N), 4.00 (1H, m, cyclopropyl CH), 4.20 (2H, m, J=7Hz, OCH 2 ), 7.95 (1H, m, C 5 -H), 8.80(1H, s, C 2 -H). Experiment 13 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2-methyl-4-ethoxycarbonyl-1- Piperazinyl)-4-oxoquinoline-3-carboxylic acid (19) 17b (R 1 = cyclopropyl, R 5 = H, R 4 = CH 3 , R 8 = F, n = 1) (50mg , 0.138mmol), ethyl chloroformate (30mg, 0.271mmol). The operation is the same as experiment 12. Yield 83%. mp225～227℃. MS (EI, m/z) [ 435+ ]. 1 HNMR (CDCl 3 ) δ: 1.25 (3H, t, J=7Hz, ethyl CH 3 ), 1.35 (3H, t, J=7Hz, piperazine ring CH 3 ), 1.65 (4H, m, cyclopropyl CH 2 CH 2 ), 3.35 (7H, m, 2×CH 2 N, NCH 2 , NCH), 3.95 (1H, m, cyclopropyl CH), 4.15 (2H, m, J=6Hz, OCH 2 ), 7.95 (1H, m, C 5 -H), 8.80 (1H, s, C 2 -H). Experiment 14 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4 -Ethoxycarbonyl-1-homopiperazinyl)-4-oxoquinoline-3-carboxylic acid (20) 17c (R 1 =cyclopropyl,, R 4 =R 5 =H, R 8 =F, n=2) (50 mg, 0.138 mmol), ethyl chloroformate (30 mg, 0.271 mmol). The operation is the same as experiment 12. Yield 75%. mp176～177℃. MS (EI, m/z) [ 435+ ]. 1 HNMR (CDCl 3 ) δ: 1.25 (3H, t, J=7Hz, ethyl CH 3 ), 1.65 (4H, m, cyclopropyl CH 2 CH 2 ), 2.05 (2H, m, homopiperazine ring CH 2 ), 3.60 (8H, m, 2×CH 2 N, 2×NCH 2 ), 4.00 (1H, m, cyclopropyl CH), 4.15 (2H, m, J=7Hz, OCH 2 ), 7.95 (1H , m, C 5 -H), 8.80 (1H, s, C 2 -H). Experiment 15 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-isobutyl Oxycarbonyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (21) 17a (40 mg, 0,115 mmol), isobutyl chloroformate (30 mg, 0.220 mmol). The operation is the same as experiment 12. Yield 90%. mp215～217℃. MS (EI, m/z) [ 449+ ]. 1 HNMR (CDCl 3 ) δ: 0.95 (6H, d, J=7Hz, 2×CH 3 ), 1.25 (2H, m, cyclopropyl CH 2 ), 1.30 (2H, m, cyclopropyl CH 2 ), 2.00 (1H, m, isobutyl CH), 3.35 (4H, m, 2×NCH 2 ), 3.65 (4H, m, 2×CH 2 N), 3.90 (2H, d, J=6Hz, OCH 2 ) , 4.00 (1H, m, cyclopropyl CH), 7.90 (1H, m, C 5 -H), 8.80 (1H, s, C 2 -H). Experiment 16 1-cyclopropyl-6, 8-di Fluoro-1,4-dihydro-7-(2-methyl-4-methoxycarbonyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (22) 17b (50mg, 0.138mmol ), ethyl chloroformate (26 mg, 0.276 mmol). The operation is the same as experiment 12. Yield 78%. mp229～230℃. MS (EI, m/z) [ 421+ ]. 1 HNMR (CDCl 3 ) δ: 1.15 (2H, m, cyclopropyl CH 2 ), 1.30 (2H, m, cyclopropyl CH 2 ), 1.38 (3H, t, J=7Hz, piperazine ring CH 3 ) , 3.35 (7H, m, 2×CH 2 N, NCH 2 , NCH), 3.75 (3H, s, OCH 3 ), 4.00 (1H, m, cyclopropyl CH), 7.90 (1H, m, C 5 - H), 8.80(1H, s, C 2 -H). Experiment 17 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methoxycarbonyl-1-piperazine yl)-4-oxoquinoline-3-carboxylic acid (23) 17a (40 mg, 0,115 mmol), ethyl chloroformate (26 mg, 0.276 mmol). The operation is the same as experiment 12. Yield 75%. mp204～205℃. MS (EI, m/z) [ 407+ ]. 1 HNMR (CDCl 3 ) δ: 1.15 (2H, m, cyclopropyl CH 2 ), 1.30 (2H, m, cyclopropyl CH 2 ), 3.35 (4H, m, 2×NCH 2 ), 3.65 (4H, m, 2×CH 2 N), 3.75 (3H, s, OCH 3 ), 4.00 (1H, m, cyclopropyl CH), 7.90 (1H, m, C 5 -H), 8.75 (1H, s, C 2 -H). Experiment 18 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7(4-4-isobutoxycarbonyl-1-homopiperazinyl)-4-oxoquinoline-3- Carboxylic acid (24) 17c (50 mg, 0.138 mmol), isobutyl chloroformate (37 mg, 0.270 mmol). The operation is the same as experiment 12. Yield 63%. mp176～177℃. MS (EI, m/z) [ 463+ ]. 1 HNMR (CDCl 3 ) δ: 0.95 (6H, d, J=7Hz, 2×CH 3 ), 1.15 (2H, m, cyclopropyl CH 2 ), 1.30 (2H, m, cyclopropyl CH 2 ), 2.00 (3H, m, isobutyl CH, homopiperazine ring CH 2 ), 3.60 (8H, m, 2×NCH 2 , 2×CH 2 N), 3.85 (2H, d, J=7Hz, OCH 2 ) , 4.00 (1H, m, cyclopropyl CH), 7.90 (1H, m, C 5 -H), 8.75 (1H, s, C 2 -H). Experiment 19 1-cyclopropyl-5-amino-6 , 8-difluoro-1,4-dihydro-7-(4-ethoxycarbonyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (25) 17d (R 1 = cyclopropane group, R 4 =H, R 5 =NH 2 , R 8 =F, n=1) (50 mg, 0,137 mmol), ethyl chloroformate (30 mg, 0.270 mmol). The operation is the same as experiment 12. Yield 75%. mp283～284℃. MS (EI, m/z) [ 436+ ]. 1 H NMR (CDCl 3 ) δ: 1.05 (2H, m, cyclopropyl CH 2 ), 1.20 (2H, m, cyclopropyl CH 2 ), 1.30 (3H, t, J=7Hz, CH 3 ), 3.30 ( 4H, m, 2×NCH 2 ), 3.60 (4H, m, 2×CH 2 N), 3.90 (1H, m, cyclopropyl CH), 4.20 (2H, m, J=7Hz, OCH 2 ), 8.65 (1H, s, C2 -H). Experiment 20 1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-7-(4-isobutoxycarbonyl-1-piperazinyl)-4-oxoquinoline- 3-Carboxylic acid (26) 17d (40 mg, 0,115 mmol), isobutyl chloroformate (37 mg, 0.270 mmol). The operation is the same as experiment 12. Yield 70%. mp257～258℃. MS (EI, m/z) [ 464+ ]. 1 HNMR (CDCl 3 ) δ: 0.95 (6H, d, J=7Hz, 2×CH 3 ), 1.05 (2H, m, cyclopropyl CH 2 ), 1.25 (2H, m, cyclopropyl CH 2 ), 2.00 (1H, m, isobutyl CH), 3.35 (4H, m, 2×NCH 2 ), 3.65 (4H, m, 2×CH 2 N), 3.95 (2H, d, J=6Hz, OCH 2 ) , 4.10 (1H, m, cyclopropyl CH), 8.65 (1H, s, C 2 -H). Experiment 21 1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro - 7-(4-Methoxycarbonyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (27) 17d (40 mg, 0,115 mmol), methyl chloroformate (26 mg, 0.276 mmol). The operation is the same as experiment 12. Yield 69%. mp277～278℃. MS (EI, m/z) [ 422+ ]. 1 HNMR (CDCl 3 ) 1.05 (2H, m, cyclopropyl CH 2 ), 1.25 (2H, m, cyclopropyl CH 2 ), 3.35 (4H, m, 2×NCH 2 ), 3.55 (4H, m, 2×CH 2 N), 3.75 (3H, s, OCH 3 ), 3.95 (1H, m, cyclopropyl CH), 8.75 (1H, s, C 2 -H). Experiment 22 1-cyclopropyl-5 -Amino-6,8-difluoro-1,4-dihydro-7-(4-ethoxycarbonyl-1-homopiperazinyl)-4-oxoquinoline-3-carboxylic acid (28) 17e( R 1 =cyclopropyl, R 4 =H, R 5 =NH 2 , R 8 =F, n=2) (50 mg, 0.137 mmol), ethyl chloroformate (30 mg, 0.271 mmol). The operation is the same as experiment 12. Yield 60%. mp216～217℃. MS (EI, m/z) [ 450+ ]. 1 HNMR (CDCl 3 ) δ: 1.05 (2H, m, cyclopropyl CH 2 ), 1.20 (2H, m, cyclopropyl CH 2 ), 1.28 (3H, t, J=7Hz, ethyl CH 3 ), 2.00 (2H, m, homopiperazine ring CH 2 ), 3.45 (4H, m, 2×CH 2 N), 3.65 (4H, m, 2×CH 2 N), 3.90 (1H, m, cyclopropyl CH ), 4.15 (2H, m, J=7Hz, OCH 2 ), 8.50 (1H, s, C 2 -H). Experiment 23 1-ethyl-6,8-difluoro-1,4-dihydro-7 -(4-ethoxycarbonyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (29) 17f (R 1 =ethyl, R 4 =R 5 =H, R 8 =F , n=1) (70 mg, 0.208 mmol), ethyl chloroformate (40 mg, 0.380 mmol). The operation is the same as experiment 12. Yield 53%. mp248～249℃. MS (EI, m/z) [ 410+ ]. 1 HNMR (CDCl 3 ) δ: 1.30 (3H, t, J=7Hz, oxyethyl CH 3 ), 1.30 (3H, t, J=6Hz, nitrogen ethyl CH 3 ), 3.40 (4H, m, 2× NCH 2 ), 3.70 (4H, m, 2×CH 2 N), 4.20 (2H, m, J=7Hz, OCH 2 ), 4.50 (2H, m, J=7Hz, NCH 2 ), 8.00 (1H, m , C 5 -H), 8.60 (1H, s, C 2 -H). Experiment 24 1-Ethyl-6,8-difluoro-1,4-dihydro-7-(4-isobutoxycarbonyl- 1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (30) 17f (70 mg, 0.208 mmol), isobutyl chloroformate (52 mg, 0.380 mmol). The operation is the same as experiment 12. Yield 55%. mp261～262℃. MS (EI, m/z) [ 438+ ]. 1 HNMR (CDCl 3 ) δ: 0.95 (6H, d, J=7Hz, 2×CH 3 ), 1.55 (3H, t, J=7Hz, nitrogen ethyl CH 3 ), 1.95 (1H, m, isobutyl CH), 3.35 (4H, m, 2×NCH 2 ), 3.75 (4H, m, 2×CH 2 N), 3.90 (2H, d, J=6Hz, OCH 2 ), 4.45 (2H, m, J= 7Hz, NCH2 ), 4.65 (4H, m, 2 x CH2N), 8.00 (1H, m, C5 -H), 8.60 (1H, s, C2- H). Experiment 25 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-methoxycarbonyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (31 )17f (70 mg, 0.208 mmol), methyl chloroformate (40 mg, 0.417 mmol). The operation is the same as experiment 12. Yield 49%. mp242～243℃. MS (EI, m/z) [ 396+ ]. 1 HNMR (CDCl 3 ) δ: 1.65 (3H, t, J=6Hz, nitrogen ethyl CH 3 ), 3.35 (4H, m, 2×NCH 2 ), 3.50 (4H, m, 2×CH 2 N), 3.55 (3H, s, OCH 3 ), 4.45 (2H, m, J=4Hz, NCH 2 ), 8.00 (1H, m, C 5 -H), 8.60 (1H, s, C 2 -H). Experiment 25 1-cyclopropyl-6-fluoro-7-(4-ethoxycarbonyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (32) 17g (R 1 = cyclopropyl, R 4 =R 5 =R 8 =H, n=1) (70 mg, 0.211 mmol), ethyl chloroformate (40 mg, 0.368 mmol). The operation is the same as experiment 12. Yield 59%. mp>295°C. MS (EI, m/z) [ 403+ ]. 1 H NMR (CDCl 3 ) δ: 1.20 (2H, m, cyclopropyl CH 2 ), 1.30 (3H, t, J=7Hz, CH 3 ), 1.40 (2H, m, cyclopropyl CH 2 ), 3.30 ( 4H, m, 2×NCH 2 ), 3.50 (1H, m, cyclopropyl CH), 3.70 (4H, m, 2×CH 2 N), 4.20 (2H, d, J=7Hz, OCH 2 ), 7.35 (H, d, J=7H, C8 -H), 8.05 (1H, d, J=7Hz, C5 - H), 8.75 (1H, s, C2- H). Experiment 27 1-cyclopropyl-6-fluoro-7-(4-isobutoxycarbonyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (33) 17g (70mg, 0.211mmol), isobutyl chloroformate (50mg, 0.367mmol). The operation is the same as experiment 12. Yield 55%. mp 286-287°C. MS (EI, m/z) [ 431+ ]. 1 HNMR (CDCl 3 ) δ: 0.95 (6H, d, J=7Hz, 2×CH 3 ), 1.20 (2H, m, cyclopropyl CH 2 ), 1.40 (2H, m, cyclopropyl CH 2 ), 1.95 (1H, m, isobutyl CH), 3.30 (4H, m, 2×NCH 2 ), 3.50 (1H, m, cyclopropyl CH), 3.70 (4H, m, 2×CH 2 N), 4.90 (2H, d, J = 6Hz, OCH 2 ), 7.35 (H, d, J = 7Hz, C 8 -H), 8.05 (1H, d, J = 7Hz, C 5 -H), 8.75 (1H, s , C 2 -H). Experiment 28 1-cyclopropyl-6-fluoro-7-(4-methoxycarbonyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (34) 17g (70 mg, 0.211 mmol), methyl chloroformate (40 mg, 0.432 mmol). The operation is the same as experiment 12. Yield 61%. mp 282-283°C. MS (EI, m/z) [ 389+ ]. 1 HNMR (CDCl 3 ) δ: 1.20 (2H, m, cyclopropyl CH 2 ), 1.40 (2H, m, cyclopropyl CH 2 ), 3.30 (4H, m, 2×NCH 2 ), 3.50 (1H, m, cyclopropyl CH), 3.70 (4H, m, 2×CH 2 N), 3.75 (3H, s, OCH 3 ), 7.40 (H, d, J=7Hz, C 8 -H), 8.05 (1H , d, J=7H, C 5 -H), 8.75 (1H, s, C 2 -H). Experiment 31 1-Ethyl-6-fluoro-7-(4-ethoxycarbonyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (35) 17h( R 1 =ethyl, R 4 =R 5 =R 8 =H, n=1) (70 mg, 0.219 mmol), ethyl chloroformate (40 mg, 0.368 mmol). The operation is the same as experiment 12. Yield 59%. mp>295°C. MS (EI, m/z) [ 391+ ]. 1 HNMR (CDCl 3 ) δ: 1.30 (3H, t, J=6Hz, oxyethyl CH 3 ), 1.65 (3H, t, J=6Hz, nitrogen ethyl CH 3 ), 3.25 (4H, m, 2× NCH 2 ), 3.50 (4H, m, 2×CH 2 N), 4.15 (2H, m, J=4Hz, NCH 2 ), 3.70 (4H, m, 2×CH 2 N), 4.90 (2H, d, J=7Hz, OCH2 ), 6.85(H, d, J=7Hz, C8 -H), 8.10(1H, d, J=7Hz, C5 -H), 8.65(1H, s, C2- H ).
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| CN85101832A (en) * | 1984-06-04 | 1987-01-31 | 拜尔股份公司 | Process for preparing 7-(3-aryl-1-piperazinyl)-3-quinolonecarboxylic acid and 7-(3-cycloethyl-1-piperazinyl)-3-quinolonecarboxylic acid |
| CN87101731A (en) * | 1986-03-04 | 1987-09-16 | 杏林制药株式会社 | Carbostyril carboxylic acid derivatives that replaces on No. 8 positions and preparation method thereof |
| CN86108942A (en) * | 1985-12-12 | 1987-11-04 | 沃纳-兰伯特公司 | Amino and the 5-hydroxyl-6 as the 5-of antimicrobial drug, 8-two fluoroquinolones |
| US4795751A (en) * | 1985-10-29 | 1989-01-03 | Dainippon Pharmaceutical Co., Ltd. | 5-substituted-6,8-difluoroquinolines useful as antibacterial agents |
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| CN85101832A (en) * | 1984-06-04 | 1987-01-31 | 拜尔股份公司 | Process for preparing 7-(3-aryl-1-piperazinyl)-3-quinolonecarboxylic acid and 7-(3-cycloethyl-1-piperazinyl)-3-quinolonecarboxylic acid |
| US4795751A (en) * | 1985-10-29 | 1989-01-03 | Dainippon Pharmaceutical Co., Ltd. | 5-substituted-6,8-difluoroquinolines useful as antibacterial agents |
| CN86108942A (en) * | 1985-12-12 | 1987-11-04 | 沃纳-兰伯特公司 | Amino and the 5-hydroxyl-6 as the 5-of antimicrobial drug, 8-two fluoroquinolones |
| CN87101731A (en) * | 1986-03-04 | 1987-09-16 | 杏林制药株式会社 | Carbostyril carboxylic acid derivatives that replaces on No. 8 positions and preparation method thereof |
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