CN110330489A - 喹诺酮噻唑肟类化合物及其制备方法和应用 - Google Patents
喹诺酮噻唑肟类化合物及其制备方法和应用 Download PDFInfo
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- CN110330489A CN110330489A CN201910695407.3A CN201910695407A CN110330489A CN 110330489 A CN110330489 A CN 110330489A CN 201910695407 A CN201910695407 A CN 201910695407A CN 110330489 A CN110330489 A CN 110330489A
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- quinolone
- compound
- thiazole
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- -1 Quinolone thiazole oxime compound Chemical class 0.000 title claims abstract description 52
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- 238000006243 chemical reaction Methods 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
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- 239000002585 base Substances 0.000 claims description 11
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明涉及喹诺酮噻唑肟类化合物及其制备方法和应用,属于化学合成技术领域,喹诺酮噻唑肟类化合物如通式I所示,该类化合物对革兰阳性菌、革兰阴性菌和真菌中的一种或多种具有一定抑制活性,可以用于制备抗细菌和/或抗真菌药物,从而有机会为临床抗微生物治疗提供更多安全、高效的多样化候选药物,有助于解决日趋严重的耐药性、顽固的致病性微生物以及新出现的有害微生物等临床治疗问题。其制备原料简单,廉价易得,合成路线短,对抗感染方面的应用具有重要意义。
Description
技术领域
本发明属于化学合成技术领域,具体涉及喹诺酮噻唑肟类化合物及其制备方法和应用。
背景技术
微生物感染已经成为多年来威胁人类健康的重大问题。市场上抗菌药物种类较多,包括天然的抗生素和化学合成的抗菌药,如头孢类、沙星类是临床上使用广泛且用量大的抗感染药物。然而,细菌耐药性的频发使传统药物无法发挥高效的作用,大多数细菌对常用抗生素已产生耐药性,特别是在发展中国家,这种现象尤为突出,因此,开发具有新结构的抗菌药物变得十分迫切,尤其是一些具有高效、低毒以及低耐药性的抗菌药的研发已经引起了广泛的关注。
喹诺酮在抗菌感染方面发挥着不可替代的作用。喹诺酮类抗菌药因其抗菌谱广,抗菌作用强,药物动力学性能好和耐受性好,被用于各种感染的治疗。从第1代萘啶酸问世以来,喹诺酮类抗菌药经历了四代的发展。喹诺酮类药物曾由于具有较好的抗菌活性而被大量应用,随着喹诺酮类药物的广泛应用,其耐药性也在快速增长。目前很多致病菌均已出现耐药菌株,临床耐药现象非常普遍,成为了此类抗菌药面临的主要问题。基于喹诺酮的结构修饰,特别是对其C-7位的结构修饰目前是许多研究者关注的焦点。
噻唑是一类重要的含硫杂环化合物,存在于许多有效的生物活性分子中,并且已成功开发了大量能广泛用于临床的药物,如头孢地尼抗菌药物,半合成第三代头孢菌素类药物、磺胺噻唑、法莫替丁、非布索坦、尼扎替丁等。因此,用噻唑肟类片段对喹诺酮的C-7位进行结构改造将是一个很有前景的研究课题,有望开发一系列新型的低毒性,高活性的广谱抗菌药。
发明内容
有鉴于此,本发明的目的之一在于提供喹诺酮噻唑肟类化合物及其可药用盐;目的之二在于提供喹诺酮噻唑肟类化合物及其可药用盐的制备方法;目的之三在于提供喹诺酮噻唑肟类化合物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用。
为达到上述目的,本发明提供如下技术方案:
1、喹诺酮噻唑肟类化合物及其可药用盐,结构如通式I所示:
式中:
R为脂肪胺、脂环胺或芳香胺;
R1为氢、烷基、环烷基、芳基、芳烷基或杂环基;
R2为氢、卤素、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、巯基、羟基、羧基或酯基;
R3为氢、烷基、环烷基、芳基、酯基、烯基、炔基、氰基、巯基、氨基、羟基、羧基或杂环基;
n为0-18的整数。
优选地,
R为脂环胺;
R1为乙基或环丙基;
R2为氢或氯;
R3为甲基、乙基、叔丁基、烯丙基、苄基或乙酸甲酯基;
n为0。
优选地,
R为环己二胺或3-氨基吡咯烷。
优选地,为下述化合物中的任一种:
优选地,所述可药用盐为钠盐、钾盐、盐酸盐、硝酸盐或醋酸盐。
2、所述的喹诺酮噻唑肟类化合物及其可药用盐的制备方法,所述方法如下:
a、中间体II的制备:2-乙酰噻唑与溴素溴化即得中间体II;
b、中间体III的制备:以中间体II为起始原料与各类羟胺盐酸盐或各类羟胺半盐酸盐在有机溶剂中经碱催化反应12小时,即得中间体III;
其中,R3为甲基、乙基、叔丁基、烯丙基、苄基或乙酸甲酯基;
c、通式I所示的喹诺酮噻唑肟类化合物及其可药用盐的制备:将中间体III溶于有机溶液中,在碱的作用下,与喹诺酮类化合物反应,即得通式I所示的喹诺酮噻唑肟类化合物及其可药用盐。
优选地,
步骤b中,所述中间体II、碱与各类羟胺盐酸盐或各类羟胺半盐酸盐的摩尔比为1:1.2:1.2,所述碱为无水乙酸钠,所述有机溶剂为甲醇,所述催化反应的温度为室温;
步骤c中,所述中间体III、喹诺酮类化合物与碱的摩尔比为1.1:1:1.5,所述碱为碳酸钾,所述有机溶液为乙腈,所述反应的温度为50℃。
3、所述的喹诺酮噻唑肟类化合物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用。
优选地,所述细菌为耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC 25923、金黄色葡萄球菌ATCC 29213、克雷白氏肺炎杆菌、大肠杆菌、铜绿假单胞菌、铜绿假单胞菌ATCC 27853、大肠杆菌ATCC 25922或鲍曼不动杆菌中的一种或多种;所述真菌为白色念珠菌、热带假丝酵母菌、烟曲霉菌、白色念珠菌ATCC 90023或近平滑假丝酵母菌ATCC 22019中的一种或多种。
本发明的有益效果在于:本发明提供了喹诺酮噻唑肟类化合物及其制备方法和应用,本发明利用药物设计拼合原理,将噻唑肟类片段引入喹诺酮,设计合成了一系列喹诺酮噻唑肟类化合物,这些化合物经体外抗微生物活性检测发现对革兰阳性菌(耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC 25923、金黄色葡萄球菌ATCC29213)、革兰阴性菌(肺炎克雷伯杆菌、大肠杆菌、铜绿假单胞菌、铜绿假单胞菌ATCC27853、大肠杆菌ATCC 25922、鲍曼不动杆菌)和真菌(白色念珠菌、热带假丝酵母菌、烟曲霉菌、白色念珠菌ATCC 90023、近平滑假丝酵母菌ATCC 22019)都有一定抑制活性,可以用于制备抗细菌和/或抗真菌药物,从而为临床抗微生物治疗提供更多高效、安全的候选药物,有助于解决日趋严重的耐药性、顽固的致病性微生物以及新出现的有害微生物等临床治疗问题。其制备原料简单,廉价易得,合成路线短,对抗感染方面的应用具有重要意义。
本发明的其他优点、目标和特征在某种程度上将在随后的说明书中进行阐述,并且在某种程度上,基于对下文的考察研究对本领域技术人员而言将是显而易见的,或者可以从本发明的实践中得到教导。本发明的目标和其他优点可以通过下面的说明书来实现和获得。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
实验例1、中间体II的制备
将2-乙酰噻唑(5.00g,39.32mmol)和冰乙酸(50mL),在100mL圆底烧瓶加入将室温搅拌下加入溴素(2.42mL)。于50℃搅拌回流,薄层色谱跟踪反应至反应结束。冷却到室温,析出的固体经抽滤、乙醚洗涤和真空干燥后得到粗产物,浅黄色固体(6.45g)。该中间体可直接使用,无需进一步提纯。
实验例2、中间体III-1的制备
将中间体II(300mg,145.6mmol)、甲氧基胺盐酸盐(146mg,174.7mmol)、无水乙酸钠(143mg,174.7mmol)加入50mL的圆底烧瓶中,再加入20mL甲醇作溶剂,室温反应12小时。反应结束后,向圆底烧瓶中加入饱和食盐水,用乙酸乙酯(3×50mL)萃取,将有机相用无水硫酸钠干燥,再将有机相减压浓缩,得到中间体III-1(316mg),产率:92.4%;油状液体。
实验例3、中间体III-2的制备
将中间体II(300mg,145.6mmol)、乙氧基胺盐酸盐(170mg,174.7mmol)、无水乙酸钠(143mg,174.7mmol)加入50mL的圆底烧瓶中,再加入20mL甲醇作溶剂,室温反应12小时。反应结束后,向圆底烧瓶中加入饱和食盐水,用乙酸乙酯(3×50mL)萃取,将有机相用无水硫酸钠干燥,再将有机相减压浓缩,得到中间体III-2(328mg),产率:90.4%;油状液体。
实验例4、中间体III-3的制备
将中间体II(300mg,145.6mmol)、苄氧基胺盐酸盐(279mg,174.7mmol)、无水乙酸钠(143mg,174.7mmol)加入50mL的圆底烧瓶中,再加入20mL甲醇作溶剂,室温反应12小时。反应结束后,向圆底烧瓶中加入饱和食盐水,用乙酸乙酯(3×50mL)萃取,将有机相用无水硫酸钠干燥,再将有机相减压浓缩,得到中间体III-3(344mg),产率:75.8%;油状液体。
实验例5、中间体III-4的制备
将中间体II(300mg,145.6mmol)、O-叔丁基羟胺盐酸盐(219mg,174.7mmol)、无水乙酸钠(143mg,174.7mmol)加入50mL的圆底烧瓶中,再加入20mL甲醇作溶剂,室温反应12小时。反应结束后,向圆底烧瓶中加入饱和食盐水,用乙酸乙酯(3×50mL)萃取,将有机相用无水硫酸钠干燥,再将有机相减压浓缩,得到中间体III-4(357mg),产率:88.6%;油状液体。
实验例6、中间体III-5的制备
将中间体II(300mg,145.6mmol)、O-烯丙基羟胺盐酸盐(191mg,174.7mmol)、无水乙酸钠(143mg,174.7mmol)加入50mL的圆底烧瓶中,再加入20mL甲醇作溶剂,室温反应12小时。反应结束后,向圆底烧瓶中加入饱和食盐水,用乙酸乙酯(3×50mL)萃取,将有机相用无水硫酸钠干燥,再将有机相减压浓缩,得到中间体III-5(326mg),产率:85.7%;油状液体。
实验例7、中间体III-6的制备
将中间体II(300mg,145.6mmol)、羧甲氧基胺半盐酸盐(191mg,174.7mmol)、无水乙酸钠(143mg,174.7mmol)加入50mL的圆底烧瓶中,再加入20mL甲醇作溶剂,室温反应12小时。反应结束后,向圆底烧瓶中加入饱和食盐水,用乙酸乙酯(3×50mL)萃取,有机相用无水硫酸钠干燥,再将有机相减压浓缩,得到中间体III-6(387mg),产率:91.3%;白色固体。
实施例8、化合物I-1的制备
将诺氟沙星(96mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-1(78mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-1(81mg),产率:56.5%;白色粉末,熔点:238.7-239.5℃;1H NMR(600MHz,CDCl3)δ15.12(bs,1H,COOH),8.65(s,1H,quinolone-2-H),8.02(d,J=12.8Hz,1H,quinolone-5-H),7.86(d,J=3.2Hz,1H,thiazole-5-H),7.33(d,J=3.2Hz,1H,thiazole-4-H),6.80(d,J=6.9Hz,1H,quinolone-8-H),4.30(dd,J=7.1,3.4Hz,2H,CH2CH3),4.19(s,1H,OCH3),4.07(s,2H,OCH3),3.96(d,J=20.2Hz,2H,piperazine-CH2),3.34(d,J=22.9Hz,4H,piperazine-2,2-N-(CH2)2),2.87(d,J=42.5Hz,4H,piperazine-3,3-N-(CH2)2),1.56(t,J=8.4,5.9Hz,3H,CH2CH3)ppm.
实施例9、化合物I-2的制备
将诺氟沙星(96mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-2(82mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-2(74mg),产率:50.6%;黄色粉末,熔点:214.8-215.5℃;1H NMR(600MHz,CDCl3)δ15.10(bs,1H,COOH),8.65(s,1H,quinolone-2-H),8.00(d,J=3.1Hz,1H,quinolone-5-H),7.86(d,J=3.2Hz,1H,thiazole-5-H),7.31(d,J=3.0Hz,1H,thiazole-4-H),6.80(d,J=6.7Hz,1H,quinolone-8-H),4.46(dd,J=14.0,7.0Hz,1H,OCH2CH3),4.33(dd,J=8.7,5.4Hz,1H,OCH2CH3),4.30(dd,J=8.4,6.0Hz,2H,NCH2CH3),3.97(s,2H,piperazine-CH2),3.35(d,J=26.5Hz,4H,piperazine-2,2-N-(CH2)2),2.88(d,J=37.9Hz,4H,piperazine-3,3-N-(CH2)2),1.56(t,J=7.0Hz,3H,CH2CH3),1.45(t,J=7.0Hz,1H,OCH2CH3),1.36(t,J=7.0Hz,2H,OCH2CH3)ppm.
实施例10、化合物I-3的制备
将诺氟沙星(96mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-3(93mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-3(66mg),产率:40.1%;淡黄色粉末,熔点:165.6-166.2℃;1H NMR(600MHz,CDCl3)δ15.11(bs,1H,COOH),8.64(s,1H,quinolone-2-H),8.01(d,J=12.8Hz,1H,quinolone-5-H),7.86(d,J=3.0Hz,1H,thiazole-5-H),7.44(dd,J=14.1,7.3Hz,2H,Ph-1,5-2H),7.38(dd,J=12.7,5.9Hz,2H,Ph-2,4-2H),7.34(d,J=7.0Hz,1H,thiazole-4-H),7.32(d,J=3.1Hz,1H,Ph-3-H),6.78(d,J=6.7Hz,1H,quinolone-8-H),5.44(s,1H,Ph-CH2),5.30(s,1H,Ph-CH2),4.29(dd,J=14.8,7.4Hz,2H,CH2CH3),3.97(s,2H,piperazine-CH2),3.30(d,J=22.0Hz,4H,piperazine-2,2-N-(CH2)2),2.80(s,4H,piperazine-3,3-N-(CH2)2),1.55(t,J=7.2Hz,3H,CH2CH3)ppm.
实施例11、化合物I-4的制备
将诺氟沙星(96mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-5(86mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物得到I-4(107mg),产率:71.5%;黄色粉末,熔点:185.5-186.2℃;1H NMR(600MHz,CDCl3)δ15.10(bs,1H,COOH),8.65(s,1H,quinolone-2-H),8.01(d,J=12.7Hz,1H,quinolone-5-H),7.86(d,J=3.0Hz,1H,thiazole-5-H),7.32(d,J=3.0Hz,1H,thiazole-4-H),6.80(d,J=7.0Hz,1H,quinolone-8-H),6.08(dddd,J=22.7,16.4,11.0,5.7Hz,1H,CH=CH2),5.40(dd,J=24.4,17.4Hz,1H,CH=CH2),5.30(dd,J=15.5,10.8Hz,1H,CH=CH2),4.91(d,J=5.4Hz,1H,OCH2),4.77(d,J=5.5Hz,1H,OCH2),4.33–4.27(m,2H,CH2CH3),3.98(s,2H,piperazine-CH2),3.34(d,J=23.0Hz,4H,piperazine-2,2-N-(CH2)2),2.88(d,J=32.1Hz,4H,piperazine-3,3-N-(CH2)2),1.56(t,J=6.9Hz,3H,CH2CH3)ppm.
实施例12、化合物I-5的制备
将诺氟沙星(96mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-4(92mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物得到I-5(95mg),产率:61.4%;白色粉末,熔点:241.5-242.3℃;1H NMR(600MHz,CDCl3)δ15.14(bs,1H,COOH),8.65(s,1H,quinolone-2-H),8.01(s,1H,quinolone-5-H),7.99(d,J=2.8Hz,1H,thiazole-5-H),7.54(d,J=3.1Hz,1H,thiazole-4-H),6.81(d,J=6.1Hz,1H,quinolone-8-H),4.31(q,J=7.1Hz,2H,CH2CH3),4.01(s,1H,piperazine-CH2),3.97(s,1H,piperazine-CH2),3.33(d,J=23.0Hz,4H,piperazine-2,2-N-(CH2)2),2.87(d,J=32.0Hz,4H,piperazine-3,3-N-(CH2)2),1.56(t,J=7.2Hz,3H,CH2CH3),1.48(s,6H,OC(CH3)3),1.39(s,3H,OC(CH3)3)ppm.
实施例13、化合物I-6的制备
将诺氟沙星(96mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-6(97mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物得到I-6(122mg),产率:76.2%;白色粉末,熔点:167.3-168.1℃;1H NMR(600MHz,CDCl3)δ15.08(bs,1H,COOH),8.65(s,1H,quinolone-2-H),8.01(d,J=13.5Hz,1H,quinolone-5-H),7.88(d,J=3.1Hz,1H,thiazole-5-H),7.35(d,J=3.1Hz,1H,thiazole-4-H),6.81(d,J=6.2Hz,1H,quinolone-8-H),4.94(s,1H,OCH2),4.83(s,1H,OCH2),4.30(dd,J=13.9,6.8Hz,2H,CH2CH3),4.01(s,2H,piperazine-CH2),3.79(s,3H,OCH3),3.34(s,4H,piperazine-2,2-N-(CH2)2),2.90(s,4H,piperazine-3,3-N-(CH2)2),1.56(t,J=6.6Hz,3H,CH2CH3)ppm.
实施例14、化合物I-7的制备
将环丙沙星(100mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-1(78mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物得到化合物I-7(99mg),产率:68.0%;白色粉末,熔点:>250℃;1H NMR(600MHz,CDCl3)δ15.02(bs,1H,COOH),8.73(s,1H,quinolone-2-H),7.98(d,J=4.2Hz,1H,quinolone-5-H),7.87(d,J=3.1Hz,1H,thiazole-5-H),7.34(d,J=8.2Hz,1H,thiazole-4-H),7.32(d,J=6.9Hz,1H,quinolone-8-H),4.20(s,1H,OCH3),4.07(s,2H,OCH3),3.97(s,2H,piperazine-CH2),3.52(d,J=3.9Hz,1H,cyclopropane-CH),3.37(d,J=25.0Hz,4H,piperazine-2,2-N-(CH2)2),2.88(d,J=45.2Hz,4H,piperazine-3,3-N-(CH2)2),1.39–1.34(m,2H,cyclopropane-CH2),1.18(s,2H,cyclopropane-CH2)ppm.
实施例15、化合物I-8的制备
将环丙沙星(100mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-2(82mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-8(74mg),产率:50.6%;黄色粉末,熔点:>250℃;1H NMR(600MHz,CDCl3)δ15.01(bs,1H,COOH),8.72(s,1H,quinolone-2-H),7.95(d,J=13.0Hz,1H,quinolone-5-H),7.86(d,J=2.6Hz,1H,thiazole-5-H),7.33(d,J=8.0Hz,1H,thiazole-4-H),7.32(s,1H,quinolone-8-H),4.46(dd,J=13.9,6.9Hz,1H,OCH2CH3),4.33(dd,J=13.8,6.8Hz,1H,OCH2CH3),3.98(d,J=16.2Hz,2H,piperazine-CH2),3.52(s,1H,cyclopropane-CH),3.36(d,J=23.2Hz,4H,piperazine-2,2-N-(CH2)2),2.88(d,J=33.8Hz,4H,piperazine-3,3-N-(CH2)2),1.45(t,J=7.0Hz,1H,OCH2CH3),1.37(d,J=6.5Hz,2H,OCH2CH3),1.36(s,2H,cyclopropane-CH2),1.18(s,2H,cyclopropane-CH2)ppm.
实施例16、化合物I-9的制备
将环丙沙星(100mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-3(93mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-9(79mg),产率:46.9%;黄色粉末,熔点:145.3-146.8℃;1H NMR(600MHz,CDCl3)δ14.98(bs,1H,COOH),8.71(s,1H,quinolone-2-H),7.97(d,J=5.7Hz,1H,quinolone-5-H),7.85(d,J=2.9Hz,1H,thiazole-5-H),7.44(dd,J=13.0,7.4Hz,2H,Ph-1,5-2H),7.37(dd,J=12.9,6.5Hz,2H,Ph-2,4-2H),7.34(d,J=7.1Hz,1H,thiazole-4-H),7.32(d,J=3.1Hz,1H,Ph-3-H),7.29(d,J=6.9Hz,1H,quinolone-8-H),5.30(s,2H,Ph-CH2),3.97(s,2H,piperazine-CH2),3.50(s,1H,cyclopropane-CH),3.32(d,J=20.7Hz,4H,piperazine-2,2-N-(CH2)2),2.80(s,4H,piperazine-3,3-N-(CH2)2),1.35(d,J=6.8Hz,2H,cyclopropane-CH2),1.17(s,2H,cyclopropane-CH2)ppm.
实施例17、化合物I-10的制备
将环丙沙星(100mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-5(86mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物得到I-10(82mg),产率:53.4%;黄色粉末,熔点:203.5-204.1℃;1H NMR(600MHz,CDCl3)δ14.98(bs,1H,COOH),8.71(s,1H,quinolone-2-H),7.95(d,J=13.1Hz,1H,quinolone-5-H),7.86(d,J=3.1Hz,1H,thiazole-5-H),7.33(d,J=9.2Hz,1H,thiazole-4-H),7.31(d,J=4.2Hz,1H,quinolone-8-H),6.08(dddd,J=22.9,16.4,11.0,5.7Hz,1H,CH=CH2),5.40(dd,J=23.2,18.0Hz,1H,CH=CH2),5.29(dd,J=14.3,11.1Hz,1H,CH=CH2),4.77(d,J=5.5Hz,2H,OCH2),3.98(s,2H,piperazine-CH2),3.52(d,J=3.8Hz,1H,cyclopropane-CH),3.36(d,J=22.9Hz,4H,piperazine-2,2-N-(CH2)2),2.88(d,J=32.0Hz,4H,piperazine-3,3-N-(CH2)2),1.36(d,J=6.3Hz,2H,cyclopropane-CH2),1.18(s,2H,cyclopropane-CH2)ppm.
实施例18、化合物I-11的制备
将环丙沙星(100mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-4(92mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物得到I-11(97mg),产率:61.2%;白色粉末,熔点:>250℃;1H NMR(600MHz,CDCl3)δ15.04(bs,1H,COOH),8.75(s,1H,quinolone-2-H),8.01(d,J=3.1Hz,1H,quinolone-5-H),7.99(d,J=13.0Hz,1H,thiazole-5-H),7.56(d,J=3.0Hz,1H,thiazole-4-H),7.35(d,J=6.5Hz,1H,quinolone-8-H),4.00(d,J=24.0Hz,2H,piperazine-CH2),3.53(d,J=3.2Hz,1H,cyclopropane-CH),3.37(d,J=23.4Hz,4H,piperazine-2,2-N-(CH2)2),2.89(d,J=31.3Hz,4H,piperazine-3,3-N-(CH2)2),1.50(s,6H,OC(CH3)3),1.41(s,3H,OC(CH3)3),1.38(d,J=6.8Hz,2H,cyclopropane-CH2),1.19(d,J=2.6Hz,2H,cyclopropane-CH2)ppm.
实施例19、化合物I-12的制备
将环丙沙星(100mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-6(97mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物得到I-12(56mg),产率:34.3%;白色粉末,熔点:178.5-180.1℃;1H NMR(600MHz,CDCl3)δ14.99(bs,1H,COOH),8.72(s,1H,quinolone-2-H),7.96(dd,J=13.0,2.2Hz,1H,quinolone-5-H),7.88(d,J=3.1Hz,1H,thiazole-5-H),7.35(d,J=3.1Hz,1H,thiazole-4-H),7.33(d,J=7.0Hz,1H,quinolone-8-H),4.83(s,2H,OCH2),4.02(d,J=20.0Hz,2H,piperazine-CH2),3.79(s,3H,OCH3),3.54–3.50(m,1H,cyclopropane-CH),3.36(s,4H,piperazine-2,2-N-(CH2)2),2.90(s,4H,piperazine-3,3-N-(CH2)2),1.37(q,J=6.4Hz,2H,cyclopropane-CH2),1.18(d,J=3.1Hz,2H,cyclopropane-CH2)ppm.
实施例20、化合物I-13的制备
将克林沙星(110mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,再加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-1(78mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物得到I-13(71mg),产率:45.2%;黄色粉末,熔点:218.6-219.5℃;1H NMR(600MHz,DMSO)δ14.50(bs,1H,COOH),8.83(s,1H,quinolone-2-H),7.98(s,1H,quinolone-5-H),7.92(d,J=10.4Hz,1H,thiazole-5-H),7.83(s,1H,thiazole-4-H),4.39(d,J=3.1Hz,1H,cyclopropane-CH),4.04(s,3H,OCH3),3.34(s,8H,NHCH2,NHCH,NHCH,pyrrolidine-2,5-2CH2),2.67(s,2H,pyrrolidine-4-CH2),1.19(d,J=6.3Hz,2H,cyclopropane-CH2),0.98(s,2H,cyclopropane-CH2)ppm.
实施例21、化合物I-14的制备
将克林沙星(110mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,再加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-2(82mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-14(103mg),产率:64.3%;黄色粉末,熔点:151.6-152.3℃;1H NMR(600MHz,DMSO)δ14.53(bs,1H,COOH),8.82(s,1H,quinolone-2-H),7.94(d,J=3.0Hz,1H,quinolone-5-H),7.89(d,J=11.7Hz,1H,thiazole-5-H),7.77(d,J=2.8Hz,1H,thiazole-4-H),4.39(dd,J=12.6,5.5Hz,2H,OCH2),4.26(q,J=6.9Hz,1H,cyclopropane-CH),3.84(d,J=5.1Hz,2H,NHCH2),3.30(s,4H,NHCH,NHCH,pyrrolidine-2-2CH2),2.69(d,J=27.1Hz,4H,pyrrolidine-4,5-2CH2),1.37(t,J=7.0Hz,1H,CH2CH3),1.29(t,J=7.0Hz,2H,CH2CH3),1.18(d,J=6.4Hz,2H,cyclopropane-CH2),0.97(s,2H,cyclopropane-CH2)ppm.
实施例22、化合物I-15的制备
将克林沙星(110mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,再加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-3(93mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-15(98mg),产率:54.8%;黄色粉末,熔点:165.9-166.7℃;1H NMR(600MHz,DMSO)δ14.53(bs,1H,COOH),8.82(s,1H,quinolone-2-H),7.96(s,1H,quinolone-5-H),7.90(d,J=11.0Hz,1H,thiazole-5-H),7.79(s,1H,thiazole-4-H),7.47(d,J=6.6Hz,2H,Ph-2,6-2H),7.40(t,J=7.1Hz,2H,Ph-3,5-2H),7.35(d,J=6.9Hz,1H,Ph-4-2H),5.31(s,2H,OCH2),4.38(s,1H,cyclopropane-CH),3.87(s,2H,NHCH2),3.31(d,J=34.2Hz,6H,NHCH,NHCH,pyrrolidine-2,5-2CH2),2.64(s,2H,pyrrolidine-4-CH2),1.19(d,J=6.2Hz,2H,cyclopropane-CH2),0.98(s,2H,cyclopropane-CH2)ppm.
实施例23、化合物I-16的制备
将克林沙星(110mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,再加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-5(86mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-16(61mg),产率:37.5%;黄色粉末,熔点:155.1-155.8℃;1H NMR(600MHz,CDCl3)δ14.44(bs,1H,COOH),8.88(s,1H,quinolone-2-H),7.98(d,J=11.7Hz,1H,quinolone-5-H),7.87(d,J=3.0Hz,1H,thiazole-5-H),7.33(d,J=3.1Hz,1H,thiazole-4-H),6.14–6.02(m,1H,CH=CH2),5.40(t,J=20.1Hz,1H,CH=CH2),5.32–5.26(m,1H,CH=CH2),4.78(d,J=5.1Hz,2H,OCH2),4.33(td,J=6.9,3.5Hz,1H,cyclopropane-CH),3.97(d,J=16.8Hz,2H,NHCH2),3.42(d,J=23.1Hz,4H,NHCH,NHCH,pyrrolidine-2-CH2),2.83(d,J=32.7Hz,4H,pyrrolidine-4,5-2CH2),1.29(q,J=6.6Hz,2H,cyclopropane-CH2),0.95(d,J=3.3Hz,2H,cyclopropane-CH2)ppm.
实施例24、化合物I-17的制备
将克林沙星(110mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,再加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-4(92mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-17(70.5mg),产率:41.8%;黄色粉末,熔点:109.8-110.5℃;1H NMR(600MHz,CDCl3)δ14.49(bs,1H,COOH),8.91(s,1H,quinolone-2-H),8.02(d,J=2.5Hz,1H,quinolone-5-H),8.01(d,J=5.7Hz,1H,thiazole-5-H),7.56(d,J=3.0Hz,1H,thiazole-4-H),4.35(dt,J=10.3,3.4Hz,1H,cyclopropane-CH),3.99(d,J=34.5Hz,2H,NHCH2),3.43(d,J=22.4Hz,4H,NHCH,NHCH,pyrrolidine-2-CH2),2.84(d,J=40.4Hz,4H,pyrrolidine-4,5-2CH2),1.50(s,6H,O(CH3)3),1.41(s,3H,O(CH3)3),1.31(d,J=6.9Hz,2H,cyclopropane-CH2),0.96(s,2H,cyclopropane-CH2)ppm.
实施例25、化合物I-18的制备
将克林沙星(110mg,0.30mmol)和碳酸钾(62mg,0.45mmol)加入50mL圆底烧瓶中,再加入20mL乙腈作溶剂,在50℃下搅拌1小时后加入中间体III-6(97mg,0.33mmol)。薄层色谱跟踪至反应结束。再经浓缩、柱层析分离、重结晶、干燥等后处理即得化合物I-18(126mg),产率:72.6%;黄色粉末,熔点:191.4-192.2℃;1H NMR(600MHz,CDCl3)δ14.42(bs,1H,COOH),8.88(s,1H,quinolone-2-H),7.99(d,J=11.6Hz,1H,quinolone-5-H),7.89(d,J=3.1Hz,1H,thiazole-5-H),7.36(d,J=3.1Hz,1H,thiazole-4-H),4.84(s,2H,OCH2),4.35–4.31(m,1H,cyclopropane-CH),4.01(s,2H,NHCH2),3.79(s,3H,OCH3),3.41(s,4H,NHCH,NHCH,pyrrolidine-2-CH2),2.85(s,4H,pyrrolidine-4,5-2CH2),1.29(t,J=6.9Hz,2H,cyclopropane-CH2),0.94(q,J=6.5Hz,2H,cyclopropane-CH2)ppm.
实施例26、喹诺噻唑肟类化合物的体外抗微生物活性
采用符合临床和实验室标准协会制定的临床实验标准(Clinical andLaboratory Standards Institute(CLSI))的96孔微量稀释法,检测实施例8-25制得的喹诺酮噻唑肟类化合物对革兰阳性菌(耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC29213、金黄色葡萄球菌ATCC 25923)、革兰阴性菌(铜绿假单胞菌、肺炎克雷伯杆菌、大肠杆菌、铜绿假单胞菌ATCC 27853、大肠杆菌ATCC 25922、鲍曼不动杆菌)和真菌(白色念珠菌、烟曲霉菌、热带假丝酵母菌、白色念珠菌ATCC 90023、近平滑假丝酵母菌ATCC 22019)的最低抑制浓度(MIC),将待测化合物用少量二甲亚砜溶解,再加水稀释制成浓度为1.28mg/mL的溶液,再用培养液稀释至256μg/mL,35℃培养24小时,将培养板至振荡器上充分摇匀后,在波长490nm处测定MIC,结果见表1-3。
表1、喹诺酮噻唑肟类化合物I-1~18的体外抗革兰阳性菌活性数据(MIC,μg/mL)
表2、喹诺酮噻唑肟类化合物I-1~18的体外抗革兰阴性菌活性数据(MIC,μg/mL)
从表1、2可以看出,本发明制得的化合物I大部分能够高效抑制所测菌种的生长,且有较宽的抗菌谱,大部分化合物显示出优于参考药物的抗菌活性。特别是制得的所有化合物I-1~18抗耐甲氧西林金黄色葡萄球菌的MIC值均在0.25~4μg/mL,活性均优于参考药物诺氟沙星(16μg/mL)和环丙沙星(8μg/mL)。
表3、喹诺酮噻唑肟类化合物I-1~18的体外抗真菌活性数据(MIC,μg/mL)
从表3可以看出,本发明制得的化合物I,对所测试的真菌表现出一定的抑制作用,化合物I-3、I-8、I-12、I-13、I-14对烟曲霉菌表现出较高的抗菌活性,化合物I-6、I-7、I-8、I-10、I-11、I-12、I-14、I-16、I-17、I-18对热带假丝酵母菌表现出较高的抗菌活性,MIC值均为0.25μg/mL。绝大部分化合物的抗真菌活性比参考药物氟康唑更强。
实施例27、喹诺酮噻唑肟类化合物的制药用途
根据上述抗微生物活性检测结果,本发明的喹诺酮噻唑肟类化合物具有较好的抗细菌、抗真菌活性,可以制成抗细菌、抗真菌药物供临床使用。这些药物既可以是单方制剂,例如由一种结构的喹诺酮噻唑肟类化合物与药学上可接受的辅料制成;也可以是复方制剂,例如由一种结构的喹诺酮噻唑肟类化合物与已有抗细菌、抗真菌活性成分(如诺氟沙星、环丙沙星、克林沙星、喹诺酮甲噁唑、氟康唑、伊曲康唑等)以及药学上可接受的辅料制成,或者由不同结构的几种喹诺酮噻唑肟类化合物与药学上可接受的辅料制成。所述制剂类型包括但不限于片剂、胶囊剂、散剂、颗粒剂、滴丸剂、注射剂、粉针剂、溶液剂、混悬剂、乳剂、栓剂、软膏剂、凝胶剂、膜剂、气雾剂、透皮吸收贴剂等剂型,以及各种缓释、控释制剂和纳米制剂。
1、化合物I-1片剂的制备
处方:化合物I-1 10g,乳糖187g,玉米淀粉50g,硬脂酸镁3g,体积百分浓度为70%的乙醇溶液适量,共制成1000片。
制法:将玉米淀粉于105℃干燥5小时备用;将化合物I-1与乳糖、玉米淀粉混合均匀,用70%的乙醇溶液制软材,过筛制湿颗粒,再加入硬脂酸镁,压片,即得;每片重250mg,活性成分含量为10mg。
2、化合物I-2胶囊剂的制备
处方:化合物I-2 25g,改性淀粉(120目)12.5g,微晶纤维素(100目)7.5g,低取代羟丙纤维素(100目)2.5g,滑石粉(100目)2g,甜味剂1.25g,橘子香精0.25g,色素适量,水适量,制成1000粒。
制法:将处方量的化合物I-2微粉化粉碎成极细粉末后,与处方量的改性淀粉、微晶纤维素、低取代羟丙纤维素、滑石粉、甜味剂、橘子香精和色素混匀,用水制软材,12-14目筛制粒,40-50℃干燥,过筛整粒,装入空胶囊,即得;每片重50mg,活性成分含量为25mg。
3、化合物I-4颗粒剂的制备
处方:化合物I-4 26g,糊精120g,蔗糖280g。
制法:将化合物I-4、糊精、蔗糖混合均匀,湿法制粒,60℃干燥,分装,即得。
4、化合物I-6注射剂的制备
处方:化合物I-6 10g,丙二醇500mL,注射用水500mL,共制成1000mL。
制法:称取化合物I-6、加入丙二醇和注射用水,搅拌溶解,再加入1g活性炭,充分搅拌后静置15分钟,用5μm钛棒过滤脱炭,再依次用孔径为0.45μm和0.22μm的微孔滤膜精滤,最后灌封于10mL安瓿中,100℃流通蒸气灭菌45分钟,即得。
5、化合物I-7粉针剂的制备
制法:化合物I-7无菌粉末在无菌条件下分装,即得。
6、化合物I-8滴眼剂的制备
处方:化合物I-8 3.78g,氯化钠0.9g,硼酸缓冲溶液适量,蒸馏水加至1000mL。
制法:称取化合物I-8、氯化钠加至500mL蒸馏水中,溶解完全后用硼酸缓冲溶液调节pH至6.5,加蒸馏水至1000mL,搅拌均匀,微孔滤膜过滤,灌装,密封,100℃流通蒸气灭菌1小时,即得。
7、化合物I-12搽剂的制备
处方:化合物I-12 4g,钾肥皂7.5g,樟脑5g,蒸馏水加至100mL。
制法:将樟脑用体积百分浓度为95%的乙醇溶液溶解,备用;将钾肥皂加热液化,备用,称取化合物I-12,在不断搅拌下加入钾肥皂液和樟脑乙醇溶液,再逐渐加入蒸馏水,乳化完全后再加入蒸馏水至全量,即得。
8、化合物I-13栓剂的制备
处方:化合物I-13 4g,明胶14g,甘油70g,蒸馏水加至100mL,共制100枚。
制法:称取明胶和甘油,加蒸馏水至100mL,水浴60℃加热熔化呈糊状时加入化合物I-13,搅拌均匀,近凝固时倒入阴道栓模具中,冷却凝固,即得。
9、化合物I-14软膏剂的制备
处方:化合物I-14 0.5-2g,十六醇6-8g,白凡士林8-10g,液体石蜡8-19g,单甘脂2-5g,聚氧乙烯(40)硬脂酸脂2-5g,甘油5-10g,尼泊金乙酯0.1g,蒸馏水100g。
制法:将十六醇、白凡士林、液体石蜡、单甘脂和聚氧乙烯(40)硬脂酸脂加热完全溶化后混匀,保温80℃,作为油相备用;将尼泊金乙酯加入甘油和蒸馏水中,加热至85℃溶解,再在不断搅拌下加入油相,乳化后加入化合物I-14,搅拌冷却,即得。
10、化合物I-15与氟康唑复方粉针剂的制备
处方:化合物I-15 50g,氟康唑50g,苯甲酸钠1g,共制成100瓶。
制法:取处方量的化合物I-15、氟康唑和苯甲酸钠,在无菌状态下混合均匀,分装100瓶,即得。
11、化合物I-17气雾剂的制备
处方:化合物I-17 2.5g,Span20 3g,滑石粉(100目)4g,三氯一氟甲烷加至适量。
制法:将化合物I-17、Span20和滑石粉(100目)分别置真空干燥箱内干燥数小时,置干燥器内冷却至室温,用气流粉碎机粉碎成微粉,再按处方量混匀,灌入密闭容器内,加入三氯一氟甲烷至规定量,即得。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (9)
1.喹诺酮噻唑肟类化合物及其可药用盐,其特征在于,结构如通式I所示:
式中:
R为脂肪胺、脂环胺或芳香胺;
R1为氢、烷基、环烷基、芳基、芳烷基或杂环基;
R2为氢、卤素、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、巯基、羟基、羧基或酯基;
R3为氢、烷基、环烷基、芳基、酯基、烯基、炔基、氰基、巯基、氨基、羟基、羧基或杂环基;
n为0-18的整数。
2.如权利要求1所述的喹诺酮噻唑肟类化合物及其可药用盐,其特征在于,
R为脂环胺;
R1为乙基或环丙基;
R2为氢或氯;
R3为甲基、乙基、叔丁基、烯丙基、苄基或乙酸甲酯基;
n为0。
3.如权利要求2所述的喹诺酮噻唑肟类化合物及其可药用盐,其特征在于,
R为环己二胺或3-氨基吡咯烷。
4.如权利要求1所述的喹诺酮噻唑肟类化合物及其可药用盐,其特征在于,为下述化合物中的任一种:
5.如权利要求1所述的喹诺酮噻唑肟类化合物及其可药用盐,其特征在于,所述可药用盐为钠盐、钾盐、盐酸盐、硝酸盐或醋酸盐。
6.权利要求1-5任一项所述的喹诺酮噻唑肟类化合物及其可药用盐的制备方法,其特征在于,所述方法如下:
a、中间体II的制备:2-乙酰噻唑与溴素溴化即得中间体II;
b、中间体III的制备:以中间体II为起始原料与各类羟胺盐酸盐或各类羟胺半盐酸盐在有机溶剂中经碱催化反应12小时,即得中间体III;
其中,R3为甲基、乙基、叔丁基、烯丙基、苄基或乙酸甲酯基;
c、通式I所示的喹诺酮噻唑肟类化合物及其可药用盐的制备:将中间体III溶于有机溶液中,在碱的作用下,与喹诺酮类化合物反应,即得通式I所示的喹诺酮噻唑肟类化合物及其可药用盐。
7.如权利要求6所述的方法,其特征在于,
步骤b中,所述中间体II、碱与各类羟胺盐酸盐或各类羟胺半盐酸盐的摩尔比为1:1.2:1.2,所述碱为无水乙酸钠,所述有机溶剂为甲醇,所述催化反应的温度为室温;
步骤c中,所述中间体III、喹诺酮类化合物与碱的摩尔比为1.1:1:1.5,所述碱为碳酸钾,所述有机溶液为乙腈,所述反应的温度为50℃。
8.权利要求1-5任一项所述的喹诺酮噻唑肟类化合物及其可药用盐在制备抗细菌和/或抗真菌药物中的应用。
9.如权利要求8所述的应用,其特征在于,所述细菌为耐甲氧西林金黄色葡萄球菌、粪肠球菌、金黄色葡萄球菌、金黄色葡萄球菌ATCC 25923、金黄色葡萄球菌ATCC 29213、克雷白氏肺炎杆菌、大肠杆菌、铜绿假单胞菌、铜绿假单胞菌ATCC 27853、大肠杆菌ATCC 25922或鲍曼不动杆菌中的一种或多种;所述真菌为白色念珠菌、热带假丝酵母菌、烟曲霉菌、白色念珠菌ATCC 90023或近平滑假丝酵母菌ATCC 22019中的一种或多种。
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